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Approach to Heme Malignancies

Lymphoma, Multiple Myeloma, Acute Leukemia and Myeloid Disorders

Dr. Michelle GeddesUniversity of Calgary and Tom Baker Cancer Centre

Nov 26, 2015

Objectives

• Organize the approach to working up possible hematologic malignancies

• Review presenting symptoms and signs in hematologic malignancies

• Outline the approach to therapy in different hematologic malignancies

• Review disease and treatment complications

Hematopoiesis

Lymphoid Malignancies

• Lymphoproliferative disorders

• B cells 80%, T cells 20% (terrible Ts)

• Chronic lymphocytic leukemia/small lymphocytic lymphoma

• Acute leukemia (B cell ALL, T cell ALL)

Hodgkins Lymphoma

– Classical HL– Nodular lymphocyte predominant HL

NonHodgkins Lymphomas

IndolentFollicular

Gastric MALT

Small lymphocytic lymphoma

Waldenstroms

Mantle cell lymphoma

Very AggressiveBurkitt

Lymphoblastic lymphoma

AggressiveDiffuse large B

cell lymphoma

Peripheral T Cell lymphoma

Double hit lymphoma

Case 1 – possible lymphoma

• 23 year old woman with cervical lymph node present for one month

• No infectious or B symptoms• Pruritis

On exam – Temp 38 C• 3 cm left anterior cervical LN, 4 cm left

supraclavicular lymph node

Labs - CBC – normal except WBC 15, neutrophils 13.2, eosinophils 1

• LDH elevated at 420

WHAT TESTS WOULD BE HELPFUL TO DETERMINE IF LYMPHOMA?

Making a Diagnosis…• BIOPSY the Node!

– Excisional biopsy>needle core>FNA

• Other bloodwork can be helpful:– CBC

– LDH

– ESR

– B2 microglobulin

– SPEP, quant immunoglobulins

• Bone marrow biopsy usually a staging procedure, not preferred as diagnostic test

A BIOPSY IS DONE…

Hodgkins lymphoma – Reed Sternberg cell

Hodgkins LymphomaB cell lymphoma with surrounding reactive T cells

NOW WHAT?STAGING LYMPHOMA

Lymph Node Regions

Staging (Ann Arbour System)

A – no B SymptomsB – presence of B Symptoms

Staging Hodgkins Lymphoma

• Physical Exam

• History of B symptoms

• CT neck, chest, abdomen and pelvis

• ? Bone marrow biopsy– Not necessary if less than stage IIB HYL as

unlikely to be involved (unlike NHL)• Hodgkins tends to have orderly spread

• PET scan– If limited stage disease, confirm with PET scan

PET scan

Treatment and Prognosis in Hodgkins Lymphoma

Treatment and prognosis of Limited Stage HL

• Favourable risk:– ABVD (adriamycin, bleomycin, vinblastine and

dacarbazine) x2 and 30 Gy involved field RT

• Unfavourable risk:– 4 cycles ABVD and 30 Gy IFRT– If B symptoms or bulky 6 cycles ABVD and

IFRT

Treatment and prognosis of advanced stage HL

• Good risk: ABVD x 6 +/- RT• If adverse risk factors:

– Escalated dose BEACOPP• Bleomycin, etoposide, adriamycin, cyclophosphamide,

vincristine, procarbazine, prednisone• More toxicities and infertility, MDS than ABVD; ABVD used in

those with few risk factors and elderly

– PET CT scan after therapy for residual disease

•

LOW GRADE NON-HODGKINS LYMPHOMAS

Case 2

• 64 year old man comes to see his GP with an enlarged lymph node in his groin

• Feels otherwise well, no B symptoms, no symptoms related to enlarged node

• Physical exam shows 2 cm LN in both axillae• CBC, LDH, SPEP normal

• A diagnostic procedure is performed…

Follicular Lymphoma

Follicular lymphoma

• 70% of all low grade lymphomas

• Older population, usually relatively asymptomatic at diagnosis with long history of waxing and waning lymph nodes– 75% with advanced stage

• Approximately 25% will transform at some time to an aggressive DLCL

Treatment of Follicular Lymphomas

• Generally watch and wait until symptomatic– Most treatment not curative– Exception – stage 1a or IIa nonbulky contiguous disease given RT for

cure

• Rituximab-Bendamustine is mainstay of first line therapy treatment indicated– fever, night sweats, weight loss, malaise, pain– Bulky or symptomatic lymphadenopathy– Impending organ compromise (compression, pleural/pericardial

effusions, ascites)– Cytopenias secondary to bone marrow infiltration

• Maintenance rituximab given q3 months for two years to prevent relapse and improve survival

Treatment of Follicular Lymphomas

Indolent Lymphomas Follicular Lymphoma

JCO 2009: 10;1607-14

Prognosis in Follicular Lymphoma

Specific indolent lymphomas have different treatment approach

• Mantle cell lymphoma – “indolent” lymphoma but relatively aggressive course with med survival 3-5y– R-CHOP then DHAP and autologous stem cell transplant

up front, maintenance Rituximab

• Gastric MALT, cutaneous indolent lymphomas• Splenic marginal zone lymphoma ‘

– Splenectomy

• Hairy cell leukemia – Splenomegaly and cytopenias– Cladrabine single 5-7 day course: 91% CR, OS at 4y 96%

AGGRESSIVE LYMPHOMAS

Case 3

• 54 year old patient presents with rapid development over 2-3 weeks of large left supraclavicular lymph node– Fevers, drenching sweats

– Appetite poor, weight loss10 lbs

• On exam: 5 cm left supraclavicular node– Cachexia

• A diagnostic procedure is performed…

Diffuse large B cell lymphoma

Diffuse large B cell lymphoma

• Most common type of lymphoma, incidence increases with age – 25% of all NHL

• Rapidly growing LNs, 30% have B symptoms• Advanced disease>localized disease• 30% bone marrow involvement, most high LDH• Can be extranodal disease

– 5-10% risk of CNS relapse

Treatment of DLCL

• Limited stage (I-IIa non-bulky)– If 0-1 IPI risk factors: R-CHOPx3 + IFRT– If 3 risk factors: R-CHOP x 6

• Advanced stage (stage III-IV, bulky, B symptoms)– R-CHOP x6– Add IFRT to sites of prior bulk

– PET scan after completion of therapy

Prognosis - International Prognotistic Index

T cell aggressive lymphomas

• Overall, prognosis is worse than B cell aggressive lymphomas

• Can present with T symptoms – terrible B symptoms, systemic symptoms

T cell lymphoma outcomes

Foss F M et al. Blood 2011;117:6756-6767

Treatment of Aggressive T cell Lymphomas

• CHOP– Overall, response in 50-70% with 5 year

disease-free survival around 30%– Compared to 50-60% for high risk DLBCL

• CHEOP – adding etoposide may improve 3y EFS (75% vs 51%) in patients 60y

• High risk fit patients often offered autologous transplantation in 1st complete remission

HIGHLY AGGRESSIVE LYMPHOMAS

Highly Aggressive Lymphomas

• B cell lymphomas∕leukemias– Burkitts lymphoma– Precursor B lymphoblastic leukemia ∕

lymphoma

• T cell lymphomas∕leukemias– Precursor T lymphoblastic

leukemia ∕ lymphoma

Highly Aggressive Lymphomas• Aggressive and prolonged inpatient protocols of combined 4

or 5 drug chemotherapy drugs– CNS prophylaxis and CNS-penetrating chemotherapy cranial

irradiation– 25% CNS relapse without treatment

• Overall survival 60% for T lymphoblastic lymphoma and Burkitts

• Pediatric-based very aggressive 2y protocols for ALL with 60% survival <age 60y– High risk patients alloBMT

Chronic Lymphocytic Leukemia

• Indolent lymphoproliferative disorders with median survival >15y overall

• Indications for treatment: – cytopenias, B symptoms, symptomatic or bulky

lymphadenopathy, consitutional symptoms

• Cytogenetics help determine prognosis and treatment options

Current CLL treatment

Overall Survival FCR vs BR

Eichhorst B, et al. ASH 2014:19

Bruton’s tyrosing kinase inhibitorIbrutinib : duration of response

OVERALL SURVIVAL

PROGRESSION-FREE SURVIVAL

0

20%

40%

60%

80%

100%

0 6 12 18 24 30 36 42

TN

R/R+ Censored

TN R/R

30-mo PFS 96.3% 68.4%

(95% CI)(76.5-99.5)

(56.1-77.9)

Median PFSNot

reachedNot

reached

0

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

Months

TN

R/R

+ Censored

TN R/R

30-month OS

96.6% 79.9%

(95% CI)(77.9-99.5)

(69.0-87.3)

Median OSNot

reachedNot

reached

O’Brien S, et al. ASCO 2014; Oral/Abstract #7014

Idelalisib + rituximab

Furman et al NEJM 2014

Idelalisib + R improves overall survival

Furman et al NEJM 2014

Lymphoma Summary

• Divided into indolent, aggressive and highly aggressive malignancies

• Indolent lymphomas are not generally curable with chemo and less symptomatic– often diagnosed in advanced stage but with long survival

ie follicular– watch and wait, less intensive chemotherapy

• Aggressive lymphomas often curable with chemoradiation and are more symptomatic– more often diagnosed in early stages– chemotherapy IFRT given at diagnosis for cure

Case 4

• 60yo man presents with pathologic fracture of the humerus

• Fatigued, generally unwell for 6 months• Labs:

– Hb 90, remainder of CBC normal– Ca+ 2.7, creatinine 160, total protein 90

– What further investigations would you need to do?

Further investigations– SPEP shows IgG kappa monoclonal protein 32g, – B2 microglobulin 4.2, albumin 30, CRP high, Ig levels shows high

IgG – Serum free light chain index elevated at 326– Skeletal survey – multiple lytic bony lesions– Urine protein electropheresis and creatinine clearance

• Dipstick may not be positive (picks up albumin)

– A bone scan is not helpful!• Osteoclastic activity not osteoblastic in myeloma, does not light up on

bone scan

Diagnosis

CRAB (A)

• Calcium (>2.7)• Renal failure (>176)• Anemia (Hb<110)• Bony lesions• (Amyloidosis)

Cytogenetics and flow cytometry are sent for prognostic markers on bone marrow aspiration

Staging multiple myeloma

• Always comes out of an MGUS

• FISH for: t(14;16), t(4;14), deletion 17 (17p-) and del13q are prognostically important on bone marrow aspiration

Stage B2Microglobulin

Albumin Median Survival(months)

I <3.5 and 35 62

II ≥3.5 and <5.5 and/or <35 44

III ≥5.5 29

Treatment Approach in Myeloma

• Transplant eligible

• Non-transplant eligible

Treatment algorithm

Stem cell mobilization, autologous stem cell transplant then VRD x 2 cycles

Maintenance with lenalidomide until progression or bortezomib for 2 years

or

All patients IV bisphosphonatemonthly x2y

Prognosis post transplant in MM

Al-Mansour, et al. Adv Hematol. 2014; 2014: 652395.

Age >65y Age <65y

In non-transplant eligible, OS 60-70% at 4y

Myeloid disorders• Myelodysplastic syndromes• Myeloproliferative disorders

– Essential thrombocytosis, polycythemia vera, myelofibrosis– CML – tyrosine kinase inhibitors

• Acute myeloid leukemia– Intensive inpatient protocols with allogeneic transplantation

in high risk patients– Hypomethylating agents or low dose cytarabine in the

elderly

What raises a red flag that there is a myeloid disorder?

• Reasons to refer urgently: – Blasts – always!

– Nucleated red blood cells

– >1 unexplained cytopenia or a severe cytopenia

– Unexplained elevated blood counts:• Hb >185 in men or Hb>165 in women – check epo levels, jak2V617F

mutation if no obvious explanation for high Hb

• Thrombocytosis >450 persistent – look for reactive causes, iron deficiency

• Elevated white blood cells with left shift

Myelodysplastic Syndromes

• Clonal disorders of the bone marrow characterized by:– Low blood counts– Ineffective production of blood cells– Abnormal red cells, neutrophils and platelets– Increased risk of developing AML

Mr. G. Olfer

• 72 yo man with anemia for 4 years• Mildly low neutrophil count, no infections• Platelets normal, no bleeding• Now hemoglobin down to 60s, transfusion

dependent with 4u red cells transfused• Bone marrow biopsy shows MDS

• Refractory anemia with ringed sideroblasts

• What does this mean for him?

WHO 2008 Classification – A collection of myelodysplastic

syndromesRefractory Cytopenias with Unilineage Dysplasia (RCUD)

Refractory Anemia with Ring Sideroblasts (RARS)

Refractory Cytopenia with Multilineage Dysplasia

Refractory Anemia with Excess Blasts-1 (RAEB-1) (5-9% BM blasts)

Refractory Anemia with Excess Blasts-2 (RAEB-2) (10-19% BM blasts)

Myelodysplastic Syndrome - Unclassified

MDS Associated with Isolated del(5q)

< 20% blasts

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4 th edition. 2008.

Goals of Therapy

• Prolong survival

• Quality of life

• Improve symptoms

• Reduce transformation to acute leukemia

How do we decide if patients have lower risk or higher risk MDS?

• Blood counts

• Chromosome analysis

• Blast counts in bone marrow

• Age

• Type of MDS

IPSS-RRevised International Prognostic Scoring System

Greenberg P, Tuechler H, Schanz J, et al. Blood. 2012;120(12):2454

Very good = del(11q)Good = Normal, del(5q), del(12p), del(20q), double including del(5q)Intermediate = del(7q), 8, 19, i(17q), any other single or double independent clonesPoor = inv(3)/t(3q)/del(3q), double including 7/del(7q), complex: 3 abnormalitiesVery poor = Complex: 3 abnormalities

Lower risk MDS• Growth factors i.e. erythropoietin

– increase red cells and reduce transfusions

• Transfusions, antibiotics, supportive care

• Iron chelation for iron overload from transfusions– Usually if ferritin>1000 and/or 20

transfusions red cells

Del 5q syndrome• 10-15% of MDS

– Anemia– Mild low white blood cells– Atypical megakaryocytes, normal to elevated

platelets– Transfusion dependence– Normal blast count

Extended survival with low frequency of AML transformation (10%)

Lenalidomide: RBC Transfusion Independence in Del(5q) MDS

Erythroid Response Rate (N=148) n (%) 95% CI

Transfusion independence* 99 (67) 59–74

≥50% decrease in no. transfusions 13 (9) 5–15

Total transfusion response 112 (76) 68–82

Transfusion Independence

Response Characteristics

Median Range

Time to response (wk) 46 1–49

Hgb increase† (g/dL) 54 11–114

N Eng J Med, 2006; 355: 1456

Mr. G. Olfer

• After 2 years, his platelets drop to 14 and he starts to have blasts in his peripheral blood

• Bone marrow biopsy shows refractory anemia with excess blasts-2• Blasts 11%, complex cytogenetics• Higher risk MDS

• What treatment options does he have?

Higher risk MDS

• Supportive care, transfusions

• Azacytidine Intermediate-2 and High risk MDS, low blast count AML– 7d subcutaneous injections every 4 weeks– Associated with improved survival, lower rate

of developing acute leukemia– Improved quality of life

Overall Survival: Azacitidine vs Conventional Care Regimen

Lancet Oncol 2009; 10:223-32.

p=0.0001p=0.0001

0 5 10 15 20 25 30 35 40

Time (months) from RandomizationTime (months) from Randomization

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

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ConventionalCare

AZA

Survival Difference 9.4 monthsSurvival Difference 9.4 monthsOral azacytidine in developmentOral azacytidine in development

Between a rock and a hard place

Transplantation iscurrently the only curative therapyfor many hematologic malignancies

Median age at diagnosis is 65-70Toxicity of transplantation can be prohibitive

Role of Clinical Trials

Other supports available

• Home care• Wellspring• AAMAC• Leukemia and lymphoma society• Psychosocial services• Dieticians• Social work, home care, mobile lab

Questions?

Blood Moon