Download - The 2012 Oncology Nurse Hematology Conference

DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information

to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for

patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by

clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s

product information, and comparison with recommendations of other authorities.

DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis activity may contain discussion of published and/or investigational uses of

agents that are not indicated by the FDA. IMER does not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of IMER. Please refer to the official prescribing

information for each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestSandra E. Kurtin, MS, RN, ANP, AOCNSandra E. Kurtin, MS, RN, ANP, AOCN®®

Reported a financial interest/relationship or affiliation in the form of: Consultant, Celgene Corporation, Millennium Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation.

Activity OverviewActivity Overview

Sandra E. Kurtin, MS, RN, ANP, AOCN®

Arizona Cancer Center

Learning ObjectivesLearning ObjectivesUpon completion of this activity, participants Upon completion of this activity, participants

should be better able to:should be better able to:

Evaluate recent research highlights for patients with DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM

Describe the diagnostic work-up and various stages of hematologic malignancies and their prognostic significance

Explain how prognostic indicators are used to determine treatment options for patients with DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM

Identify the current and ongoing treatment regimens available for patients with newly diagnosed, relapsed, and refractory DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM

Describe the optimal administration and schedule of current and novel agents used in the treatment of DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM

Apply effective oncology nursing toxicity assessment and monitoring strategies to help patients achieve positive clinical outcomes

Develop individualized patient and family education strategies for patients receiving therapies for hematologic malignancies

Activity AgendaActivity Agenda 8:00 – 8:30 AM Registration and Breakfast 8:30 – 8:35 AM Welcome and Activity Overview 8:35 – 8:55 AM Introduction to Lymphoma 8:55 – 9:25 AM Diffuse Large B-Cell Lymphoma 9:25 – 9:55 AM T-Cell Lymphoma 9:55 – 10:05 AM BREAK 10:05 – 10:35 AM Follicular Lymphoma 10:35 – 11:05 AM Mantle Cell Lymphoma 11:05 – 11:25 AM Supportive Care Case Study Breakout Session 1 11:25 – 11:35 AM Panel Discussion / Q&A 11:35 – 12:35 PM LUNCH 12:35 – 1:05 PM Chronic Lymphocytic Leukemia 1:05 – 1:35 PM Chronic Myeloid Leukemia 1:35 – 2:05 PM Multiple Myeloma 2:05 – 2:15 PM BREAK 2:15 – 2:45 PM Myelodysplastic Syndrome 2:45 – 3:05 PM Supportive Care Case Study Breakout Session 2 3:05 – 3:15 PM Panel Discussion / Q&A 3:15 – 3:25 PM Survivorship 3:25 – 3:30 PM Closing Remarks and Evaluations

Introduction to LymphomaIntroduction to Lymphoma

Sandra E. Kurtin, MS, RN, NP, AOCN®

The University of Arizona Cancer Center

IncidenceIncidence NHL

– A heterogeneous group of neoplasms with differing patterns of growth and response to treatment

Cases

– ~ 70,130 estimated new cases for 2012

– There were ~ 66,360 new cases in 2011

– NHL ranks 7th among men and women as the most frequently newly diagnosed cancer in the US

Deaths

– NHL accounted for ~ 19,320 deaths in 2011 (~ 3% of all cancer deaths)

– NHL is the 9th leading cause of cancer deaths in men and the 7th leading cause of cancer deaths in women

NHL = non-Hodgkin lymphoma.Siegel et al, 2012; ACS, 2012, 2011.

Risk Factors Associated With NHLRisk Factors Associated With NHL

Age

Immunodeficiency

– AIDS, organ transplants, autoimmune disorders

Infectious agents

– HTLV-1: Adult T-cell lymphoma

– EBV: Burkitt’s lymphoma (Africa)

– Helicobacter pylori (MALT lymphomas)

Environmental exposure

– Drugs, chemicals, occupational exposure

AIDS = acquired immune deficiency syndrome; HTLV-1 = human T-lymphotropic virus type I; EBV = Epstein-Barr virus. Lister, 2004.

Common Sites of Disease in LymphomaCommon Sites of Disease in Lymphoma

Lymphatic vessels, nodes, and organs

Primary organs

– BM, thymus

Secondary organs

– LNs

– Spleen

– MALT

– Waldeyer’s ring

Waldeyer’s ring

BM = bone marrow; LNs = lymph nodes; MALT = mucosa-associated lymphoid tissue.Lister, 2004.

Yarbro et al, 2000; Canellos et al, 2006.

Lymphoma: A Blood-Related CancerLymphoma: A Blood-Related Cancer

Yarbro et al, 2000; Canellos et al, 2006.

B-Cell DevelopmentB-Cell Development

Malignancies occur at all stages

Specific disease depends upon when malignancy occurs

Where Do B-Cell Lymphomas Originate?Where Do B-Cell Lymphomas Originate?

Jaffe et al, 2008.CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; MALT = mucosa-associated lymphoid tissue.

Normal LN OrganizationNormal LN Organization

Adapted from Willard-Mack, 2006.

Ann Arbor Staging SystemAnn Arbor Staging System Stage I

– Single LN group

Stage II– Multiple LNs on same side of

diaphragm

Stage III– Multiple LNs on both sides of the

diaphragm

Stage IV– Multiple extranodal sites or LNs

and extranodal disease

Substaging – Extranodal extension (E)

– Systemic symptoms (A/B)

– Bulk > 10 cm (X)

Lister, 2004; NCCN, 2012a.

REAL = Revised European American Lymphoma; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; MCL = mantle cell lymphoma; PTCL = peripheral T-cell lymphoma; SLL = small lymphocytic lymphoma.Armitage et al, 1998; Lichtman, 2006.

NHL SubtypesNHL Subtypes

N = 1,403

Clinical Behavior of NHL SubtypesClinical Behavior of NHL Subtypes

CLL/SLL

Lymphoplasmacytic/WM

MZL

Follicle center lymphoma, follicular, grade 1/2

Most are incurable

Goal is control and minimize symptoms

Indolent

MCL

Follicle center lymphoma, follicular, grade 3

DLBCL

Primary mediastinal large B-cell lymphoma

Require immediate therapy

Variable treatment goals

Cure rates vary

Aggressive

Precursor B-lymphoblastic

lymphoma/leukemia

B-cell acute leukemia

Therapy undertaken with curative intent

Cure rates vary

Very Aggressive

WM = Waldenström’s macroglobulinemia.Ansell et al, 2005; Goroll et al, 2009.

General Diagnostic Workup General Diagnostic Workup for Lymphomafor Lymphoma

History and Physical

– Physical exam

• Particular attention to node-bearing areas, including Waldeyer’s ring, hepatomegaly, splenomegaly, abdominal masses, skin nodules

• Presence of distal swelling or lymphedema

– Performance status

– B symptoms

Laboratory analysis

Tissue biopsy

Bone marrow biopsy and aspirate

Imaging studies for completion of staging

NCCN, 2012b.

Diagnostic Evaluation: Tissue BiopsyDiagnostic Evaluation: Tissue Biopsy

Diagnostic Study Clinical Significance

Morphology – Review of cytology using low-power microscope to define basic architecture of the lymphatic tissue

Immunohistochemistry – Excisional biopsy is the standard for initial diagnosis of NHL (fine needle aspirates are inadequate)

– Used to isolate cellular proteins which correlate with phases of B-cell differentiation

Flow cytometry – Immunophenotyping used to describe antigen expression on B-cells using peripheral blood and bone marrow

– Used to correlate with the tissue biopsy for WHO classification of subtype

Molecular profiling – Newer molecular profiling has identified key prognostic markers

as well as potential targets for new therapies

WHO = World Health Organization.Kurtin, 2008; Morice et al, 2008; LeBien et al, 2008; NCCN, 2012b.

Diagnostic Evaluation: Peripheral BloodDiagnostic Evaluation: Peripheral Blood


CBC + differential + platelets reticulocyte count

– Evaluate presence of cytopenias, lymphocytosis, morphological abnormalities, and bone marrow response to anemia

LDH, haptoglobin, coombs, and reticulocyte count

– Evaluate for underlying hemolysis - particularly important in CLL

LDH – Necessary for risk stratification – Evaluate for aggressive disease, risk for TLS, and

hemolysis

Serum β2m – Prognostic relevance– Reflects WBC membrane turnover– Levels are affected by renal function

Hepatic profile – Treatments have potential renal and hepatic toxicities or may be affected by renal or hepatic insufficiencies

– Dose modification may be required for elevated bilirubin levels

– Serum albumin reflects nutritional status and is used to estimate prognosis

CBC = complete blood count; LDH = lactate dehydrogenase; β2m = beta-2-microglobulin; IPI = International Prognostic Index; TLS = tumor lysis syndrome; WBC = white blood cell.Federico et al, 2007; NCCN, 2012b; Kurtin, 2009; WebMD, 2010; MedlinePlus, 2012.

Diagnostic Evaluation: Bone Marrow Diagnostic Evaluation: Bone Marrow


Aspirate

Should include spicules and be cellular enough to assess at least 500 cells

– Evaluation of morphological abnormalities of hematopoietic precursors to allow WHO classification

– Used for flow cytometry, FISH analysis, and cytogenetics

Biopsy

Should be of adequate size for evaluation (1–2 cm)

Evaluate cellularity, topography, presence of lymphocytic infiltrates, exclusion of other bone marrow disorders or infiltration by solid tumors

Cytogenetics – Evaluate for possible non-random chromosomal abnormalities

t(11;14) is the hallmark for MCL

– Based on evaluation of 20 metaphases

– Greater than 2 metaphases is considered non-random

Molecular Testing Newer molecular profiling has identified key prognostic markers as well as potential targets for new therapies

FISH = fluorescent in situ hybridization.Kurtin, 2008; Jaffe et al, 2008; NCCN, 2012b.

CML-LBC = chronic myeloid leukemia-lymphoid blast crisis; HL = Hodgkin lymphoma.LeBien et al, 2008.

Flow Cytometry: The Zip Code for Flow Cytometry: The Zip Code for Primary Cell Type of B-Cell NeoplasmsPrimary Cell Type of B-Cell Neoplasms

FL (G)

HCL in Peripheral Blood (L) and BM (K)

Normal LN With Germinal Center and Surrounding MZL (C) Normal Germinal Center (F)

ALL – Peripheral Blood (A) and

BM (B)

MZL (M)

BL (I)

CLL in Peripheral Blood (E)

MM (O)

MCL (D)

Growth Pattern May Be Diffuse,

Nodular, or Blastoid

WM (N)

PL (P)

Hodgkin Disease (J)

DLBCL (H)

ALL = acute lymphoblastic leukemia; HCL = hairy cell leukemia; PL = plasmablastic lymphoma; MM = multiple myeloma.LeBien et al, 2008.

Immunohistochemistry: Immunohistochemistry: Unraveling the Patchwork of B-Cell MalignanciesUnraveling the Patchwork of B-Cell Malignancies

Diagnostic Evaluation: ImagingDiagnostic Evaluation: Imaging


MUGA scan or echocardiogram

– Baseline evaluation for patients receiving anthracycline therapy

CT chest, abdomen, and pelvis

– Current standard of care for initial staging on NHL

– Estimation of anatomic extent of disease and areas of abnormal LNs (> 1 cm)

18FDG-PET – PET with FDG shows functional metabolic status reported as SUV

– Useful in evaluation of LNs < 1 cm

– Not useful in all subtypes of NHL

– Scanning after a few cycles of therapy have been shown to predict treatment outcomes in MCL

CXR – Baseline evaluation for any underlying disease and as a source of comparison

MUGA = multi-gated acquisition scan; CT = computed tomography; 18FDG-PET = 18-fluorodeoxyglucose-positron emission tomography; CXR = chest X-ray; LNs = lymph nodes; SUV = standardized uptake value. NCCN, 2012b; Kurtin, 2009; Dupuis et al, 2007; Podolofff et al, 2007.

The Role of PETThe Role of PET

PET is most useful for aggressive lymphomas

More susceptible to false positives

– Rituximab

– Myeloid growth factors

– If used for restaging, wait 8 wks after completion of chemotherapy/radiotherapy

PET/CT notable radiation risk – NCCN: “optional”

Cost and convenience

Pfreundschuh, 2010; Friedberg et al, 2003.

Recommendations for PET Scans Recommendations for PET Scans in Lymphoma Therapy and Trialsin Lymphoma Therapy and Trials

Histology Pre-Tx Mid-Tx Post-Tx F/U

DLBCL Yesa Trial Only Yes No

HL Yesa Trial Only Yes No

FL Nob Trial Only Nob No

MCL Nob Trial Only Nob No

Other Aggressive NHL Nob Trial Only Nob,c No

Other Indolent NHL Nob Trial Only Nob,c No

a Strongly recommended but not mandated.b Only if response is a primary study end point. c Only if PET+ pretreatment.HL = Hodgkin lymphoma; MCL = mantle cell lymphoma; Tx = treatment; F/U = follow-up.Seam et al, 2007.

Risk Stratification in NHL: Risk Stratification in NHL: IPI, FLIPI, MIPI, and BeyondIPI, FLIPI, MIPI, and Beyond

Risk stratification systems

– IPI: Diffuse Large B-Cell Lymphoma

– FLIPI: Follicular Lymphoma

– MIPI: Mantle Cell Lymphoma

Cytogenetic and molecular factors

– Hallmark translocations for common subtypes with associated molecular abnormalities

NCCN, 2012b.

IPI Stratifies Risk by Clinical IPI Stratifies Risk by Clinical Factors in Aggressive NHLFactors in Aggressive NHL

Prognostic factors (APLES)

– Age > 60 yrs

– PS > 1

– LDH > 1 x normal

– Extranodal sites > 1

– Stage III or stage IV

Risk category

Factors

0 2 4 6 8 100

50

100

HHI

LIL

OS (all)

Patients (%)

Patients (%)

0 2 4 6 8 100

50

100

HHI

L

OS (age ≤ 60)

LI

aExtranodal sites of disease are excluded from the AAIPI.PS = performance status; AAIPI = age-adjusted IPI. Sehn et al, 2007.

Low (L) 0 or 1

Low-Intermediate (LI) 2

High-Intermediate (HI) 3

High (H) 4 or 5

CHOP-R = cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab; PFS = progression-free survival.Sehn et al, 2007.

Revised IPI CriteriaRevised IPI Criteria Proposes 3 risk groups based on the

number of IPI risk factors with recommendations for treatment strategies

Very good = no risk factors

– 90% chance of long-term PFS

– Large trials will be necessary to propose treatment approaches other than CHOP-R

Good = 1–2 risk factors


– Treatment strategies without excessive toxicity will be necessary due to favorable survival

Poor = 3–5 risk factors


– Clinical trials are recommended to evaluate disease characteristics and novel treatment approaches

A = PFS in 365 patients treated with CHOP-R

Follicular Lymphoma IPIFollicular Lymphoma IPI

FLIPI Risk Factors

(1 patient each)– Age > 60 yrs

– LDH > ULN

– Hgb < 12 g/dL

– Ann Arbor stage III/IV

– > 4 involved node regions

ULN = upper limt of normal; Hgb = hemoglobin.Solal-Céligny, 2006.

N = 1,795

Su

rviv

al P

rob

abili

ty (

%)

Low Risk (0–1)

0.0

0.2

0.4

0.6

0.8

1.0

12 24 36 48 60 72 84 96Time (mos)

Intermediate Risk (2)

High Risk (≥ 3)

Survival as defined by FLIPI

Gene Profiling and Survival Rates in Gene Profiling and Survival Rates in Different DLBCL Genetic GroupsDifferent DLBCL Genetic Groups

OS (Yrs)

Pro

bab

ility

(%

)

PMBL 64%

GCB 59%

5-Yr Survival

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8 10

ABC 30%

Activated B-cell–like diffuse large B-cell lymphoma (ABC)

Germinal center B-cell–like (GCB)

Primary mediastinal B-cell lymphoma (PMBL)

Genes

Lymphoma Biopsies

Dave et al, 2006; Rosenwald et al, 2003; Lenz et al, 2008.

Mantle Cell Lymphoma IPIMantle Cell Lymphoma IPI Established in 2008 to identify

prognostic factors relevant to MCL

Multivariate analysis of 455 patients from 3 randomized clinical trials

4 independent prognostic factors for survival (age, PS, LDH, leukocyte counts)

– LR: 0–3 points– IR: 4–5 points– HR: 6–11 points

Ann Arbor stage, BM involvement, number of extranodal sites used in the IPI were not prognostically relevant in MCL

More recent studies have added the proliferation index (Ki67 > 30)

Hoster et al, 2008; Smith, 2008; Schaffel et al, 2010.

IR: Median 51

LR: Median not reached

HR: Median 29

0

0.30.4

0.6

0.8

1.0

0 36 48 96

Time (mos since registration)P

roba

bilit

y of

OS

(%

)

847212

0.20.1

0.5

0.7

0.9

p = .108

6024

OS According to MIPI

PS = performance score; LR = low risk; IR = intermediate risk; HR = high risk.

Molecular Indices in Molecular Indices in Lymphocytic MalignanciesLymphocytic Malignancies

Lymphoma Subtype

Morphology ImmunophenotypingFavorable = fUnfavorable = u

Common Cytogenetic Abnormalities

Molecular Testing

Diffuse large B-cell (DLBCL)

Diffuse pattern with distortion of the normal architecture of the lymph node or extranodal site

CD20+, CD45+, CD3- T(14;18), t(3;v), t(8;14)

Testing for bcl-2, bcl-1, c-mycAll offer a survival advantage to the lymphoma cells. u

Follicular lymphoma (FL)

Nodal lymphoma with a follicular growth pattern

CD10+,CD20+, sIg+, CD23+/-, CD22+, CD25+/-

T(14;18)(q32;q21) 85%

IgH re-arrangement with bcl-2 expression which leads to cellular resistance to apoptosis u

Small lymphocytic lymphoma/chronic lymphocytic leukemia

Usually appear normal, may be large, smudge cells may be present, pro-lymphocytes are common

CD5+, CD20dim+, sIgdim+,

CD23+, CD22-, CD25-(+)

CD38+ - u

Trisomy 12t(11q;v) udel(11q) udel(17p) udel(13q) f

Patients with variable region Ig mutations have a more favorable prognosis u

Kurtin, 2009.

Molecular Indices in Molecular Indices in Lymphocytic Malignancies (cont.)Lymphocytic Malignancies (cont.)

Lymphoma Subtype

Morphology ImmunophenotypingFavorable = fUnfavorable = u

Common Cytogenetic Abnormalities

Molecular Testing

Mantle cell lymphoma (MCL)

Cells populating the mantle zone of the follicle

CD5+, CD20+, sIg+, CD22+, CD45+

CD10-, CD23-, CD25-

Cyclin D1+

t(11;14)(q13;q32)de-regulates Cyclin D1 expression interfering with cell cycle regulation

IgH re-arrangement with bcl-1 (increased cell proliferation), and bcl-6 expression (resistance to apoptosis) u

Peripheral T-cell lymphoma (PTLC)

Peripheral T-cells and no features of other subtypes

CD4+, CD7-, CD8- Clonal re-arrangements of the receptor genes seen in non-cancerous T-cell disease are common

Kurtin, 2009.

Response Criteria for NHL Response Criteria for NHL (not including PET)(not including PET)

Response Category

Physical Examination

LNs LN Masses BM

CR Normal Normal Normal Normal

CRu Normal Normal > 75% decreaseNormal or indeterminate

PRNormal or decrease in liver/spleen

Normal or ≥ 50% decrease

Normal or ≥ 50% decrease

Positive or irrelevant if other parameters are not normal

Relapse/ Progression

Enlarging liver/spleen or new sites

New or increasedNew or increased

Reappearance

PET = positron-emission tomography; CR = complete response; CRu = complete response unconfirmed; PR = partial response.NCCN, 2012b.

Revised Response Criteria for NHL Revised Response Criteria for NHL (including PET)(including PET)

Response Definition Nodal Masses Spleen, Liver BM

CR Disappearance of all evidence of disease

a) FDG-avid or PET+ prior to therapy; mass of any size permitted if PET-

b) Variably FDG-avid or PET-; regression to normal size on CT

Not palpable, nodules disappeared

Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative

PR

Regression of measurable disease and no new sites

50% decrease in SPD of up to 6 largestdominant masses; no increase in size of other nodes

a)FDG-avid or PET+ prior to therapy; 1 or more PET+ at previously involved site

b)Variably FDG-avid or PET-; regression on CT

≥ 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen

Irrelevant if positive prior to therapy; cell type should be specified

SD Failure to attain CR/PR or PD

a) FDG-avid or PET+ prior to therapy; PET+ at prior sites of disease and no new sites on CT or PET

b) Variably FDG-avid or PET-; no change in size of previous lesions on CT

Relapsed Disease or PD

Any new lesion or increase by ≥ 50% of previously involved sites from nadir

Appearance of new lesion > 1.5 cm in any axis, ≥ 50% increase in SPD of > 1 node or ≥ 50% increase in longest diameter of a previously identified node > 1 cm in sort axis

Lesions PET+ if FDG-avid lymphoma or PET+ prior to therapy

> 50% increase from nadir in the SPD of any previous lesions

New or recurrent involvement

SD = stable disease; PD = progressive disease; FDG = fludeoxyglucose; SPD = sum of the product of the diameter.NCCN, 2012b.

General Treatment StrategiesGeneral Treatment Strategies

Dependent on

– Type of disease

– Indolent or aggressive

– Age of patient

– General health/comorbidities

– Initial/relapsed/refractory/transformed NHL

NCCN, 2012b.

Key TakeawaysKey Takeaways

Non-Hodgkin lymphomas are a heterogeneous group of neoplasms with differing patterns of growth and response to treatment

Several prognostic indices have been developed that have predictive and prognostic significance

Diagnosis requires bone marrow evaluation, peripheral blood tests, tissue biopsy, and/or imaging

Revised treatment response criteria take into account PET scan results, physical exam, and bone marrow findings

Diffuse Large B-Cell Diffuse Large B-Cell LymphomaLymphoma

Kevin E. Brigle, PhD, NPMassey Cancer Center at

Virginia Commonwealth University Hospital System

Diffuse Large B-Cell LymphomaDiffuse Large B-Cell Lymphoma

Most common form of adult NHL: 30%

– Peak incidence in 6th decade

Curable in 40% or more of cases but median survival weeks to months if not treated

Complex and heterogeneous disease with variable clinical outcomes

– WHO classification includes 15 subtypes

– Molecular classification includes 3 subtypes

Large cells with loss of follicular architecture of the node

– 30%–40% present with a rapidly enlarging, symptomatic mass with B symptoms

– May present as extranodal disease (stomach, CNS, testis, skin)

Michallet et al, 2009.

Gene Profiling and Survival Rates in Gene Profiling and Survival Rates in Different DLBCL Genetic GroupsDifferent DLBCL Genetic Groups

OS (Yrs)

Pro

bab

ility

(%

)

PMBL 64%

GCB 59%

5-Yr Survival

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8 10

ABC 30%

Activated B-cell–like diffuse large B-cell lymphoma (ABC)

Germinal center B-cell–like (GCB)

Primary mediastinal B-cell lymphoma (PMBL)

Genes

Lymphoma Biopsies

Dave et al, 2006; Rosenwald et al, 2003; Lenz et al, 2008.

Molecular Markers and SurvivalMolecular Markers and Survival

Cell of Origin

Molecular Markerbcl-2

expressionbcl-6

expressionActivated

NF-kappa BCD 10

expressionGCET1

expressionFoxP

expression

Germinal Center B-Cell like (GCB) - + - + + -Activated B-Cell like (ABC) + - + - - +

Lenz et al, 2010.

74%

40%

3-year

All Patients Selected Patients

General workup

• History and physical• B symptoms• Performance status• Labs: CBC, differential,

LDH, CMP

• Coagulation studies• Erythrocyte sed rate• HBV, HCV, HIV• Serum β2m• Uric acid, phosphate• Pregnancy testing in women of child-bearing potential

Identification of subtypes

• Lymph node biopsy• Hematopathology review• Immunophenotyping• Molecular studies• Cytogenetic studies

• Ki-67 index

Staging• CT scan: neck, trunk, pelvis

• Bone marrow biopsy

• PET scan• MRI• Ultrasound

Site-specific assessment, occult involvement

• Lumbar puncture, if paranasal sinus, testicular, epidural, bone marrow involvement with large cell lymphoma, HIV lymphoma or ≥ 2 extranodal sites

• Thoracentesis• MUGA scan/echocardiogram

Evaluating the New Patient With DLBCLEvaluating the New Patient With DLBCL

CBC = complete blood count; CMP = complete metabolic panel; CT = computed tomography; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; PET = positron emission tomography.NCCN, 2012b.

The Fusion PET/CT Scan for StagingThe Fusion PET/CT Scan for Staging

Provides information on both structure and activity

Recommended both pre- and post-treatment

– PET negative complete response at end of treatment associated with longer PFS

– Role of interim PET less clear

NCCN, 2012b.

Interim PET Analysis in DLBCLInterim PET Analysis in DLBCL

Study of 112 patients with DLBCL treated with rituximab- anthracycline-based chemotherapy had an interim PET after 2 cycles of therapy

Positive/Negative PET scans were significantly predictive of both PFS and OS (p < .001 and p = .003, respectively)

– 3-yr PFS 84% with negative PET vs. 47% with positive PET

– 3-yr OS 88% with negative PET vs. 62% with positive PET

May lead to an early change in treatment strategy

– Decrease therapy (side effects) for good responders

– Intensify treatment for poor responders

Safar et al, 2012.

Initial Treatment RegimensInitial Treatment Regimens

RCHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; RCEPP = rituximab, cyclophosphamide, etoposide, prednisone, procarbazine; RCDOP = rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone; RCNOP = rituximab, cyclophosphamide, mitoxantrone, vincristine, prednisone; DA-EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; RCEOP = rituximab, cyclophosphamide, etoposide, vincristine, prednisone; HDT = high-dose therapy. NCCN, 2012b.

First-Line Therapy NCCN Category

R-CHOPDose-Dense R-CHOP 14Dose-Adjusted R-EPOCH

12B2B

For Patients With Poor Left Ventricular Function

R-CEPPR-CDOPR-CNOPDose-Adjusted R-EPOCHR-CEOP

2A2A2A2A2A

First-Line Consolidation

HDT with autologous stem cell transplant in high-risk patients

2B

First-Line Consolidation With First-Line Consolidation With HDT and ASCTHDT and ASCT

No clear consensus but recommended if patient has high risk of recurrence

– < 60 yrs of age

– High LDH level at diagnosis

– Multiple extranodal sites of disease

– Ann Arbor stage III or stage IV disease

– IPI 4–5

ASCT = autologous stem cell transplant.NCCN, 2012b.

Treatment by Stage for DLBCLTreatment by Stage for DLBCL

Disease Stage Regimens

Localized disease (stage I, II)(considerations based on nonbulky vs. bulky > 10 cm and whether adverse risk factors present in nonbulky disease)

• R-CHOP x 3 cycles + RT• R-CHOP x 6 cycles ± RT

Advanced disease (stage III, IV)• R-CHOP x 6 cycles• Clinical trials

R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RT = radiation therapy.NCCN, 2012b.

Second-Line Therapy for DLBCLSecond-Line Therapy for DLBCL

Patient Considerations Regimens

Patients who are candidates for HDT with ASCT

• DHAP ± rituximab• ESHAP ± rituximab• GDP ± rituximab• GemOx ± rituximab• ICE ± rituximab• MINE ± rituximab

Patients who are not candidates for HDT with ASCT

• Clinical trial• Rituximab• CEPP ± rituximab• Lenalidomide ± rituximab• CEOP ± rituximab• DA-EPOCH ± rituximab• GDP ± rituximab• GemOx ± rituximab

CEPP = cyclophosphamide, etoposide, prednisone, procarbazine; DHAP = dexamethasone, cisplatin, cytarabine; DA-EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; ESHAP = etoposide, methylprednisone, cytarabine, cisplatin, GDP = gemcitabine, dexamethasone, cisplatin; GemOx = gemcitabine, oxaliplatin; ICE = ifosfomide, carboplatin, etoposide; MINE = mesna, ifosfamide, mitoxantrone, etoposide; CEOP = cyclophosphamide, etoposide, vincristine, prednisone. NCCN, 2012b.

HDT With ASCT in HDT With ASCT in Relapsed/Refractory DLBCLRelapsed/Refractory DLBCL

HDT with ASCT is the treatment of choice for relapsed or refractory DLBCL

Patients require salvage therapy prior to ASCT

– No single preferred salvage regimen

– Transplant recommended only for chemo-sensitive disease

– May be combined with radiotherapy for better local control

Patients relapsing after ASCT should be treated on a clinical trial or with best supportive care

Allogeneic transplantation has shown limited benefit in multiple relapsed disease

– High non-relapse mortality

– Minimal graft vs. lymphoma effect

NCCN, 2012b; Dreger, 2011; van Kampen et al, 2011; Rigacci et al, 2012.

Prevention of CNS RelapsePrevention of CNS Relapse CNS involvement uncommon at diagnosis

– Most events occur during therapy or shortly after completion of treatment

– Risk estimated 2%–7% and median survival is < 6 months

Risk factors include paranasal sinus, testicular, epidural, or bone marrow involvement, HIV lymphoma, or ≥ 2 extranodal sites but predictive models are poor

Benefit of CNS prophylaxis is controversial as studies have been equivocal

– Intrathecal chemotherapy with 4–6 doses methotrexate or cytarabine

• NCCN recommended but little supporting data, inconsistent tissue concentrations, poor brain penetration

– High dose (> 3 g/m2 methotrexate)

• Higher toxicity but better CNS penetration and distribution

– Should be given early in the course of treatment for systemic disease

NCCN, 2012b.

DLBCL Key TakeawaysDLBCL Key Takeaways

DLBCL is a heterogeneous disease with unique molecular subtypes that respond differently to treatment

– Gene profiling may lead to tailored treatment plans

R-CHOP chemotherapy continues to be the standard of care

– For patients with cardiac dysfunction, non-anthracycline containing regimens are recommended

CNS relapse is rare but occurs early in the course of the disease and carries a poor prognosis

– Chemo-prophylaxis remains controversial

PET scans are recommended pre- and post-treatment

– Use early in therapy to guide treatment requires further study

HDT with ASCT is the standard for relapsed disease

Tumor Lysis Syndrome (TLS)Tumor Lysis Syndrome (TLS)

Oncologic emergency that occurs as a result of rapid tumor cell breakdown and the consequent release of intracellular contents

– Commonly occurs following cytotoxic therapy

– Occurs spontaneously in rapidly growing cells

Mainly involves calcium, phosphorous, potassium, and uric acid

– Levels increase too rapidly for the body’s homeostatic mechanisms to deal with

– Renal excretion is the primary means of clearing these ions and optimal management involves preservation of renal function

May lead to acute kidney failure, cardiac arrhythmias and sudden death, seizures, and neuromuscular irritability

Primary management involves identifying patients at risk and starting treatment prior to initiating chemotherapy

NCCN, 2012b; Elitek® prescribing information, 2011.

Features of TLSFeatures of TLS

Salient Features of TLS

Lab Hallmarks

• High potassium (> 6.0 nmol/L), phosphorus (> 4.5 mg/dL),

and uric acid (> 8.0 mg/dL)

• Low calcium (< 7.0 mg/dL corrected)

Clinical Symptoms

• Nausea and vomiting, shortness of breath, irregular heartbeat,

clouding of urine, lethargy, joint discomfort

High-Risk Features

• Burkitt’s and lymphoblastic lymphoma, occasionally DLCBL and CLL

• Elevated WBC and bulky tumors

• Bone marrow involvement and organ infiltration by cancer cells

• Renal disease or renal involvement by tumor

• Dehydration

• Exposure to nephrotoxins (IV contrast, NSAIDs)

• Spontaneous TLS

• Pre-existing elevated uric acid

• Ineffectiveness of allopurinol

NCCN, 2012b.

TLS PathophysiologyTLS Pathophysiology

Howard et al, 2011.

TLS: Prevention and TreatmentTLS: Prevention and Treatment Identify patients at risk

– Obtain baseline labs and identify disease- and patient-related risk factors

Initiate allopurinol

– Oral xanthine-oxidase inhibitor that blocks production of UA (takes several days to impact UA levels)

– Begin 2–3 days prior to chemotherapy and continue for 10–14 days

Utilize rasburicase

– Recombinant urate oxidase (enzyme not found in humans) that catalyzes UA to a soluble compound with a peak effect in 4 hours

– Given 0.2 mg/kg IV over 30 mins and may be repeated once daily

– Black box warnings: Anaphylaxis and hemolysis in patients with G6PD deficiency

– Indicated for patients with high-risk features, especially compromised renal function and those presenting with spontaneous TLS

UA = uric acid.NCCN, 2012b.

TLS: Prevention and Treatment TLS: Prevention and Treatment (cont.)(cont.)

Aggressive intravenous fluid and monitoring of urine output

Frequent monitoring of electrolytes, UA, and creatinine q4–8hrs

Telemetry for hyperkalemia

Decrease the rate of tumor lysis with the use of low intensity initial therapy prior to starting initial therapy

– Common in Burkitt’s lymphoma regimens

NCCN, 2012b.

Anthracycline-Induced Anthracycline-Induced CardiomyopathyCardiomyopathy

Clinical heart failure: 1%–5%

Asymptomatic decrease in left ventricular function: 5%–20%

Impacts long-term survival and quality of life

Reduces range of suitable anticancer therapies

Cause unclear but likely multifactorial

– Free radical-mediated myocyte damage

– Circulating pro-inflammatory cytokines

Granger, 2006.

Anthracycline-InducedAnthracycline-InducedCardiomyopathy Risk FactorsCardiomyopathy Risk Factors

Risk Factor Comment

• Cumulative dose

• Rate of administration• Concurrent or prior mediastinal

radiation• Concomitant administration of other

cardiotoxic drugs

• Age at time of exposure

• Female• Pre-existing cardiovascular disease

• Longer duration of survival

• Higher incidence as cumulative dose increases

• Bolus dosing more toxic than CIV• Especially radiation to left side of chest

• Cyclophosphamide, ifosfamide, methotrexate, cytarabine

• < 18 yrs or > 65 yrs have greater risk at lower cumulative doses

• Unclear• CAD, hypertension, left ventricular

dysfunction• Chronic cardiotoxicity may occur > 30 yrs

after completion of treatment

Dolci et al, 2008; Shakir et al, 2009.

Types of Anthracycline-Induced Types of Anthracycline-Induced CardiomyopathyCardiomyopathy

Type Onset Main Features

AcuteImmediately after single dose or course of therapy

• Uncommon and transient; • May involve transient ECG abnormalities (ST and T wave changes, QT interval prolongation and arrhythmias) and rarely, CHF and pericarditis/myocarditis syndromes

Early-onset chronic progressive

Within 1 yr of therapy; typically rapid onset and progression

• Most frequent type and related to cumulative anthracycline dose

• Often starts with asymptomatic decline in myocardial function and then manifests as CHF with ventricular dilation, pulmonary and venous congestion, poor perfusion, and pleural effusions

• Frequently unresponsive to therapy

Late-onset chronic progressive

1 yr to decades after therapy

• Often starts with asymptomatic decline or with symptoms of clinical heart failure

• Ultimately, manifests as symptomatic CHF as a result of slowly progressive decline following earlier myocyte injury

Maradia et al, 2009; Shakir et al, 2009.

Anthracycline-Induced Anthracycline-Induced CardiomyopathyCardiomyopathy

Cumulative Doxorubicin Dose (mg/m2) Incidence (%)

300 1–2

400 3–5

450 5–8

500 6–20

The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2

Adriamycin® prescribing information, 2006.

Common Cumulative Doses Common Cumulative Doses of Doxorubicinof Doxorubicin

< 5% risk based on anthracycline exposure for first-line treatment

Regimen Cumulative Doxorubicin (mg/m2)

R-CHOP x 650 mg/m2 per cycle 300

R-EPOCH x 640 mg/m2 per cycle (10 mg/m2/day CIV Days 1–4) Note: Doxorubicin dose may progressively increase with DA-EPOCH

240–397

R-HyperCVAD x 450 mg/m2 CIV Day 4 each cycle 200

Monitoring High-Risk PatientsMonitoring High-Risk Patients

There are no specific guidelines for monitoring for chemotherapy-induced cardiomyopathy

Serial monitoring: Baseline, throughout treatment, and post treatment

Monitor for signs and symptoms by

– Physical exam

– ECHO, radionuclide angiography (MUGA), EKG

– CXR

– Troponin levels

Following therapy, provide a survivor care plan for the patient and their other providers related to their cancer treatment and its potential long-term side effects

Dolci et al, 2088; Cardinale et al, 2006.

Preventing Cardiomyopathy in Preventing Cardiomyopathy in High Risk PatientsHigh Risk Patients

Maintain adequate blood pressure control (all patients)

Be aware of total cumulative anthracycline dose (all patients)

Use continuous infusion dosing

Add cardioprotectants (dexrazoxane)

Use anthracycline analogs

– Pixantrone (R-CPOP) 2011 ASH Annual Meeting Abstract 4966

– Liposomal anthracycline (R-COMP14)

Use of non anthracycline-containing regimens

– Gemcitabine (R-GCVP) 2011 ASH Annual Meeting Abstract 1634

Cardinale et al, 2006; Fields et al, 2011; Herbrecht et al, 2011.

Anthracycline-Induced Anthracycline-Induced Cardiomyopathy TreatmentCardiomyopathy Treatment

ACE inhibitors

– Enalapril

Beta blockers

– Carvedilol

Appropriate supportive care

– Diuretics

– Weight monitoring

– Fluid restriction

Assistive devices

Heart transplant if permanent damageACE = angiotensin-converting enzyme.

Dolci et al, 2008; Shakir et al, 2009.

Anthracycline-Induced Anthracycline-Induced Cardiomyopathy Patient EducationCardiomyopathy Patient Education

Discuss short- and long-term risks based on individual patient risk assessment and treatment

Discuss the plan for monitoring before, during, and after treatment

Educate patients about the signs and symptoms of heart failure and convey the importance of prompt reporting

Encourage strict compliance with current cardiac medications to avoid serious, negative, long-term sequelae

Provide a survivor care plan for the patient and their other providers related to their cancer treatment and its potential long-term side effects

Shakir et al, 2009; Granger, 2006.

TLS Case StudyTLS Case Study 62-yr-old Caucasian man with a PMH of hypertension and

hypercholesterolemia both well controlled with HCTZ, amlodipine, and simvastatin. He also takes ASA 81 mg.

Diagnosis: Ann Arbor Stage IVB DLBCL with bulky abdominal LAN, spleen and bone marrow involvement

– IPI stage high intermediate (age > 60, stage IV, ↑LDH)

– Drenching night sweats, 20 pound unintentional weight loss

– Persistent nausea

Baseline studies

– Echocardiogram 62% LVEF

– Normal EKG

PMH = past medical history; LAN = lymphadenopathy; LDH = lactate dehydrogenase; LVEF = left ventricular ejection fraction.Shakir et al, 2009; Granger, 2006.

TLS Case Study (cont.)TLS Case Study (cont.) Baseline laboratory analysis

– WBC: 6.0 × 109/L (normal); Hgb: 11.2 g/dL (low); Platelets: 135 × 109/L (low)

– Potassium: 5.9 nmol/L (high), Phosphorous: 3.8 mg/dL (normal), UA: 10.8 mg/dL (high), Corrected Calcium: 7.2 mg/dL (low)

– LDH: 920 U/L (250 U/L ULN - high)

– BUN/creatinine: 30/1.3 mg/dL (high), Creatinine Clearance: 70 ml/min (low)

– LFTs: normal

Clinical Decisions:

– What therapy would he receive to treat his disease?

– How would you interpret his laboratory data?

– What are his risk factors for TLS?

– What specific steps should be taken to prevent or treat TLS in this patient?


Cardiotoxicity Case StudyCardiotoxicity Case Study

67-yr-old Caucasian woman with PMH of HTN and osteoporosis. Meds include HCTZ, monthly ibandronate, and Calcium-Vitamin D.

Diagnosis: Ann Arbor Stage IIIA DLBCL with cervical, axillary, and inguinal LAN

– IPI stage high intermediate (age > 60, ↑ LDH, stage III)

– Asymptomatic

Baseline studies

– Echocardiogram 54% LVEF

– Normal EKG


Cardiotoxicity Case Study (cont.)Cardiotoxicity Case Study (cont.)

Baseline laboratory analysis– WBC: 5.2 × 109/L (normal); Hgb: 11.5 g/dL (low); Platelets: 205 × 109/L

(normal)

– Potassium: 3.5 nmol/L (low), Phosphorous: 2.7 mg/dL (normal), UA: 5.1 mg/dL (normal), Corrected Calcium: 8.1 mg/dL (low)

– LDH: 305 U/dL (250 U/L ULN - high)

– BUN/creatinine: 17/1.0 mg/dL (normal), Creatinine Clearance: 80 ml/min (low)

– LFTs: normal except ALT 75 U/L (high)

Clinical Decisions:

– What therapy would she receive to treat her disease?

– How would you interpret her laboratory data?

– What are her risk factors for anthracycline-induced cardiomyopathy?

– What specific steps would you take to monitor for or prevent anthracycline-induced cardiotoxicity?


T-Cell Non-Hodgkin T-Cell Non-Hodgkin LymphomaLymphoma

Barbara Barnes Rogers, MN, CRNP, ANP-BC, AOCN®

Fox Chase Cancer Center

N = 1,403


NHL SubtypesNHL Subtypes

2008 WHO Classification of 2008 WHO Classification of T-Cell NeoplasmsT-Cell Neoplasms

Cutaneous Extranodal Nodal LeukemicMycosis Fungoides

Sézary Syndrome

Primary Cutaneous CD30+

Lymphoproliferative Disorders:

•Primary Cutaneous ALCL•Lymphomatoid Papulosis*•Borderline Lesions

Primary cutaneous peripheral T-cell lymphomas, rare

subtypes:•Primary Cutaneous γδ TCL•Primary Cutaneous CD8+ aggressive epidermotropic TCL•Primary Cutaneous CD4+ small/medium TCL

Extranodal NK/TCL, Nasal Type

Enteropathy-Associated TCL

Hepatosplenic TCL

Subcutaneous Panniculitis-Like TCL

Peripheral TCL-NOS

Angioimmunoblastic TCL

Anaplastic Large Cell Lymphoma (ALK -)

Anaplastic Large Cell Lymphoma (ALK +)

T-cell Prolymphocytic Leukemia

T-Cell Large Granular Lymphocytic Leukemia

Adult T-Cell Leukemia/Lymphoma

Aggressive NK-cell Leukemia

Chronic Lymphoproliferative disorders of NK cells

EBV+ T-cell Lymphoproliferative

disorders of Childhood

Hydroa Vacciniforme-like Lymphoma

Systemic EBV+ T-cell Lymphoproliferative

Disease of Childhood

Jaffe et al, 2008.

Peripheral T-Cell Lymphoma SubtypesPeripheral T-Cell Lymphoma Subtypes

International T-Cell Lymphoma Project, 2008; O’Leary et al, 2009; de Leval et al, 2008.ALCL = anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; PTCL = peripheral T-cell lymphoma.

Presenting Symptoms of PTCLPresenting Symptoms of PTCL

Generalized lymphadenopathy

Mild anemia or thrombocytopenia

B symptoms (fevers, weight loss, and night sweats)

Extranodal disease

– Spleen

– Liver

– Bone Marrow

– Skin

Rash

Rodriguez-Abreau, 2008.

Clinical Presentations of PTCL and Clinical Presentations of PTCL and B-Cell LymphomaB-Cell Lymphoma

Clinical Characteristics PTCL (%) BCL (%)

Disseminated disease 78 58

B symptoms 57 40

Bone marrow positive 31 17

Skin lesions 21 4

Gisselbrecht et al, 1998.

Workup of Patients With Workup of Patients With Suspected TCLSuspected TCL

Physical exam Biopsy

– Lymph node

– Bone marrow Laboratory tests

– Complete blood count with differential, platelets

– Comprehensive metabolic panel • Hepatic transaminase levels

(AST, ALT)

• Alkaline phosphatase

• LDH

• Uric Acid

Radiographic test– CT scan of

chest/abdomen/pelvis

– PET/CT scan

– Head CT or MRI

(if appropriate) Calculation of IPI or PIT Discussions of fertility issues

ALT = alanine aminotransferase; AST = aspartate aminotransferase; LDH = lactate dehydrogenase; IPI = International Prognostic Index; PIT = Prognostic Indicator PTCL-NOS.Yarbro et al, 2000.

IPI/PIT: Prognostic Indices for PTCL-NOSIPI/PIT: Prognostic Indices for PTCL-NOS

Gallamini et al, 2004; Ansell et al, 1997.

Prognostic Factors

IPI PIT

Age Age

PS PS

LDH LDH

Stage BM involvement

No. of extranodal

sites

OS: PITN = 322

Overall Survival in PTCL Overall Survival in PTCL The International PTCL and NK/T-Cell Lymphoma StudyThe International PTCL and NK/T-Cell Lymphoma Study

PTCL Subtypes

ALK+ ALCL

ALK– ALCL

PTCL-NOS

AITLNK/T-Cell

LymphomaATLL

5-Yr OS Rate (%) 70 49 32 32 32 14

ATLL = adult T-cell leukemia/lymphoma; OS = overall survival.

International T-Cell Lymphoma Project, 2008.

Front-Line Treatment Regimens Front-Line Treatment Regimens for Management of PTCLfor Management of PTCL

Front-line chemotherapy typically consists of doxorubicin-containing regimens– CHOP

– HyperCVAD alternating with high-dose methotrexate and cytarabine No clear benefit from use of anthracycline-containing regimen No universally agreed-upon standard treatment Other combinations

– CHOP plus alemtuzumab (ORR 75%–80%; OS 2 yrs 53%; PFS 2 yrs 48%)

– CHOP plus denileukin diftitox (ORR 80%–100%, depending on subtype; PFS 2 yrs 41%)

– CHOP plus rituximab (ORR 80%, CR 44%, 2-yr PFS 43%, OS 62%): No better than CHOP alone

CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; HyperCVAD = cyclophosphamide, vincristine, doxorubicin, dexamethasone.Lichtman, 2006; Foss, 2009.

ASCT in the Management of PTCLASCT in the Management of PTCL

Front-line consolidation with high-dose chemotherapy and stem cell rescue

– For all patients except those who are low risk and those with ALK+ ALCL

– Is controversial, based on retrospective and phase II data

– Multiple phase II trials

• Overall Survival = 39%–73% (3 yrs)

• Event-free Survival = 30% (4 yrs)

• Transplant-related Mortality = 4%

– Patients with high IPI/PIT score might not benefit from ASCT

IPI = International Prognostic Index; PIT = Prognostic Index for T-cell lymphoma.

Reimer et al, 2009; Mercadal et al, 2008; Rodriguez et al, 2007.

ASCT as First-Line Therapy in ASCT as First-Line Therapy in PTCL: SurvivalPTCL: Survival

OS in Transplanted and Non-Transplanted Patients

(n = 83)Non-transplanted (n = 28)

Transplanted (n = 55)

Reimer et al, 2009.

Treatment Options for PTCLTreatment Options for PTCL

Romidepsin – ORR 30%–38%, CR 16%– DOR 8.3–12 mos– Side effects: Anemia, leukopenia,

neutropenia, thrombocytopenia, infection, EKG changes, asthenia, decreased appetite, headache, cough, rigors, weight loss

Brentuximab Vedotin– ORR 86%, CR 53%– DOR 12.6 mos– Side effects: Peripheral

neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation, neutropenia

Pralatrexate– ORR 27%, CR 6%– DOR 9.4 mos – Side effects: Stomatitis,

thrombocytopenia, nausea, fatigue, anemia, neutropenia, dyspnea, hypokalemia, altered LFTs, abdominal pain, leukopenia, febrile neutropenia, sepsis, hypotension

– B12 and folate supplements administered to minimize toxicity (myelosuppression and stomatitis

ORR = overall response rate; DOR = duration of response.O’leary & Salvage, 2008.

Treatment Options for PTCL (cont.)Treatment Options for PTCL (cont.)

Denileukin diftitox– ORR 50%, Cr 30% for CD25+,

18% for CD25-– DOR 8 mos– Side effects: Fever, fatigue, rigors,

nausea, headache, edema, cough, dyspnea, pruritus, rash, hypotension, back pain, myalgia, chest pain, tachycardia, hypoalbuminemia, asthenia, altered LFTs, capillary leak syndrome, infusion reactions, visual impairment

Alemtuzumab– ORR 36%–50%, CR 21%–33%– Side effects: Anemia, neutropenia,

thrombocytopenia, fever, infection, viremia (CMV, EBV), hypotension, rash, urticaria, diarrhea, nausea, vomiting, myalgias, insomnia, anxiety, bronchospasm, dyspnea

ORR = overall response rate; DOR = duration of response.O’leary & Salvage, 2008.

Therapies Under Investigation for Therapies Under Investigation for the Management of PTCLthe Management of PTCL

Class of Agent Agent

HDAC inhibitors • Vorinostat

Farnesyl transferase inhibitors • Tipifarnib

Multikinase inhibitors • Dasatinib

IMIDS • Lenalidomide

Proteasome inhibitors • Bortezomib

Investigational agents • Belinostat• Plitidepsin• Zanolimumab

Clinicaltrials.gov

Management of PTCL: Management of PTCL: How to Improve Beyond CHOP?How to Improve Beyond CHOP?

CHOP will not cure most patients with PTCL

Transplant might consolidate remissions

– But we need better front-line therapies

New combinations make sense with the blockade of different pathways

Limited number of patients on clinical trials

Slow to make progress

Cutaneous T-Cell LymphomaCutaneous T-Cell Lymphoma

Patient With Stage IB Disease With Patient With Stage IB Disease With Folliculotropic Plaques on the TrunkFolliculotropic Plaques on the Trunk

© 2009 by American Society of Hematology; Prince et al, 2009.

Patient With Stage IB Disease Patient With Stage IB Disease With Patches and Thin PlaquesWith Patches and Thin Plaques

© 2009 by American Society of Hematology; Prince et al, 2009.

Mycosis Fungoides: Tumor StageMycosis Fungoides: Tumor Stage

Habif, 2010.

Mycosis Fungoides: Mycosis Fungoides: TNM Staging SystemTNM Staging System

Primary Tumor (T)– T1: Limited patch/plaque (< 10% of skin surface involved)

– T2: Generalized patch/plaque (> 10% of skin surface involved)

– T3: Cutaneous tumors (one or more > 1cm in diameter)

– T4: Generalized erythroderma (with or without patches, plaques or tumors) > 80% body surface area

Regional Lymph Nodes (N)– N0: No clinically abnormal peripheral lymph nodes; biopsy not required

– N1: Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr1 or NCI LN 0–2

– N2: Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr2 or NCI LN 3

– N3: Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr3–4 or NCI LN 4

– NX: Clinically abnormal peripheral lymph nodes; no histologic confirmation

NCCN, 2012b.

Mycosis Fungoides: Mycosis Fungoides: TNM Staging System (cont.)TNM Staging System (cont.)

Visceral (M)

– M0: No visceral organ involvement

– M1: Visceral disease present (must have pathology confirmation)

Blood Involvement (B)

– B0: Absence of significant blood involvement: < 5% of peripheral blood lymphocytes are atypical (Sézary) cells

– B1: Low tumor burden: > 5% of peripheral blood lymphocytes are atypical (Sézary) cells but does not meet the criteria for B2

– B2: High tumor burden: > 1,000/mcL Sézary cells

NCCN, 2012b.

Mycosis Fungoides: Mycosis Fungoides: TNM Staging System (cont.)TNM Staging System (cont.)

Stage IA: T1, N0, M0, B0-1

Stage IB: T2, N0, M0, B0-1

Stage IIA: T1-T2, N1-2, M0, B0-1

Stage IIB: T3, N0-N2, M0, B0-1

Stage IIIA: T4, N0-2, M0, B0

Stage IIIB: T4, N0-2, M0, B1

Stage IVA1: T1-T4, N0-2, M0, B2

Stage IVA2: T1-4, N3, M0, B0-2

Stage IVB: T1-4, N0-3, M1, B0-2

NCCN, 2012b.

Sézary SyndromeSézary Syndrome

Leukemic form of mycosis fungoides

Aggressive lymphoma

Accounts for 2.5% of CTCL

Estimated 5-yr survival rate 11%

Consists of triad of

– Erythroderma

– Lymphadenopathy

– Cerebriform lymphocytes (Sézary Cells) in peripheral blood, lymph nodes, and skin

Willemze et al, 1997; Sibaud et al, 2003.

Sézary CellSézary Cell

Anderson & Poulsen, 2003.

General Approach to Management General Approach to Management of Cutaneous T-Cell NHLof Cutaneous T-Cell NHL

Lack of evidence based approach

Appreciate unique features of skin disease

– Chronic control of skin infections (staph, HSV)

– Use anti-itch regimens and emollients/sealants

– Agents that work in lymph nodes may not work in skin

– Can recycle therapies

– Therapy is stage-based

Kim, 2011.

Skin Directed TherapiesSkin Directed Therapies Topical steroids: Triamcinolone, clobetasol

– ORR 75%–95%

Topical chemotherapy-mechlorethamine, carmustine– ORR mechlorethamine 75%–90%

Topical retinoids (bexarotene)– ORR 50%–75%

Phototherapy-UVB (narrow or broad band) or PUVA– ORR nb UVB 75%–100%

– ORR PUVA 85%–100%

– TSEBT (> 30Gy) 100%

Radiation-local or total skin electron beam therapy

nb = narrow-band; ORR = overall response rate; PUVA = psoralen and ultraviolet A; TSEBT = total skin electron-beam therapy.Zackheim, 2003; Navi et al, 2011.

Stage Based Therapy for CTCLStage Based Therapy for CTCL

IA: Limited Patch/Plaque

– Topical steroids - triamcinolone, clobetasol

– Retinoid (bex)

– Phototherapy

– Local XRT

– Clinical Trial

IB/IIA: Generalized Patch/Plaque– Topical steroids-triamcinolone,

clobetasol– Retinoid (bex)– Local XRT– Phototherapy– TSEBT + ECP, IFN– Bex, denileukin diftitox, IFN, vorinostat,

romidepsin (single agent or in combination)

– Clinical Trial

Bex = bexarotene - topical retinoid

Topical chemotherapy - mechlorethamine, carmustine

Phototherapy = UVB (narrow or broad band) or PUVA (psoralen + UVA)

Radiation-local or total skin electron beam therapy

TSEBT = total skin electron beam therapy

ECP = extracorporeal phototherapy (photopheresis)

Stage Based Therapy for CTCL (cont.)Stage Based Therapy for CTCL (cont.)

IIB Tumors

– Topical steroids-triamcinolone, clobetasol

– Retinoid (bex)

– Phototherapy

– Local XRT

– Single-agent chemotherapya

– Phototherapy

– TSEBT + ECP, IFN

– Bexarotene, denileukin diftitox, IFN, vorinostat, romidepsin (single agent or in combination)

– Clinical Trial

– Allo-HSCT

aMethotrexate, liposomal doxorubicin, gemcitabine, chlorambucil, pentostatins, pralatrexate.NCCN, 2012b.

Stage Based Therapy for CTCL (cont.)Stage Based Therapy for CTCL (cont.) III Erythroderma

– Topical steroids-triamcinolone, clobetasol

– Retinoid (bex)

– Phototherapy

– Local XRT

– ECP

– Single-agent chemotherapy

– Phototherapy = bexarotene or IFN

– Alemtuzumab


– Bex, denileukin diftitox, IFN, vorinostat, romidepsin (single agent or in combination)

– Clinical Trial

– Allo-HSCT ECP = photopheresis

NCCN, 2012b.

Stage Based Therapy for CTCL (cont.)Stage Based Therapy for CTCL (cont.)

IV Extracutaneous Disease

– ECP

– Single-agent chemotherapy

– Combination chemotherapy

– Phototherapy = bexarotene or IFN

– Alemtuzumab


– Bexarotene, denileukin diftitox, IFN, vorinostat, romidepsin (single agent or in combination)

– Clinical Trial

– Allo-HSCT

NCCN, 2012b.

Systemic Therapies for MF or SS Systemic Therapies for MF or SS CTCLCTCL

Category A in NCCN Guidelines (Milder)– Retinoids– IFN – HDAC inhibitors– Photopheresis– Denileukin diftitox– Low-dose methotrexate

Category B in NCCN Guidelines (Single-agent cytotoxic therapies)– First-line: Liposomal doxorubicin,

gemcitabine– Other single-agent cytotoxic

therapies

Category C in NCCN Guidelines/Use for aggressive disease– Liposomal doxorubicin– Gemcitabine– Denileukin diftitox– Romidepsin– Pralatrexate– PTCL regimens

NCCN, 2012b.

Systemic TherapiesSystemic Therapies

Pralatrexate– Dose 15 mg/m2 wkly for 3 wks (4-wk cycle)

– B12 IM q9wks

– Folic acid 1 mg/day

– ORR 58%; OS 13 mos; DOR 4.4 mos

Alemtuzumab– ORR 55%–86%

– CR 32%

IM = intramuscular; OS = overall survival; DOR = duration of response.Folotyn® prescribing information, 2011; Campath® prescribing information, 2012.

TCL Key TakeawaysTCL Key Takeaways

T-cell lymphomas are rare disorders

Behavior is different from B-cell lymphomas-often less responsive to therapies

CTCL should first be treated with therapies focused to the skin, unless aggressive

New therapies need to be developed to optimize response and survival

Chemotherapy-Induced Peripheral Chemotherapy-Induced Peripheral Neuropathy (CIPN)Neuropathy (CIPN)

Common dose-limiting side effect of:

Occurs in 30% – 40% of patients

Symptoms of peripheral neuropathy:

– Include sensory neuropathies with parasthesias and pain

– Start in fingers and toes and spread in glove and stocking distribution

– Can begin weeks to months after initial treatment

– In most cases is only partially reversible and can be permanent

Pachman et al, 2011.

CIPNCIPN

Exact mechanism not clear

Can be disabling and negatively impact functional ability and quality of life

Should assess for common metabolic causes of neuropathy:

– Diabetes

– Vitamin B12 deficiency

– Hypothyroidism

– Paraproteinemias

No universally-accepted, well-validated measurement of assessment of CIPN

Pachman et al, 2011.

CIPNCIPN No well-accepted proven therapy for CIPN

Agents with strongest preliminary data for preventing CIPN:

– IV calcium and magnesium infusions

– Glutathione

Therapies with strongest evidence for first-line treatment of CIPN:

– Gabapentin

– Topical pain relievers such as baclofen/amitriptyline/ketamine gel or 5% lidocaine patch

– Seratonin and norepinephrine reuptake inhibitors such as venlafaxine and duloxetine

– Opioid analgesics

– Tramadol hydrochloride

– Tricyclic antidepressants (nortriptyline hydrochloride or desipramine hydrochloride)

– Cutaneous electrostimulationPachman et al, 2011; Vadalouca et al, 2006.

Neuropathy Case StudyNeuropathy Case Study 68-yr-old man with anaplastic large cell NHL (ALK neg) that

presented in his right calf

Treatment

– 6 cycles of CHOP

– Slight increased FDG uptake on PET/CT at the completion of therapy and was treated with involved field XRT

– He achieved a metabolic CR

6-mos follow-up

– Complained of right upper arm discomfort and was diagnosed with recurrent ALCL

– Radiation therapy to the site with a PR

– Given pralatrexate with gemcitabine on a clinical trial with SD

– Treated with MINE with anticipation of an autologous transplant

Neuropathy Case Study (cont.)Neuropathy Case Study (cont.)

He had PD while receiving MINE

Brentuximab vedotin was initiated on a clinical trial

Clinical findings

– Numbness and tingling in his hands and feet

– Sensitivity to cold and feeling “like his hands were always cold”

Clinical decision

– How would you assess for PN?

– How do you manage PN at your institution?

– What co-morbidities are frequently associated with neuropathy?

– What is the best evidence-based management strategy for peripheral neuropathy?

BREAKBREAK

Follicular LymphomaFollicular Lymphoma

Amy L. Goodrich, MSN, RN, CRNP-BCThe Sidney Kimmel Comprehensive Cancer Center

at Johns Hopkins

Follicular Lymphoma (FL)Follicular Lymphoma (FL)

Median age: 60 yrs

Treatment is not curative in most cases

Focus is disease control and quality of life

Median survival: 9 yrs or 4.5 yrs after first relapse

Transformation common (affects ~ 30% of patients)

Tan et al, 2008.

Follicular Lymphoma: Grades 1–3Follicular Lymphoma: Grades 1–3

Grade 1 Grade 2 Grade 3

Predominantly small cells

Mixture of small and large cells

Predominantly large cells

Accounts for 40%–45% of FL

Accounts for 30% of FL

Accounts for 20% of FL

Indolent Indolent Clinically aggressive

Generally incurable Generally incurable May be curable

Tan et al, 2008.

Follicular Lymphoma: Grades 1–2Follicular Lymphoma: Grades 1–2

70%–85% present with Stage III or IV disease

Grade 1: 50% with bone marrow involvement

Grade 2: 30%–35% with bone marrow involvement

Patients typically present with painless adenopathy

< 20% with symptoms

– Fever

– Night sweats

– Weight loss

Clinical course highly variable

Leukemic phase uncommon

Friedberg et al, 2009; Tan et al, 2008.

Follicular Lymphoma: Grade 3Follicular Lymphoma: Grade 3

Biology not well-defined due to routine exclusion from clinical trials

No specific treatment guidelines

Recent A and B designations do not drive treatment decisions

Most commonly treated like DLBCL without watch and wait

Only 40%–50% are cured

Buske et al, 2008.

Follicular Lymphoma:Follicular Lymphoma:Diagnostic Work-UpDiagnostic Work-Up

EssentialUseful Under Certain Circumstances

• Hematopathology review of pathology sample

• FNA often not suitable, excisional/incisional biopsy preferred

• Immunophenotyping - Typical findings: CD10+, BCL2+, CD23+/-, CD43-, CD5-, CD20+, cyclin D1-, BCL6+, rarely BCL2- and CD10-

• Molecular genetic analysis to detect antigen gene receptor arrangements and BCL2 rearrangement

• Cytogenetics or FISH for t(14:18), t(8;14) or variants

• Paraffin section immunuohistochemistry for Ki67

FNA = fine needle aspiration; FISH = fluorescence in situ hybridization.NCCN, 2012b; Vitolo et al, 2008.

Leich et al, 2009.

t(14;18)(Q32;Q21) Translocation t(14;18)(Q32;Q21) Translocation in Follicular Lymphomain Follicular Lymphoma

Follicular Lymphoma:Follicular Lymphoma: Initial Staging Work-Up Initial Staging Work-Up

Essential Useful in Selected Cases

Physical exam with attention to node-bearing areas, Waldeyer’s ring, liver, and spleen

MUGA or ECHO

Performance status Neck CT

B-symptoms β2m

Labs (CBC w/differential, comprehensive panel, LDH, hepatitis B testing, HCG)

Additional labs (uric acid, SPEP, quantitative immunoglobulins, hepatitis C testing)

CT chest, abdomen, pelvis PET-CT

Bone marrow aspirate and biopsyDiscussions of fertility issues and banking

CBC = complete blood count; LDH = lactate dehydrogenase; HCG = human chorionic gonadotropin; CT = computed tomography; MUGA = multigated acquisition scan; ECHO = echochardiogram; β2m = beta-2 microblobulin; SPEP = serum protein electrophoresis; PET = positron emission tomography.NCCN, 2012b.

Recommendations for PET Scans Recommendations for PET Scans in Lymphoma Therapy and Trialsin Lymphoma Therapy and Trials

Histology Pre-TX Mid-TX Post TX F-Up

DLBCL YES* Trial Only YES NO

HL YES* Trial Only YES NO

FL NO** Trial Only NO** NO

MCL NO** Trial Only NO** NO

Other Agg NHL NO** Trial Only NO**# NO

Other Ind NHL NO** Trial Only NO**# NO

* Strongly recommended but not mandated.** Only if response is a primary study end point. # Only if PET positive pre-TX.HL = Hodgkin lymphoma; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma.

Why CanWhy Can’’t We Use PET Results t We Use PET Results in Therapy of FL?in Therapy of FL?

FL usually has low SUV (standardized uptake values)

BUT these overlap with large cell lymphoma SUV It does demonstrate nodes that may be small

BUT it can’t pick up marrow involvement It can demonstrate extranodal disease

BUT extranodal disease is rare in FL It can still be positive after therapy

BUT this occurs rarely, especially with rituximab It may be positive early in therapy

BUT it can’t predict need for change of therapy SO why do we do PET for FL? Studies are needed.

Shoder et al, 2005; MacManus et al, 2007; Jerusalem et al, 2006.

Follicular Lymphoma IPIFollicular Lymphoma IPI

FLIPI Risk Factors

(1 patient each)– Age > 60 yrs

– LDH > ULN

– Hgb < 12 g/dL

– Ann Arbor stage III/IV

– > 4 involved node regions

FLIPI = Follicular Lymphoma International Prognostic Index; ULN = upper limt of normal; Hgb = hemoglobin.Solal-Céligny, 2006.

N = 1,795

Su

rviv

al P

rob

abili

ty (

%)

Low Risk (0–1)

0.0

0.2

0.4

0.6

0.8

1.0

12 24 36 48 60 72 84 96Time (mos)

Intermediate Risk (2)

High Risk (≥ 3)

Survival as defined by FLIPI

Outcomes According to Outcomes According to FLIPI Risk GroupFLIPI Risk Group

Cartron & Solal-Celigny, 2007.

Risk GroupNumber of

Factors5-yr OS (%) 10-yr OS (%)

Low 0–1 90.6 70.7

Intermediate 2 77.6 50.9

High > 3 52.5 35.5

Biomarkers and Prognosis in FLBiomarkers and Prognosis in FL

Biomarker Effect on OS Other Effects Comments

ALC Longer if elevated

β2m Shorter if elevated Poor response and shorter remission Grades I–III

LDH Shorter if elevatedNo effect if early stage

AlbuminShorter if

decreasedPoor response and shorter remission

VEGF Shorter if elevatedAssociated with other poor

prognostic factorsOnly 13% FL

FGF Shorter if elevated Strong prognostic factor Only 14% FL

VEGF + FGF Shorter if elevated No correlation with IPI 14%–30% FL

Endostatin Shorter if elevated Associated with high VEGF Only 16% FL

TNF Shorter if elevated Shorter remission 40% indolent NHL

TNF + sCD23 Poor response if elevated Indolent NHL

sICAM-1 Shorter if elevated Advanced disease and B-symptoms Minority FL

VEGF = vascular endothelial growth factor; FGF = fibroblast growth factor; TNF = tumor necrosis factor; sICAM-1 = soluble intercellular adhesion molecule.Relander et al, 2010.

Indications for Therapy in Indications for Therapy in Follicular LymphomaFollicular Lymphoma

Candidate for a clinical trial

High tumor burden

Progressive local disease or change in tempo

Systemic or constitutional symptoms

High-risk disease based on FLIPI score

Cytopenias due to marrow involvement

Organ invasion

Leukemic phase

Transformation

Tan et al, 2008; Vitolo et al, 2008.

Therapy for Grade I–II FLTherapy for Grade I–II FL For patients with early stage, locally bulky or symptomatic disease,

consider involved field radiation +/- systemic therapy

RCHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RCVP = rituximab, cyclophosphamide, vincristine, prednisone; FR = fludarabine, rituximab; RFND = rituximab, fludarabine, mitoxantrone, dexamethasone.NCCN, 2012b.

First-Line Therapy

First-Line Therapy for

Elderly or Infirm

First-Line Consolidation or Extended

Dosing

Second-Line or Subsequent

Therapy

Second-Line Consolidation or Extended

Dosing

• Bendamustine+R• RCHOP• RCVP• FR• RFND• Radio-

immunotherapy• Rituximab

• If unable to tolerate first-line therapy options:• Radioimmunoth

erapy• Rituximab

(preferred)• Single agent

alkylator +/- R

• Chemotherapy followed by radio-immunotherapy

• Rituximab maintenance up to 2 yrs

• Any unused first-line options

• FCMR• Radio-

immunotherapy• Any second-line

option for DLBCL

• HDT with autologous stem cell rescue

• Allogeneic stem cell transplant for highly selected patients

• Rituximab maintenance up to 2 yrs

Bendamustine in Bendamustine in Follicular LymphomaFollicular Lymphoma

Hybrid: Alkylating agent with purine analog properties

FDA indicated for recurrent NHL

– Indolent lymphomas progressing ≤ 6 mos after a rituximab-containing regimen

Single-agent regimen

– 120 mg/m2 on Days 1, 2 of 21-day cycle

• Up to 8 cycles

• Lower doses and 28-day cycles utilized in trials studying combination regimens

– IV infusion over 30–60 mins

– Premedicate for nausea

Treanda® prescribing information, 2010.

Phase III Randomized Trial of B-R Vs. Phase III Randomized Trial of B-R Vs. RCHOP in Patients With Untreated FL, RCHOP in Patients With Untreated FL,

Indolent Lymphoma, and MCLIndolent Lymphoma, and MCL

549 patients enrolled

Patient characteristics similar in both arms

– Histology, age, stage, LDH, bone marrow involvement, extranodal involvement

Patients randomized to receive

– Bendamustine 90 mg/m2 (Days 1, 2) + rituximab 375 mg/m2 (Day 1) q28days for up to 6 cycles

– Standard CHOP+R q21days for up to 6 cycles

Rummel et al, 2009.

Median observation time of 32 mos

CR rate significantly higher with B-R (40%) vs. RCHOP (30%)

Median progression-free survival, event-free survival, and time to next treatment all significantly longer with B-R

Time to next treatment 40.7 mos with RCHOP and not yet reached with B-R

Deaths from any cause equal between arms

CR = complete response.Rummel et al, 2009.

Phase III Randomized Trial of B-R Vs. Phase III Randomized Trial of B-R Vs. RCHOP in Patients With Untreated FL, RCHOP in Patients With Untreated FL, Indolent Lymphoma, and MCL (cont.)Indolent Lymphoma, and MCL (cont.)

EventB-R

(n = 260)R-CHOP (n = 253)

p Value

Serious adverse events 49 (19%) 74 (29%)

Grade 3/4 neutropenia 10% 46% < .0001

Grade 3/4 leukopenia 12% 38% < .0001

G-CSF use 4% of all cycles 20% of all cycles —

Adverse events Infectious complications Peripheral neuropathy Stomatitis Urticaria, rash Alopecia

95 (37%) 18 (7%)16 (6%)42 (16%)

15% (Grade 1)

121 (48%)73 (29%)47 (19%)23 (9%)

62%

.0403< .0001< .0001.0122

—

Safety: R-B Vs. RCHOPSafety: R-B Vs. RCHOPPatients With Untreated FL, Patients With Untreated FL,

Indolent Lymphoma, and MCLIndolent Lymphoma, and MCL

G-CSF = granulocyte colony stimulating factor.

Rummel et al, 2009.

Frontline Therapies for Frontline Therapies for Patients With FL: Phase III TrialsPatients With FL: Phase III Trials

Regimen n RR (%) TTF/PFS (mos)

High-risk patients

CHOP 205 90 31

Rituximab + CHOP (R-CHOP) 223 96 Not reached(median f/u: 18 mos)

CVP 159 57 15

Rituximab + CVP (R-CVP) 162 81 34

Mitoxantrone, chlorambucil, prednisolone 96 75 29

Rituximab + mitoxantrone, chlorambucil, prednisolone 105 92 Not reached

(median f/u: 47 mos)

CHVP/IFN-α 182 86 36

Rituximab + CHVP (R-CHVP)/IFN-α 175 94 Not reached(median f/u: 42 mos)

Hiddemann et al, 2005, 2004; Foussard et al, 2006; Marcus et al, 2006, 2005; Herold et al, 2006.

TTF = time to treatment failure; PFS = progression-free survival; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CVP = cyclophosphamide, vincristine, and prednisone; IFN-α = interferon alfa.

Methods of Rituximab Methods of Rituximab ““MaintenanceMaintenance””

Author Dosing Frequency

Hainsworth, ECOG

4 Wkly Doses q6mos for 2 yrs

Ghielmini 1 Dose q2mos for 1 yr

Gordon 1 DoseBased on levels – monthly

for 1 yr

ECOG 1 Dose q3mos until relapse

BNLI 1 Dose q3mos for 2 yrs

Hainsworth et al, 2002; Ghielmini et al, 2004; Gordan et al, 2005; Hochster et al, 2005; Van Oers et al, 2006. ECOG = Eastern Cooperative Oncology Group; BNLI = British National Lymphoma Investigation.

PDs/SDsoff study

Indolent NHLstages III–IV,

untreated

Maintenance 1 dose q8wks

for 24 mos

Observation

R-CVP, R-CHOP, R-FCM,

or R-MCP

x 6–8 cycles

CR/PROnly

US NIH, 2009.

PRIMA Study: Protocol DesignPRIMA Study: Protocol Design

PRIMA = Primary Rituximab and Maintenance.

PRIMA Study Follow-UpPRIMA Study Follow-Up

Parameter Maintenance Observation

Median follow-up 36 mos 36 mos

Progressive disease 130 of 505 patients 218 of 513 patients

Conversion to CR/u in PR after chemotherapy

52% 30%

Progression-free survival 78.6% 60.3%

Median time to progression Not yet reached 48.3 months (4 yrs)

Required other therapy 102 of 505 patients 167 of 513 patients

Death due to any cause 5% 6%

Salles, Seymour, Offner, et al, 2010; Salles, Seymour, Feugier, et al, 2010.

PRIMA Study Follow-Up (cont.) PRIMA Study Follow-Up (cont.)

Adverse EventMaintenance

Grade 3/4 – (Leading to treatment discontinuation)

ObservationGrade 3/4 – (Leading to treatment discontinuation)

Number of patients 501 508

All adverse events 121 (19) 84 (8)

Neoplasia 20 (5) 17 (6)

Neutropenia 18 (0) 5 (0)

Febrile neutropenia 1 (1) 2 (0)

Infections 22 (4) 5 (0)

CNS disorders 10 (0) 13 (0)

Cardiac disorders 11 (1) 5 (0)

Pregnancy NA (3) NA (2)

CNS = central nervous system.

Salles, Seymour, Offner, et al, 2010.

Rituximab Maintenance DosingRituximab Maintenance Dosing

Pros

– Increases depth of remission

– Increases length of remission

– Increases time to next therapy

Cons

– No survival benefit

– No standard schedule

– Increased infection risk at about 2 yrs

– Small but increased risk of progressive multifocal leukoencephalopathy

– Hypothetical risk of drug resistance

– Cost

Cheson, 2009; Ghielmini et al, 2004; Van Oers et al, 2010.

Administration Schedule for Administration Schedule for Rapid Rituximab Infusion Rapid Rituximab Infusion

Eligibility for Rapid Infusion

– Second or subsequent dose of rituximab

– No severe reaction to previous dose of rituximab

– Lymphocyte count < 50,000/mm3

– Previous dose of rituximab was < 4 mos prior to this dose

Premedications

– Diphenhydramine 50 mg PO

– Acetaminophen 650–1,000 mg PO

– Daily prednisone dose according to chemotherapy protocol

Cycle 1

– Rituximab 375 mg/m2 IV infused according to product monograph

Cycles 2–8

– Rituximab 375 mg/m2 IV in 250 mL

• 20% of dose infused over30 mins

• Remaining 80% of dose infused over 60 mins

• Total infusion time of 90 mins

Sehn et al, 2005; Rituxan® prescribing information, 2011.

Transformed NHLTransformed NHL Development of aggressive NHL in the setting of an

underlying indolent lymphoma

Most frequently DLBCL

Frequency reported from 10%–70%

– Most likely 3% per year or 30% over disease course

Clinically suspected in the setting of

– Rapid localized nodal growth

– New B symptoms

– Rapidly rising LDH

– New hypercalcemia

Biopsy confirmation whenever possible

Montoto et al, 2007; Al-Tourah et al, 2008.

Transformed NHL (cont.)Transformed NHL (cont.)

High risk factors

– Advanced stage disease

– High risk FLIPI or IPI score at diagnosis

– Low hemoglobin

– High LDH

– High risk FLIPI score at first recurrence

Median survival 1.2 yrs

Treat as if de novo DLBCL

Transplant (autologous or allo if prior auto)

Montoto et al, 2007; Al-Tourah et al, 2008.

Autologous Transplant in FLAutologous Transplant in FL

Randomized trials studied autologous transplant in newly diagnosed or in first remission

High response rates

Improved PFS

Only one trial (CUP trial) reported improved OS

Relapse after transplant is common

Not curative

Many trials ongoing and in development

Tomblyn, 2011.

Allogeneic Transplant in FLAllogeneic Transplant in FL

Lower relapse rates than autologous

– Harnesses graft-versus-lymphoma effect

– Circumvents tumor contamination associated with autologous harvests

Benefit is offset by increased treatment-related mortality

Potentially curative

Many reduced intensity regimens under study

Tomblyn, 2011.

Current ResearchCurrent Research

Bortezomib

Lenalidomide

Bendamustine-based regimens

Novel monoclonals

Novel combination regimens

Kinase inhibitors

Targeted therapies

Vaccines

Gene profiling

Stem cell transplantation

FL Key TakeawaysFL Key Takeaways

Follicular lymphomas are a heterogeneous group of diseases

Biomarkers under study for better prognostics and guidance of treatment decisions

No significant historic improvement in overall survival in decades, but may be changing with immunotherapy and stem cell transplant

Side-effect management is essential to maintain high quality of life

Many new agents currently under study

Emetogenic Potential of Common Emetogenic Potential of Common Antineoplastic TherapiesAntineoplastic Therapies

Emetic Risk Agents

High (> 90%) Carmustine MechlorethamineDactinomycin Streptozocin

Cyclophosphamide (> 1,500 mg/m2)DacarbazineCisplatinDoxorubicin

Moderate (> 30%–90%)

Carboplatin DoxorubicinIdarubicin IfosfamideIrinotecan

Cyclophosphamide (< 1,500 mg/m2)Cytarabine (> 1 g/m2) OxaliplatinDaunorubicin Epirubicin

Ettinger, 2007; NCCN, 2011.

Emetogenic Potential of Common Emetogenic Potential of Common Antineoplastic Therapies (cont.)Antineoplastic Therapies (cont.)

Emetic Risk Agents

Low (10%–30%)

Bortezomib MethotrexateCetuximab MitomycinMitoxantronePaclitaxelDocetaxel

Cytarabine (> 1,000 g/m2) PemetrexedEtoposide TopotecanFluorouracil Trastuzumab

Moderate (< 10%)

Bevacizumab VinblastineBleomycin VincristineBusulfan

2-ChlorodeoxyadenosineFludarabineRituximabVinorelbine

Ettinger, 2007; NCCN, 2011.

Patient-Specific High Risk Patient-Specific High Risk Features for CINVFeatures for CINV

Younger age

Female sex

History of low alcohol intake (< 4 drinks per wk)

History of morning sickness with pregnancy

Motion sickness

Anxiety

CINV = chemotherapy-induced nausea and vomiting.Exkert, 2001; Stricker et al, 2010.

Principles of Nausea and Vomiting Principles of Nausea and Vomiting ControlControl

Prevention

– Risk of N/V at least 3 days for highly emetogenic and at least 2 days for moderately emetogenic

Consider side effects of antiemetics

Risk is based on emetogenic potential of treatment, prior antiemetic experience, and patient factors

NCCN, 2011.

Principles of Nausea and Vomiting Principles of Nausea and Vomiting Control (cont.)Control (cont.)

Consider other causes of N/V

– Bowel obstruction

– Vestibular dysfunction

– Brain mets

– Electrolyte imbalances

– Uremia

– Concomitant meds, esp. opiates

– Gastroparesis

– Anxiety

– Anticipatory N/V

NCCN, 2011.

Antiemetic RecommendationsAntiemetic RecommendationsNCCN guidelines for moderate emetic risk

C1 C2 C3 C4 C5 and 6

Day 1•5-HT3 antagonist premedication•Steroid•+/- Neurokinin 1 antagonist•+/- Lorazepam•+/- H2 blocker or PPI

X (0)

X

XX

X (O)

XX

XX

X (G)

XX

XX

X (O)

XX

XX

X (O)

XX

XX

Days 2 and 3•5-HT3 antagonist OR•Steroid OR•Continue Neurokinin 1 antagonist•+/- lorazepam•+/- H2 blocker or PPI

X* (D2-4)X* (D2-5)

XX

XXX

X* (RTC)X

XXX

XX* (both)

XXX

XX

XXX

XX

• Additional Measures Prochlorperazine* XOlanzapine

XMassageAcupuncture

XXXHaloperidol*Imagery/Meditation*

XXXXX

* All cycles.NCCN, 2011.

CINV Key TakeawaysCINV Key Takeaways

Nausea, with or without vomiting, can be a significant management challenge

Can be life altering, emotionally, physically, financially for patients

Aggressive assessment, multidisciplinary, multimodality approach needed for successful management

CINV Case StudyCINV Case Study 54-yr-old woman presents with abdominal discomfort

Work-up

– H/O anxiety (on venlafaxine) and chronic constipation

– CT reveals extensive non-bulky mesenteric adenopathy

– EGD reveals gastritis, symptoms resolve with PPI

Diagnosis

– Lymph node biopsy reveals Grade I FL

– Staging consistent with Stage II disease

– Asymptomatic

Clinical Decision:

– Would you treat or observe?

H/O = history of; CT = computed tomography; EGD = esophagogastroduodenoscopy; PPI = proton-pump inhibitor.

CINV Case Study (cont.)CINV Case Study (cont.)

18 mos observation

– High anxiety level continues, venlafaxine increased

– Presents with rapidly increasing cervical adenopathy

– Biopsy reveals transformation to DLBCL

Treatment

– Starts R-CHOP; 6 cycles planned

– Develops intractable nausea with minimal vomiting

Clinical Decisions: What is this patient’s risk?

– What do you give your R-CHOP patients in Cycle 1?

– What would you do differently, if anything during Cycle 2?

– If regimen changes have no impact on nausea during Cycle 3, what would be your clinical decision?

Mantle Cell LymphomaMantle Cell Lymphoma

Kevin E. Brigle, PhD, NPMassey Cancer Center at

Virginia Commonwealth University Hospital System


NHL Subtypes: MCL Is an Uncommon SubtypeNHL Subtypes: MCL Is an Uncommon Subtype

N = 1,403

The Mantle ZoneThe Mantle Zone

Originates in the mantle zone surrounding the germinal centers present in the lymph node

Germinal Germinal centercenter

Goy et al, 2011; Bertoni et al, 2007.

Mantle Cell Lymphoma Mantle Cell Lymphoma PresentationPresentation

Median age: 67 yrs Male predominance

– 2.5 men for every woman

B symptoms common 70%–90% present with Stage III–IV disease Extranodal disease is common

– Bone marrow, spleen, and gatsrointestinal tract (90%)• Colonoscopy necessary for restaging

• Presents as lymphomatous polyposis or normal appearing mucosa

Weigert er al, 2007; Witzig, 2005.

Mantle Cell Lymphoma Mantle Cell Lymphoma Presentation (cont.)Presentation (cont.)

Generally poor prognosis with few long-term survivors

– OS is poor with range of 4–5 yrs

– Subset of patients have indolent disease and enjoy longer survival of 7–10 yrs

Most patients require aggressive treatment at diagnosis

Patients typically experience frequent relapses and the development of chemo-resistant disease

– After first relapse, median survival is 1–2 yrsWeigert er al, 2007; Witzig, 2005.

The t(11;14)(q13;q32) TranslocationThe t(11;14)(q13;q32) Translocation

Translocation t(11;14)(q13;q32) is the hallmark cytogenetic abnormality

– bcl-1 gene encodes cyclin D1

• Cyclin D1 regulates cell cycle progression and growth

• ↑ Cyclin D1 expression increases cell proliferationSander, 2011.

Progression From Indolent to Progression From Indolent to Aggressive Mantle Cell LymphomaAggressive Mantle Cell Lymphoma

Sander, 2011; Royoa et al, 2011.

Secondary AberrationsPrimary Aberrations

t(11;14) or variants

3q,7p,8q

1p,6q,8p,9,11q2,13q

TP53 mut/del (17p13)CDKN2A del (9p21)MYC ampl/rearr (8q24)High genomic instability

BMNaïve B-cell

“in situ” MCLIndolent MCL

Conventional MCL

Blastoid MCL

Survival

Number of genetic alterations

Clinical Presentation, Molecular Clinical Presentation, Molecular Markers, and SurvivalMarkers, and Survival

CLINICAL COURSE

Molecular Marker

t(11;14) ↑Ki-67 Sox11Hypermutated

IGHV gene Complex karyotype

Indolent + - - + -Aggressive + + + - +

CLINICAL COURSE

Clinical Presentation

Nodal disease

Leukemic disease

B symptoms

High LDH Splenomegaly

Indolent - + - - +

Aggressive + - + + -

Fernàndez, 2010; Royoa et al, 2011.

All Patients Selected Patients

General work-up

• History and physical• B symptoms• Performance status• Labs: CBC, differential,

LDH, CMP

• Coagulation studies• Erythrocyte sed rate• HBV, HCV, HIV• Serum β2m• Uric acid, Phosphate• Pregnancy testing in women of child-bearing potential

Identification of subtypes

• Lymph node biopsy• Hematopathology review• Immunophenotyping• Molecular studies• Cytogenetic studies

• Ki-67 index

Staging• CT scan: Neck, trunk, pelvis

• Bone marrow biopsy

• Endoscopy/colonoscopy• PET scan• MRI• Ultrasound

Site-specific assessment, occult involvement

• Lumbar puncture, if paranasal sinus, testicular, epidural, bone marrow involvement with large cell lymphoma, HIV lymphoma or > 2 extranodal sites

• Thoracentesis• MUGA scan/echocardiogram

Evaluating the New Patient With MCLEvaluating the New Patient With MCL

CBC = complete blood count; CMP = complete metabolic panel; CT = computed tomography; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; PET = positron emission tomography.

NCCN, 2012b.

(1996–2004)

(1975–1986)

p < .0001

1975–1986 1996–2004

Median OS (yrs) 2.7 4.8

5-yr survival (%) 22 47

Reasons for improved survival

Improved diagnosis, new and aggressive treatments, better supportive care

0 1 2 3 4 5 6 7 8 9 10

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al P

rob

abil

ity

(%)

Survival Time (yrs)

Improved Survival Over Last Improved Survival Over Last 3 Decades3 Decades

Herrmann et al, 2009.

First-Line Treatment SelectionFirst-Line Treatment Selection There is no established standard of care

– Difficult to predict the clinical behavior: Indolent vs. aggressive

– Chemotherapy regimens have never been compared head-to-head Conventional chemotherapy is not curative

– Remission rates of 40%–90% but short lived averaging 1–2 yrs Intensive regimens and consolidation with ASCT improve remission

duration– Treatment plans for first-line and subsequent therapies are highly

individualized using a risk-adapted approach

– MIPI and proliferative index

– Transplant eligibility

– Age, performance status, and comorbidites

– Expected toxicity profile

– Clinical trials, if available, are recommended for all patients

SCT = stem cell transplant.NCCN, 2012b; Ruan et al, 2009; Goy et al, 2011.

First-Line Risk-Adapted TherapyFirst-Line Risk-Adapted Therapy

Risk stratify by MIPI, proliferation index, age, and comorbidities

Young patient Age < 65 yrs

Elderly patientAge > 65 yrs

Compromised pt with comorbidities

and poor PF

Dose intense induction therapy followed by HDT

with ASCT

Less aggressive induction regimen

Monotherapy or low intensity induction

regimen

NCCN, 2012b; Harris et al, 2008.

First-Line Treatment Regimens and First-Line Treatment Regimens and ConsolidationConsolidation

Disease Stage Recommended RegimensStage IA or II non-bulky disease

• Induction therapy as in late-stage disease ± radiation therapy

Stage IIX, III, IVAggressive

• R-HyperCVAD

• NORDIC regimen: Alternating maxi R-CHOP/high-dose R-cytarabine)

• Sequential R-CHOP/R-ICE or alternating R-CHOP/R-DHAP

Stage IIX, III, IVLess aggressive

• R-Bendamustine

• R-CHOP

• R-CVP

• Dose Adjusted R-EPOCH

• Modified R- HyperCVAD + maintenance Rituximab for patients > 65 yrs

• R-Cladribine

First-line consolidation

• Clinical trial

• HDT with autologous stem-cell transplant

• For patients without intention for HDT with SCT:

• If RCHOP administered previously, consider rituximab maintenance

Weigert et al, 2007; NCCN 2012b.

CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; hyperCVAD = cyclophosphamide, doxorubicin, vincristine, dexamethasone alternating with high-dose methotrexate and cytarabine; maxi-CHOP = dose-intensified induction immunochemotherapy with rituximab and CHOP.

Intensive Therapy Plus HDT and ASCTIntensive Therapy Plus HDT and ASCT Nordic MCL-2 Trial Nordic MCL-2 Trial

Geisler et al, 2008.

Su

rviv

al (

%)

4-yr OS (n = 160)

4-yr PFS (n = 145)

4-yr EFS (n = 160)

63%

81%73%

20

40

60

80

100

00 2.5 5.0 7.5 10.0

Time (yrs)

PFS = progression-free survival; EFS = event-free survival.

The Rituximab-HyperCVAD RegimenThe Rituximab-HyperCVAD RegimenAgent Dose and Frequency (alternating q21days)

Cycles 1, 3, 5 – given in the inpatient setting

Rituximab 375 mg/m2 IV Day 1

Cyclophosphamide 300 mg/m2 IV over 2 hrs given q12hrs x 6 doses with MESNA Days 1–3

Doxorubicin 50 mg/m2 continuous infusion over 24 hrs Day 4

Vincristine 1.4 mg/m2 (maximum 2 mg) IV Days 1, 11

Dexamethasone 40 mg/day Days 1–4, 11–14

Cycles 2, 4, 6 – given in the inpatient setting

Rituximab 375 mg/m2 IV Day 1

Methotrexate 200 mg/m2 IV over 2 hrs, then 800 mg/m2 continuous infusion over 22 hrs Day 1

Cytarabine 3 gm/m2 over 2 hrs q12hrs x 4 doses Days 2, 3 (1 gm/m2 for age ≥ 60)

Leucovorin rescue Leucovorin 50 mg IV q6hrs starting 12 hrs after completion of MTX until MTX level < 0.05 uM

Aggressive supportive care including IV fluids, blood products, growth factors, and infection prophylaxis (fluconazole, acyclovir, and trimethoprim-sulfamethoxazole) is required

MTX = methotrexate; Ara-C = cytarabine; IV = intravenous; prn = as needed.Thomas et al, 2010; Courtesy of Arizona Cancer Center — University Medical Center–North.

Common HyperCVAD Side EffectsCommon HyperCVAD Side EffectsToxicity Intervention

Myelosuppression

• Hematopoietic growth factor support generally required

• Delay next cycle until counts recover

• Dose-reduction protocols may be required

Infection

• PCP prophylaxis until 1 month after regimen completed

• Systemic oral antifungal prophylaxis

• Antiviral prophylaxis if previous history of VZV or HSV reactivation

Stomatitis, mucositis

• Daily oral care; keep mouth moist; lip balm

• Adequate hydration

• Wound care, anti-infective therapy as indicated

Neurotoxicity

• Patient education/early detection

• Vincristine dose reduction

• Cytarabine dose reduction for age > 60

Hyperglycemia

• Dietary modifications

• Glucose monitoring

• Insulin and oral agents

Treatment for Relapsed/Recurrent MCLTreatment for Relapsed/Recurrent MCL

Therapy Recommended Regimens

Second-line

• Bortezomib ± rituximab (FDA approved)

• Bendamustine ± rituximab

• Cladribine + rituximab

• FC ± rituximab

• FCMR

• FMR

• Lenalidomide ± rituximab

• PCR

• PEPC ± rituximab

• Any second-line DLBCL regimens

Second-line consolidation

• Allogeneic stem-cell transplant (myeloablative or nonmyeloablative)

FC = fludarabine, cyclophosphamide; FCMR = fludarabine, cyclophosphamide, mitoxantrone, rituximab; FMR = fludarabine, mitoxantrone, rituximab; PCR = pentostatin, cyclophosphamide, rituximab; PEPC = prednisone, etoposide, procarbazine, cyclophosphamide.NCCN, 2012b.

Allogeneic Transplant in RelapseAllogeneic Transplant in Relapse

ASCT not useful with relapsed disease

– Chemoresistant clones selected during first-line therapy comprise the bulk of the disease at relapse

Evidence does support the recommendation for an allogeneic transplant in second remission

– Studies have shown a graft-versus-lymphoma effect with some increased survival but:

• Patients must have chemosensitive disease

• Myeloablative transplants have very high transplant-related mortality (50%)

• Non-myeloablative transplants have less treatment-related mortality (10%)

• Many patients are older, have significant comorbidities, and are not candidates for allogeneic transplants

• Many patients die from chronic graft versus host disease

Khouri et al, 2003; Maris et al, 2004; Tam et al, 2009.

MCL Key TakeawaysMCL Key Takeaways

This NHL subtype is associated with very poor survival

– There is a subset of patients who present with very indolent disease

MCL is characterized by a translocation of genetic material between chromosomes 11 and 14

– Results in an upregulation of Cyclin D1, a protein that regulates cell growth

There is no standard of care for the treatment of MCL

First-line regimens vary on their level of aggressiveness and toxicity

– A risk adapted approach is used to choose the best regimen

– HyperCVAD, a commonly used first-line regimen, can be very toxic with many side effects

– Conventional chemotherapy alone is generally not curative

– HDT and ASCT is recommended in first remission for patients who are eligible

Relapse is common and survival is often short

– Allogeneic transplant may be an option for these patients

Invasive Fungal Infections (IFI)Invasive Fungal Infections (IFI)

Cause of significant morbidity and mortality in immunocompromised patients

Candida and Aspergillus species most common cause in patients with hematologic malignancies

– With use of antifungal prophylaxis, previously rare pathogens (Fusarium species and Zygomycetes) emerging

Candidia species can affect relatively non-immunocompromised patients

Aspergillus species and molds generally involve severely immunocompromised patients

– Found widely in soil, dirt, dust, compost or decaying matter

Alangaden, 2011; Zitella, 2011.

IFI Risk FactorsIFI Risk Factors

State of immunocompetence

– Risk increases with duration and severity of neutropenia

– All stem cell transplant recipients

– Allogeneic transplant patients on long term immunosuppression

Type of chemotherapy agents used

– Purine analogs (fludarabine); alemtuzumab (Anti-CD22 Ab)

Sources of entry

– Mucositis, Graft versus Host disease, central lines

Exposure

– Home and nosocomial

Alangaden, 2011; Zitella, 2011.

IFI Management StrategyIFI Management Strategy

Treatment of established IFI is clinically challenging– Symptoms similar to bacterial and viral infections

– Few lab techniques to detect mold infections

– Identification of the specific pathogen can be slow

Key management strategies– Prophylactic approaches in patients at high risk

• Widely used since the late 1980’s and has reduced rates of IFI by 50%

– Empiric therapy for “suspected” infections

– Specific treatment once pathogen is identifiedRobenshtok et al, 2007; Michallet et al, 2009.

IFI SymptomsIFI Symptoms

Most common presentation is persistent fever in a patient with prolonged neutropenia or immunosuppression despite antimicrobial therapy

– Empiric antifungal therapy is started for patients still febrile after 3 to 5 days of antibiotic therapy

Invasive aspergillosis symptoms manifest as fever, cough, dyspnea, pleuritic chest pain, and hemoptysis, but often not until late in the course of the infection

Robenshtok et al, 2007; Michallet et al, 2009.

IFI DiagnosisIFI Diagnosis

Blood tests readily identify Candidia but Aspergillus not generally found in routine blood cultures

Serologic tests

– Aspergillus galactomannan and D-glucan assays

– Significant rates of false positives and false negatives

High-resolution CT scans with classic “halo” or “crescent” signs

Bronchoscopy is low yield with 50% sensitivity

Biopsy positive only in 30%–50% of cases

Ito et al, 2010; Hope et al, 2005.

IFI Diagnostic AlgorithmIFI Diagnostic Algorithm

Persistent fever on day 5 despite

empiric antibiotic therapy

Start empiric antifungal

therapy while awaiting

laboratory test results

Obtain a CT scan of chest to evaluate for

infiltrates (chest radiographs are not sensitive enough)

Order a galactomannan antigen assay

Ito et al, 2010; NCCN, 2012b.

IFI TreatmentIFI Treatment Selection of antifungal agent

– Intent: Prophylaxis or empiric treatment

– Underlying disease state

– Comorbidities

– Renal and hepatic function

– Prior antifungal exposure

– Site of infection

– Infecting organism

3 main classes of antifungal agents

– Polyenes, azoles, echinocandins

– The indication for use of these agents is outlined in NCCN guidelines

NCCN, 2012b.

IFI Treatment: PolyenesIFI Treatment: Polyenes

Indication Comments

Amphotericin B

• Broad Spectrum• Empiric use for

persistent neutropenic fever

• Substantial infusional and renal toxicity• Similar activity to Caspofungin but with

much greater toxicity

Amphotericin B Liposomal formulations

• Broad Spectrum• Empiric use for

persistent neutropenic fever

• Reduced infusional and renal toxicity compared to Amphotericin B

• Similar activity to Caspofungin but with much greater toxicity

Binds to sterols in fungal cell membranes

NCCN, 2012b.

IFI Treatment: AzolesIFI Treatment: Azoles

Inhibits fungal cell wall synthesis

Indication Comments

Fluconazole• Prophylaxis for Candidiasis• Inactive against molds

• Inactive against molds• Hepatotoxicity • Drug interactions

Itraconazole

• Braod Spectrum: Active against Candida, Aspergillus, and rare molds

• Variable absorption and plasma levels• Significant drug interactions• Visual disturbances• Contraindicated with systolic dysfunction

Voriconazole

• Extended Spectrum: Active against Candida, Aspergillus, and rare molds

• Standard of Care for invasive aspergillosis

• Significant drug interactions• Variable plasma concentrations with need

to monitor blood levels• Caution in patients with renal dysfunction• Visual disturbances and hallucinations

Posaconazole

• Extended Spectrum• Use as prophylaxis in very

high risk patients• Use as salvage therapy in

invasive aspergillosis

• Administer with a full high fat meal• Low drug interaction potential

NCCN, 2012b.

IFI Treatment: EchinocandinsIFI Treatment: Echinocandins

Indication Comments

Caspofungin

• Primary therapy for candidemia and invasive candidiasis

• Salvage therapy for aspergillosis

• Similar activity to Polyenes but with much less toxicity

• Excellent safety profile• IV only

Micafungin• Primary therapy for

candidemia and invasive candidiasis

• Similar activity to Polyenes but with much less toxicity

• Superior for prophylaxis compared with fluconazole in HSCT patients


Anidulafungin• Primary therapy for

candidemia and invasive candidiasis


Inhibits fungal cell wall synthesis

Ito et al, 2010; Hope et al, 2005; NCCN, 2012b.

Invasive Fungal Infection Case StudyInvasive Fungal Infection Case Study

61-yr-old Caucasian man with PMH of HTN and reflux. Meds include HCTZ and OTC omeprazole. He has no drug allergies.

Diagnosis: Ann Arbor Stage IVA MCL with bilateral axillary, mediastinal, and retroperitoneal LAN

– Both EGD and Bone Marrow positive for MCL

– MIPI High Risk, Ki-67 85%

He was started on Rituxan-HyperCVAD with the intent to have HDT and an ASCT in first remission

– What prophylactic agents would you initiate prior to starting HyperCVAD therapy?


Invasive Fungal Infection Invasive Fungal Infection Case Study (cont.)Case Study (cont.)

6 days following the start of his 5th cycle of HyperCVAD he comes to your clinic with mucositis, a fever of 101 F, ⁰and an ANC of 0.2

– What is your detailed plan for treating his fever?

While hospitalized, he continues to have fevers and an increased oxygen requirement in spite of negative blood cultures and the appropriate antimicrobial therapy

– What additional diagnostic studies would you order?

– What changes would you make to his antimicrobial therapy?


Post-Assessment Question 5Post-Assessment Question 5

Mantle cell lymphoma (MCL) is commonly associated with what specific chromosomal translocation and resulting biological change?

1. t(14,18): decreased apoptosis, programmed cell death

2. t(11,14): prolonged cell cycle

3. del(5q): macrocytic anemia

4. t(9,22): accelerated cell division

5. None of the above

Supportive Care Case Study Supportive Care Case Study Breakout Session 1Breakout Session 1

Supportive Care Case Study Supportive Care Case Study Breakout Session 1 InstructionsBreakout Session 1 Instructions

Appoint a moderator for your table

You will have 10 minutes to discuss the case among yourselves and record your group’s answers

Faculty will be visiting your tables to discuss the case and collect the moderator handout

Panel Discussion / Panel Discussion / Questions & AnswersQuestions & Answers

Cardiotoxicities (DLBCL)

Tumor Lysis Syndrome (DLBCL)

Neuropathy (TCL)

Chemotherapy-Induced Nausea/Vomiting (FL)

Invasive Fungal Infections (MCL)


Select ONE of the following topics for your 2nd case discussion

– Venous Thromboembolism (MM)

– ITP (CLL)

– Neutropenia (CML)

– Metastatic Bone Disease (MM)

– Cancer-Related Fatigue and Anemia (MDS)

Moderators: please collect your chosen case topic at the back of the room during lunch

LUNCHLUNCH

Chronic Lymphocytic Chronic Lymphocytic LeukemiaLeukemia

Amy L. Goodrich, MSN, RN, CRNP-BCThe Sidney Kimmel Comprehensive Cancer Center

at Johns Hopkins

Pre-Assessment Question 6Pre-Assessment Question 6

Which of the following is used for prognostic/therapy determination in CLL?

1. Expression of Zap-70 and/or CD-38

2. Beta-2-microglobulin

3. Ejection fraction assessment

4. IgVH mutational status

5. Only 2 & 3

6. Only 1 & 4

Chronic Lymphocytic Leukemia (CLL)Chronic Lymphocytic Leukemia (CLL)

Most commonly diagnosed leukemia in the US

Classified as NHL

95% B-cell; 5% T-cell or NK-cell

Characterized by abnormal proliferation of malignant mature B-cells

Multiply and replace normal lymphocytes

Crowd out normal hematopoietic cells

Malignant lymphocytes unable to fight infection

NHL = non-Hodgkin lymphoma; NK = natural killer.TLLS, 2010; Jemal et al, 2010; Shanafelt et al, 2010; Pinilla-Ibarz et al, 2010; Alterkruse et al, 2009.

CLL IncidenceCLL Incidence

~ 16,000 cases diagnosed annually in the US

~ 4,500 deaths annually

Median age at diagnosis: 72 yrs

Incidence increases after 50 yrs

Small number of young adults

Rarely seen in children

Widely variable clinical course

Median survival: 8–10 yrs

ACS, 2011; Shanafelt et al, 2010; Pinilla-Ibarz et al, 2010; Alterkruse et al, 2009.

CLL Causes and Risk FactorsCLL Causes and Risk Factors

No association with environmental or external factors, although

– There is evidence to support an association between Agent Orange and CLL

1.7 males per 1.0 females

Most common in Caucasians

Rare familial cases

– Not well understood

– Refer for laboratory-based study

Marwick, 2003; Kipps, 2010; Grever, 2007; Altekruse et al, 2009.

CLL Vs. SLL CLL Vs. SLL

In CLL, malignant cells accumulate in BM and blood stream

In SLL, malignant cells accumulate primarily in LNs

Pathologically identical diseases

Clinical diagnosis

SLL = small lymphocytic leukemia; BM = bone marrow; LNs = lymph nodes.Kastenbaum et al, 2010; Tan, 2009.

Presenting Signs and SymptomsPresenting Signs and Symptoms

Incidental finding in 70%–80% of cases

– Up from 30%–40% in the 1970s

Signs and symptoms

– Fatigue/malaise

– Dyspnea on exertion

– Lymphadenopathy

– LUQ discomfort/early satiety

– Infection

– B-symptoms uncommon (15%)

LUQ = left upper quadrant.Rozman et al, 1995; Oscier et al, 2004.

CLL Defining FeaturesCLL Defining Features

≥ 5,000 clonal B-lymphocytes in peripheral blood

Peripheral blood smear: small, mature lymphocytes

Peripheral blood flow cytometry is diagnostic

– Characteristic surface antigens: CD5, CD 19, CD20, and CD23 with kappa or lambda light chains

Cramer et al, 2011; Damle et al, 2010; Hallek et al, 2008.

CLL Diagnostic Work-UpCLL Diagnostic Work-Up

Essential Informative for Prognostic Purposes

Peripheral blood flow cytometry (biopsy not required)

If LN or BMB performed, hematopathology review recommended

Incisional or excisional LN biopsy preferred

Adequate immunophenotyping by immunohistochemistry or flow cytometry

Absolute lymphocyte count

Cytogenetics or FISH to detect: t(11;14), deletions of chromosomes 11q, 13q, 17p, or trisomy 12

Molecular genetic analysis to establish IgVH mutational status

Flow cytometry or immunohistochemistry for CD38 and/or ZAP-70 expression

BMB = bone marrow biopsy; FISH = fluorescent in situ hybridization.Rozman et al, 1995; Oscier et al, 2004; NCCN, 2012b.

CLL Staging/Safety Work-UpCLL Staging/Safety Work-Up

Essential Useful in Certain Circumstances Physical exam (nodal areas,

organomegaly) Performance status B symptoms CBC w/diff and platelets LDH Comprehensive metabolic panel Hepatitis B testing (if using

rituximab) Ejection fraction assessment (if using anthracyclines) Pregnancy testing (in women of

childbearing potential prior to treatment)

Quantitative immunoglobulins (if recurring infections) Direct coombs and/or reticulocyte

count (if anemic) CT scan chest/abdomen/pelvis β2m Uric acid Unilateral BMB Fertility discussion/sperm banking

CBC = complete blood count; LDH = lactate dehydrogenase; CT = computed tomography; β2m = beta-2-microglobulin.Rozman et al, 1995; Oscier et al, 2004; NCCN, 2012b.

Immune Dysfunction in CLLImmune Dysfunction in CLL

Immune Component

Dysfunction

B cells Poor antigen presentationB-cell unresponsivenessHypogammaglobulinemia (immune disorder characterized by a reduction of all types of gamma globulins)

T cells Decreased response to mitogensIncreased regulatory T-cellsAbberant T-cell receptor and molecular expression on T cellsDepletion of effecive cytotoxic T-cell pool

Cellular cross talk Interference in natural killer cell activityAberrant CD30-CD30 Ligand interactions

Cytokines IL-2 downregulationHigh serum levels of soluble IL-2 receptorOverexpression of IL-10 in advanced diseaseTransforming growth factor beta expression

Phagocytic function Neutropenia, abnormal chemotaxis

Tadmor et al, 2010.

CLL: Rai Staging SystemCLL: Rai Staging System

Stage Risk Features Survival (yrs)

0 Low Lymphocytosis only > 12.5

I Intermediate Lymphocytosis +lymphadenopathy

8.4

II Intermediate Lymphocytosis + > spleenand/or liver

5.9

III High Lymphocytosis + anemia(Hgb < 11.0 g/dL)

1.6

IV High Lymphocytosis + platelets< 100

1.6

Hgb = hemaglobin.Rai et al, 1975, 1990.

Genomic Alterations in CLLGenomic Alterations in CLL

Alteration Risk (with sole

abnormality)

Median Survival Median TFS

13q deletion Favorable 133 mos (11 yrs) 92 mos (7.6 yrs)

Normal Neutral 111 mos (9.25 yrs) 49 mos (4.1 yrs)

Trisomy 12 Neutral 114 mos (9.5 yrs) 33 mos (2.75 yrs)

11q deletion Unfavorable 79 mos (6.5 yrs) 13 mos

17p deletion Unfavorable 32 mos (2.6 yrs) 9 mos

TFS = treatment-free survival.Cramer et al, 2011; NCCN, 2012b.

Other Prognostic BiomarkersOther Prognostic Biomarkers

Biomarker Implication

Beta-2 microglobulin Associated with high disease burden and advanced disease stateSerial values may be useful in monitoring disease progression

CD38- surrogate marker for IgVH

If ≥ 30%, more likely to have aggressive disease course and poor response to chemotherapy

ZAP-70- surrogate marker for IgVH

If ≥ 20%, poor prognosis and clonal evolution likely

Immunoglobulin heavy chains (IgVH) mutational status

If unmutated (< 2% mutated) aggressive disease course anticipated and clonal evolution likely

PD = progressive disease. Moreno et al, 2008; Pittner et al, 2005; Hamblin, 2007; Dighiero et al, 2008.

Indications for TherapyIndications for Therapy

Eligible for a clinical trial

Significant disease-related symptoms

– Fatigue, night sweats, weight loss, fever without infection

Threatened end-organ function

Bulky disease

– Spleen > 6 cm below costal margin, lymph nodes > 10 cm

Lymphocyte doubling time < 6 months

Progressive cytopenias

Progressive high risk disease

Cramer et al, 2011; NCCN, 2012b.

Initial Therapy OptionsInitial Therapy Options

If treating after an initial watch and wait period → repeat FISH studies to assess for evolution of genomic abnormalities

Consider repeating CT scans and bone marrow examination

NCCN, 2012b.

Initial Therapy Options (cont.)Initial Therapy Options (cont.)Frail/Comorbidities; Favorable or Neutral

Risk

Age > 70 yrs; Favorable or Neutral Risk

Age < 70 yrs; Favorable or Neutral Risk

del(17p); Unfavorable

del(11q); Unfavorable

Oral alkylator +/- R

Rituximab

Pulse steriods


Bendamustine +/- R

Alkylator-based combinations

Alemtuzumab

Rituximab

Fludarabine +/- R

Cladribine

Chemo-immunotherapy

(FCR, FR, PCR, BR)

Alemtuzumab +/- R

High dose steroids + R

Chemo immunotherapy (FCR, FR)

Bendamustine + R

Consider allogeneic BMT consolidation if CR/PR

Age 70+


Bendamustine + R

Alkylator-based combinations

Modified FCR

Alemtuzumab

Rituximab

Age < 70

Chemo- immunotherapy (FCR, FR, PCR)

Consider allogeneic BMT consolidation if PR

R = rituximab; FCR = fludarabine, cyclophosphamide, rituximab; FR = fludarabine, rituximab; PCR = pentostatin, cyclophosphamide, rituximab; BR = bendamustine, rituximab; BMT = bone marrow transplant; CR = complete response; PR = partial response. NCCN, 2011; Moreno et al, 2008.

CLL Response DefinitionCLL Response DefinitionParameter Complete

ResponsePartial Response Progressive

DiseaseStable Disease

Lymphadenopathy None above 1.0 cm Decrease > 50% Increase > 50% Change from -49% to +49%

Liver and/or spleen size

Normal Decrease > 50% Increase > 50% Change from -49% to +49%

Constitutional symptoms

None Any Any Any

Leukocytes > 1,500/m3 > 1,500/m3 or > 50% improvement

Any Any

Circulating B lymphocytes

Normal Decrease > 50% over baseline

Increase > 50% Change from -49% to +49%

Platelets > 100,000/m3 > 100,000/m3

or increase > 50% over baseline

Decrease > 50% over baseline

Change from -49% to +49%

Hgb > 11.0 g/dL (untransfused)

> 2 g/dL from baseline Decrease of > 2 g/dL from baseline

Hgb < 11 g/dL or increase < 50% over baseline or

decrease < 2 g/dL

Marrow Normocellualr, < 30% lymphocytes, no

B-lymphoid nodules

Hypocellular, or > 30% lymphocytes, or B-lymphoid

nodules or not done

Increase of lymphocytes to > 30%

from normal

No change of marrow infiltrates

SD = stable disease.Eichhorst et al, 2007.

Fludarabine in CLLFludarabine in CLL “Gold standard”

Nucleotide analog

Response rate 80% in untreated patients

FDA approved in 1991 for use in CLL

Common single-cytotoxic dosing 25 mg/m2 IV on Days 1–5 of 28-day cycles x 6

Hematologic toxicity common

– ANC ≤ 500 in 59%

– Long-term depletion of CD4+ T-lymphocytes

– ≥ 2 gm drop in Hgb in 60%

– ≥ 50% drop in platelets in 55%

Sorensen et al, 1997; Fludara® prescribing information, 2007; Keating et al, 1993.

Fludarabine-Based Fludarabine-Based ChemoimmunotherapyChemoimmunotherapy

Fludarabine + R

Fludarabine + cyclophosphamide + R

– Increased incidence of hematologic and non-hematologic toxicity

– Modified dosing for elderly or frail

Pentostatin-based regimens

– Some studies suggest reduced hematologic toxicity but no significant difference in a randomized trial of PCR vs. FCR

Reynolds et al, 2008.

Bendamustine in CLLBendamustine in CLL

FDA-approved for front-line treatment in 2008

Hybrid agent: Nitrogen mustard with purine analog properties

100 mg/m2 IV on Days 1, 2

28-day cycles x 6

Administered over 30–60 mins

Antiemetic premedication

Lower doses being utilized in many ongoing clinical trials using combination regimens

Knauf et al, 2009.

Relapsed/Refractory CLL Relapsed/Refractory CLL Treatment OptionsTreatment Options

Relapsed/Refractory Treatment OptionsRelapsed/Refractory Treatment Options

Favorable, Neutral Risk Disease, del(11q) or del(17p)

Long Response

(> 3 yrs)

Short Response (< 2 yrs)

for Age ≥ 70 yrs

Short Response (< 2 yrs)

for Age ≤ 70 yrs

del(17p)

Retreat with first-line options until short response is noted

Chemoimmunotherapy (modified FCR/PCR, B +/- R, high-dose steroids + R)

Alkylator +/- steriods Ofatumumab Alemtuzumab +/- R Dose-dense R

Chemoimmunotherapy

(FCR/PCR, BR, alemtuzumab + R, CHOP + R, HyperCVAD + R, EPOCH + R, OFAR)

Ofatumumab Alemtuzumab +/- R High-dose steroids + R

CHOP + R CFAR HyperCVAD + R OFAR Ofatumumab Alemtuzumab + R High-dose

dexamethasone + R Bendamustine + R

B = bendamustine; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; OFAR = oxaliplatin, fludarabine, cytarabine, rituximab. CFAR = cyclophosphamide, fludarabine, alemtuzumab, rituximab; HyperCVAD = cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine.NCCN, 2012b.

AlemtuzumabAlemtuzumab

Anti-CD52 humanized monoclonal antibody

FDA approved for use in B-cell CLL in 2001

Stepped up dosing (3 mg, 10 mg, 30 mg)

3 x per wk x 12 wks

Premedicate with antihistamines and acetaminophen

Untreated CLL Previously Treated CLL

83% ORR 21%–31% ORR

24% complete remission 0%–2% complete remission

Campath® prescribing information, 2009.

AlemtuzumabAlemtuzumab

Black Box Warnings

– Cytopenias: Severe/fatal pancytopenia, ITP, AIHA; do not administer > 30 mg daily or > 90 mg wkly

– Infusion reactions: Serious/fatal, hold for Grade 3 or 4 infusion reactions

– Infections: Serious/fatal bacterial, viral, fungal and protozoan infections, PCP, and herpes prophylaxis

ITP = immune thrombocytopenic purpura; AIHA = autoimmune hemolytic anemia; PCP = pneumocystis pneumonia.Campath® prescribing information, 2009.

Rituximab, Ibritumomab tuxetan Tositumomab

Alemtuzumab

Molecules Targeted by Molecules Targeted by Monoclonal AntibodiesMonoclonal Antibodies

CD20 is found on immature and mature B cells

CD20 is not found on normal antibody-secreting plasma cells

CD52 is found on B cells and T cells

Rituxan® prescribing information, 2011; Campath® prescribing information, 2009; Bexxar® prescribing information, 2012; Zevalin® prescribing information, 2011; Arzerra® prescribing information, 2011.

OfatumumabOfatumumab

Fully human anti-CD20 monoclonal antibody

FDA-approved in 2009 for use in CLL patients with disease refractory to fludarabine and alemtuzumab

Premedicate with acetaminophen, antihistamine, and corticosteroid

12 doses

– 300 mg followed in 1 wk by

– 2,000 mg wkly x 7, followed in 4 wks by

– 2,000 mg q4wks x 4

Arzerra® prescribing information, 2011.

Ofatumumab (cont.)Ofatumumab (cont.) No Black Box Warnings

Warnings and precautions include

– Infusion reactions (44% w/ first infusion; 29% w/ second infusion)

– Cytopenias

– Progressive multifocal leukoencephalopathy

– Hepatitis B reactivation

Results in Fludarabine and Alemtuzumab Refractory Rate

Overall response rate (%) 42

Complete response rate (%) 0

Median duration of response (mos) 6.5


Ofatumumab Side EffectsOfatumumab Side Effects

Adverse event Total population (n = 154; %)

Neutropenia 60

Pneumonia 23

Fever 20

Cough 19

Diarrhea 18

Anemia 16

Fatigue 15

Rash 14

Dyspnea 14

Nausea 11

Upper Respiratory Tract Infection

11

Bronchitis 11


Autologous Stem Cell TransplantAutologous Stem Cell Transplant

Controversial

Early in disease course with minimal disease = better outcomes

Careful patient selection is crucial

Feasible and safe

5-yr OS: 75%–80%

5-yr PFS: 50%–55%

No plateau in survival curves

García-Escobar et al, 2010.

Autologous Stem Cell Transplant Autologous Stem Cell Transplant (cont.)(cont.)

In summary

– Prolongs PFS

– No impact on OS

– Not recommended as routine clinical practice

– Further trials needed


Allogeneic Transplant in CLLAllogeneic Transplant in CLL

Only curative option for CLL due to graft-versus-leukemia effect

Considered mainly in patients with

– del(17p)

– Fludarabine refractory disease

– Relapse within 2 yrs of autologous BMT

Myeloablative approaches carry high toxicity and mortality


Allogeneic Transplant in CLL Allogeneic Transplant in CLL (cont.)(cont.)

Reduced intensity/non-myeloablative/mini transplant

Developed in the 1990s

Allow allogeneic transplant in elderly or young with comorbidities

Many studies show lower non-relapse mortality than myeloablative allogeneic BMT

Graft-versus-leukemia effect seen


CLL Related ComplicationsCLL Related Complications

Autoimmune hemolytic anemia (AIHA)

Immune thrombocytopenia purpura (ITP)

Red cell aplasia

Infection

Transformation in 5%–10%

– DLBCL

– Prolymphocytic leukemia

– Median survival: 5 mos

DLBCL = diffuse large B-cell lymphoma.NCCN, 2012b.

CLL and AutoimmunityCLL and Autoimmunity

Well recognized

Poorly understood

Includes

– Autoimmune hemolytic anemia (AIHA)

– Immune thrombocytopenia purpura (ITP)

– Red cell aplasia

– Autoimmune granulocytopenia (rare)

Occurs in all stages of disease

No independent prognostic significance

Hamblin et al, 2008; Rozman et al, 1995.

Novel Agents Under StudyNovel Agents Under Study

Study Drug Study phase

No. patients

Doses OR (%)

CR (%)

Salles et al. Obinutuzumab I 13 5–2,000 mg 62 7

Byrd et al. Lumiliximab I 46 125–500 mg/m2 28 0

Furman et al. Dacetuzumab I 12 3–8 mg/kg/wk 5 0

O’Brien et al. Obilmersen I/II 40 3–7 mg/kg/3 wks 8 0

O’Brien et al. Obatoclax I 26 q3wks 4 0

Chanan-Khan et al.

Lenalidomide II 45 25 mg/day 47 9

Ferrajoli et al. Lenalidomide II 44 10–25 mg/day 32 7

Lin et al. Alvocidib II 117 30–80 mg/m/2wk 48 8

García-EscobarI et al, 2010; Hillmen et al, 2011.

CLL Key TakeawaysCLL Key Takeaways

CLL varies tremendously in aggressiveness and OS

Several prognostic tests are available and many are under study

Therapy is tailored to disease risk, overall health, and age

Infection and autoimmune complications are significant challenges requiring diligent nursing management

Allogeneic transplant is the only curative option

Many novel agents under study

Cytopenias in CLLCytopenias in CLL

Potential causes

– Reduced or ineffective production

• Therapy/drugs (systemic therapy, other drugs, RT)

• Disease-related (packed marrow or heavily treated)

• Infection (viral)

– Accelerated removal

• Disease-related (splenic sequestration)

• Autoimmunity (disease or therapy induced)

• Infection (bacterial or fungal)

Kumar et al, 2005.

Management of Cytopenias Due to Management of Cytopenias Due to Reduced ProductionReduced Production

Treat if due to bone marrow infiltration

– Expect initial worsening before improvement

If possible, discontinue other drugs

Use growth factors and transfusion support for therapy-induced

Treat viral infection when possible

Kumar et al, 2005; Ferri, 2009.

CytopeniasCytopenias

Etiology must be uncovered for proper management and intervention

May be multi-factorial and thus require multiple treatment strategies

Rice et al, 2006, Sloand, 2009.

Immune Thrombocytopenia Immune Thrombocytopenia Purpura (ITP)Purpura (ITP)

Characterized by autoantibodies that target platelets; leads to low platelet count

Primary (Idiopathic) vs. secondary ITP Audlt onset

– Insidious

– Chronic

– Spontaneous remission rare

Lifetime risk of fatal hemorrhage: 5%; increases with– Age

– Decreases in platelet count

– Chronic ITP

– Failure to respond to treatment

Cines et al, 2002; Cohen et al, 2000; George et al, 1996.

Immune Thrombocytopenia Immune Thrombocytopenia Purpura (ITP) in CLLPurpura (ITP) in CLL

Self-destruction of platelets

Occurs in 2%–5% of CLL patients

Occurs most frequently in unmutated IgVh, positive Coombs, or with AIHA

Common diagnostic criteria/work-up

– Rapid, severe thrombocytopenia

– Normal megakaryocytes in bone marrow

– Spleen not palpable

– No cytotoxic treatment in the past month

Hamblin et al, 2008; Rozman et al, 1995; Visco et al, 2008.

Most commonly treated with

– Corticosteroids

– IV IgG

– Rituximab

– Cytotoxic agents

– Cyclosporin

– Concurrent or sequential

Autoimmunity in CLLAutoimmunity in CLL

Hamblin et al, 2008; Rozman et al, 1995; Visco et al, 2008; Diehl et al, 1998.

ITP Case StudyITP Case Study

A 71-yr-old man diagnosed with typical B-cell CLL on incidental finding with:

– WBC 39.2

– ALC 27.4

– ANC 8.7

– H & H: 12.9 & 38.0

– Plts: 190,000

– Rai Stage I disease

– FISH: del(11q)

– IGVh mutational status: Unmutated

– Asymptomatic

ITP Case Study (cont.)ITP Case Study (cont.)

What is this patient’s prognosis?

Is there anything else you would want to know about this patient?

How would you expect this patient to be managed?

Time Point Diagnosis 3 mos 6 mos 9 mos 12 mos 15 mos

WBC 36.2 48.9 84.5 100.1 120.8 163

ALC 25.4 39.7 72.3 90.9 111.6 155.9

ANC 8.7 7.6 7.4 6.3 4.9 3.5

H & H 12.9/38.0 12/37.1 12.1/37.3 11.5/35.0 11.1/34.4 8.7/28.5

Plts 190K 170K 156K 120K 115K 21K

Symptoms None None None None Minor fatigue

Worsening fatigue


Does this patient need therapy?

Why is he thrombocytopenic?

Why is he anemic?

What work up is appropriate in this patient?

Bone marrow examination reveals extensive involvement with CLL, slightly reduced megakaryocytes and elevated erythroid precursors

Minor reduction in megakaryocytes does not account for severe thrombocytopenia

ITP diagnosed


Coombs positive

Haptoglobin nearly undetectable

LDH elevated

Reticulocytes significantly elevated

Consistent with AIHA

How would your practice treat this patient’s ITP/AIHA (Evans Syndrome)?

Begun on prednisone 1 mg/kg daily

What supportive care is appropriate?

What is happening to WBC?

Steroid initiation

3 days later

7 days later

Plts 21K 47K 69K

WBC 163K 189K 100K

H & H 8.7/27.2 9.0/28 10/29.8


Improved plts and H/H continue

Energy normalizes

Steroid taper begun

Clinical Decision Questions:

– Does this patient still need systemic therapy?

– How would your practice treat this patient?

– How often do you see ITP and/or AIHA in your CLL patients?

– Do you think of ITP and/or AIHA in your patients with CLL and cytopenias?

Chronic Myeloid Leukemia Chronic Myeloid Leukemia (CML)(CML)

Barbara Barnes Rogers, MN, CRNP, ANP-BC, AOCN®

Fox Chase Cancer Center

CMLCML

Accounts for 12% of all leukemias in adults

Approximately 5,500 new cases per year in US

Median age: 65 yrs (SEER data)

Can occur in all age groups

Slight male predominance

Phases

− Chronic

− Accelerated

− Blastic

ACS, 2012, 2011.

Philadelphia Chromosome (Ph)Philadelphia Chromosome (Ph)

Reciprocal translocation between chromosomes 9 and 22: t(9;22)(q34;q11)

Discovered by Nowell and Hungerford in 1960

The first association of a human malignant disease with a consistent chromosomal marker

Associated with a BCR-ABL fusion gene

– Oncoprotein from this fusion gene is the critical pathophysiological factor in the genesis and evolution of CML

– Disrupts regulation of downstream targets that are essential to the proliferation and survival of normal cells

– Results in uncontrolled growth of malignant cells

Hanicar, 2011; Kishore et al, 2011.

22

ABL BCR

9

BCRABL

9+

(Ph)22-Translocation

Savage & Antman, 2002.

The Philadelphia ChromosomeThe Philadelphia Chromosome

PresentationPresentation Symptoms related to anemia, splenomegaly, and increased cell turnover

– Fatigue– Left upper quadrant pain– Abdominal distention or discomfort– Early satiety– Weight loss– Night sweats

Ecchymosis common but not frank bleeding Splenomegaly is common

– Degree of splenomegaly correlates with the degree of leukocytosis Occasional symptoms of hyperviscosity

– Stroke– Priapism– Stupor– Visual changes caused by retinal hemorrhage

Savage et al, 1997.

Laboratory TestsLaboratory Tests Blood Counts:

– WBC

• Usually exceeds 50 X 10 /L

• Can range up to 800 X 10/L

• In chronic phase, the WBCs differentiate and function normally

• Peripheral blood smear shows full spectrum of myeloid cells

• Basophilia invariably present (absence should prompt consideration of another disorder)

• Eosinophilia commonly present

– Platelets

• Majority of patients have thrombocytosis

• May be more than 1,000 X 10/L

– RBCs

• Often a mild normochromic/normocytic anemia

• Inversely proportional to the degree of leukocytosis

• LAP (leukocyte alkaline phosphatase)-low or undetectable in most patients

• Uric acid and LDH frequently elevated

• Serum B12 levels are increased in proportion to total WBC count

Druker & Lee, 2011.

Bone MarrowBone Marrow

Hypercellular

Predominance of myeloid cells with full maturation

Blasts < 15%, most commonly < 5%

Basophilia present

Megakaryocytes increased in number

Requires chromosome analysis of the bone marrow for Ph chromosome

– 5% have variant translocations

– Cytogenetics can also detect other chromosomal abnormalities that may be an indication of disease progression

Druker & Lee, 2011.

Molecular TestingMolecular Testing Diagnosis requires presence of BCR-ABL

– In 95%, presence of BCR-ABL inferred by presence of Ph chromosome

– 5% have hematologic picture resembling CML, lack detectable Ph

chromosome will have BCR-ABL detectable by FISH or RT-PCR

• Clinical course same as Ph chromosome-positive, BCR-ABL positive

disease

Atypical CML-more aggressive clinical course

– Ph chromosome negative

– BCR-ABL negative

Druker & Lee, 2011.

Normal Abnormal

Faderl et al, 2004.

FISHFISH

Quantitative PCR for BCR-ABLQuantitative PCR for BCR-ABL

Highly sensitive technique

Ideal for detection of minimal residual disease

Preferred for monitoring

Provides prognostic value

May allow early detection of resistance to therapy

False-positive and false-negative results possible

Uhrmacher et al, 2010.

Disease Burden and TestsDisease Burden and Tests

Radich, 2009.

Prognostic Scores/Risk CalculationPrognostic Scores/Risk Calculation(Sokal & Hasford)(Sokal & Hasford)

Prognostic Factors– Age (yrs)– Spleen size (maximum distance from costal margin in cm)– Platelets– Basophils (%)– Eosinophils (%)– Myeloblasts (%)

Relative Risk Calculator: www.icsg.unibo.it/rrcalc.asp

Sokal et al, 1984; Hasford et al, 1998.

Treatment Options: Tyrosine Kinase Treatment Options: Tyrosine Kinase Inhibitors (TKIs)Inhibitors (TKIs)

Imatinib – First TKI developed for CML– Oral agent– Standard dose 400 mg/day– OS: 89% at 5 years and 85% at 8 years

– ~ 7% progress to accelerated phase or blast crisis at 5 years

– 8% risk of hematologic or cytogenetic relapse – Risk of relapse has trended down over time and

was less than 1% per year in years 5–8

Gleevec® prescribing information, 2012.

Treatment Options – TKIs (cont.)Treatment Options – TKIs (cont.)

Dasatinib

– Significantly more potent ABL inhibitor than imatinib

– A distinct chemical compound that inhibits significantly more kinases, notably SRC family members

– Dose 100 mg/day

– Higher rate of complete cytogenetic responses, MMR, and improved PFS than imatinib

Sprycel® prescribing information, 2011.

Treatment Options – TKIs (cont.)Treatment Options – TKIs (cont.)

Nilotinib

– More potent ABL inhibitor than imatinib

– A structurally modified imatinib

– Inhibits similar spectrum of kinases as imatinib

– Dose 300 mg twice/day

– Higher rate of complete cytogenetic responses, MMR, and improved PFS than imatinib

Tasigna® prescribing information, 2011.

Responses to TKIsResponses to TKIs

Rapid responses

Decrease in WBC count after 1–2 wks

Normalization of WBC within 4–6 wks in majority of patients

Decline in platelet count typically delayed by 1–2 wks

Majority of patients obtain CHR within 3 mos

Bone marrow morphologies revert to normal in most patients

TKI therapy viewed as a chronic, non-curative therapy

WBC = white blood cell; CHR = complete hematologic response.NCCN, 2012.

Criteria for Cytogenetic, Criteria for Cytogenetic, Hematologic, and Molecular ResponseHematologic, and Molecular Response

CHR– Complete normalization of peripheral blood counts with leukocyte count < 10 x 10 9/L

– Platelets < 450 x 10 9/L

– No immature cells, such as myelocytes, promyelocytes, or blasts in peripheral blood

– No signs and symptoms of disease with disappearance of palpable splenomegaly

Cytogenetic Response– Complete: No Ph+ metaphases

– Partial: 1%–35% Ph+ metaphases

– Major: 1%–35% Ph+ metaphases (complete + partial)

– Minor: > 35% Ph+ metaphases

Molecular Response– Complete molecular response: BCR-ABL mRNA undetectable by RT-PCR

– Major molecular response ≥ 3-log reduction in International Scale of BCR-ABL mRNA

NCCN, 2012.

Definitions of Response in Definitions of Response in Chronic Phase CMLChronic Phase CML

Timeframe Optimal Suboptimal Failure

Baseline NA NA NA

3 mos CHR and ≤ 65% Ph- CHR and > 95% Ph+ Lack of CHR

6 mos ≤ 35% Ph+ 35%–95%Ph+ > 95% Ph+

12 mos CCyR (0% Ph+) 1%–35% Ph+ > 35% Ph+

18 mos MMR < MMR > 0%Ph+

Anytime during treatment

Stable or improving Loss of MMR, development of BCR-ABL kinase domain mutations still sensitive to imatinib

Loss of CHR, loss of CCyR, new chromosome abnormalities in presence of Ph, BCR-ABL kinase domain mutations insensitive to imatinib

Defined by European LeukemiaNet (ELN).

Disease MonitoringDisease Monitoring

CBC weekly to every 2 weeks during first 2 months

LFTs

Bone marrow cytogenetics every 6 months until CCR

QT-PCR every 3–6 months on peripheral blood

NCCN, 2012.

ResistanceResistance

Signs of resistance

– Loss of CHR

– Loss of CCR or MCR

– Rise in QT-PCR (5-fold change should prompt retesting) with further increases prompting additional evaluation such as mutation testing

NCCN, 2012.

Definition of Intolerance to Definition of Intolerance to TherapyTherapy

Any life-threatening grade 4 non-hematologic toxicity

Any grade 3 or 4 non-hematologic toxicity that has recurred despite dose reduction

Any grade 2 non-hematologic toxicity that persists for > 1 month despite optimal supportive measures

Grade 3 or 4 hematologic toxicity that is unresponsive to supportive measures and would require dose reductions below the accepted minimal effective dose

Jabbour, 2011.

Side Effects of TKIsSide Effects of TKIs

Myelosuppression– Grade 3/4 common

– Use of myeloid or erythroid growth

factors while continuing therapy with

imatinib appears to be safe

– For CP disease, treatment should only

be interrupted for ANC < 1,000 and

platelets < 50,000

Nausea/Vomiting

Diarrhea

Edema/Fluid Retention

Rash

Muscle spasms

Nilotinib specific– Increased bilirubin

– Increased amylase

– Increased lipase

Dasatinib specific– Pleural effusion

Drug-drug interactions-

cytochrome P450 CYP3A4

Gleevec® prescribing information, 2012; Tasigna® prescribing information, 2011; Sprycel® prescribing information, 2011.

Management of Side Effects of Management of Side Effects of TKIsTKIs

Fluid Retention– Diuretics– Dose Adjustment

Nausea/vomiting– Take imatinib with

small meal– Anti-emetics

– Diarrhea– Diet and use of anti-

diarrhea agents

Pleural effusion– Diuretics– Dose adjustment– Dose interruption– Glucocorticoids

Myalgias– Tonic water– Magnesium

Hochhaus, 2011.

Management of Side Effects of Management of Side Effects of TKIs (cont.)TKIs (cont.)

QTc Prolongation

– K+ supplement– Mg++ supplement– EKG monitoring

ALT/AST/bilirubin alteration– Dose interruption for

grade 3 or 4– Dose adjustment

Lipase/amylase increase– Dose interruption for

grade 3 or 4– Dose adjustment

Glucose alteration– Adapt anti-diabetic

therapy Hypophosphatemia

– Phosphate supplementation

Hochhaus, 2011.

Management of Side Effects Management of Side Effects of TKIs (cont.)of TKIs (cont.)

Rash, pruritus

– Topical steroids

Neutropenia/thrombocytopenia

– Mainly transient during initial phase of therapy

– Treatment interruption

– Dose adjustment

– Growth factors in individual cases

Hochhaus, 2011.

Discontinuance of TKI Therapy: Discontinuance of TKI Therapy: STIM TrialSTIM Trial

Patients on imatinib for at least 3 yrs

Sustained CMR for at least 2 yrs

100 patients on trial

Molecular relapse occurred in 54 patients

(46 remained free of molecular relapse at

median follow-up of 14 mos)

– Most relapsed within 6 mos

– 7 patients after 1 mos

– 13 after 3 mos

– 1 after 4 mos

– 1 after 6 mos

– 1 after 7 mos

– 1 at 19 mos

Overall probability of maintenance of

CMR at 12 mos was 43%

Probability of sustained CMR at 12

mos did not differ between patients

with previous interferon-α and

patients with imatinib as initial

treatment

Potential predictive factors

– Sex-worsen prognosis

– Sokal score-highest Sokal scores

worsen prognosis

– Duration of imatinib therapy:

Improved prognosis

STIM = Stop Imatinib.Mahon et al, 2010.

Hematopoietic Stem Cell Hematopoietic Stem Cell TransplantationTransplantation

5-yr survival with HLA matched sibling donor (CP; 60%–80%)

10-yr DFS 50%–60% 20-yr survival 38% Adverse Prognostic Factors for HCT

– Accelerated or blastic phase– Disease duration > 12 mos– Patient age > 20 or 40 yrs– Female donor for a male patient– Transplantation from an unrelated donor

Stage of disease before transplant is one of most consistent predictors of outcome in related and unrelated donor HSCT

NCCN, 2012.

Novel AgentsNovel Agents

Unmet need-management of CML with T315I mutation– Highly resistant to all 3 approved agents

– Ponatinib (AP24534)• New multikinase inhibitor

• Significant activity against T315I and other BCR-ABL mutations

• Responses highly durable

– DCC-2046• Promises to be active for treatment of a broad range of TKI-resistant

BCR-ABL mutations, including T315I

– Omacetaxine• Expected to be useful for treatment of a broad range of TKI-resistant

BCR-ABL mutations

• Associated with a high degree of myelosuppression

• Unknown mechanism of action

Clinicaltrials.gov

Adherence to Oral TherapyAdherence to Oral Therapy

Studies have shown that full adherence rate to imatinib therapy may be as low as 14%

Non-adherence may have a significant impact on patient’s outcome

Low adherence has been identified as the main reason for failure to achieve major or complete molecular responses

Patients in stable CCyR with adherence rate < 85% have higher 2-yr probability of losing CCyR than patients who are adherent

Reasons for non-adherence

– Intentional-most commonly to deal with side effects

– Unintentional-most commonly due to forgetting doses

Marin et al, 2010.

Pregnancy and CMLPregnancy and CML Children fathered by men taking imatinib at the time of conception

appear healthy– Current advice is not to discontinue treatment

Data related to children born to women exposed to imatinib during pregnancy less encouraging– Numbers are small– Disturbing cluster of rare congenital malformations– Imatinib cannot be safely recommended, particularly during the period of

organogenesis– Limited information regarding alterations in successful management of

CML during pregnancy– Outcome of pregnancies after nilotinib and dasatinib is limited

Recommendation for women desiring to get pregnant to wait for at least an MMR before discontinuing therapy for pregnancy– To reduce risk of treatment failure after reintroduction of therapy– TKI therapy should be discontinued at least 3 mos before conception in

both parents

Hochhaus, 2011.

CML Key TakeawaysCML Key Takeaways

CML is a rare disorder that is caused by the

translocation of chromosomes 9 and 22 There are 3 TKIs approved for the treatment of CML Therapy adherence is an important factor in response to

therapy Therapy is considered life-long but some data exists that

shows some patients will remain in long-term remission

after discontinuation of therapy

NeutropeniaNeutropenia

Definition: A significant reduction in the absolute number of circulating neutrophils in the blood

Classification levels:– Mild: ANC < 1.5 X 109/L

– Moderate: ANC 1.0–0.5 X 109/L

– Severe: ANC < 0.5 X 109/L Normal WBC varies between genders and ethnic

groups– Ethnic groups with lower ANC

• African ancestry

• Yemenite Jews

Watts, 2011.

Risk Factors for NeutropeniaRisk Factors for Neutropenia

Infection Treatment Related

– Previous chemotherapy

– Planned relative dose intensity

– Concurrent or prior irradiation to bone marrow

– Pre-existing neutropenia (prolonged) Comorbidities

– Chronic obstructive pulmonary disease

– Cardiovascular disease

– Liver disease

– Renal insufficiency

– Diabetes mellitus

– Baseline anemia

Freifeld et al, 2011; ONS, 2009.

Risk Factors for NeutropeniaRisk Factors for Neutropenia

Patient Related

– Increased age (>65 years)

– Female

– Poor performance status

– Poor nutritional status

– Decreased immune function

– Decreased body surface area

– Inpatient versus outpatient Cancer Related:

– Bone marrow involvement of tumor

– Advanced cancer

– Type of malignancy: leukemia, lymphoma, lung cancer

– Elevated lactate dehydrogenase level (LDH)

Freifeld et al, 2011; ONS, 2009.

High and Low Risk Characteristics for High and Low Risk Characteristics for Fever and NeutropeniaFever and Neutropenia

High Risk Low Risk

Anticipated prolonged (> 7days) duration of neutropenia

Anticipated brief (< 7 days) duration of neutropenia

Profound neutropenia (ANC ≤ 100 cells/mm3)

No or few comorbidities

Significant medical co-morbid conditions including hypotension, pneumonia, new-onset abdominal pain or neurologic changes

Candidates for oral empirical therapy

Freifeld et al, 2011.

Treatment of NeutropeniaTreatment of Neutropenia

Guided by underlying etiology and severity of neutropenia

Can range from observation to growth factor support and antibiotics

Preventive measures to limit the number and severity of infections

Direct efforts to rapidly identify and treat infections that do arise

Prophylactic Antibiotic IndicationsProphylactic Antibiotic Indications Antibacterial Indications

– Anticipated prolonged neutropenia > 7–10 days– Significant co-morbid conditions (e.g., cardiac disease)– Acute leukemia induction/consolidation– GVHD treatment with high dose steroids– ANC > 100 cells/mm3

Antifungal Indications– Allogeneic HCT– Induction therapy for acute leukemia/MDS– Previous fungal infection– Significant GVHD

Antiviral Indications– HSV seropositivity in patients undergoing allogeneic stem cell transplant or

acute leukemia induction– Treatment with bortezomib, purine analogs, CD20 monoclonal antibodies– Autologous stem cell transplant

Empiric Antibiotic Therapy for Empiric Antibiotic Therapy for Neutropenic FeverNeutropenic Fever

Hospitalization for IV empirical antibiotic therapy

Monotherapy with an anti-pseudomonal β-lactam agent

– Cefepime

– A carbapenem (meropenem or imipenem-cilastatin)

– Piperacillin-tazobactam

Other antimicrobial may be added for management of complications (hypotension or pneumonia) or if antimicrobial resistance is suspected or proven:

– Aminoglycoside

– Fluoroquinolone

– Vancomycin

Freifeld et al, 2011.

Dose Modifications of Imatinib due to Dose Modifications of Imatinib due to Neutropenia / ThrombocytopeniaNeutropenia / Thrombocytopenia

Chronic Phase CML– If ANC is less than 1 X 109/L and/or platelet count less

than 50 X 109/L:• Stop imatinib until:

– ANC is at least 1.5 X 109/L

– Platelet count at least 75 X 109/L

• Restart imatinib at original dose

– If neutropenia or thrombocytopenia recurs:• Stop imatinib until:

– ANC greater than or = 1.5 X 109/L and

– Platelet count greater than or = to 75 X 109/L

• Resume at decreased dose:– Adult from 400 mg/day to 300 mg/day

– Pediatrics-from 340 mg/day to 260 mg/day


Dose Modifications of Imatinib due to Dose Modifications of Imatinib due to Neutropenia / ThrombocytopeniaNeutropenia / Thrombocytopenia

Accelerated Phase or Blast Crisis

– If ANC is less than 0.5 X 109/L and/or platelet count less than 10 X 109/L and cytopenias are unrelated to leukemia:

• Reduce dose from 600 mg/day to 400 mg/day

• Further reduce to 300 mg/day if cytopenia persists for 2 weeks

– If cytopenia persists for 4 weeks and is still unrelated to leukemia:

• Stop imatinib

• Resume it at 300 mg/day when ANC is at least 1.0 X 109/L and platelet count is at least 20 X 109/L


Neutropenia Case StudyNeutropenia Case Study

CM is a 55-yr-old who presented to his primary physician with fatigue − A CBC was completed that demonstrated a WBC of 54.0, Hgb

13.8, Hct 39.7, Plts 284,000, ANC 47.2

− Eosinophils and basophils were elevated

A BMB was completed and by FISH was noted to have t(9;22)

He was started on imatinib− Repeat CBC 1 wk later indicated a WBC of 1.0 with an ANC of

< 500

− He reports not having a fever that he has noticed

Neutropenia Case Study (cont.)Neutropenia Case Study (cont.)

Clinical Decisions/Considerations:

– How would you interpret this laboratory data?

– What is your treatment recommendation based on this lab data?

– What are the high-risk factors associated with neutropenic fever?

– Which population may have a lower ANC historically?

– In which situations should a prophylactic antibacterial agent be used?

Multiple MyelomaMultiple Myeloma

Beth Faiman, PhDc, MSN, APRN, BC, AOCN®

Cleveland Clinic Taussig Cancer Institute

What Is Multiple Myeloma (MM)?What Is Multiple Myeloma (MM)?

Cancer of bone marrow plasma cells

Excess production of normal Ig Plasma cells turn malignant “M” protein or “M spike” Heavy chains involved

– IgG, IgA, IgD, IgE

– Light chains: Kappa (κ) or Lambda (λ)

Presentation: Protein in serum, urine, non-secretory

Not everyone who presents with M protein has myeloma

– MGUS

M = monoclonal; Ig = immunoglobulin; MGUS = monoclonal gammopathy of unknown significance.Kyle et al, 2010; Tariman, 2010, Bergsagel et al, 2005.

Normal Plasma Cell

Hematopoietic Stem Cell

Genetic Damage

NRAS, KRAS

Mutation

FGFR3 mutation

c-myc dysregulation

p53 and p18

Abnormalities

del(13)

1, 3, 5, 7, 9, 11,15, 19, 21trisomies

IgHtranslocations11q136p214p1616q2320q12

Pre B-Cell

Myeloma Cell

Pre B-Cell

Multiple Myeloma Disease ContinuumMultiple Myeloma Disease Continuum

MGUS (Monoclonal Gammopathy of

Undetermined Significance)

Smoldering

Multiple Myeloma

MultipleMyeloma

M protein (per dL) < 3 g 3 gM-spike or

plasmacytoma

Clonal PC in bone marrow

< 10% 10% > 10%

End-organ damage None None 1 or more CRAB criteria

Likelihood of progression

1% per yr10% per yr for 5 yrs;

73% by 15 yrs--

Symptoms Asymptomatic Asymptomatic Symptomatic (~ 89%)

Active treatment No No or Clinical Trial Yes

Premalignant Conditions Malignant

Kyle et al, 2007; IMWG, 2003; Jagannath et al, 2010; Kyle et al, 2010; Mateos et al, 2009.

Immunoglobulin Structure Immunoglobulin Structure and Light Chain Disease and Light Chain Disease

Roughly 30% of patients with MM produce more light chains (incomplete Ig)

Light chains are small enough to pass into urine and overwhelm the kidneys

κ or λ light chain MM: Highest risk of renal failure

Dispenzieri et al, 2009.

Free Light Chain (Kappa/Lambda)

Heavy Ig Chain

(IgG, IgA)

http://upload.wikimedia.org/wikipedia/commons/2/2d/Antibody.svg

Diagnosis of MMDiagnosis of MM

❖ Clonal bone marrow PCs ≥ 10%

❖ Serum and/or urinary monoclonal protein

❖ CRAB features

– Hypercalcemia

– Renal insufficiency

– Anemia

– Bone disease

Durie et al, 2006. Image courtesy of Cornell University Medical College.

Epidemiology and Risk FactorsEpidemiology and Risk Factors

Prevalence− > 100,000 are living with

MM in the US Risk factors

− Age− Gender − Race

Clinical presentation− Back, bone pain: 58%− Asymptomatic: 20%− 13% will have neuropathy

Causes− Benzene− Herbicides− Agent Orange? − First-degree relatives

First case− Sarah Newbury in 1844

First effective treatment− Melphalan in 1962

Tariman et al, 2010; Altekruse et al, 2009.

What Causes MM?

Risk Factors for MMRisk Factors for MM

FISH: Looks at genes, chromosomes, and their aberrations

Chromosomal changes and abnormalities present in 80%–90% patients on FISH analysis

High risk– t(4;14) or t(14;16) by FISH– del(17p) by FISH– del(13) by cytogenetics– Hypodiploidy

– High β2m (≥ 5.5 mg/L)

– IgA isotype

Stewart et al, 2005, 2007; Barlogie et al, 2004; Richardson, 2005; Avet-Loiseau et al, 2002; Fonseca, 2007. FISH = fluorescent in situ hybridization; β2m = beta-2-microglobulin.

Low to intermediate risk

– t(11;14)

– Hyperdiploidy

– Low β2m (< 3.5 mg/L)

Signs and Symptoms Signs and Symptoms Not all inclusive; everyone is

different

General subjective complaints, history

– Back/bone pain is the leading symptom (58%)

– Generalized weakness and fatigue

– Flu-like symptoms, N/V (electrolytes)

– Easy bruisability, recurrent infections (low platelets)

– Neurologic

• Headaches, Blurred Vision, Ataxia, Vertigo

Objective

– Pallor

– Tenderness over affected bony areas

– Altered mental status

– Incontinence, loss of sphincter tone, lower extremity weakness with pain may signify an oncologic emergency (spinal cord compression must be ruled out)

– Tachycardia/arrhythmias due to electrolyte imbalance and associated renal impairment

N/V = nausea/vomiting.US NIH, 2008; IMF, 2009.

Diagnostic TestsDiagnostic Tests

Laboratory analysis

– CBC and metabolic panel

• Ca+, UA, creatinine

• Alb, β2m, LDH

– M proteins

• SPEP, UPEP, immunofixation

• Quantitative Ig

• sFLC assay

Radiologic imaging

– Skeletal survey or X-rays

– MRI

– PET/CT

BMB

CBC = complete blood count; Ca+ = calcium; UA = uric acid; Alb = albumin; LDH = lactate dehydrogenase;

SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis; sFLC = serum free light chain;

MRI = magnetic resonance imaging; CT = computed tomography; PET = positron emission tomography; BMB = bone marrow biopsy.

NCCN, 2012.

MM is like a puzzle. You have to put all the pieces together before

you see the big picture.

Laboratory Findings in Myeloma: Laboratory Findings in Myeloma: CBCCBC

Anemia (73%)

– Cytokine mediated or from crowded BM microenvironment (MM related)

– Blunted erythropoiesis and shortened red cell survival(MM treatment related)

– Bleeding/blood loss

– Renal disease (decreased erythropoeisis)

– Macrocytic anemia (B12 deficiency)

– Myelodysplastic syndrome

Leukopenia

Thrombocytopenia

NCCN, 2012; Baz et al, 2004.

Laboratory Findings: Renal Failure (RF)Laboratory Findings: Renal Failure (RF) Myeloma kidney

– Occurs when proximal and distal tubules overwhelmed by LC, obstructed by protein casts

Hypercalcemia from bone destruction, cytokines

Dehydration

Hyperuricemia

– Secondary to RF, tumor lysis (rare)

NSAIDs, ACE inhibitors, IV contrast

Infection, sepsis

Amyloidosis

Durie et al, 2003; Chanan-Khan et al, 2007; Rajkumar & Kyle, 2005; Sanders et al, 1992; Dimopolous et al, 2010.

Renal impairment is not an independent adverse prognostic factor in MM treated with novel agents

NSAIDs = non-steroidal anti-inflammatory drugs; ACE = angiotensin-converting enzyme; IV = intravenous.

Laboratory Findings: HypercalcemiaLaboratory Findings: Hypercalcemia Hypercalcemia in 25% of patients

Pathobiology

– Increased osteoclastic bone resorption mediated by cytokines

– Efflux of Ca+ into extracellular fluid

– Not all patients with bone disease develop hypercalcemia

– Osteoclast stimulation can lead to extensive osteolysis, severe bone pain, and pathologic fractures with or without hypercalcemia

Widespread tumor induced bone destruction– Increased Ca+ levels can lead to decreased renal perfusion– Can cause a decline in eGFR secondary to renal vasoconstriction

Treatment – Pamidronate 60–90 mg IV over 4 hrs or zoledronic acid 4 mg IV – Hydration– Treat the disease itself – Correct Ca+ for Alb

eGFR = estimated glomerular filtration rate.Oyajobi, 2007; Roodman, 2008; Tariman et al, 2010.

Laboratory Findings: M Protein Laboratory Findings: M Protein

Immunofixation investigates abnormal bands

Serum and urine are evaluated to improve detection

– SPEP, presence of M protein; could miss 15% of patients with MGUS

– Not performing a urine evaluation could miss 10% of patients with hypogammaglobulinemia where the M spike is “hiding” under the gamma region and is undetected

sFLC

– Quantitative marker of disease activity

– Especially useful in “non-secretory” MM patients

– Light chain escape

Faiman et al, 2010; Malpas, 1998.

Serum Free Light ChainsSerum Free Light Chains

Normal Abnormal Kappa light chain: 3.3–19.4 mg/L Normal: Kappa/Lambda 0.26/1.65

Elevation of Kappa/Lambda ratio suggests Kappa light chain

Lambda light chain: 5.7–26.3 mg/L Kappa/Lambda ratio < 0.26 =

monoclonal Lambda FLC

Reduced Kappa/Lambda ratio suggests Lambda light chain

Example of Serum Free Light Chain Results

Component Ref Range Result

Kappa, free, serum 3.3–19.4 mg/L 1123.0 (H)

Lambda, free, serum 5.7–26.3 mg/L 4.2 (L)

Kappa/Lambda ratio, serum 0.26–1.6 mg/L 26.7 (H)

Faiman et al, 2010; Dispenzieri et al, 2008; Drayson et al, 2001; Kuhnemund et al, 2009.

Radiologic Imaging: Skeletal Survey/X-RaysRadiologic Imaging: Skeletal Survey/X-Rays

Bone X-rays are the standard to diagnose MM related bone damage

Less sensitive than MRI, PET, or CT

30%–40% bone loss must be present before damage is visible on X-ray

MRI or CT: Evaluate suspicious lesions found on X-ray

Bone scan imaging is not performed in MM (absent osteoblastic response)

Tariman et al, 2010; Roodman, 2008.

Bone Disease in MMBone Disease in MM

Malignant cells produce osteoclast-activating factors (hormones, cytokines) that destroy bone cells

– Leads to osteolysis, bone pain, and pathologic fracture

BP (pamidronate, zoledronic acid) inhibit bone destruction

– Monitor patients for

• Acute phase reactions (flulike sxs, chills)

• Renal dysfunction

– Dose reduce BP for decreased CrCl, longer infusion time

– Monitor for albuminuria, a sign of tubular damage

• ONJ

– Baseline and ongoing dental exams

– Hold BP if jaw pain

BP = bisphosphonates; CrCl = creatinine clearance; ONJ = osteonecrosis of the jaw.Tariman et al, 2010; Kyle et al, 2007; Morgan et al, 2010a.

Infections in MMInfections in MM

A leading cause of death in myeloma patients

Ig levels decreased and patients are hyporesponsive to antigen stimulation, deficient antibody production

Infiltration of BM by plasma cells

Cytotoxic therapy

Transplant

Interventions

– Prompt reporting of symptoms

– IV Ig prophylaxis for frequent infections

– Poor response to pneumococcal and influenza vaccines

– Herpes zoster oral prophylaxis (bortezomib)

Barlogie et al, 2006; Durie at al, 2003; Malpas, 2004; NCCN, 2012.

Laboratory Findings: BMBLaboratory Findings: BMB

Suggested at baseline and end of therapy

As myeloma disease may be assessed with serum and urine testing, BM does not need to be repeated unless clinically indicated

Cytogenetics and FISH are helpful with prognosis

– Incorporating novel agents into treatment up-front can eliminate negative prognostic significance of certain abnormalities

GEP

GEP = gene expression profiling.NCCN, 2012; Vescio, 2001; Tan et al, 2010; Jakubowiak, Martin, et al, 2010; Qu et al, 2010.

International Staging System (ISS)International Staging System (ISS)

Stage CriteriaMedian Survival

(mos)

ISerum β2m < 3.5 mg/LSerum Alb ≥ 3.5 g/dL

62

II Serum β2m < 3.5 mg/LSerum Alb < 3.5 g/dL

OR

Serum β2m 3.5 through < 5.5 mg/L

44

III Serum β2m ≥ 5.5 mg/L 29

Greipp, 2005; Dimopoulos et al, 2010.

ASH Update: ISS remains a robust prognostic tool unaffected by the degree of renal function (or dysfunction) in a review of 1,516 MM patients

Serum β2m reflects tumor load and is elevated in RF

How Do You Treat Myeloma UPFRONT?How Do You Treat Myeloma UPFRONT?

NCCN, 2012; Rajkumar et al, 2007; San Miguel et al, 2008; Kumar et al, 2008; Ludwig et al, 2009; Jagannath et al, 2004; Thalomid® prescribing information, 2010.

PO = oral; MPV = melphalan, prednisone, bortezomib; PLD = pegylated liposomal doxorubicin.

Transplant CandidateBortezomib +dexamethasone

Bortezomib 1.3 mg/m2 Days 1, 4, 8, 11 + Dexamethasone 20 mg PO Day 1, 2, 4, 5, 8, 9, 11, 12

Lenalidomide +dexamethasone (+/- bortezomib?)

Lenalidomide 25 mg PO Days 1–21, q28d + Dexamethasone 40 mg PO wkly (+ bortezomib 1.3mg/m2 wkly or twice wkly?)

Thalidomide +dexamethasone (+ bortezomib or PLD?)

Thalidomide 200 mg Days 1–28 + Dexamethasone 40 mg PO Days 1–4, 9–12, 17–20 x 4 28-day cycles (+ bortezomib or PLD?) – LESS COMMON TO GIVE THAL UPFRONT

Non-Transplant Candidate

Any of the novel agents

Prednisone is often substituted for dexamethasone (elderly poor tolerance)

Melphalan + any of the above

MPV: 9 6-wk cycles of melphalan 9 mg/m2 + prednisone 60 mg/m2 Days 1–4 Bortezomib 1.3 mg per square meter on Days 1, 4, 8, 11, 22, 25, 29, 32 during Cycles 1–4 and on Days 1, 8, 22, 29 during Cycles 5–9

Maintenance May improve PFS; ongoing studies

Stem Cell Transplant (SCT) in MMStem Cell Transplant (SCT) in MM Due to young age, SCT should be an option Transplant candidates

– Age– Performance status– Desire– Insurance– Prior treatment history

Depth of response is a prognostic factor for long-term survival

– CR– VGPR

ASCT: Infusion of patient’s own HSCs AlloSCT: Infusion of donor HSCs

– Graft vs. myeloma effect– Tumor-free grafts– Reduced risk of relapse vs. ASCT but 1-yr transplant-related mortality:

Around 50% in males

CR = complete response; VGPR = very good partial response; ASCT = autologous SCT; AlloSCT = allogeneic SCT; HSCs = hematopoietic stem cells.

NCCN, 2012.

Side Effects of Novel AgentsSide Effects of Novel Agents

PN– Bortezomib, thalidomide

Myelosuppression– Bortezomib, lenalidomide

VTE– Lenalidomide, thalidomide

GI– Bortezomib, lenalidomide, thalidomide

Steroid-related side effects Emerging agents

– Carfilzomib– Pomalidomide– Elotuzumab

NCCN, 2012; Nabhan et al, 2010.

Peripheral NeuropathyPeripheral Neuropathy

Damage to the peripheral nervous system caused by injury, inflammation, or degeneration of peripheral nerve fibers (sensory, motor, autonomic)

A challenging event that can affect QOL and compromise optimal treatments for patients with MM

Incidence of CIPN is increasing

– More neurotoxic drugs have been developed

– Patients are living longer and receiving multiple chemotherapy regimens

Thalidomide and bortezomib are 2 novel agents used for MM that can cause PN.

– Patients with pre-existing or at high risk of PN should be considered for subcutaneous administration of bortezomib.

Other agents: Vincristine, Cisplatin

Signs and symptoms

Monitoring

QOL = quality of life; CIPN = chemotherapy-induced peripheral neuropathy.Tariman et al, 2008; Wickham, 2007; Thalomid® prescribing information, 2010; Velcade® prescribing information, 2012.

Thromboembolic Events in MMThromboembolic Events in MM MM is an intrinsically hypercoagulable disease

associated with a higher risk of thromboembolic events

Higher risk for DVT/PE in patients treated with conventional chemotherapies plus novel therapies (thalidomide, lenalidomide)

Dx: Duplex ultrasound, spiral CT if PE suspected

Mechanical

– Ambulate, SCDs, antiembolism stockings (questionable benefit)

– Encourage activity or even mild exercise regimen

DVT = deep vein thrombosis; PE = pulmonary embolism.Rome et al, 2008; Musallam et al, 2010; Menon et al, 2008.

Myelosupression Myelosupression Novel Agents Incidence Intervention

Thalidomide Neutropenia:

15%–25%

Do not initiate if ANC < 750 mm3

If ANC < 500 mm3 withhold thalidomide until ANC > 500 mm3 and restart at 50% lower dose

Lenalidomide/

Dexamethasone

All Grades

Neutropenia: 28%

Anemia: 24%

Thrombocytopenia: 17%

(2% febrile neutropenia)

Interrupt therapy if platelets fall to < 30,000 mcL or ANC falls to < 1,000 mcL Resume therapy at same dose on first recovery Drop dose by 5 mg on subsequent recoveries

Bortezomib Neutropenia

Overall: 17%

Grade ≥ 3: 12%

Thrombocytopenia

Overall: 36%

Grade ≥ 3: 29%

(< 1% febrile neutropenia)

Cyclical with lowest levels on Day 11 of cycle Consistent pattern that is not cumulative Hold if platelets < 25,000 µL and reintroduce at a 25% lower dose with recovery

ANC = absolute neutrophil count.Velcade® prescribing information, 2012; Thalidomid® prescribing information, 2010; Miceli et al, 2008.

General: Monitor CBC, educate re: precautions

Side-Effect Assessment and ManagementSide-Effect Assessment and Management Important to develop individualized patient and family education

strategies for patients receiving therapies for MM

VTE = venous thromboembolism; IMiDs = immunomodulatory drugs; GI = gastrointestinal.

IMF, 2010; Kyle et al, 2007; NCCN, 2012.

What is the risk of VTE? Increased if prior VTE, receiving IMiDs, etc.

Bone health Do they require bisphosphonates?

Infectious diseases Is your patient at high risk for infection? (myelosuppression from disease/treatment)

– Wkly CBC, differential for 8 wks with lenalidomide– Acyclovir prophylaxis with

bortezomib– IV Ig for recurrent infections (a result of hypogammaglobulinemia)

GI Antiemetic prior to bortezomib, doxorubicin

Assess for diarrhea, constipation

PNPN Review increased risk of PN with bortezomib and thalidomide

Prompt intervention can prevent irreversible PN symptoms

Monthly monitoring of disease parameters

SPEP, UPEP, 24-hr urine, sFLC

MPR = melphalan, prednisone; NDMM = newly diagnosed MM; MPR-R = MPR followed by lenalidomide; MP = melphalan, prednisone, placebo followed by placebo; R/R = relapsed/refractory. Palumbo et al, 2010, 2011.

Melphalan 0.18 mg/kg Days 1–4 Prednisone 2 mg/kg Days 1–4 Lenalidomide 10 mg QD PO Days 1–21

Melphalan 0.18 mg/kg Days 1–4 Prednisone 2 mg/kg Days 1–4 Lenalidomide 10 mg QD PO Days 1–21

Melphalan 0.18 mg/kg Days 1–4 Prednisone 2 mg/kg Days 1–4 Placebo Days 1–21

LenalidomidePlacebo

Lenalidomide

Pro

gre

ssio

n

Placebo

9 28-Day Cycles Cycles 10+

MPR-R regimen reduced risk of progression

Maintenance improved PFS

Phase III MM-015 StudyPhase III MM-015 StudyPhase III MM-015 Study to Determine the Efficacy and Safety of Lenalidomide in Phase III MM-015 Study to Determine the Efficacy and Safety of Lenalidomide in Combination With MPR in Elderly Patients With NDMM MPR-R Vs. MPR Vs. MPCombination With MPR in Elderly Patients With NDMM MPR-R Vs. MPR Vs. MP

http://ash.confex.com/data/abstract/ash/2011/4/0/Paper_37604_abstract_65254_0.jpg

Post-ASCT Maintenance Post-ASCT Maintenance With LenalidomideWith Lenalidomide

Study Regimen N Outcome (Len Vs. Placebo)

McCarthy

CALGB 100104

Lenalidomide maintenance

post-ASCT

Vs.

placebo

460 Maintenance improved Median TTP

43.6 mos Vs. 21.5 mos;

HR 0.43

Maintenance improves OS

21 deaths Vs. 37 deaths;

Unadjusted p < .019

Attal

IFM-2005

Lenalidomide maintenance post-ASCT

Vs.

placebo

314 Consolidation improved VGPR (p < .0001)

Maintenance improved PFS

42 mos Vs. 24 mos;

HR: 0.5, p < 10-8

McCarthy et al, 2011; Attal et al, 2011.

GEM2005MAS65GEM2005MAS65

260 elderly untreated myeloma patients

Induction: Once per wk dosing of bortezomib in combination with prednisone plus either melphalan (VMP) or thalidomide (VTP)

After 6 cycles: Randomly assigned to maintenance with VP or VT

Maintenance consisted of 1 conventional cycle of bortezomib (1.3 mg/m2 on Days 1, 4, 8, 11) q3mos, plus either oral prednisone 50 mg q other day or oral thalidomide 50 mg daily, for up to 3 yrs

Results

– Median PFS was 30 mos (95% CI 21–39) for patients receiving VT vs. 24 mos (95% CI 15–33) for those receiving VP (p = 0.1)

– The slight benefit of VT vs. VP as maintenance was independent of the type of induction therapy (VMP or VTP; p = 0.9)

– VT arm was associated with a higher incidence of non-heme toxicity

Mateos et al, 2011.

Maintenance Therapy with Bortezomib Plus Thalidomide (VT) or Bortezomib Plus Maintenance Therapy with Bortezomib Plus Thalidomide (VT) or Bortezomib Plus Prednisone (VP) In Elderly Myeloma Patients Included In the GEM2005MAS65 Prednisone (VP) In Elderly Myeloma Patients Included In the GEM2005MAS65

Spanish Randomized Trial Spanish Randomized Trial

MMY-3021MMY-3021

222 patients: Efficacy of bortezomib in patients with relapsed MM was similar with SC and IV administration

The data highlight the efficacy of bortezomib irrespective of its route of administration

– Median PFS 10.2 mos SC arm vs. 8.0 mos in IV arm– 1-yr OS 72.6% in SC group and 76.7% IV group

Less toxicity with SC – Any PN: 38% SC vs. 53% IV – Less Grade 3 and higher PN – Gl disorders: 37% SC vs. 58% IV

Bortezomib SC is not inferior to IV by ORR after 4 cycles (p = .002) Bortezomib SC not different from IV by

– TTP (p = .387)– 1-yr OS (p = .504)

Moreau et al, 2010; Johnson & Johnson, Inc., 2010.

OS = overall survival; SC = subcutaneous.

A Phase III Prospective Randomized International Study (MMY-3021) Comparing A Phase III Prospective Randomized International Study (MMY-3021) Comparing SC and IV Administration of Bortezomib in Patients With Relapsed MM SC and IV Administration of Bortezomib in Patients With Relapsed MM

PX-171-004PX-171-004

CFZ is a next-generation proteosome inhibitor

This study evaluated patients who had not received bortezomib

Patients received either 20 mg/m2 for all treatment cycles (Cohort 1) or a dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2

for all treatment cycles thereafter (Cohort 2)

Carfilzomib was administered over 2–10 mins on Days 1, 2, 8, 9, 15, and 16 of q 28-day cycle, for a maximum of 12 cycles

Patients receiving higher overall dose and bortezomib naïve did best

Incidence of ≥ grade 3 PN < 1%, side effects mostly hematologic

Nearly one-third completed 12 cycles and 22 > 1 yr in the extension protocol PX-171-010

Vij et al, 2011.

CFZ = carfilzomib; ORR = overall response rate; PR = partial response; DOR = duration of response.

Final Results From the Bortezomib-naïve Group of PX-171-004, Final Results From the Bortezomib-naïve Group of PX-171-004, a Phase 2 Study of Single-Agent Carfilzomib (CFZ)a Phase 2 Study of Single-Agent Carfilzomib (CFZ)

POM With or Without LoDex in Relapsed POM With or Without LoDex in Relapsed and Refractory MM: Phase II Resultsand Refractory MM: Phase II Results

Results: 56% patients on POM alone crossed over to POM/Dex Most common grade 3/4 AEs: Myelosuppression, severe PN was not seen All grades: Pneumonia, fatigue, DVT, and renal failure Pomalidomide is a promising agent for patients with R/R MM as patients with

advanced MM responded to POM +/- Dex

POM = pomalidomide; LoDex = Low-dose dexamethasone; R/R = relapsed/refractory; LEN = lenalidomide; BORT = bortezomib.

Richardson et al, 2011.

Arm A: Pomalidomide 4 mg Days 1–21 of 28 days + Dexamethasone 40 mg Days 1, 8, 15, 22

Arm B: Pomalidomide 4 mg Days 1–21 of 28 days

* > 2 regimens, > 2 cycles len/bort

All patients received low dose ASA

http://ash.confex.com/data/abstract/ash/2011/0/5/Paper_38850_abstract_64037_0.jpg

ElotuzumabElotuzumab Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1,

an antigen highly and uniformly expressed on MM cells but with restricted expression on normal cells

– Elotuzumab in combination with bortezomib in patients with R/R MM: Phase I: Generally well tolerated with 48% response

Elotuzumab in combination with lenalidomide and dexamethasone in patients with R/R MM: Ongoing phase II study

73 patients randomized to elotuzumab 10 or 20 mg/kg IV (Days 1, 8, 15, 22 q28days in the first 2 cycles and Days 1, 15 of subsequent cycles), and len 25 mg PO (Days 1–21) and dexamethasone 40 mg PO wkly or 28 mg PO plus 8 mg IV on elotuzumab dosing days

– Generally well tolerated with 92% response

– 22% of patients progressed after a median of 11.4 mos follow-up

– Elotuzumab-associated AEs were primarily Grade 1 and 2 infusion-related reactions. Incidence and severity mitigated by premedication: Methylprednisolone, diphenhydramine, ranitidine, and acetaminophen

Richardson et al, 2010; Jakubowiak et al, 2010; Lonial et al, 2011.

Vantage 088Vantage 088

Between January 2009 and January 2011: 637 patients

Patients had received a median of 2 prior regimens (range 1–3)

Randomized to receive 21-day cycles of BTZ (1.3 mg/m2 IV; Days 1, 4, 8, 11) in combination with oral VOR 400 mg/d, or matching placebo, on Days 1, 14

Results: 23% reduction in the risk of progression compared to bortezomib alone

PFS was 7.6 mos in the BTZ/VOR arm, and 6.8 mos in the BTZ arm

BTZ = bortezomib; VOR = vorinostat.

Dimopoulos et al, 2011.

Vantage 088: Vorinostat in Combination With Bortezomib in Patients With Vantage 088: Vorinostat in Combination With Bortezomib in Patients With Relapsed/Refractory MM: Results of a Global, Randomized Phase III Trial Relapsed/Refractory MM: Results of a Global, Randomized Phase III Trial

MM Key TakeawaysMM Key Takeaways

MM is a very complex diagnosis Nurses are in the unique position to manage side effects

and encourage adherence to the selected regimen Although incurable, OS has improved dramatically in the

last decade as a result of newer agents, better supportive therapy

Clinical trials yield promising results for MM treatment Emerging therapies will provide additional options for our

patients

General Considerations/Nursing Care General Considerations/Nursing Care Plan for Newly Diagnosed MM PatientPlan for Newly Diagnosed MM Patient

Educate regarding side effects of treatment: Bort, Len, Dex– Diarrhea, increased risk of blood clots, fatigue, myelosuppression

– Mood swings, insomnia, hyperglycemia, and bone loss with dexamethasone

Disease monitoring – CBC q2wks for 3 mos

– Then “myeloma” labs q month per standard of care (SPEP, UPEP, CBC, CMP, 24-hr urine and serum free light chains)

Bisphosphonates

– To prevent further skeletal complications

– Ongoing orthopedics for L1 compression fracture, surveillance for new

– Pamidronate 90 mg IVPB or ZA 4 mg monthly after dental exam

Faiman et al, 2008; Celgene® prescribing information, 2009.

General Considerations/Nursing Care General Considerations/Nursing Care Plan for Newly Diagnosed MM PatientPlan for Newly Diagnosed MM Patient

Risk of Blood Clots

– Prevention with aspirin 81 mg daily (< 2 risk factors)

– Avoid use of erythropoiesis stimulating agents (ESAs) as this will increase risk (unless ESRD)

Infection surveillance – Acyclovir while on bortezomib; high risk of bacterial infections

(hypogam)

Diabetic monitoring – Will be worse with steroids, exercise can help mobilize insulin

Faiman et al, 2008; Celgene® prescribing information, 2009.

Treatment Options: Treatment Options: Renal InsufficiencyRenal Insufficiency

❖ Dialysis for severe renal failure: HD filters can remove light chains

❖ Bortezomib

– No need to dose adjust even in ESRD

– Since dialysis may reduce bortezomib concentrations, the drug should be administered after dialysis

– Reversal of renal failure

❖ Thalidomide

– Metabolism unchanged in renal insufficiency

– No dose modification in dialysis

❖ Lenalidomide

– Careful dose adjustment and observation required as LEN is substantially excreted by the kidney

– Myelosuppression is the consequence

❖ Newer agents: Safety unknown

HD = hemodialysis; ESRD = end-stage renal disease; LEN = lenalidomide.Hutchinson et al, 2011; Thalomid® prescribing information, 2010; Revlimid® prescribing information, 2011.

Preventing Fractures With Preventing Fractures With BisphosphonatesBisphosphonates

❖ FDA approved

– Pamidronate 60–90 mg IV monthly

– Zoledronic Acid 4 mg IV monthly

– NCCN recommends giving monthly (no recommendation for duration)

– ASCO recommends giving monthly for 2 yrs

❖ Considerations

– Dose reduce with renal insufficiency

– Baseline dental exam prior to infusion (ONJ)

– Albuminuria: Suggests tubular damage from prolonged use

– Oral calcium and Vitamin D supplementation

– Exercise

• Weight bearing exercise will increase muscle strength and bone mass and decrease the risk of falls

ASCO = American Society of Clinical Oncology.Kyle, Yee, et al, 2007; NCCN, 2012; Aredia® prescribing information, 2011; Zometa® prescribing information, 2011.

Supportive Care: Supportive Care: Vertebroplasty and Balloon Kyphoplasty Vertebroplasty and Balloon Kyphoplasty

Vertebroplasty Balloon Kyphoplasty

Images courtesy of the Central Texas Spine Institute.

CAFE: CAFE: CACAncer Patient ncer Patient FFracture racture EEvaluation in MM valuation in MM

BKP showed significantly greater improvement

– Mean improvement from baseline, -8.3 points

– Change exceeded the 2.5 point MCID

– This and vertebroplasty should be considered if pain r/t VCF

0

4

8

12

16

20

24

Baseline 1 Month

Ro

lan

d-M

orr

is S

co

re

BKP

NSM

Roland-Morris Back Disability

0

4

8

12

16

20

24

Baseline 1 Month

Ro

lan

d-M

orr

is S

co

re

BKP

NSM

Roland-Morris Back Disabilityp<0.0001

N=56N=59 N=47N=53

Berenson et al, 2011.

Patients enrolled within 3 mos of diagnosis of VCF

Optional crossover at 1 mos

VCF = vertebral compression fractures; MCID = minimally clinically important differences.

Metastatic Bone Disease Case Metastatic Bone Disease Case StudyStudy

59-yr-old man; Lower back pain (rated 8/10)

– Tylenol and Ibuprofen 4qd did not help

– Urgent care visit

H/O mild high blood pressure and “blood sugar problems.” He was told, “if I lose weight, my blood sugar will be ok.”

Review of systems: Lower than normal urine output; Fatigue and SOB when walking; Bilateral ankle swelling

4qd = 4x everyday; H/O = history of; ROS = review of systems; SOB = shortness of breath.

Metastatic Bone Disease Case Study (cont.)Metastatic Bone Disease Case Study (cont.)Lab/Normal Reference Range Value

WBC 3.0–11.0 k/uL 11.55 (H)

Plt Ct 150–400 k/uL 140(L)

Hgb 13.0–17.0 g/dL 8.3 (L)

Hct 39.0%–51.0% 24.4 (L)

MCV 80–100 fL 110.6 (H)

RDW-CV 11.5%–15.0% 14.7

Neut 38.5%–75.0% 76.2

Abs Neut 1.00–7.50 k/uL 5.07

Lab/Normal Reference Range Value

BUN 8–25 mg/dL 53

Creatinine 0.7–1.4 mg/dL 3.9 (H)

Calcium 8.5–10.5 mg/dL 13.2 (H)

Alb 3.5–5.0 g/dL 2.9 (L)

Alk Phos 40–150 U/L 192 (H)

β2m 20.8 (H)

Glucose 208 H

Serum total protein 6.4

WBC = white blood count; Plt Ct = platelet count; Hgb = hemoglobin; Hct = hematocrit; MCV = mean corpuscular volume; RDW = coefficient variation of red-blood cell-distribution width; Neut = neutrophil; Abs Neut = absolute neutrophil count; BUN = blood urea nitrogen; Alb = albumin; Alk Phos = alkaline phosphatase; β2m = beta-2-microglobulin; UPEP = urine protein electrophoresis; MPA = microscopic polyangiitis.

Urinalysis showed 3+ proteinuriaUPEP; Lab/Normal Reference Range Value

Urine Alb 20.9%

α-1 globulin; 0.2–0.3 mg/dL 3.6

α-2 globulin 4.1

β globulin; 0.70–1.00 mg/dL 69.1

γ globulin; 0.7–1.6 mg/dL 2.3

Urine M spike g/dL; (normally absent) 4.10

Immunofixation: Lambda

Serum Monoclonal Protein Analysis (MPA); Normal Reference Range

Value

MPA serum IgG; 717–1,411 mg/dL 338 (!)

MPA serum IgA; 78–391 mg/dL < 7 (!)

MPA serum IgM; 53–334 mg/dL 8 (!)

MPA serum κ; 534–1267 mg/dL 382 (!)

MPA serum λ; 253–653 mg/dL 0.65 (!)

> 4 gms proteinuria “hypogammaglobulinemia”

Metastatic Bone Disease Case Study (cont.)Metastatic Bone Disease Case Study (cont.)

BMB: 30% plasma cells, lambda restricted

– Cytogenetics: Normal male chromosome

– FISH is negative for 17p, del(13) and t(4;14)

Skeletal survey: Widespread osteopenia; L1 compression fracture

Diagnosis: Lambda light chain MM; stage III (ISS): B2M > 5.5

Clinical Decision

– What would you consider to be part of the treatment plan?

BMB = bone marrow biopsy; FISH = fluorescent in situ hybridization; ISS = International Staging System.Greipp, 2005.

Component Reference Range

Result

Kappa, free, serum 3.3–19.4 mg/L < 3.0 (L)

Lambda, free, serum 5.7–26.3 mg/L 11,150.4 (H)

Kappa/Lambda ratio, serum 0.26–1.6 mg/L 0.00 (L)

Vertebral Vertebral Compression Compression Fracture Fracture (VCF) (VCF)

Venous Thromboembolism (VTE) Venous Thromboembolism (VTE) Case StudyCase Study

Discussion Questions

– Which drugs cause an increased risk of VTE in MM?

• Name 4 risk factors for VTE in MM in patients receiving these drugs

– What can nurses do to educate patients on VTE prevention?

– What are the signs of VTE that nurses can anticipate?

– How do you protect patients?

Venous Thromboembolism (VTE) Venous Thromboembolism (VTE) Case Study (cont.)Case Study (cont.)

Your patient has MM. She is 72 yrs and remains active, however slipped and broke her right hip

Never had a DVT

She is in a very good partial remission and remains on lenalidomide 10 mg po Days 1–21 (x 4 yrs; no steroids)

She has renal insufficiency secondary to years of HTN and type 2 DM

Is your patient at increase risk of developing VTE?

Your patient underwent hip replacement 4 days ago. Her pain is much better. She is to be discharged to a rehab facility tomorrow but is complaining of unilateral leg swelling and pain behind her right calf.

Which is the most appropriate course of action?

BREAKBREAK

Myelodysplastic Syndrome Myelodysplastic Syndrome (MDS) (MDS)

Beth Faiman, PhDc, MSN, APRN, BC, AOCN®

Cleveland Clinic Taussig Cancer Institute

Barzi et al, 2010; Kurtin et al, 2006; List et al, 2002; List et al, 2004.

Pathobiology of MDSPathobiology of MDS

MDS represents a spectrum of clonal stem cell malignancies characterized

– Dysplastic clones and ineffective hematopoiesis

– Progressive cytopenias, risk of bone marrow failure, and leukemic transformation

– Complex interactions between malignant progenitor cells, bone marrow stroma, and the microenvironment

– Identification of key molecular, immunologic, and hematologic factors has provided insight into potential therapeutic targets

Age-Related Incidence of MDSAge-Related Incidence of MDS

Williamson et al, 1994.

Age in 5-Yr Blocks

Age-Specific Incidence Rates (per 100,000), Yrs

< 50 0.5

50–59 5.3

60–69 15

70–79 49

> 80 89

Nu

mb

er o

f P

atie

nts

When Should You Suspect MDS?When Should You Suspect MDS?

Typically older at presentation

Males > females

Can occur following chemotherapy, radiation

With or without symptoms

Fatigue is common presenting symptom (anemia)

Easy bruising, bleeding (thrombocytopenia)

Frequent infections

Anemia is not a normal sign of aging!

MDS: Diagnostic EvaluationMDS: Diagnostic Evaluation

Peripheral blood counts + retic

Bone marrow biopsy and aspiration

– Hematopathology

• Bone marrow blasts (%), cellularity, dysplastic features

– Cytogenetics

– Iron stain, reticulin stain

Chemistry panel

– Liver, organ function

Miscellaneous hematology

– Iron saturation, ferritin

– B12, folate levels

– EPO level

Goals of testing

1) Establish diagnosis of MDS (rule out other causes of cytopenias)

2) Determine subtype and prognosis

– FAB/WHO, IPSS score

EPO = erythropoietin; FAB = French-American-British, WHO = World Health Organization.

Barzi et al, 2010; NCCN, 2012.

MDS: Diagnostic FindingsMDS: Diagnostic Findings

Laboratory

Anemia, neutropenia, and/or thrombocytopenia

Peripheral blasts may be present (depending on subtype)

Bone Marrow

Usually hypercellular, yet can be hypocellular

Dysplasia present

Excess blasts (> 5%) observed in RAEB, RAEB-T, and CMMoL

– Associated with poorer prognosis and decreased survival rate

Cytogenetics

Should be obtained with bone marrow

Some karyotypes are associated with good/poor prognosis

Lubbert, 2003.

Survival: Bone Marrow BlastsSurvival: Bone Marrow Blasts

According to the IPSS, excess blasts are the strongest predictor of poor outcomes

Per

cen

t (%

)

100

90

80

70

60

50

40

30

20

10

01 2 3

Time (yrs)

5 6 7 8 109 11 12 13 14 15 1716 184

Survival

Median

< 5% 483 pts 5%–10% 183 pts11%–20% 114 pts

21%–30% 36 pts

Greenberg et al, 1997.

FAB ClassificationFAB Classification

NameBone Marrow

BlastsPeripheral Blood

BlastsRinged

Sideroblasts

RA < 5% < 1% < 15%

RARS < 5% < 1% > 15%

RAEB 5%–20% < 5% Variable

RAEB-T 21%–30% > 5% Variable

CMMoL ≤ 20% < 5% –

Classifies MDS according to morphology and percentage of blasts in the bone marrow, peripheral blood

FAB = French-American-British..List et al, 2003; Faderl et al, 2005.

* Good = normal, -Y, del(5q), del(20q); Intermediate = other karyotypic abnormalities; Poor = complex ( 3 abnormalities) or chromosome 7 abnormalities † Hgb < 10 g/dL; ANC < 1,800/L; platelets < 100,000/L

IPSS Scoring SystemIPSS Scoring System

Score Value

Prognostic Variable 0 0.5 1.0 1.5 2.0

Bone Marrow Blasts < 5% 5%–10% – 11%–20% 21%–30%

Karyotype* Good Intermediate Poor

Cytopenias† 0/1 2/3

All 3 prognostic variables are required to generate IPSS score

Greenberg et al, 1997.

Revised IPSS-RRevised IPSS-R

Revised Prognostic Scoring System (IPSS-R)Revised Risk Category Median Survival (yrs) Evolution to AML (yrs; 25%)

Very low 6.8 NR

Low 4.3 10.1

Intermediate 2.3 2.8

High 1.5 1.2

Very high 0.9 0.7

Greenberg, Tuechler, et al, 2011; Greenberg, Attar, et al, 2011.

MDS Treatment PrinciplesMDS Treatment PrinciplesCurative Goals

Allogeneic bone marrow transplantation is the only known curative modality

– Approximately 5% of patients qualify

– Approximately 40% of patients who undergo bone marrow transplantation are likely to be cured

– 38% mortality rate in patients > 55 yrs

Noncurative Goals

Decrease bone marrow blasts

Decrease transfusion needs and infection, QOL

Supportive Care Should Always Be Present

Bennett, 2002; Polsdorfer, 2005; Gore, 2004.

Treatment OptionsTreatment Options

Supportive care/growth factors

Demethylating agents

Chemotherapy

Immunosuppressive therapy

Angiogenesis inhibitors

Immunomodulatory agents

Bone marrow or stem cell transplant

Kurtin & Demakos, 2010; Sekeres, 2011.

A Few Considerations…A Few Considerations… Myelosuppression is a common DLT in all types of active therapy for

MDS

Results are not immediate; several mos of treatment are needed before determining response to treatment

Cytopenias are expected to worsen before improving

ESAs and GCSF

– Patients with a higher average baseline serum EPO level (≥ 500 U/l) have a smaller Hb change and a lower rate of Hb response (27.3%) than groups with a lower baseline serum EPO level (34.9%)

Treatment with ESAs should start at 450 IU/kg/wk for at least 8–∼10 wks

Predictors of response to ESAs include a normal karyotype, endogenous EPO levels < 100–200 mU/mL and the refractory anemia subtype

Kurtin & Demakos, 2010; Schrijvers et al, 2010.

NCCN GuidelinesNCCN Guidelines Treatment: IPSS Categories Int-1 and Low

Adapted from NCCN, 2012.

Clinically significant cytopenias

Supportive care

Del(5q) ± othercytogenetic abnormalities

Lenalidomide No responseFollow appropriate pathway below

ThrombocytopeniaNeutropenia

Symptomatic anemia

Serum EPO<500 mU/mL

Epoetin α(rHu EPO) G-CSF orDarbepoetin α

Azacytidine/Decitabine orClinical trial

No response

No response

Clinicaltrial

Serum EPO>500 mU/mL

Candidate forimmunosuppressive Therapy (IST)

Not a candidate forimmunosuppressive therapy

No response

Antithymocyte globulin,Cyclosporin A


No response

No response

IST orClinical trial

Clinical trial


EPO = erythropoietin.

NCCN GuidelinesNCCN Guidelines Treatment: IPSS Categories Int-2 and HighTreatment: IPSS Categories Int-2 and High

Based on age, performance status, and absence of major comorbid medical conditions precluding high-dose therapy

Donor available

Yes

No

Intensivetherapy

candidate

Hematopoietic stem cell transplant

High-intensity therapy or azacytidine/ decitabine or clinical trial or

supportive care

Azacytidine/decitabine orclinical trial or supportive care

Non-intensivetherapy

candidate

Adapted from NCCN, 2012.

Agents to Treat MDSAgents to Treat MDS

Agent FDA Approval Mechanism of Action Route of Administration

Azacitidine May 2004 DNA methylation SC or IV; oral compound in clinical trials

Lenalidomide December 2005 Immunomodulatory Oral

Decitabine May 2006 DNA methylation IV/SQ

Kurtin & Demakos, 2010.

Alemtuzumab, clofarabine, oral azacitidine are only 3 of the many drugs under investigation

LenalidomideLenalidomide Antiangiogenic analog of thalidomide, works at the level of the bone marrow RevAssist – lenalidomide education and prescribing safety for safety in prescribing Given orally 10 mg/d as starting dose (5 mg if renal) Thrombocytopenia and neutropenia limiting toxicities Chromosomal abnormality 5q- present in 20%–30% 99/148 (67%) patients achieved transfusion independence in phase II study

lenalidomide in the treatment of transfusion-dependent Low- or Int-1 risk MDS with a del(5q) chromosomal abnormality with or without additional cytogenetic abnormalities

MDS-004 trial: Randomized trial 1:1:1 (LEN 10 mg/d Days 1–21, or 5 mg/d Days 1–28; or placebo)

– For LEN group

• 2-yr OS and AML risk were 56.6%, 25.1%

• RBC-TI for ≥ 8 wks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (p = .021, .048)

Fenaux et al, 2011.

Azacitidine: Mechanism of ActionAzacitidine: Mechanism of Action

Pyrimidine analog that is incorporated into replicating DNA

Inhibits hypermethylation of DNA (epigenetic)

– May restore normal expression to silenced genes critical for cell differentiation and proliferation

Causes death of rapidly dividing cells

– Including cancer cells no longer responsive to normal growth control mechanisms

– Cells that do not divide are relatively insensitive to VIDAZA

Vidaza® prescribing information, 2011.

Minimum duration of supportive care = 4 mos unless transformation to AML; death or platelets < 20 x 109/L at Wk 8 or later

Growth factors were prohibited Considered to have failed if

– Advanced to high-risk category (RAEB or RAEB-T) or AML– Remained blood transfusion dependent before and during study– Developed progressive bone marrow failure

BM = bone marrow; AZA = azacitidine.

Supportivecare*Stratify:

• RA• RARS• RAEB• RAEB-T• CMMoL

AZA 75 mg/m2/d SC x 7 days q28 x 4

Exit criteria

No Continue untilend point +

Yes AZA(dose as per arm #2)

ASSESS

Response• Continue Rx

No Response• Off study

BMBM BM

0 5729 113Day

Study 9221: Study 9221: A Randomized Phase III Controlled Trial of A Randomized Phase III Controlled Trial of

Subcutaneous Azacitidine in MDSSubcutaneous Azacitidine in MDS

Silverman, 2001; Silverman et al, 2002; Kornblith et al, 2002.

RANDOMIZE

Study 9221: Efficacy Study 9221: Efficacy

Azacitidine delivered 44% RBC transfusion independence

Azacitidine delivered 53% platelet transfusion independence

Nearly half of higher-risk patients achieved transfusion independence

Response (CR + PR) was independent of FAB subtype

No overall differences in efficacy were observed between older and younger patients

Silverman, 2001; Silverman et al, 2002; Kornblith et al, 2002.

Duration of TherapyDuration of Therapy

92.9% of responding patients achieved initial positive effect by the end of 6 treatment cycles

Treatment may be continued as long as the patient continues to benefit

2 3–4 5–6 > 6

Number of Cycles

% R

esp

on

din

g P

atie

nts

(C

R +

PR

)A

chie

vin

g In

itia

l Po

siti

ve E

ffec

t (N

= 1

4)

21.4

42.9

28.6

7.1

Data on file, Courtesy of Beth Faiman, PhDc, MSN, APRN, BC, AOCN®.

92.9%

*Initial positive effect was defined as the first day of achievement of target for 4 wks for at least 1 cell line abnormality.

Azacitidine for High-Risk MDS: Azacitidine for High-Risk MDS: AZA-001 Phase III StudyAZA-001 Phase III Study

Patients with int-2/high-risk IPSS with RAEB, RAEB-T,

or CMML (N = 358)

Azacitidine • 75 mg/m2/d for 7 days q28days• (n = 179)

Conventional Care Regimen• BSC only or• LDAC 20 mg/m2/d for 14 days q28–42days or standard chemotherapy (7 + 3 regimen)• (n = 179)

Fenaux et al, 2007.

Overall Survival on AZA-001Overall Survival on AZA-001

CCR = conventional care regimen.Fenaux et al, 2007.

Log-rank p = .0001HR: 0.58 (95% CI: 0.43–0.77)Deaths: Azacitidine = 82; CCR = 113

Number at riskAzacitidine 179 152 130 85 52 30 10 1CCR 179 132 95 69 32 14 5 0

Time From Randomization (mos)

CCRAzacitidine

0 5 10 15 20 25 30 35 40

0.10

0.20.30.40.50.60.70.80.91.0

Pro

po

rtio

n S

urv

ivin

g (

%)

9.5 mos

Can Patients Receive Azacitidine Can Patients Receive Azacitidine at Home?at Home?

Home Azacitidine Administration in High-Risk MDS:

Favorable Results of a Pilot Study in 48 Patients 68 patients were included in the home chemotherapy program 75% were MDS patients and 48 received azacitidine > 2,000 days of hospitalization were performed at home during

18 mos Similar median number of cycles and delays were observed in

the 2 groups as well as same level of adverse events and hospitalizations between 2 cycles

In few cases administration was not possible at home due to unresolved infection, cytopenia, or drug availability (excessive time between preparation and distribution)

Guillevic et al, 2011.

DecitabineDecitabine Decitabine is indicated for treatment of MDS patients

including:

– Previously treated and untreated, de novo, and secondary MDS of all FAB subtypes RA, RARS, RAEB, RAEB-t, and CMMoL

– Intermediate-1, intermediate-2, and high-risk IPSS groups

In a recent study, decitabine administered in 6-wk cycles was found to be active in older patients with higher-risk MDS

– Improved OS, PFS, QOL

– Less likelihood of AML transformation

Short MDS duration was an independent adverse prognosticator

Dacogen® prescribing information, 2010; Lübbert et al, 2011.

Decitabine Phase III MDS Trial Decitabine Phase III MDS Trial Study DesignStudy Design

Open-label, multicenter, 1:1 randomized study IPSS: Int-1, Int-2, and high-risk MDS patients eligible Primary end points: response and time to AML/death

– IWG response criteria utilized for assessment

Kantarjian et al, 2007.

Decitabine + Supportive Care15 mg/m2/over 3 hrs q8hrs x 3 days q6wks(N = 89)

Supportive CareABX, growth factors, and/or transfusions(N = 81)

Stratification- IPSS- Types of MDS

(primary or secondary)

EligiblePatients(N = 170)

RANDOMZIED

Decitabine Phase III MDS Trial Decitabine Phase III MDS Trial ResultsResults

ITT Analysis Decitabine*(N = 89)

Supportive Care (N = 81)

Overall Response (IWG Criteria)† 17% 0%

Complete Response 9% 0%

Partial Response 8% 0%

Hematologic Improvement (IWG) 13% 7%

Overall Clinical Benefit (CR + PR + Hematologic Improvement) 30% 7%

Median Time to Response (CR + PR) 93d (55-272) Not Assessed

Median Duration of Response (CR + PR) 288d (116-388) Not Assessed

†p < .001

*FDA approval based on response analysis; decitabine treatment did not significantly delay the median time to AML or death vs. supportive care.

Dacogen® prescribing information, 2010; Silverman et al, 2002.

DNA Methylation Inhibitors:DNA Methylation Inhibitors:WhatWhat’’s the Difference? s the Difference?

Azacitidine Used in all 5 FAB subtypes

(RA, RARS, RAEB, CMML, RAEB-T)

Given SC or IV x 7 days (outpatient regimen)

When using either SC or IV, the recommended starting dose for the first treatment cycle for all patients, regardless of baseline hematology values, is 75 mg/m2 daily for 7 days

Decitabine Int-1/int-2/high risk per IPSS

as well as tMDS

Recommended dose from registration trial:15 mg/m2/hr over 4 hrs q8hrs for 3 days, q6wks for up to 10 cycles

tMDS = transformed MDS.

Dacogen® prescribing information, 2010; Vidaza® prescribing information, 2011.

ASH 2011 Update: ASH 2011 Update: Prognostic Factors: GeneticsPrognostic Factors: Genetics

IPSS-R was discussed earlier LR-PSS recently evaluated to identify higher risk MDS patients among

those with lower IPSS score

Bejar et al 2011.

The Lower-Risk M. D. Anderson Prognostic Scoring System (LR-PSS)

http://ash.confex.com/data/abstract/ash/2011/6/8/Paper_41586_abstract_64943_0.png

ASH 2011 Update: ASH 2011 Update: Prognostic FactorsPrognostic Factors

Impact of iron chelation therapy on OS and AML transformation in lower risk MDS patients was evaluated

– 97 patients at Moffitt 2001–2009

– Forty five (46.4%) received ICT and 52 did not

– Median OS was 59 mos (95% CI 22–48) for patients who received ICT compared to 33.7 mos (95% CI 38–80) for patients who did not

– ICT was associated with better OS

– AML transformation was 21.2% in patients who did not receive ICT compared to 15.6% in those who had ICT (p = .33)

– Elevated serum ferritin ≥ 1,000 ng/mL was associated with improved OS and a trend to lower AML transformation

– Also, elevated serum ferritin level ≥ 1,000 ng/mL in int-2 and high risk IPSS MDS was independently associated with worse OS and higher rate of AML progression

Komoroni et al, 2011; Komrokji et al, 2011.

ASH 2011 Update: ASH 2011 Update: Treatment Treatment

Phase I study of the combination of 5-azacitidine sequentially with high-dose lenalidomide in higher-risk MDS and AML

– Sequential combination of 5-azacitidine followed by LEN

– No DLT was documented and MTD was therefore not reached

– Safe and active in patients with higher risk MDS and AML

Azacitidine treatment of LEN-resistant MDS with del(5q)

– 2005–2011, 18 patients treated with 5-azacitidine were identified

– Patients had median f/u from date of 5-azacitidine of 645 days

– Median duration of treatment 183 days, some had heatologic improvement (7) or stable disease (4), while only 4 had progressive disease

– 5-azacitidine was found to be effective in patients who failed LEN with 5q-

Garcia-Manero et al, 2011; Komrokji, 2011.

ASH 2011 Update: ASH 2011 Update: Phase I/II Studies (Treatment)Phase I/II Studies (Treatment)

Final results from the phase 2 continuation study of the lenalidomide and azacitidine combination in patients with higher-risk MDS

– 36 patients received azacitidine 75 mg/m2 daily x 5 days, and lenalidomide 10 mg daily x 21 days of a 28-day cycle (maximum of 7 cycles)

– All had higher-risk MDS (IPSS score ≥ 1.5, or World Health Organization (WHO) classification with ≥ 5% myeloblasts); not previously treated with azacitidine or lenalidomide

– Median OS at last assessment among CR patients was 27 mos (range, 7–55). 7 CR patients (50%) evolved to AML a median of 20 mos from achieving CR (range, 9–31); 10 (71%) remain alive at last study assessment

Low-dose clofarabine (interim results) of the GFM Clo08 dose escalating phase I/II study (NCT0106325)

– 19 patients in a dose-escalation study received outpatient therapy; myelosupppression frequent even at low doses

Sekeres et al, 2011; Braun et al, 2011.

New Treatments on the HorizonNew Treatments on the Horizon

Panobinostat in combination with a 5-day schedule of azacitidine in high-risk MDS and AML

– Planned interim analysis of a phase Ib/II study

– In previously untreated MDS/AML, panobinostat and azacitidine is well tolerated

– Preliminary assessments demonstrate clinical activity

– MTD was determined to be 30 mg of panobinostat in combination with a 5-day azacitidine schedule of 75 mg/m2 daily

– Fatigue was common and resulted in dose – reduction of panbinostat in many cases

Tan et al, 2011.

Key TakeawaysKey Takeaways

MDS encompass a variety of disorders

New insight to the genetics, risks of each individual are coming to light

Nurses play a critical role ensuring treatment is delivered, appropriate supportive care techniques are employed

Cancer-Related Fatigue and Cancer-Related Fatigue and Anemia Case StudyAnemia Case Study

Mrs. A is a 68-yr-old woman in good health. Recently retired as a school teacher. No previous history of illness.

Went to PCP for complaints of fatigue. “Watching my grandkids twice weekly.” (ages 2 and 4)

– Hgb: 9.9 g/dL

– WBC: 2,700/mm3

– ANC: 351/mm3

– Plt: 105,000/mm3

Iron, ferritin were within normal limits

Vitamin B12 and MMA were normal

VTE = venous thromboembolism; LEs = lower extremities; DVT = deep venous thrombosis.

Cancer-Related Fatigue and Cancer-Related Fatigue and Anemia Case Study (cont.)Anemia Case Study (cont.)

Referred to Hematology and BMB was performed – BM blasts: 13%

– Normal female karyotype (good)

– What is her IPSS score?

Questions– What are some strategies to manage anemia in patients with MDS?

– What are some strategies to manage fatigue in patients with MDS?

– What are some strategies you find helpful to manage cancer-related fatigue and anemia in your practice?

SurvivorshipSurvivorship

Sandra E. Kurtin, MS, RN, NP, AOCN®

The University of Arizona Cancer Center

Survivorship: Survivorship: Who, What, When, and HowWho, What, When, and How

There are 12 million cancer survivors in the US

68% of people diagnosed with cancer today are expected to live at least 5 yrs

Approximately 15% of all cancer survivors were diagnosed > 20 yrs ago

Most cancer survivors today are > 65 yrs

In 2005, the Institute of Medicine (IOM) issued the report, From Cancer Patient to Cancer Survivor: Lost in Transition

Cancer.org.

Survivorship: Who, What, When, Survivorship: Who, What, When, and How (cont.)and How (cont.)

The increase in survival rates is largely attributed to the following 4 developments

– Improved screening and early detection

– Improvements in treatment

– More effective treatment of side effects, making it possible to give patients higher, more effective doses of cancer drugs

– The development of targeted therapies which are more specific and often less toxic than standard chemotherapy

Cancer.org.

Palliative Cancer Treatment

Screening

Metastatic Disease

Local or Regional Disease

Cancer

Diagnosis

PRIMARY CARE PROVIDERS /OTHER MEDICAL SPECIALISTS

Recurrent or Progressive Disease

End of Life Care

ONCOLOGY PROVIDERS

Primary Cancer TreatmentLong-Term Follow-Up

Prevention

Kurtin, in press.

The Continuum of Cancer SurvivorshipThe Continuum of Cancer Survivorship

Element Description

Cancer-focused medical history

Description of the cancer diagnosis including stage, treatment plan, response and duration, any recurrences and subsequent treatment and any treatment related adverse events

Three-generation family history

Evaluation of risk for secondary cancers, hereditary risk, or increased risk for other disease states

Lifestyle and Health Habits

Details of diet, nutrition, exercise habits, tobacco, alcohol and illicit drug use

Social and Personal History

Marital status, caregiver and social support, employment, hobbies, educational level, depression, self-care capabilities and learning styles

Emotional history Assessment of depression, stress-response

Financial History Review of financial resources, insurance

Kurtin, in press; Ganz, 2009; Hahn & Ganz, 2011; Smith et al, 2011.

Key Elements of Oncology Key Elements of Oncology Survivorship CareSurvivorship Care

Element DescriptionMedication profile Review of prescription medications including prescriber and

rational, any complimentary or alternative therapies, over the counter medications, nutritional supplements. Incorporates mandatory regulatory medication reconciliation

Cancer-focused review of systems

Review of systems will identify potential late-effects of cancer treatment as well as identify areas for health promotion and prevention.

Comprehensive review of systems (ROS)

Standard review of systems questionnaire to identify any changes in symptoms, new symptoms, or improvement after interventions. This ROS incorporates mandatory regulatory questions for pain and safety. Patient questionnaires completed at the time of the visit provide a useful tool for focused discussion with providers.


Key Elements of Oncology Key Elements of Oncology Survivorship Care (cont.)Survivorship Care (cont.)

Element Description

Detailed cancer treatment related exposures

Review of all treatment including surgeries, radiation, and systemic therapies (chemotherapy, targeted therapies, hormonal therapy, transfusions, antibodies, etc.) Will allow focused assessment for late-effects and secondary health problems.

ASCO and ACS Cancer Surveillance Guidelines

Health maintenance history which incorporates screening guidelines for breast, colorectal, prostate, lung, cervical, endometrial and skin cancer – adapted for the individual risk for age at diagnosis, familial risk, and risk of treatment-related or second malignancies.



Element DescriptionCommunication between providers and with the patient

Ongoing written and when necessary verbal communication between primary providers relative to the phase of treatment, in particular at key transition points. Written communication may be incorporated into the electronic health record (EHR), faxed to key providers, and shared with the patient to improve self-care management and continuity of care



ASCO Survivorship ResourceASCO Survivorship Resource

Document your Journey

Manage Side Effects

Stay Well

Take Action

CancerCarewww.cancercare.org

LIVESTRONGwww.livestrong.org

LIVESTRONG Survivorship Centers of Excellence

National Coalition for Cancer Survivorshipwww.canceradvocacy.org

National Cancer Survivors Day Foundationwww.ncsdf.org

National Cancer Institute: Office of Cancer Survivorshiphttp://dccps.nci.nih.gov/ocs

OncoLink: LIVESTRONG Care Planwww.oncolink.org/oncolife


Venous Thromboembolism (MM)

ITP (CLL)

Neutropenia (CML)

Metastatic Bone Disease (MM)

Cancer-Related Fatigue and Anemia (MDS)

Download - The 2012 Oncology Nurse Hematology Conference

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