1

New10_1.ppt

Lymphoma Reporting Basics

January 31, 2012

Disclosures

Janet Brunner, PA-CI have nothing to disclose

P. Hari, MD MSI have nothing to disclose

G. Laport, MDI have nothing to disclose

Objectives

1. Be able to report the correct NHL disease classification.

2. Be able to determine & report the disease status at time of HCT & at post-HCT follow-up intervals.

3. Be able to report the correct primary NHL disease & date of diagnosis for HCT when a transformation has occurred.

SPOTLIGHT ON LYMPHOMASDLBCL

FOLLICULAR NHLT-CELL NHL

GINNA LAPORT, MD

Indications for Hematopoietic Stem Cell Transplants in the United States, 2009

SUM-WW11_8.ppt

Num

ber

of T

rans

plan

ts

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

5,500

MultipleMyeloma

NHL AML HD ALL MDS/MPD AplasticAnemia

CML OtherLeuk

Non-Malig

Disease

OtherCancer

Allogeneic (Total N=7,012)Autologous (Total N=9,778)

Non-Hodgkin Lymphoma

DLCL 31%

Follicular 22%

Discordant 12%

Mantle cell 6%

Small lymphocytic 6%

Peripheral T-cell 6%

MALT 5%

Lymphoplasmacytic 1%

Anaplastic T-cell 2%

Mediastinal B-cell 2%Burkitt-like 2%

Lymphoblastic 2%

Burkitt < 1%

2

Diffuse Large Cell Lymphoma:Background

Diffuse Large Cell Lymphoma:Background

Most common subtype of NHL

Median age ~ 65-70 yr

Frontline chemotherapy (anthracycline-based + RTX)

Long term remission 50-60%

High-dose chemotherapy with autologous SCT

Relapsed/Refractory

• Chemosensitive 40-60%

• Chemo-refractory 10-20%

Relapse is most common cause of failure

DLBCL: International Prognostic IndexDLBCL: International Prognostic Index

Risk Group Risk Factors, n

CR, %

5-Yr OS, %

Patients (all ages)

Low 0-1 87 73

Low intermediate 2 67 51

High intermediate 3 55 43

High 4-5 44 26

Patients 60 yrs of age or younger

Low 0 92 83

Low intermediate 1 78 69

High intermediate 2 57 46

High 3 46 32

Adverse risk factors correlated with response to chemotherapy and survival– Older than 60 yrs of age

– LDH > normal

– PS ≥ 2

– Ann Arbor stage III/IV

– Extranodal involvement > 1 site*

International NHL Prognosis Factors Project. N Engl J Med. 1993;329:987-994.

*Prognostic for patients older than 60 yrs of age only.

CHOP vs R-CHOP Elderly Patients With Diffuse Large B-Cell NHL

CHOP vs R-CHOP Elderly Patients With Diffuse Large B-Cell NHL

Coiffier B, et al. N Engl J Med. 2002;346:235-242.

R-CHOP = rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone

R-CHOP

Ove

rall

Su

rviv

al

Years

CHOP

P < .007

For DLCL patients with relapsed or refractory disease Median survival is 6 months w/o further therapy

Standard of care Autologous SCT

Platinum-based regimens

R-ICE (ifosfamide/carboplatin/etoposide)

R-DHAP (dexameth, high dose araC, cisplatin)

R-ESHAP (etoposide, solumedrol, high dose araC, cisplatin)

Other regimens

R-bendamustine

Diffuse Large Cell Lymphoma:Autologous SCT for Relapsed/Refractory Disease

Diffuse Large Cell Lymphoma:Autologous SCT for Relapsed/Refractory Disease

Years

0 2 61 3 4 5

Survival after Autologous Transplants for Diffuse Large B-Cell Lymphoma, 2000-2009

- By Disease Status -

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Prob

abili

ty o

f Sur

viva

l, %

P < 0.0001

SUM-WW11_36.ppt

Slide 37

Sensitive (N=6,337)

Resistant (N=453)

Years

0 2 61 3 4 5

Survival after Allogeneic Transplants for Diffuse Large B-Cell Lymphoma, 2000-2009

- By Disease Status -

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Prob

abili

ty o

f Sur

viva

l, %

P < 0.0001

SUM-WW11_37.ppt

Slide 38

Sensitive (N=383)

Resistant (N=124)

3

Summary: Diffuse Large Cell LymphomaSummary: Diffuse Large Cell Lymphoma

• Diffuse large cell lymphoma is the most common NHL

• R-CHOP is the standard of care for first line therapy

• Autologous HSCT• Offered to patients with relapsed or primary refractory disease

(after platinum-based salvage therapy)

• May benefit patients in CR1 with high IPI at diagnosis

• Allogeneic HSCT Failed prior auto HSCT

BM involvement

Chemosensitive preferred

Characteristics• 24,000 cases/yr• Median age: 59 yr• 50% of patients present as stage IV disease• Most are asymptomatic at diagnosis

Histologic transformation• Occurs in 30%-40% of patients• New symptoms, rapid progression, elevated LDH,

increased activity on PET imaging• Generally poor prognosis

Follicular Lymphoma: Background

Follicular Lymphoma: Background

Waxing and waning course• Spontaneous regressions

Sensitive to chemotherapy and radiotherapy• Remission usually achieved• Continuous pattern of relapses shorter

remission durations• Very treatable…difficult to cure

Median survival ~ 8-12 yr

FL: Characteristics and Clinical Course FL: Characteristics and Clinical Course Follicular Lymphoma International Prognostic Index (FLIPI)

Follicular Lymphoma International Prognostic Index (FLIPI)

• Age > 60 yr• Ann Arbor stage III/IV

disease• LDH > ULN• Hemoglobin < 120 g/L• > 4 nodal sites

FLIPI Risk Group

Risk Factors, N 5-Yr OS 10-Yr OS

Low 0-1 91% 71%

Intermediate 2 78% 51%

High ≥ 3 53% 36%

Solal-Céligny P, et al. Blood. 2004;104:1258.

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72 84 96Time (mo)

108 120

P < .00001

Low

Int

High

0

20

40

60

80

100

0 2 4 6 8 10

n 4-yr PFS 4-yr OSCHOP + MoAb 179 61% 91%ProMACE + MOPP 425 48% 79%CHOP 356 46% 69%

OS

(%

)

Years After Registration

Fisher RI, et al. J Clin Oncol. 2005;23:8447-8452.

Changes in the Natural History of FL Overall Survival by Treatment (1974-2000)

Changes in the Natural History of FL Overall Survival by Treatment (1974-2000)

Treatment of Follicular NHL:Indications

Treatment of Follicular NHL:Indications

Disease-related symptoms • Cytopenias

• Fevers, sweats, weight loss, fatigue

Enlarging or bulky lymph nodes

Enlarging liver, spleen

Bone marrow or organ compromise

Autoimmune complications (AIHA, ITP)

Evidence of histologic transformation

Patient preference

4

Considerations Regarding InitialTherapy

Considerations Regarding InitialTherapy

Patients with low tumor burden

• Watchful waiting

• Single-agent antibody therapy

• R-CVP

• R-CHOP

• BR

• R-FND

Patients with high tumor burden

• R-CVP

• R-CHOP

• BR

• R-FND

NCCN Guidelines: Non-Hodgkin lymphomas. Version 4.2011.

Years

0 2 61 3 4 5

Probability of Survival after Autologous Transplants for Follicular Lymphoma,

2000-2009- By Disease Status -

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Prob

abili

ty o

f Sur

viva

l, %

P < 0.0001

SUM-WW11_34.ppt

Slide 35

Sensitive (N=2,030)

Resistant (N=172)

Overall Survival After HLA-Matched Sib Allogeneic SCT: FL 1998-2008

Overall Survival After HLA-Matched Sib Allogeneic SCT: FL 1998-2008

Years0 2 61 3 4 5

Chemosensitive, reduced intensity (n = 388)

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Pro

bab

ilit

y o

f S

urv

ival

(%

)

Chemosensitive, myeloablative (n = 351)

P = .011

Chemoresistant, reduced intensity (n = 64)

Chemoresistant, myeloablative (n = 85)

Pasquini MC, et al. CIBMTR summary slides, 2010. http://www.cibmtr.org Accessed December 19, 2011.

Summary: Follicular NHLSummary: Follicular NHL

• Treatment needs to be individualized– Age– Comorbidities

• Frontline – Watchful waiting– Involved field radiation– R + chemotherapy

• Relapsed/Refractory– Involved field radiation– R + chemotherapy + maintenance R– Novel agents– HSCT

Summary: Follicular NHL (cont)Summary: Follicular NHL (cont)

HSCT• Should be offered to patients who progress after

1-2 prior regimens

Autologous HSCT• No role as first-line therapy • May prolong OS in chemosensitive, less heavily treated

patients

Allogeneic HSCT• Less relapse compared with autologous HSCT• Myeloablative regimens have high treatment-related

mortality• Reduced intensity regimens are promising• Chemosensitivity is best predictor of survival

Peripheral T cell LymphomaBackground

Peripheral T cell LymphomaBackground

T-NHL accounts for 10-15% of all NHL

Geographic variation Nodal disease: Western hemisphere Extranodal: Asia

Clinical features Middle aged to elderly Systemic symptoms Generalized lymphadenopathy Marrow and blood Extranodal

Prognosis• Low response rates to chemotherapy• Most patients relapse within 2-3 years 5 year survival < 30%

5

Most Common PTCL SubtypesMost Common PTCL Subtypes

• PTCL-NOS is the most common subtype

• Anaplastic large cell lymphoma (ALCL) ALK+/- and angioimmunoblastic lymphoma are also common subtypes

1. Armitage J, et al. J Clin Oncol. 2008;26:4124–4130.

Poor Outcome For Most Subtypes With Standard Tx:International PTCL Project

Poor Outcome For Most Subtypes With Standard Tx:International PTCL Project

Vose et al. J Clin Oncol, 2008

PTCL PrognosisPTCL Prognosis

Most PTCL subtypes have a worse prognosis than aggressive B-cell NHL Median overall survival for most subtypes of PTCL is 1–3 years ALK+ ALCL is an exception, with a 5-year survival = 65–90%

1. Armitage JO, et al. Ann Oncol. 2004;15:14472. Savage KJ. Blood Rev. 2007;21:2013. Rüdiger T, et al. Ann Oncol. 2002;13:140

Initial Treatment of PTCLInitial Treatment of PTCL

• NCCN guidelines recommend clinical trials for initial treatment of PTCL1

• CHOP is the most commonly prescribed regimen in the first-line setting2,3

1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. 2011. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.

2. Rosenstein LJ, Link BK. Clin Lymphoma Myeloma. 2008;8:S180–S186. 3. Horwitz SM. Hematology Am Soc Hematol Educ Program. 2008;2008:289–296.

Suggested Treatment Regimens for PTCL (in alphabetical order)1

First-line therapy Clinical trial preferred

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)

HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine

First-line consolidation All patients except low-risk (aaIPI) should be consolidated with high-dose therapy and stem cell rescue (autologous)

ALK-1+ ALCL is a subtype with good prognosis and does not need consolidative transplant if in remission

n = 83Only CR1/PR1 pts autoSCT

3 yrs OS and PFS = 48% and 36%

Overall SurvivalOverall Survival

SCT

no SCT

Le Gouill, S. et al JCO 2008.

n=77

HLA identical = 60Myeloablative = 57Prior AutoSCT = 19 1 yr TRM = 32%

OS

EFS

AITL

PTCL

ALCL

Other

6

Summary: Peripheral T cell LymphomaSummary: Peripheral T cell Lymphoma

• PTCL are a heterogeneous group of rare entities

• Compared to B cell NHL, prognosis is poor (OS <30%)

• Best initial therapy is undefined

• Autologous HSCT more efficacious in early disease

• CR1 pts have better outcomes compared to >CR1 pts

• Moderately better PFS/OS than population based series with CHOP

• 30-50% pts do not reach transplant due to PD or toxicity

• Does auto HSCT as consolidation improve results or just selecting for healthier people with chemosensitive disease?

• Myeloablative allogeneic HSCT associated with high TRM

• Reduced intensity conditioning promising

Disease ClassificationQuestions

The surgical pathology reports the lymph node biopsy to be a follicular lymphoma grade I-II, how should the subtype be reported on the Pre-TED form (2400)?

 Grade I

 Grade II

 Grade III

33% 33%33%

a) Grade Ib) Grade IIc) Grade III

Answer Now

Form 2400

Question 2 (please answer on next slide)

How should the disease be reported on the Pre-TED if it’s described as a ‘composite NHL’? The patient’s bone marrow biopsy reports 80% of the abnormal cells are follicular & 20% classic Hodgkin.

Answer Now …

NHL

Hodgkin

Other

33% 33%33%

a)Follicular NHL

b)Hodgkin lymphoma

c)Other disease, specify

Answer Now

7

Question 3 (please answer on next slide)

A patient is diagnosed with Hodgkin & NHL at the same time. Both are in remission at the time of HCT. Which disease should be reported as the primary on the Pre-TED for HCT?

Answer now…

 NHL

 Hodgkin 

Other

33% 33%33%

Answer Now

a. NHLb.Hodgkin

lymphomac. Other

disease, specify

Reporting Disease Status for Lymphoma

P. Hari, MD MS

CR, PR ….

Cheson et al JCO- 2007 vol 25: 5; 579

PIF, REL , Sens, Res ???? Basic things

1. Make sure responses tally and make sense.

e.g. Person in CR has to have sensitive disease

2. In order to relapse, person should first have established CR

3. Induction failure – NEVER achieved a CR.

8

Rule 1. Response and Disease State should tally CASE STUDY

53 yr old woman with DLBCL Initial Therapy – RCHOP chemo After 6 cycles – Lymph Nodes all normal

sized. Spleen still enlarged and PET positive.Disease response: Sensitvity:Disease Status:

Case continued

Patient had a splenectomy which showed residual disease PET Scan – no evidence of disease Consideration of transplant at this

time Response SensitivityDisease Status

Case continued Patient declined transplant but

relapsed 4 mo later with abdominal LNReceived salvage chemotherapy with

full resolution of all imaging abnormalities. Transplant at this timeDisease Response SensitivityDisease Status

Case continued

What if she had residual PET abnormalities after the salvage chemotherapy prior to the transplant?Disease Response SensitivityDisease Status

Disease Status Questions

9

Question 1 (please answer on next slide)

A patient with NHL has undergone their pre-HCT evaluation and the only evidence of disease is a positive molecular study on bone marrow for t(11;19). Can the disease status be reported as CR at the time of HCT despite the positive molecular study?

Answer now …

 Yes  N

o

 Unknown

33% 33%33%

a)Yesb)Noc)Unknown

Question 2(please answer on next slide)

A patient with NHL has no morphologic evidence of disease on the bone marrow biopsy, but flow results from the marrow indicate disease prior to the start of the prep regimen. What disease status should be reported at time of HCT?

Answer now …

 CR

 PR

 Unknown

33% 33%33%

a)CRb)PRc)Unknown

Answer Now

Question 3

A 55 yo WM has PET positive & biopsy proven NHL in the inguinal nodes at diagnosis. He was treated & relapsed before achieving a 4th CR prior to HCT. Day 100 PET/CT scan revealed positivity in the inguinal area. The transplant physician decides not to biopsy an inguinal node, but would obtain a PET/CT scan a few weeks after tapering immunosuppression.

Is it acceptable to report a relapse based on the PET/CT

scan only?

 Yes  N

o

 Unknown

33% 33%33%

a)Yesb)Noc)Unknown

10

Transformed Lymphoma Questions

Question 1.1(please answer on next slide)

A patient was diagnosed with follicular NHL in 2005. The NHL transformed to DLBCL in 2009 and the patient is now scheduled for an upcoming auto HCT. What is the correct NHL subtype to report on the Pre-TED (F2400) as the primary diagnosis for HCT?

Answer now…

NHL

DLBCL

Other

33% 33%33%

a)Follicular NHL

b)DLBCLc)Other B cell

lymphoma, specify

Answer Now

What is the correct date of diagnosis to report?

2005

2009

 Neither

33% 33%33%

a)2005b)2009c)Neither

Answer Now

Question 2.1(please answer on next slide)

A 55 yo WM is diagnosed with CLL in 2007 & achieved a CR with fludarabine. They are monitored at regular intervals & three years later they are noted to have bilateral inguinal masses. A biopsy reveals DLBCL. This patient’s disease underwent a Richter’s transformation. What disease should be reported as the primary diagnosis for HCT?

Answer now …

 CLL

 DLBCL

Other

33% 33%33%

Answer Now

a)CLLb)DLBCLc)Other B cell

lymphoma, specify

11

What is the correct date of diagnosis to report?

2007

2010

 Neither

33% 33%33%

a)2007b)2010c)Neither

Answer Now

Questions