Lenalidomide Therapy for MDS

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Lenalidomide Therapy for MDS

• Todd Fehniger, MD/PhD
• Hematology/Oncology
• Grand Rounds
• 6/10/05

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Case Report

• 68yo M presented to his PCP with the complaint of
  fatigue, PS1.
• PE unremarkable
• CBC reveled WBC 4.1 (ANC 2.3), Hb 6.1, MCV 101,
  Plts 142,000)
• Referred to Hematology
• Retic 0.5, B12/Folate/ferritin normal
• Bone marrow biopsy myelodysplastic syndrome
  (erythroid), refractory anemia
• Cytogenetics 5q-, 8

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WHO MDS Classification
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WHO MDS Classification
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Myeloid maturation arrest
Refractory Anemia ASH Image Bank/ Peter
Maslak http//www.ashimagebank.org
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IPSS
Cytogenetic Categories Good normal, -Y,
del(5q), del(20q) Poor complex, ch 7 abnl Int
all others
Greenberg Blood 89 2079, 1997
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Case Report

• Transfused PRBCs
• Epogen 20,000 units 3X/wk
• Followed for 3-4 months
• Continued to require 2 units PRBCs / 4 wks

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NCCN Guidelines - Anemia

• Rule out other causes of anemia / contributing
  factors (Fe-def, b12, folate)
• Check EPO level
• No ringed sideroblasts, Epo lt 500 mU/ml
• Epo 150-300 U/kg/d SC for 2-3 months
• If no response, consider G-CSF 1 mcg/kg/d x 2-3
  months
• If no response, PRBC transfusion or clinical
  trial

NCCN Guidelines for MDS v 1.2005
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• Any other treatment, besides supportive care?

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NCCN Treatment Guidelines
IPSS Category
Characteristics
Treatment Options
Supportive Low-Intensity
Age gt 60
Low/ Int-1
PS Poor (3-4)
Supportive
Age lt60 PS Good (0-2)
Clinical trial Low-Intensity Supportive HSCT in
Int-1
NCCN Guidelines for MDS v 1.2005
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Low Intensity Therapy Options

• Preferably in clinical trials limited clinical
  data available and/or investigational
• ATG
• CSA
• Thalidomide
• CC-5013 (lenalidamide, Revlimid)
• Anti-TNF fusion protein (etanercept, remicade)
• Vitamin D analogues
• 5-Azacytidine

NCCN Guidelines for MDS v 1.2005
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Thalidomide and IMiD History

• 1950s widely used for its sedative and
  anti-emetic effects in pregnant women in Europe
• Teratogenic underdeveloped limbs in babies born
  from mothers taking Thalidomide
• FDA approved in 1998 for Erythema Nodusum Leprosa
  (ENL)
• Inflammatory condition caused by lepromatous
  leprosy, very high TNF-a levels
• Clinical Trials investigating thalidomide
  activity in MM, MDS, solid tumors based on
  anti-TNF and anti-angiogenic properties
• Development of IMiDs related chemical compounds
  selected for their ability to inhibit TNF-a

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Thalidomide/IMiD Potential Mechanisms of Action

• Inhibits TNF-a
• Inhibited TNF-a production by monocytes mRNA
  instability Sempaio EP J Exp Med 173699, 1991
• Inhibits Angiogenesis, blocks VEGF/bFGF
• DAmoto RJ PNAS 914082, 1994
• T cell costimulator increased proliferation and
  IL-2 production
• Haslett PA J Exp Med 1871885, 1998
• Augments NK cell activity (via T cell-IL-2)
• Davies Blood , 2001

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Mechanisms of IMiD in MM
Bartlett JB Nat Rev Ca 4314, 2004
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Rationale for Thalidomide Treatment of MDS

• Increased BM neo-angiogenesis and VEGF levels
  observed in MDS marrow
• Excessive TNF-a other cytokine-driven apoptosis
  observed in MDS marrow
• T cell changes in MDS modulating lymphocyte
  function
• Deficient NK cell number / function in MDS
• Thalidomide active in Multiple Myeloma

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Potential Mechanisms of IMiD in MDS
MDS Cell
Adopted from Bartlett JB Nat Rev Ca 4314, 2004
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Raza A et al Blood 98958, 2001
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Thalidomide and MDS

• N83, retrospective study
• Primary (n77) and Secondary (n6) MDS any
  histology, any IPSS
• PRBC dependent (n60) or independent (n23)
• New Dx and prior Dx
• Supportive care only treatment allowed for 4 wks
  prior
• Thalidomide started at 100mg qD, increased over
  several weeks to 400 mg qD as tolerated

Raza A et al Blood 98958, 2001
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Thal and MDS Patients

• FAB
• RA 36
• RARS 13
• RAEB 24
• RAEB-t 6
• CMML 4

• IPSS
• Low 21
• Int-1 37
• Int-2 12
• High 13

Raza A et al Blood 98958, 2001
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Thal and MDS Toxicity

• 32 of the 83 patients could not complete 4 weeks
  of therapy
• Disease progression 6
• Other medical problems 12
• Side effects of drug 14
• Most Common Dose Limiting Side Effects
• Fatigue (71)
• Constipation (79)
• SOB (54)
• Edema (54)

Raza A et al Blood 98958, 2001
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Thal and MDS Responses

• Hematologic response
• 16/83 (19), No CR
• 15 Erythroid (11 major, 4 minor)
• 1 minor platelet
• Time to response 12-20 wks
• Median duration 306 days (90-620)
• No cytogenetic responses (15/16 responders had
  cytogenetic data available)
• 3pts 5q-, 7nl kary, 1 Y, 18, 1 del(20q), 1
  t(28), 1 der7

Raza A et al Blood 98958, 2001
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Major Studies Evaluating Thalidomide as single
agent in MDS
Musto et al. Leuk Res 28325, 2004
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A Better Thalidomide?
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Lenalidomide (Revlimid)

• 4-amino glutarimide analog of thalidomide
• Potent inhibitor of TNF-a, IL-6, VEGF
• Potently blocks angiogenesis
• Potent costimulator of T cells proliferation, and
  IL-2 and IFN-g production
• Activates NK cell cytotoxicity
• Less toxicity c/w Thalidomide in MM pts. (no
  sedation, constipation, neuropathy)

Corral LG J Immunol 163380, 1999 Richardson PG
Blood 1003063, 2002
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N Engl J Med 352549, 2005
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Lenalidomide MDS Trial

• Open label, single center
• 43 MDS pts, diagnosed gt 3 months
• Anemia
• Hb lt 10
• Requiring 4 units PRBCs/8 weeks
• No response to Epo or Epo lvl gt 500
• Excluded anc lt 500, plts lt 10k, t-MDS,
  significant co-morbidities

N Engl J Med 352549, 2005
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Dosing

• Three PO dosing schedules
• 25 mg qD
• 10 mg qD
• 10 mq qD for 21 / 28 day cycle
• Held for CTC AE gt grade 3
• Dose reductions
• 10 mg qD, 10 mg qD 21/28 days, 5 mg qD, 5 mg
  qD 21/28 days, 5 mg qOD

N Engl J Med 352549, 2005
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Assessment and Dose Reductions

• Assessed toxicity q4wks, responses q8wks, and
  final response at 16 wks
• Response
• Continue until PD, treatment failure, DLT
• Hematologic improvement that did not qualify as
  response
• 8 additional wks of Rx, then re-assess response
• If on 10mg 21/28d arm, could change to continual
  dosing x 8 wks, re-assess response

N Engl J Med 352549, 2005
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Response Criteria

• Major erythroid response
• Freedom from need for transfusion
• Increase in Hb gt 2 g/dl
• Minor erythroid response
• gt 50 reduction in transfusion need
• Increase in Hb 1-2 g/dl
• Major Cytogenetic Response
• Absence of pre-tx cytogenetic abnl on standard
  chromosome analysis (20 metaphases)
• Minor Cytogenetic Response
• gt 50 reduction in abnl cells

N Engl J Med 352549, 2005
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N Engl J Med 352549, 2005
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N Engl J Med 352549, 2005
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Median followup 81 wks (42-110) Median duration
of response not reached gt48 wks (gt13 to gt101 wks)
N Engl J Med 352549, 2005
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N Engl J Med 352549, 2005
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Post-Tx
Pre-Tx
N Engl J Med 352549, 2005
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MDS-003 Study

• Low or Int-1 IPSS MDS with 5q31.1 del
• Transfusion dependent (gt 2 PRBC/8wk)
• N 148
• Median Age 71 yrs
• Median MDS duration 3.4 yrs
• Median PRBCs / wk 5 (2-16)
• Median followup 48 wks
• n111 Isolated 5q- n, n37 5q- other

List AF et al Plenary Session, Abstract 5, ASCO
2005
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MDS-003

• FAB Subtype
• RA 52
• RARS 12
• RAEB 20
• CMML 2
• Other 14

• IPSS
• Low 37
• Int-1 44
• Int-2/High 5
• Unknown 14

List AF et al Plenary Session, Abstract 5, ASCO
2005
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MDS-003 Dosing

• 10 mg PO qD n104
• 10 mg PO qD 21/28 days n44

List AF et al Plenary Session, Abstract 5, ASCO
2005
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MDS-003 Responses

• Erythroid
• Transfusion Independence 66 95 CI 55-71
• gt56 days transfusion free and gt 1g/dl increase
  in Hb
• Median increase 3.9 g/dl (1.1-11.4)
• Time to response 4.4 wks (0.4-19)
• Duration of response gt47 wks (max 166 wks)

List AF et al Plenary Session, Abstract 5, ASCO
2005
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MDS-003 Responses

• Histologic
• CR - 36 (31/87)
• RAEB to RA or RARS - 75 (12/16)
• RARS to RA - 79 (11/14)
• Cytogenetic
• 76 (gt 50 decrease in abnl metaphases)
• Complete CR - 55

List AF et al Plenary Session, Abstract 5, ASCO
2005
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MDS-003 Toxicity and Dose Mods

• gt Grade III thrombocytopenia - 54
• gt Grade III neutropenia - 55

• Dose Reductions
• 10 mg qD 87
• 10 mg qD 21/28 days 64

List AF et al Plenary Session, Abstract 5, ASCO
2005
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Lenalidomide for MDS

• Lenalidomide appears well tolerated in patients
  with MDS
• Significant clinical benefit in anemic pts with
  IPSS low/int-1
• Potential for altering the course of disease,
  evidenced by large numbers of cytogenetic
  responses
• While potential mechanisms are abundant, critical
  ways that lenalidomide acts in MDS is not clear
• FDA is currently evaluating L for MDS and MM via
  fast-track status