Lenalidomide Therapy for Lymphoma

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Lenalidomide Therapy forLymphoma

• Todd Fehniger, MD/PhD
• Hematology/Oncology Grand Rounds
• 4/18/08

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Case 1 relapsed FL

• 60 year old woman with stage IVA follicular
  lymphoma (grade 1)
• Left inguinal LNs, positive BM
• R-CHOP X 6 -gt CR
• Left inguinal LN recurrence 9 months after CR
• Biopsy recurrent FL (g1), no evidence of
  transformation
• Relapse lt1 year from R-CHOP (poor prognosis)
• Treatment options?
• Salvage chemotherapy followed by auto SCT
• Phase II trial of Lenalidomide versus
  Lenalidomide Rituximab (CALGB 50401)

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Case 2 rel/ref cHL

• 43 yo F with relapsed classical Hodgkin lymphoma
• Dx 12/01 Stage IIB (non-bulky) cHL (NS, fevers,
  wt loss)
• Neck, mediastinum, axilla
• ABVD x 6 Residual disease (mediastium, hilum),
  IFRT -gt CR
• Relapse 3/04 (spleen, axilla, supraclav) 2 years
  after CR1
• Salvage ESHAP x 1 c/w sepsis, mech vent
• 8/04 PD (left axilla, paraspinal mass)
• Gem Vinorelbine liposomal Doxo (GVD) -gt PR
• BEAC Auto 8/2/05 -gt CR
• Relapse 9/06 (left axilla), observed until 1/07
  waiting for studies
• SGN-35 trial 1/07-5/07 (4 cycles) -gt SD, but off
  study due to MI
• PD 8/07
• Treatment options?
• Allogeneic SCT
• 10/07 Phase II study of lenalidomide in rel/ref
  cHL (WU 07-0233)

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Lenalidomide
Actimid
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Lenalidomide
Potential Mechanism(s)
Activity
Alter cytokine profiles
Multiple Myeloma
MDS (w/ 5q-)
Block Angiogenesis
Direct Effects on tumor
CLL
Costimulate T cells
?NHL
Lenalidomide (Revlimid)
Augment NK cells
?cHL
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Lenalidomide and Lymphoma Mechanism?
Chanan-Khan JCO 2008
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Hodgkin Lymphoma
Non Hodgkin Lymphoma
Classical HL (NS, MC, LR, LD) Nodular lymphocyte
Predominant (NLPHL)
Highly Aggressive
Aggressive
Indolent
B cell Follicular SLL/CLL Marginal zone LP
(WM) T/NK cell Mycosis fungoides Sezary
syndrome Primary cut ALCL
B cell Pre-B lymphoblastic Burkitt T/NK
cell Pre-T lymphoblastic
B cell DLBCL FLg3 and tFL Mantle cell Primary
effusion T/NK cell ALCL Angioimmunoblastic Subq
panniculitis-like Blastic NK Extnanodal NK/T
nasal Enteropathy-type Hepatosplenic PTCL nos
Multiple Myeloma
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Lenalidomide in CLL/SLL

• n45 (relapsed/refractory)
• Len 25 mg d1-21/28 day cycle (Phase II)
• If PD, add Rituximab (n3), all achieved a PR
• ORR 47
• PR 38
• CR 9
• SD 18
• (PFS at 1 year 81)
• Toxicity I-IV (IV)
• Fatigue 83 (10)
• Thrombocytopenia 78 (45)
• Neutropenia 78 (70)
• Tumor flare reactions occurred

Chanan-Khan JCO 245343, 2006
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Lenalidomide in CLL/SLL

• CLL, n44, (relapsed/refractory)
• Len 10 mg/d, escalated in 5 mg increments q28
  days to max dose of to 25 mg/d
• Median dose 10 mg/day
• ORR 32 (time to best response 6-9 months)
• PR 25
• CR 7
• (SD 25)
• Toxicity III-IV (IV)
• Fatigue 22 (1)
• Thrombocytopenia 15 (16)
• Neutropenia 52 (41)

Ferrajoli et al, Blood, doi10.1182, 2008
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Lenalidomide in Indolent NHL

• n43 SLL n18, FL n23, MZL n3
  (relapsed/refractory)
• Len 25 mg d1-21/28 day cycle (Phase II), up to 52
  weeks total
• ORR 11/43 26 (median time to response 4 months)
• PR 8/43 (19)
• CR/CRu 3/43 (7)
• SD 15/43 (35)
• SLL 4/18 (22), 7/22 FL (32)
• Toxicity Grade III/IV (IV)
• Neutropenia 35 (14)
• Thrombocytopenia 12 (0)
• Thalidomide in CALGB 50002 RR 3/25 12.5 (2CR,
  1PR)
• 200 mg/day w/ escalation to 600 mg max Smith BJH
  2008
• Long remission durations

Witzig ASH 2560 2007
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Lenalidomide in Aggressive NHL

• n49 DLBCL n26, MCL n15, FLg3 n5, tFL n3
  (relapsed/refractory)
• Len 25 mg d1-21/28 day cycle (Phase II), up to 52
  weeks total
• ORR 17/49 36 (median time to response 4-6
  months)
• PR 11 (22)
• CR/CRu 6 (12)
• SD 11 (22)
• RR DLBCL 5/26 (19), 8/15 MCL (53), 1/3 tFL
  (33), 3/5 FLg3 (60)
• RR equal with or without prior Rituximab (30 vs
  31)
• Responses with 2 favorable factors (RR 67 vs.
  4, Plt0.001)
• Low disease burden lt50cm2, 52 vs 0, P0.03
• Time from last Rituximab gt230 days, 52 vs. 6,
  Plt0.03
• Toxicity Grade III/IV (IV)
• Neutropenia 33 (8)
• Thrombocytopenia 20 (8)
• DVT/PE 2 (2)

Wiernik ASH 2565 2007
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Lenalidomide in Aggressive NHL 2

• n18 DLBCL n11, MCL n5, tFL n2
  (relapsed/refractory)
• Len 25 mg d1-21/28 day cycle (Phase II), up to 52
  weeks total
• ORR 4/18 22
• PR 4/11 36
• CR/CRu 0/11
• SD 5/11 45
• PR DLBCL 2/11 (18), 2/5 MCL (40)
• Responses associated with favorable factors (RR
  57 vs. 0)
• Low disease burden (lt50cm2, 29 vs 0)
• Time from last Rituximab gt230 days, 36 vs. 0
• Toxicity Grade III/IV (IV)
• Neutropenia 33 (22)
• Thrombocytopenia 22 (11)
• Fatigue 17 (0)

Witzig ASH 762 2007
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Lenalidomide in Aggressive NHL 3

• n26 DLBCL n26 (relapsed/refractory)
• Len 25 mg d1-21/28 day cycle (Phase II), up to 52
  weeks total
• ORR 5/26 19
• PR 2 (8)
• CR/CRu 3 (12)
• SD 7, 27
• Responses with 2 favorable factors (RR 50 vs.
  0, Plt0.001)
• Low disease burden lt50 cm2, 33 vs 0, P0.06
• Time from last Rituximab gt 230 days, 33 vs. 0,
  P0.05
• Toxicity Grade III/IV (IV)
• Neutropenia 27 (8)
• Thrombocytopenia 19 (4)
• Leukopenia 16 (4)

Lossos ASH 754 2007
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Lenalidomide in Aggressive NHL 4

• n49 total DLBCL n14/49 prior auto SCT
  (relapsed/refractory)
• post-auto subset DLBCL n5, FLg3 n2, MCL
  n5, tFL n2
• Len 25 mg d1-21/28 day cycle (Phase II), up to 52
  weeks total
• ORR 7/14 50
• PR 6 (8)
• CR/CRu 1 (12)
• (SD 5, 27)
• 4/6 patients with auto as last treatment
  responded
• Responses with 2 favorable factors (RR 6/8 vs.
  1/6)
• Low disease burden lt50cm2
• Time from last Rituximab gt230 days
• Toxicity Grade III/IV (IV)
• Neutropenia 50 (14)
• Thrombocytopenia 35 (14)
• Leukopenia 14 (0)

Vose ASH 2570 2007
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Lenalidomide in Mantle Cell Lymphoma

• Mantle cell lymphoma n15, (relapsed/refractory)
• Len 25 mg d1-21/28 day cycle (Phase II), up to 52
  weeks total
• ORR 8/15 53
• PR 6/15 40
• CR/CRu 2/15 13
• (SD 35)
• Toxicity Grade III/IV (IV)
• Neutropenia 46 (13)
• Thrombocytopenia 20 (13)
• DVT (13)

Tuscano ASH 2563 2007
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Lenalidomide Rituximab in Mantle Cell Lymphoma

• n18 total (relapsed/refractory), n10 evaluable
  at MTD
• Rituximab 375 mg/m2 IV d1, 8, 15, 21 of cycle 1
• (Single Agent R RR 27 Ghielmini JCO 2005)
• Phase I 10, 15, 20, 25 mg daily d1-21 / 28 day
  cycle
• DLT G3 hypercalcemia, G4 fever (non-neutropenic)
• Phase II 20 mg daily d1-21 / 28 day cycle
• ORR 7/10, 70
• PR 4/10, 40
• CR/CRu 3/10, 30
• (SD 1, 10)
• No responses seen at 10 (n3) or 15 mg (n3) dose
  levels
• Toxicity Grade III/IV (IV)
• Neutropenia 16/18, 88 (5/18, 28)
• Neutropenic fever 2/18, 11
• Thrombocytopenia 2/18, 11 (0)

Wang ASH 2562 2007
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Lenalidomide in PTCL

• n10 (8 relapsed/refractory, 2 untreated), n9
  evaluable
• Len 25 mg d1-21/28 day cycle (Phase II,
  multi-center)
• N4 PTCL nos, n4 AITL, n1 cut ALCL, n1 hsgd
  TCL
• ORR 4/9, 44
• PR 4/9, 44
• CR/CRu, 0/9
• SD 1/9,11
• Responses 2 AILT, 2 T cell NHL NOS
• Toxicity
• 3/9 grade III/IV hematologic toxicity
• 3/9 grade III/IV infection
• 1/9 grade 3 rash

Reiman T ASH 2579 2007
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Lenalidomide in NHL Summary
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Lenalidomide in Classical Hodgkin Lymphoma

• Hodgkin-Reed-Sternberg (HRS) cells surrounded by
  heterogeneous immune cell infiltrate
  microenvironment
• Len may alter this microenvironment
• Len may directly effect malignant HRS cells
• Cytokine dysregulation (Th2 predominant)
• Len shifts cytokine responses toward Th1
• Autocrine TNF-alpha implicated in HRS survival
• Len blocks TNF-a
• Decreased NK, CD8, Th1 cell responses (general
  and EBV specific)
• Len augments NK cell responses and T cell
  responses
• Increased angiogenesis (VEGF)
• Len blocks angiogenesis
• Len active in other B cell malignancies

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Multicenter Study of Lenalidomide in rel/ref
cHLWU 07-0233

• Multi-center Phase II led by Washington
  University
• 5 other sites participating, IRB approvals
  pending
• Relapsed/refractory classical HL
• Prior auto or allo SCT allowed
• 2 stage design, 12 evaluable in stage 1, 35 total
  in stage 12
• Len 25 mg PO d1-21/28 day cycle until
  unacceptable toxicity or PD
• Objectives
• Response rate (CR PR SD gt 6 months)
• CR/PR/SD rates
• PFS, Duration of Response
• Correlative studies (NK cell and cytokine
  modulation)

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Len in rel/ref cHL 07-0233

• Enrollment n13 patients
• Since 10/07 (6 months) at Wash University
• Too early for efficacy analysis
• Stay tuned
• Very preliminary toxicities
• Grade III/IV (IV)
• Neutropenia 2/13 (0)
• Anemia 3/13 (0)
• Thrombocytopenia 1/13 (0)
• Infection without neutropenia 1/13 (0)
• 2 patients off study for AE
• 1 grade 4 bilirubin/ALT (cycle 1, resolved off
  therapy)
• 1 recurrent rash/hives

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Clinical trials open with lenalidomide for
lymphoma at Wash University

• Rel/ref classical HL
• 07-0233 Multi-center Phase II trial of Len
• Rel/ref Follicular NHL
• CALGB 50401 Randomized Phase II, Len vs.
  Rituximab plus Len
• Rel/ref Mantle cell NHL
• CALGB 50501 Phase II, Velcade plus Len
• Untreated CLL
• CALGB 10404 Phase II, untreated CLL that are
  symptomatic requiring therapy
• FR vs FR consolidating Len vs FCR

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Case 1 relapsed FL
Recurrence
PR after 6 cycles of RLen
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Case 2 rel cHL
SD after 6 cycles of Len (decrease by 39)
Recurrence
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Lenalidomide Key Issues in Lymphoma

• Tumor flare reaction look for it, dont confuse
  with PD
• DVT prophylaxis
• Long duration to response / best response
  compared to traditional chemotherapy agents
  (think about study design)
• Correlative studies are needed (how is Len
  working?)
• Identification of clinical and laboratory
  predictors of response needed
• Single agent activity will lead to new
  combinations with lenalidomide
• Remarkably broad activity in many different
  lymphomas (and other hematologic malignancies) !

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Acknowledgments

• Nancy Bartlett
• Tim Ley
• John DiPersio
• Sarah Larson (CRA for 07-0233)
• ASCO Foundation
• Siteman Cancer Center