copyright © 2010, research to practice, all rights reserved. part vii: mantle-cell lymphoma, t-cell...

Copyright © 2010, Research To Practice, All rights reserved.

Part VII: Mantle-Cell Lymphoma, T-Cell Lymphomas, Diffuse Large B-Cell Lymphoma Monday, November 1, 20107:30 PM - 8:30 PM ET

Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

Steven M Horwitz, MDAssistant AttendingLymphoma Service, Division of Hematologic OncologyMemorial Sloan-Kettering Cancer CenterNew York, New York

Mitchell R Smith, MD, PhDDirector, Lymphoma ServiceFox Chase Cancer CenterPhiladelphia, Pennsylvania

Neil Love, MDModeratorResearch To PracticeMiami, Florida

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abraxis BioScience Inc, a wholly owned subsidiary of Celgene Corporation, Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Lilly USA LLC, Millennium Pharmaceuticals Inc, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.

Consulting Agreements

Allos Therapeutics, Celgene Corporation, Millennium Pharmaceuticals Inc

Paid ResearchAllos Therapeutics, Genzyme Corporation

Disclosures for Steven M Horwitz, MD

Advisory Committee Cephalon Inc, Wyeth

Speakers Bureau

Allos Therapeutics, Celgene Corporation, Cephalon Inc, Genentech BioOncology, Millennium Pharmaceuticals Inc, Spectrum Pharmaceuticals Inc

Disclosures for Mitchell R Smith, MD, PhD

Approximately how many new patients do you see per year with the following diseases?

Patterns of Care Survey of US-Based Practicing Oncologists (n = 100) and Clinical Investigators (n = 25), 2010.

CI (n = 25)

Median

PO (n = 100)

Median

Mantle-cell lymphoma (MCL) 15 2

Diffuse large B-cell lymphoma (DLBCL) 45 15

T-cell lymphoma (TCL) 10 2

Case History: Dr Smith

• An asymptomatic 82-year-old man presents with slowly progressive left cervical adenopathy

– Past medical history of hypertension, diabetes, high cholesterol and peripheral vascular disease

• Histopathology: Mantle cell lymphoma with t(11;14) on FISH

• CT scans: Adenopathy on both sides of diaphragm

• LDH normal

• No B symptoms

1) How would you initially treat this patient?

18%

11%

32%

13%

21%

5%

0%

0% 5% 10% 15% 20% 25% 30% 35%

R-Hyper-CVAD

Modified R-Hyper-CVAD (without methotrexate/Ara-C)

R-CHOP

R-CVP

R-bendamustine

Single-agent rituximab

Observation

Case History: Dr Smith (continued)

• Treated with single agent weekly-rituximab x 4 weeks

• Attained stable disease for approximately 10-months and then developed progressive adenopathy and mild anemia (Hb = 10.0 g/dL)


• Patient treated with R-CVP x 6 and achieved PR

• CBC continues to show cytopenias

(Hb = 10.0 g/dL, Platelets = 110,000/mm3)

2) How would you manage the patient at this time?

8%

13%

3%

73%

3%

0%

0%

0%

0%

0% 10% 20% 30% 40% 50% 60% 70% 80%

Observation

Repeat single agent rituximab

R-bendamustine

Repeat R-CVP

R-CHOP

Modified R-Hyper-CVAD (without methotrexate/Ara-C)

Bortezomib

Lenalidomide

Cladribine


• Patient treated with single-agent bortezomib on standard twice-weekly schedule

• Dramatic response with regression of nodes and normalization of blood counts

• Remained in near CR for two years

• CHOP rituximab – older patients who cannot tolerate more intensive therapy

• R-HyperCVAD/R-HDMtx + Ara-C (< 60-65?)• R-EPOCH • Modified R-HyperCVAD (part A) + rituximab maintenance

– in patients > 65 yrs• R-Bendamustine• Nordic regimen (R-Maxi-CHOP alt R-HiDAC auto SCT)• Cladribine + rituximab• Clinical trial• Observation for selected stage III-IV patients

*Select patients will undergo HDT/ASCT consolidation

Frontline Treatment Options for MCL*

Treatment Options for MCL in the Salvage Setting*

• Bendamustine ± rituximab• Bortezomib ± rituximab• Fludarabine based regimens ± rituximab• Lenalidomide ± rituximab• Temsirolimus• Thalidomide ± rituximab• PEPC (Prednisone, etoposide, procarbazine,

cyclophosphamide) ± rituximab

* Select patients will undergo HDT with allogeneic stem cell rescue (nonmyeloablative or myeloablative)

What is your usual initial treatment regimen for the following patients with newly diagnosed MCL?

60-Year-Old 75-Year-Old

CI

(n = 25)

PO

(n = 100)

CI

(n = 25)

PO

(n = 100)

R-CHOP Transplant 32% 19% 8% 5%

R-hyper-CVAD 20% 36% 4% 8%

Modified-R-hyper-CVAD 8% 27% 20% 9%

R-CHOP 8% 14% 20% 51%

Bendamustine + rituximab 8% 2% 44% 22%

Other 24% 2% 4% 4%


Do you use R maintenance for patients with MCL?

22%

23%

54%

8%

32%

60%No

Yes, occasionally

Yes, usually


= Clinical Investigator

= Practicing Oncologist

When administering bortezomib for MCL, either alone or in combination with another agent (eg, rituximab) what schedule do you generally use?

11%

2%

35%

52%

4%

0%

12%

84%Biweekly

Weekly

Other

I do not administer bortezomib for MCL




GOELAMS French Randomized Phase III Study of Maintenance Rituximab in Mantle Cell Lymphoma

www.clinicaltrials.gov, October 2010.

N = 199

Rituximab Maintenance500mg/m2 q-2 monthly x 3 Years

Primary Endpoint: Event Free Survival

Estimated Study Completion Date: September 2011

Observation

• Mantle Cell Lymphoma

• Age 18-65

• CD20-Positive

• Untreated Disease

Initial Treatment followed by High-Dose Chemotherapy

with Auto-transplant

Eligibility

CR or PR following Auto-Transplant

Ongoing Studies Incorporating Novel Agents Into First-Line Therapy of MCL

Study Phase N Treatment

BRIGHT III 296Bendamustine + rituximab

vsR-CVP or R-CHOP

NCT00114738 II 80EPOCH-R + bortezomib bortezomib

vsobservation

SWOG-S0601 II 60 CHOP-R + bortezomib bortezomib

ECOG-E1405 II 72Bortezomib + rituximab-CVAD

rituximab

GOELAMS-MANTEAU-2006-SA

II 39Bortezomib, rituximab, doxorubicin,

dexamethasone, chlorambucil

LENA-BERIT I/II 60 Lenalidomide, bendamustine, rituximab



Bendamustine, Bortezomib and Rituximab in Patients with Relapsed/Refractory Indolent and Mantle Cell Non-Hodgkin Lymphoma (NHL): A Multicenter Phase II Clinical Trial

Friedberg JW et al.Proc ASH 2009;Abstract 924.

Efficacy of Bendamustine, Bortezomib and Rituximab in Relapsed Indolent and Mantle Cell Lymphoma

Overall Response

All Patients (n = 29) 79%

Relapsed or Refractory FL (n = 16) 85%

Relapsed or Refractory MCL (n = 7) 71%

Median of 4 prior treatment regimens

Friedberg JW et al. Proc ASH 2009;Abstract 924.

Studies of Bortezomib-Rituximab in Relapsed/Refractory NHL

Weekly Bortezomib in Non-Follicular and Mantle Cell Lymphomas (N = 49)1

Overall Response 1-Year Survival1-Year Progression-Free

Survival

53% 89% 45%

1Chiappella A et al. Proc EHA 2010;Abstract 271.2Agathocleous A et al. Br J Haemotol 2010;151(4):346-53.

Follicular and Mantle Cell Lymphomas (N = 42)2

Twice-Weekly Bortezomib (n = 21)

Weekly Bortezomib (n = 21)

Complete Response 14% 19%

Overall Response 67% 67%

Lenalidomide in Relapsed/Refractory MCL

Lenalidomide-Dexamethasone1 (N = 21)

Complete Response Overall Response

14% 52%

1Zaja F et al. Proc ASH 2009;Abstract 1713.2Wang L et al. Proc ASH 2009;Abstract 2719.

Lenalidomide-Rituximab2 (N = 45)

Complete Response Overall Response

Median Duration of Response

Median Progression-Free

Survival

31% 53% 18 months 14 months

— Margaret Deutsch, MDRaleigh, NC

Mantle cell is a real challenge, and my primary question is how aggressive to be with younger patients who have MCL? Are these patients really curable or is this just not a curable disease?

Does the panel really go the route of using hyper-CVAD in younger patients, and does that really end up producing long-term cures?

13%

3%

38%

46%

8%

8%

56%

28%

How would you compare the efficacy of R-hyper-CVAD versus R-CHOP followed by transplant in the front-line treatment of MCL?

R-hyper-CVAD is more efficacious than R-CHOP

followed by transplant

R-hyper-CVAD is about as efficacious as R-CHOP followed by transplant

R-hyper-CVAD is lessefficacious than R-CHOP

followed by transplant

I don’t know




— Frank Rodriguez, MDFort Myers, FL

I have a 62-year-old patient with Stage I MCL, who underwent radiation therapy alone and did fantastically well. Now she is about a year out from diagnosis.

If she were to experience disease relapse, would the panel recommend chemotherapy or chemotherapy plus an autologous transplantation at this point?

Case History: Dr Horwitz

• A 45-year-old man with limited lymphadenopathy in the neck, mild fatigue

– Primary physician treats with antibiotics without response

• Needle biopsy: Questionable lymphoma, mostly T-cells

• Excisional biopsy: Apparent PTCL

• PET: Lymphadenopathy above and below the diaphragm

• Stage IV PTCL, NOS

– High LDH

– Good performance status

3) What treatment would you generally recommend?

4%

9%

36%

11%

39%

0% 10% 20% 30% 40% 50%

CHOP

HyperCVAD

CHOP + consolidation HDT/ASCR

Pralatrexate

Other

Case History: Dr Horwitz (continued)

• Patient treated with “accelerated” CHOP, ICE x 3 cycles and consolidation autotransplant

– In remission 8 months after therapy

4) If the patient relapsed one year after completing transplant, what treatment would you generally recommend?

5%

47%

2%

10%

10%

2%

19%

5%

0% 10% 20% 30% 40% 50%

DHAP

ESHAP

GDP

GemOx

ICE

MINE

Pralatrexate

Romidepsin

Classification of T-Cell Lymphomas

Mycosis FungoidesSezary SyndromePrimary cutaneous anaplastic large cell lymphoma

Other ExtranodalExtranodal NK/T cell lymphoma, nasal typeEnteropathy-type T cell lymphomaHepatosplenic T cell lymphomaSubcutaneous panniculitis-like T cell lymphoma

NodalAngioimmunoblastic T cell lymphomaPeripheral T cell lymphoma, unspecifiedAnaplastic large cell lymphoma

Neoplasm of Uncertain Lineage Blastic NK cell T-lymphomaPrecursor T-lymphoblastic leukemia/lymphoma

CTCL PTCL


International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes

Vose J et al.J Clin Oncol 2008;26(25):4124-30.

Pathology Review of 1314 Cases of Peripheral T-Cell Lymphomas

PTCL, NOS

Angioimmunoblastic

Natural killer/T celllymphoma

Adult T-cellleukemia/lymphoma

Anaplastic large celllymphoma, ALK+

Anaplastic large celllymphoma, ALK-

Others

Vose J et al. J Clin Oncol 2008;26(25):4124-30.

Clinical Outcome by Histologic Subtype of Peripheral T-Cell Lymphomas

5-Year Overall Survival

5-Year Progression-Free

Survival

PTCL, NOS 32% 20%

Angioimmunoblastic 32% 18%

NK/T cell lymphoma (Nasal) 42% 29%

NK/T cell lymphoma (Extranasal) 9% 6%

Adult T-cell leukemia/lymphoma 14% 12%

Anaplastic large cell lymphoma ALK+ 70% 60%

Anaplastic large cell lymphoma ALK- 49% 36%

Vose J et al. J Clin Oncol 2008;26(25):4124-30.


Phase II Study of Denileukin Diftitox with CHOP Chemotherapy in Newly-Diagnosed PTCL: CONCEPT Trial

Foss FM et al.Proc ASCO 2010;Abstract 8045.

Phase II Study of Denileukin Diftitox + CHOP in Initial Treatment of PTCL (n = 49)

Complete Response

Overall Response

Median Response Duration Median PFS

2-Year Overall Survival

51% 65% 29 months 12 months 60%

The most frequent grade 3/4 AEs (>5%) were leukopenia (20%), thrombocytopenia (12%), and febrile neutropenia (12%).

Based on these results, a multi-center randomized trial comparing CHOP to denileukin diftitox + CHOP is being initiated.

Foss FM et al. Proc ASCO 2010;Abstract 8045.


• A 71-year-old man with Stage II PTCL NOS with right cervical and right axillary nodes only

• Normal LDH

• Bone marrow negative

• Patient treated with CHOP x 6 and IFRT (Involved Field Radiation Therapy) and achieves CR

5) Would you advise high dose chemotherapy with stem cell transplant, while the patient is in 1st CR after treatment of stage II PTCL?

84%

16%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

Yes

No


• Patient underwent active surveillance while in 1st CR

– 1-year later, disease recurs with diffuse lymphadenopathy without involvement of the bone marrow

6) How would you treat the patient at this time?

14%

3%

49%

3%

31%

0%

0%

0%

0% 10% 20% 30% 40% 50%

Salvage chemotherapy (like ICE, DHAP or MINE), with auto-

transplant if chemosensitive

Allogeneic transplantation

Pralatrexate

Romidepsin

Gemcitabine/oxaliplatin

Bortezomib

Lenalidomide

Denileukin diftitox


• Patient receives pralatrexate and achieves a PR that is maintained for 10 months before progression

• Enrolls on a Phase II study of romidepsin and achieves a PR that is maintained for 8 months

– Restaging after cycle 8: Enlarging lymphadenopathy

What treatment do you generally recommend for relapsed/refractory PTCL?

15%

2%

36%

5%

32%

9%

0%

4%

16%

28%

48%

4%

Gemcitabine-based regimen

Romidepsin

Other*

* CHOP, fludarabine-based regimen, alemtuzumab, denileukin diftitoxPatterns of Care Survey of US-Based Practicing Oncologists (n = 81) and Clinical Investigators (n = 25), 2010.

Pralatrexate

I do not have any experience treating

relapsed PTCLSalvage regimens such

as ICE, ESHAP, DHAP



Newly Approved Drugs in T-Cell Lymphomas

Pralatrexate• Chemotherapy• Folate analogue (Anti-metabolite)• FDA Indication: Relapsed or refractory Peripheral-T Cell Lymphoma• Recommended Dose: 30mg/m2 as IV push over 3-5 minutes, weekly

for six weeks in 7-week cycles

Romidepsin• Epigenetic Therapy• Histone Deacetylase (HDAC) Inhibitor• FDA Indication: Cutaneous T-Cell Lymphoma who have received at

least one prior systemic therapy• Recommended Dose: 14mg/m2 as IV infusion over 4 hrs; d 1, 8 and

15 of 28-day cycle


PROPEL: Results of the Pivotal, Multicenter, Phase II Study of Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)

O’Connor O et al.Proc ASCO 2009;Abstract 8561.

Efficacy and Safety of Single Agent Pralatrexate in Relapsed-Refractory PTCL

Complete Response (n = 109)

Partial Response (n = 109)

Overall Response(n = 109)

10% 17% 27%

Grade 3 / 4 Mucositis 21%

Grade 3 / 4 Thrombocytopenia 33%

O’Connor O et al. Proc ASCO 2009;Abstract 8561.

Median Prior Treatments = 3


Pralatrexate Activity in Patients with Relapsed-Refractory PTCL: Relationship between Response at Cycle 1 and Subsequent Survival

Coiffier B et al.Proc EHA 2010;Abstract 305.

Relationship of Response at Cycle 1 and Subsequent Survival: Pralatrexate PROPEL Trial

Per Independent Review (n = 90)

Per Investigators (n = 95)

RespondersNon-

Responders RespondersNon-

Responders

N 20 70 33 62

Median Survival

17.6 months 13.4 months 21.3 months 8.6 months

Hazard Ratio 0.69 0.46

p-value 0.32 0.01

Coiffier B et al. Proc EHA 2010;Abstract 305.


Romidepsin Experience in 317 Patients with T-Cell Lymphomas

Coiffier B et al.Proc EHA 2010;Abstract 572.

Activity of Romidepsin in Relapsed/Refractory PTCL and CTCL

PTCL CTCL

Overall Response 38% 34%

Complete Response 15% 6%


10 months 13.7 months-15 months

Romidepsin resulted in clinically meaningful responses in CTCL and PTCL

Coiffier B et al. Proc EHA 2010;Abstract 572.


• A 50-year-old man with extensive Stage IB CTCL who was treated at another institution with gemcitabine then bortezomib

• Presented with very extensive patch/ plaque disease and weepy sores

7) What treatment would you generally recommend?

38%

28%

21%

13%

0% 5% 10% 15% 20% 25% 30% 35% 40%

Some form of skin-directed therapy

Systemic therapy

Skin-directed therapy followed by

systemic therapy

I would refer to a tertiary center


• Patient treated with total skin electrons

– Skin cleared

– Rapid relapse

• Patient treated with bexarotene but progressed


• Patient treated with low-dose pralatrexate on protocol

– Doing well 9 months later

Treatment Options for CTCL

Skin-Directed Therapies

Topical SteroidsTopical nitrogen mustard, carmustineTopical retinoidsPhototherapy (PUVA, UVB)Localized RadiationTotal Skin Electron Beam Therapy

Systemic Therapies

RomidepsinVorinostatOral retinoids (e.g. bexarotene)InterferonsDenileukin diftitoxExtracorporeal photopheresisLiposomal doxorubicinGemcitabineEtoposideTemozolomideMethotrexateBortezomib

NCCN Clinical Practice Guidelines on Non-Hodgkin's Lymphomas, V.1.2010.


Final Results From a Multicenter, International, Pivotal Study of Romidepsin in Refractory Cutaneous T-Cell Lymphoma

Whittaker SJ et al.J Clin Oncol 2010;28(29):4485-91.

Efficacy of Romidepsin in Relapsed/Refractory CTCL (N = 96)

Overall Response Rate

Complete Response

Partial Response


Time to Progression

34% 6% 28% 15 months 8 months

Whittaker SJ et al. J Clin Oncol 2010;28(29):4485-91.

Adverse Events All Grade Grade 3/4

Nausea 56% 2%

Asthenic conditions 44% 6%

Vomiting 26% 1%

Anorexia 20% 0%

Diarrhea 14% 1%


Pralatrexate Efficacy and Tolerability in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma (CTCL)

Horwitz M et al.Proc EHA 2010;Abstract 0300.

Efficacy of Pralatrexate in Relapsed/Refractory CTCL

Overall Response

(N = 47)Complete Response

Partial Response

Overall Response at Optimal Dose*

(N = 22)

40% 4% 36% 45%

*15 mg/m2 x 3/4 week

• 2 patients experienced Grade 3 mucositis• No patients experienced Grade 4 toxicity

Horwitz M et al. Proc EHA 2010;Abstract 0300.

Median Prior Systemic Therapies = 4 (Range 1-11)

Case History: Dr Smith

• A 52-year-old woman presents in 2002 with large mid-abdominal mass

• Diagnosed with Stage IIA diffuse large B-cell lymphoma (DLBCL)

• Patient received R-CHOP x 8 and achieves CRu

• No PET Scan is done

8) If PET scan is done, and shows focal residual activity, then what would be your next step?

12%

22%

56%

10%

0% 10% 20% 30% 40% 50% 60%

Observation

Involved field RT

2nd line chemotherapy followed by high-dose chemotherapy and

autologous transplant

Go directly to high-dose chemotherapy and autologous

transplant as her disease is chemo-responsive


• Patient receives involved field radiation and remains in remission for two years

• Disease recurs above the diaphragm

• Patient treated with ICE followed by high-dose chemotherapy and autologous transplant

R-CHOP2 Cycles

R-ICE 4 Cycles


Eligibility Criteria

Bulky Stage II or Stage III/IV DLBCL

Target Accrual: 99

ECOG-E3404: Response-Adapted Therapy for Aggressive NHL Based on Early PET Scanning

R-CHOP3 to 4

Cycles

PETSCAN

+

-

Do you use interim PET scanning in patients being treated for DLBCL?

After how many treatment cycles do you generally perform a PET scan?

CI (n = 14) Median PO (n = 84) Median

4 4

84%

56%

Yes




— Frank Rodriguez, MDFort Myers, FL

I have a patient who presented with lymphadenopathy, was diagnosed with Stage III DLBCL, was treated with R-CHOP and did relatively well. However, he recurred in the same area 8 months later.

He wasn’t keen on using RICE salvage chemo as an inpatient (or as an outpatient) before transplant. He was hoping there was another regimen we could use on an outpatient basis.

What does the panel think about using GEM/OX-R as salvage chemotherapy prior to transplant? Are there any concerns about long-term toxicities that may preclude the patient from going to transplant, or should this regimen not be used outside of clinical trial in that setting?

— Neal Fischbach, MDFairfield, CT

I am curious about transplant for patients with primary, high-risk DLBCL.

There was a study from Sloan-Kettering where patients received risk-adapted therapy with three cycles of CHOP, then RICE. For patients who had high-risk disease at the outset or who did not respond well in the first three cycles of CHOP, they were getting transplanted at that point.

Does the panel think that we should be doing more of that in our young, healthy, high-risk patients?

— Richard Polkinghorn, MDBrunswick, ME

I have a 22-year-old patient who has DLBCL with Burkitt's-like features — Molecular testing was negative. Should we treat this patient with a Burkitt’s-like protocol, such as hyper-CVAD or R-CHOP, despite the negative molecular testing?

Also, does the panel believe that regimens like hyper-CVAD are more effective than R-CHOP in terms of overall survival?

copyright © 2010, research to practice, all rights reserved. part vii: mantle-cell lymphoma, t-cell...

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