Treatment Options for Myelodysplastic Syndromes * Add dose

1
Treatment Options for Myelodysplastic Syndromes
2
Overview

• Describe the background pathophysiology of MDS
• Review the treatment goals  current treatment
  options for low high-risk MDS
• Describe adjunctive/supportive therapies that
  compliment the overall treatment plan

3
Definition

• A heterogenous group of clonal stem cell
  disorders
• Characterized by dysfunctional hematopoietic
  progenitor cells
• Resulting in low blood count

4
Background

• 1930s-first described as a pre-leukemic condition
• 1976-considered as a separate disease entity
• 15,000 new cases/year in US (adults)
• MDS is at least as common as chronic lymphocytic
  leukemia

5
Disease Characteristics

• Typically cellular to hypercellular marrows
• Dysplastic hematopoiesis in gt 1 cell line
• Erythroid Anemia
• Granulocytes Leukopenia
• Megakaryocytes Thrombocytopenia
• Ineffective hematopoiesis
• failure of differentiation
• increased cell death or apoptosis

6
Etiology

• Unknown in gt80 of patients
• Older age
• Male gender
• Secondary MDS
• Immunosuppressants
• Ionizing radiation
• Chemotherapy
• Industrial agricultural chemicals (benzene)

7
Pathophysiology Contributing Factors
Apoptosis
Immune dysfunction
Stem Cell Dysfunction
Stem cell dysfunction
Epigenetic changes
Environmental direct toxicity
Mutations/ DNA damage
Stromal/ angiogenic factors
MDS
With Permission of J. Maciejewski, M.D. Taussig
Cancer Center/ Cleveland Clinic Foundation
8
Age-related Incidence of MDS
Age-specific incidence rates (per 100,000) Less
than 50 0.5 50-59 5.3 60-69 15 70-79 49 80 and
over 89
Age in 5-year blocks
Williamson PJ, et al. Br J Haematol.
199487743-5.
9
Differential Diagnosis

• B12/folate deficiency
• Drug-induced or recent cytotoxic therapy
• HIV
• Anemia of chronic diseases
• Autoimmune cytopenias
• Chronic liver disease excess alcohol intake
• AML (M7), aplastic anemia, myelofibrosis, and PNH

10
MDS Diagnostic Evaluation

• Peripheral blood counts reticulocyte count
• Bone marrow biopsy aspiration
• Bone marrow blasts
• Cytogenetics
• Iron stain
• Reticulin stain
• Additional tests (iron saturation, ferritin, EPO,
  HLA-DR15, HLA typing)

11
Classifications

• French American British (FAB), 1982
• World Health Organization (WHO), 2001
• Prognostic Scoring
• International Prognostic Scoring System (IPSS),
  1997
• World Prognostic Scoring System (WPSS), 2007

12
Germing U. et al. Leuk Res. 200024938-92.
13
Relative of Various Cytogenetic Abnormalities
in De Novo MDS

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International Prognostic Scoring System (IPSS)
All 3 prognostic variables required to generate
IPSS score
Score Value Prognostic
Variable 0 0.5 1.0 1.5 2.0 Bone marrow blasts
() lt5 510 1120 2130 Karyotype Good
Int Poor Number of cytopenias
0/1 2/3
Good Normal, -Y, del(5q), del(20q) Intermediat
e (Int) Other karyotypic abnormalities Poor
Complex ( ? 3 abnormalities) or chromosome 7
abnormalities Hgb lt10 g/dL ANC lt1800/?L
Platelets lt100,000/?L
15
Survival Transformationto AML by IPSS Score
From diagnosis in untreated patients. Greenberg
P, et al. Blood. 1997892079-88.
16
Survival MDS vs. Lung Cancer
The survival of MDS Int-2 patients is similar to
survival of patients with stage 4 lung cancer.
17
WHO Prognostic Scoring System (WPSS)

• Defined as 1 U pRBC q 8 wk

18
Survival Based on WPSS
136
8
Malcovati L, et al. Blood. 2005 106232a
(abstract 788
19
Low Risk MDS - Treatment Goals

• Definition
• IPSS low or intermediate-1
• Goals
• Delay disease progression
• Prolong survival
• Improve blood cell deficiencies
• Improve quality of life

20
High Risk MDS - Treatment Goals

• Definition
• IPSS Intermediate-2/High
• Goals
• Possible cure of disease
• Delay AML
• Prolong survival

21
Approach in Low-Risk MDS with Clinically
Significant Cytopenia/(s)
www.nccn.org/MDS v2.2008
22
Approach in High-Risk MDS
www.nccn.org/MDS v2.2008
23
Supportive Care Components

• Transfusions (Leukocyte-depleted RBCs, platelets)
• Growth Factors
• Iron Chelation
• Antibiotics

www.nccn.org/MDS v2.2008
24
Erythropoietic Stimulating Agents (ESA)

• Often initial therapy
• low-risk
• transfusion-dependent patients
• Features that predict response
• endogenous epo lt 500 U/ml
• low transfusion requirement (lt2U/month)
• bone marrow blasts lt 10

25
Erythropoietic Stimulating Agents (ESA) /-
G-CSF Dosing

• Epoetin 20,000 U sq 3x / week or
• Epoetin 60,000 U sq weekly or
• Darbepoetin 300 mcg sq weekly
• If no response after 6-week trial, add G-CSF 100
  mcg sq 3x/week to maintain neutrophil count 5
  10 x 109/l
• Discontinue if no response after 12 weeks

• Hellstrom-Lindberg E, et al. Br J Haematol.
  2003 120 1037.
• Perk S, et al. Bloo.d 2008 111 574.

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Iron Chelation

• 1 PRBC transfusion 200mg iron
• Chronic transfusions (20-30 U) ? iron overload
• Iron overload ? oxygen free radicals
• Oxygen free radicals ? cardiac, liver, pancreas
  toxicity
• Possible hematopoietic toxicity?

27
Iron Chelation and Survival

• OS significantly better for pts who received iron
  chelation therapy
• Results consistent across all subgroups analyzed
  (IPSS low and intermediate-1, sex, age)

1.00
Median survival 63 months (whole group)115 vs
51 months (P lt .0001)
0.75
Survival Distribution Function
0.50
CT
0.25
No CT
0.00
0
50
100
150
200
250
Diagnosis to Death Time (Mos)
28
Iron Chelation Considerations

• Who can benefit?
• Low-risk, intermediate-1 risk
• Life expectancy gt 1-2 years
• Continued need for RBC transfusions
• Existent cardiac or hepatic dysfunction
• Monitoring
• Ferritin levels (goal lt 1000 mcg/L)
• Preferred route of therapy

29
Iron Chelation Options

• Deferoxamine (Desferal)
• Route SQ
• t ½ 0.5 hours
• Dosing Infused over 8-12 hrs
• 5-7 nights/week
• Deferasirox (Exjade)
• Route PO
• t ½ 12-16 hours
• Dosing Dissolved in solution, taken daily

30
Prevention Treatment of Infections

• Prevention
• Prophylactic antibiotics ? no role
• Patient education ? know your nadir
• report a fever
• recognize signs of infection
• avoid illness, crowds
• update vaccinations
• Treatment ? Febrile neutropenia guidelines

www.nccn.org/MDS v1..2008
31
Pharmacotherapy In MDS

• Azacitidine
• Decitabine
• Lenalidomide
• Anti-thymocyte Globulin (ATG)

32
Indications for Azacitidine for Injection
(Vidaza)

• First FDA-approved treatment for MDS
• Azacitidine is indicated for treatment of
  patients with all MDS subtypes
• RA or RARS if accompanied by neutropenia or
  thrombocytopenia or requiring transfusions
• RAEB
• RAEB-T
• CMMoL (chronic myelomonocytic leukemia)

According to the FAB (French, American, British)
Classification System. VIDAZA full prescribing
information
33
Phase III Clinical Trial Design 5-Azacitidine
(Azacitidine)

• Trial Design A randomized, cross over, Phase III
  
• Subjects Treatment-naïve RA, RARS, RAEB/T, CMMoL
  
• Arms Azacitidine (75 mg/m2 SQ x 7 days q 28
  days) plus Best Supportive Care versus Best
  Supportive Care (BSC) Alone
• Primary endpoints CALGB Response rate

Silverman LR, et al. J Clin Oncol. 2002 20 2429.
34
Indications for Decitabine (Dacogen TM)

• Decitabine is indicated for treatment of patients
  with MDS including
• Previously treated untreated, de novo
  secondary MDS of all FAB subtypes (RA, RARS,
  RAEB, RAEB-t, CMMoL)
• Intermediate-1, intermediate-2, high-risk IPSS
  groups

Decitabine full prescribing information
35
Clinical Trial Data Decitabine

• Trial Design An open-label, multicenter, 11
  randomized study
• Subjects De novo or secondary MDS IPSS Int-1,
  Int-2 and high-risk MDS
• Arms Decitabine (15 mg/m2 IV q8 hrs x 3 days q6
  weeks) versus Best Supportive Care
• Primary endpoints IWG Response rate, Time to
  AML/death

Cancer 2006 106 1794.
36
Comparison of Decitabine Azacitidine Phase 3
Trials
Kantarjian H, et al. Cancer. 20061061794-803.
Silverman LR, et al. J Clin Oncol.
2002202429-40 Kaminskas E. Clin Cancer Res.
2005113604-8 Cheson BD. Blood.
2000963671-74. NA Not available.
37
Comparison of Decitabine Azacitidine Phase 3
Trials
Kantarjian H, et al. Cancer. 20061061794-1803.
Silverman LR, et al. J Clin Oncol.
2002202429-40 Kaminskas E. Clin Cancer Res.
2005113604-8 Cheson BD. Blood.
2000963671-74. NA Not available.
38
Dosing Side Effects Azacitidine

• FDA-approved dosing
• 75mg/m2/day SQ/IV for 7 days every 4 weeks
• May ? 100mg/m2/day after 2 cycles
• Treat for minimum of 4 cycles
• A/E ? neutropenia (48)
• anemia (69)
• thrombocytopenia (65)
• Emetic potential ? moderate (30-90)

Silverman LR, et al. J Clin Oncol.
2002202429-40.
39
Monitoring Alternative Dosing Schedules
Azacitidine

• Monitoring WBC, ANC, platelet count
• Serum creatinine serum bicarbonate
• Alternative dosing methods
• AZA 75mg/m2/day x 5 (on)-2 (off)-2 (on)
• AZA 50mg/m2/day x 5 (on)-2 (off)-5 (on)
• AZA 75mg/m2/day x 5 days

ASH 2007 110 abstract 819
40
Dosing Side Effects Decitabine

• FDA-approved dosing
• 15mg/m2 IV over 3 hours every 8 hours
  x 3 days
• Repeat every 6 weeks
• Treat for minimum of 4 cycles
• A/E ? neutropenia (90)
• anemia (82)
• thrombocytopenia (89)
• Emetic potential ? minimal (lt 10)

Kantarjian H, et al. Cancer. 20061061794-1803.
41
Monitoring Alternative Dosing Schedules
Decitabine

• Monitoring WBC, ANC, platelet count
• Serum creatinine
• LFTs
• Alternative dosing methods
• 20mg/m2 IV daily x 5 days
• 20mg/m2 SQ daily x 5 days
• 10mg/m2 IV daily x 10 days

Kantarjian H, et al. Cancer. 20061061794-1803.
Kantarjian H, et al. Blood. 200710952.
42
Azacitidine vs. Decitabine Practical
Considerations

• Azacitidine data shows improvement in overall
  survival
• Data supports decitabine use after azacitidine
  failure
• Emetic potential azacitidine gt decitabine
• Decitabine as approved needs hospital stay,
  whereas azacitidine treatment is outpatient

Blood (ASH Annual Mtg) 2007 110 abs 817.
Borthakur G, et al. Leuk Lymphoma. 2008 49 690.
43
Lenalidomide (Revlimid)

• Indicated for the treatment of patients with
  transfusion-dependent anemia due to Low- or
  Intermediate-1-risk MDS
• Associated with deletion 5q cytogenetic
  abnormality with or without additional
  cytogenetic abnormalities

44
Lenalidomide MDS-003 Clinical Trial

• Trial Design Multicenter, International
• Subjects 5q31 deletion, low/Int-1 risk,
• gt 2 U PRBC / 8 weeks
• Arms lenalidomide 10mg PO daily vs.
• lenalidomide 10mg PO daily x 21 d
• Primary endpoint ? transfusion
  independence

List A, et al. NEJM. 20063551456-65.
45
Lenalidomide in MDS Results in 5q-
RBC transfusion independence 99/148 (67)
by week 24 Median time to transfusion
independence was 4.6 weeks (range 1 - 49) Median
Duration of transfusion independence not reached
by median 104 weeks
List A, et al. NEJM. 2006 3551456-65.
46
Lenalidomide MDS 003 Adverse Events (N148)
List A, et al. NEJM. 2006 3551456-65.
47
Lenalidomide Kinetics
Chen N, et al. J Clin Pharmacol. 2007471466.
48
Lenalidomide Dosing in Renal Insufficiency

• Renal function (Clcr)
• Normal gt 80 ml/min
• Mild 50 lt 80 ml/min
• Moderate 30 lt 50 ml/min
• Severe lt 30 ml/min
• (no dialysis)
• ESRD lt 30 ml/min
• ( dialysis)

• Dosing in MDS
• 10mg PO every 24 hrs
• 10mg PO every 24 hrs
• 5mg PO every 24 hrs
• 5mg PO every 48 hrs
• 5mg PO 3x/week (post-dialysis)

Chen N, et al. J Clin Pharmacol. 2007471466.
49
Predictive Model for Responseto
Immunosuppression (ATG CSA)
Patients Age in Years Duration of RCTD in
Months
Predicted Probability of Response
DR15-positive patients
DR15-negative patients
gt57 57
gt71 71
Low (0-40) High (41-100)
RCTD red-cell transfusion dependence
Saunthararajah Y, et al. Blood. 20031023025-7.
50
Life Expectancy BMT in MDS
Cutler C, et al. Blood. 20041042.
51
VANTS Call

• May 28, 2008 _at_ 200 pm ET
• June 26, 2008 _at_ 1200 pm ET
• 800-767-1750
• Access code 86360

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Supplemental Slides
53
MDS (9980/3 to 9989/3) Incidence by Year-VACO
Tumor Registry
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Anemia in the Elderly

• Definition Hb lt13 g for males and lt12 g for
  females
• Prevalence of anemia is 11 in men and 10.2 in
  women 65 years (2.8 Million)
• About 1/3 are nutritional anemias 1/3 are
  associated with chronic diseases and 1/3 are
  unexplained

55
Anemia in the Elderly
Unexplained Anemia (UA)

• What proportion of UA have either macrocytosis
  (MCV gt100fl) leukopenia (lt3000/cmm) and/or
  thrombocytopenia (lt150,000/cmm)?
• 17 met the criteria or 5.8 of the total anemic
  population or 163,000 patients (Do all have
  MDS???)

56
WPSS WHO-Based Prognostic Scoring System for
Predicting Survival in MDS
Malcovati L, et al. Blood. 2005 106232a
(abstract 788
57
Predictive Model for Response to Treatment with
rhuEPO G-CSF
Response Probability
Good (74, n34)
Score gt 1
Intermediate (23, n31)
RA, RARS, RAEB
Score -1- 1
Poor (7, n29)
Score lt -1
Treatment Response Criteria
Treatment Response Score
Hellstrom-Lindberg E, et al. Br J Hematol, 2003
120 1037-46.
58
Transfusion Status and Outcomes
Cazzola M, et al. N Engl J Med. 2005353536-38.
59
Iron Chelation Agents
60
Survival p15 Methylation Status in MDS
Unmethylated
Methylated
P .049
Quesnel B, et al. Blood. 1998912985-90.
61
Azacitidine Survival Study
Survival Study Design
61
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Overall Survival Azacitidine vs CCR ITT
Population
Log-Rank p0.0001 HR 0.58 95 CI 0.43,
0.77Deaths AZA 82, CCR 113

• Proportion Surviving

AZA
CCR
Time (months) from Randomization
63
Decitabine versus intensive chemotherapy in MDS
Jabbour, ASH 2006
64
Intensive AML chemotherapy in MDS

• Advanced age is a barrier lt 65 y
• Anthracycline-Ara C
• 50 to 60 CR
• Median CR duration 10 to 12 months
• Cytogenetics major prognostic factor for CR
  achievement and CR duration
• Very few long term survivors

65
Immune Modulation Lenalidomide

• RevAssist - restricted distribution program
• ? drug provided to registered providers
• ? via contract pharmacies
• ? requires patient enrollment
• ? requires patient compliance with contract

66
Immunosuppressive Therapy ATG /- CSA

• Dosing
• ATG 40 mg/kg IV daily for 4 days
• Corticosteroids daily x 4 days, then tapered off
• Cyclosporine PO daily, titrate to levels
• A/E ? Allergic reactions (42 6 grade ¾)
• Fever (47 3 grade ¾)
• Elevated LFTs (19 10 grade ¾)
• Renal insufficiency (13)

67
Challenges for HSCT in MDS Tolerance, GVHD,
Relapse

• Elderly patients Reduced intensity HSCT
• Abnormal stroma Block inhibitory cytokines,
  immune dysregulation
• Primitive stem cells Target mutations
• ?Tumor burden Bridge to HSCT w/ targeted
  chemotherapy