Todd A Fehniger

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• Todd A Fehniger
• Hematology Grand Round
• March 13, 2009

Lenalidomide therapy for untreated acute myeloid
leukemia in older adults (gt 60 years of age)
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Disclosure

• Clinical study funded in part by Celgene
• Non-FDA approved use of Revlimid (lenalidomide)

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Case

• 71 yo M presented with dyspnea, fatigue, and
  pancytopenia
• Performance status ECOG 1
• PMH HTN, GERD, BPH
• PE petechiae, pale
• CBC
• WBC 1900/uL (ANC 190/uL)
• Hgb 6.7 g/dL
• Plts 74,000/uLf
• Differential 33 blasts

Blood 113 1002, 2009
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Case

• Bone marrow biopsy and aspirate
• 30 cellular
• 90 myeloblasts
• FAB M0 (undifferentiated)
• Flow CD34CD33CD13CD117
• Routine cytogenetics trisomy 13
• 47,XY135/46,XY15
• FLT3ITD Positive

Blood 113 1002, 2009
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Case Dx Bone Marrow and Cytogenetics
BM Aspirate
Leder stain
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Acute Myeloid Leukemia in patients gt 60 year old

• Median age of AML is 65-70
• 13, 410 new AML cases / 8,990 deaths in 2007
• 14.5/100,000 in adults gt 60 years
• 0.7/100,00 in adults lt 60 years
• Majority of patients do not receive specific
  therapy (best supportive care)
• Median survival lt 1 year

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Older AML Prognosis and Standard Therapies?

• 73 median survival 8-13 months
• Low dose ara-c 9 months
• NCCN Investigational agents recommended as 1st
  line therapy
• Prognosis, Results with current therapy options,
  and overview of investigational agents
• Summarized in Mike Martins WashU Heme/Onc grand
  rounds presentation from February 2008
• Martin and Abboud. Bood Rev 22311, 2008
• Eliah Estey J Clin Oncol 251908, 2007

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Older AML biology continuum with myelodysplastic
syndrome (MDS)

• Cytogenetics in older AML
• lower percentage of favorable risk cytogenetics
• t(814), t(1517), inv(16)
• Higher percentage of unfavorable cytogenetics
• -5, -7, 8, complex
• Frequently arises from MDS or initial diagnoses
  as AML with multilineage dysplasia
• Resistant to traditional chemotherapy (MDR1)
• Presentation with a hypoproliferative, MDS type
  picture common

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MDS and lenalidomide

• Efficacy of lenalidomide in MDS. List A et al.
  NEJM 352549 2005
• Lenalidomide in MDS with 5q deletion. List A et
  al. NEJM 3551456,2006
• Phase 2 study of lenalidomide in
  transfusion-dependent, low and int-1 risk MDS
  with karyotypes other than deletion 5q. Blood
  11186, 2008.
• A small number of patients with clonal
  cytogenetic abnormalities (non-5q-) and excess
  blasts had cytogenetic responses and CRs

(I presented this topic at WashU Heme/Onc Grand
Rounds 6/10/2005 as a fellow my interest led to
the current study!)
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Hypothesis Lenalidomide has activity in acute
myeloid leukemia
One of my fellow clinical protocols (with Ravi
Vij)
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Study design

• Phase II, single-institution, investigator-initiat
  ed, prospective, open-label study
• Simon 2 stage design (n12 evaluable in stage 1)
• Primary Endpoint CR (CRc/CRm/CRi)
• IWG criteria with addition of SD
• Secondary Endpoints safety, IWG response
  criteria, overall survival, event-free survival,
  and duration of remission
• Eligibility Untreated AML age gt 60 yo (prior
  MDS, therapy related, de novo all eligible)
• Exclude 5q- and favorable risk cytogenetics

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Stage 1 / Cohort 1 Schema
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(No Transcript)
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(No Transcript)
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IWG Criteria for AML
Cheson JCO 2007
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06-0907 Stage 1 (Cohort 1) Results

• WHO IWG Criteria (n15 total patients)
• CRc 1 (duration 9 months)
• PR 2 (duration 6 and gt12 months - ongoing)
• SD 4 (duration 3, 3, 4, 7 months)
• Treatment failure indeterminate cause 6
• Rash, Sepsis, Cardiac Arrest
• Progressive disease lt 2 cycles Len (n3)
• Morphologic leukemia free BM at d15 w/ PD at d30
• Treatment failure resistant disease 2

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(No Len)
Len
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Stage 2 / Cohort 2 Schema
Stage 2 Cohort 2 N27 patients Independent
analysis
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Preliminary Results Cohort 2 (n25 so far)
Unpublished
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Case Clinical Course Pt. 007
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Case Follow-up
BM blasts
BM cellularity
Hemoglobin
100
12
10.0
300
WBC count
Platelets
10
250
80
8.0
200
8
60
6.0
Platelets (x103/?L)
BM ()
Hemoglobin (g/dL)
WBC (x 103/?L)
150
6
40
4.0
4
100
20
2.0
50
2
0
0
0
0
Day 0
Day 15
Day 30
Day 75
LD
Day 0
Day 15
Day 30
Day 75
LD
cycle 1
cycle 1
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CR Leder 10X
CR Aspirate 100X
CR Leder 100X
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Lenalidomide Mechanism?
Potential Mechanism(s)
Activity
Alter cytokine profiles
Multiple Myeloma
MDS (w/ 5q-)
Block Angiogenesis
Direct Effects on tumor
CLL
Immune modulation
Lymphoma
Lenalidomide (Revlimid)
AML
Phosphatase modulation
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Lenalidomide has activity in AML how does it
work?

• Modulation of NK cell responses?
• Correlative studies evaluating NK cells prior to,
  during, and after therapy
• Direct effects on AML?
• BM blasts at Dx In vitro lenalidomide exposure,
  follow blast cell death compared to vehicle
  correlation to response?
• Leukemia microenvironment?
• Flow for CXCR4 on AML blasts

This would be a great project for a fellow!
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Acknowledgments

• Ravi Vij
• Alissa Nelson
• Kim Trinkaus
• Jackie Payton
• BMT/leukemia physicians and team members
• ASCO Foundation
• Siteman Cancer Center

• Disclosures
• This study was funded in part by Celgene
• Non-FDA approved (investigational) use of
  Revlimid (lenalidomide)
• No financial interest