11/20/2015 normal blood and bone marrow … is mds.pdf · •one of the most common hematological...

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MYELODYSPLASTIC SYNDROMESRami Komrokji, MDProfessor of Oncologic SciencesClinical DirectorMalignant HematologyMoffitt Cancer CenterTampa, Florida

Normal Blood and Bone Marrow

What is MDS

Myelodysplastic Syndromes (MDS) are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells.

What is MDS• Myelodysplastic syndromes-

• Myelo- prefix means marrow• Dysplasia-refers to the abnormal shape and appearance — or

morphology — of the blood cells. • Syndromes means a set of symptoms that occur together.

• MDS has been known as “smoldering leukemia,”“preleukemia” or “oligoleukemia.”• These terms may be misleading by implying that MDS is only

problematic and fatal after it has evolved to AML.• MDS can progress such that the abnormal blast cells take over the

marrow and the disease “evolves” into AML.

What is MDS• MDS originates from “mis-happenings” in the stem cell control center

(chromosomal abnormalities or gene mutations) which leads to a clone of new cells which carry the same abnormalities.

• The new clone of cells dominates the bone marrow and it is effective in producing blood cells as the normal clone “the MDS cells die earlier than normal cells”

• Normally, immature cells known as “blasts” make up less than five percent of all cells in the marrow. In Some MDS patients, blasts comprise more than five percent of the cells. “cells get stuck in the early assembly line”

• The number of blast cells from cases with lower proportions of blast cells to cases with higher proportions of blast cells—is one of the principal determinants of disease severity.

What is MDS• Is MDS a “cancer” ?

• MDS is a diagnosis of cancer.

• Cancer means that a mutation of a normal cell leads to the development of cells that no longer behave normally.

• MDS is spectrum of disorders and the effect of a disease on a patient’s life is more important than the term used to describe the disease.

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How common is MDS• One of the most common hematological malignancies “Blood cancers”.

• At least 40,000-50,000 new cases in the united states diagnosed every year.

• Majority of patients are above age of 60.

• Slightly more in males.

What causes MDS? • The exact causes of MDS are unknown in majority of

patients. • Senescence of stem cells “aging” plays major role in

developing MDS.• MDS may be “primary” (also called “de novo”) or “secondary” (cases that arise following treatment with chemotherapy and radiotherapy for other cancers, such as lymphoma, myeloma or breast cancer).

What causes MDS?• Repeated exposure to the chemical benzene—which

damages the DNA of normal stem cells—is another predisposing factor in MDS development.

• Benzene in cigarette smoke is now the most common known cause of exposure to this toxin.

• Benzene is also found in certain industrial settings. However, the stringent regulation of its use has diminished benzene exposure in the workplace.

What causes MDS?• There are no known food or agricultural products that

cause MDS.

• Alcohol consumed on a daily basis may lower red blood cell and platelet counts, alcohol does not cause MDS.

• Prior chemotherapy or radiation therapy for other types of cancer is known to cause therapy related MDS in subset of patients treated.

Can You give MDS to your loved ones?

• No evidence exists to suggest that MDS is contagious disease; thus, MDS cannot be transmitted to loved ones.

• Inherited genetic predisposition to MDS is very rare. Rare Certain inherited gene mutations may predispose patients for developing MDS.• Familial thrombocytopenia and RUNX1 mutation

What are the Symptoms of MDS?• In the early stages of MDS patients may experience no

symptoms at all. A routine blood test may reveal reduced blood counts.

• Patients with blood cell counts well below normal, experience definite symptoms related to low blood counts.

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ANEMIA = LOW RED CELL COUNT

• The majority of MDS patients are anemic.• Anemic patients generally experience fatigue. • Anemia varies in its severity:

• Mild anemia, patients may feel well or just slightly fatigued. • Moderate anemia, almost all patients experience some fatigue,

which may be accompanied by heart palpitations, shortness of breath, and pale skin.

• Severe anemia, almost all patients appear pale and report chronic overwhelming fatigue and shortness of breath.

• Because severe anemia reduces blood flow to the heart, older patients may be more likely to experience cardiovascular symptoms, including chest pain.

NEUTROPENIA=LOW WHITE CELL COUNT

• A reduced white cell count lowers the body’s resistance to bacterial infection.

• Patients may be susceptible to: • skin infections• sinus infections• lung infections

• urinary tract infections

• Fever may accompany these infections.

THROMBOCYTOPENIA=LOW PLATELET COUNT

• Patients with thrombocytopenia have an increased tendency to bruise and bleed even after minor bumps and scrapes.

• Nosebleeds are common and patients often experience bleeding of the gums, particularly after dental work.

What Tests are used to diagnose MDS?

• Blood counts “CBC”

• Peripheral Blood smear• Bone marrow aspirate and biopsy• Cytogenetic Testing • FISH• Molecular testing for gene mutations.• Other tests ordered

• Vitamin b12 level• Folate• Iron and ferritin• Serum erythropoietin level.

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Diagnosis of MDS• An experienced hematopathologist should examine the

peripheral blood smear and bone marrow.

• Diagnosis of MDS is made if• Patient has persistent cytopenia.

• Demonstration of increased “blasts”.• Demonstration of “dysplasia”.• Demonstration of certain cytogenetic abnormalities.

Cytologic Dysplasia:

Courtesy of Dr List and Bennett

Cytogenetics del(5q) by FISH

Reprinted with permission from Heaney ML, Golde DW. N Engl J Med. 1999;340:1649

FISH with probe for 5p (green) and probe for 5q (red)

What type of MDS do you have?FAB classification Bone Marrow Blasts Peripheral Blood

BlastsRinged Sideroblasts

Refractory Anemia (RA) <5% <1% <15%

Refractory anemia with ringed sideroblasts (RARS)

<5% <1% >15%

Refractory anemia with excess blasts (RAEB)

5%-20% <5% Variable

Refractory anemia with excess in blasts in transformation (RAEB-T)

21%-30% >5% Variable

Chronic myelomonocytic leukemia (CMML)

≤20% <5%

Monocytosis >1000/l

World Health Organization MDS Categories (2008)

Name Abbreviation Blood Findings Bone Marrow findings

Refractory cytopenia with unilineage dysplasia

(RCUD)

Refarctory anemia (RA)• Unicytopenia; occasionally bictyopenia• No or rare blasts (<1%)

• Unilineage dysplasia (>10% of cells in one myeloid lineage)• <5% blasts• <15% of erythroid precursors are ring sideroblasts

Refractory neutropenia (RN)

Refractory thrmbocytopenia (RT)

Refractory anemia with ring sideroblasts

RARS • Anemia• No blasts

• ≥15% of erythroid precursors are ring sideroblasts • Erythroid dysplasia only • <5% blasts

MDS associated with isolated del(5q)

Del(5q)

• Anemia• Usually normal or increased platelet count• No or rare blasts (<1%)

• Isolated 5q31 deletion • Normal to increased megakaryoctyes with hypolobated nuclei • <5% blasts • No Auer rods

Refractory cytopenia with multilineage dysplasia

RCMD

• Cytopenia(s)• No or rare blasts (<1%)• No Auer rods• <1x109/L monocytes

• ≥10% of cells in ≥2 myeloid lineages dysplastic • <5% blasts • No Auer rods• 15% ring sideroblasts

Refractory anemia with excess blasts, type 1

RAEB-1

• Cytopenia(s)• No or rare blasts (<1%)• No Auer rods• <1x109/L monocytes

• Unilineage or multilineage dysplasia• 5%-9% blasts • No Auer rods

Refractory anemia with excess blasts, type 2

RAEB-2

• Cytopenia(s)• 5-19% blasts• Auer rods• <1x109/L monocytes

• Unilineage or multilineage dysplasia• 10%-19% blasts • Auer rods

MDS-unclassified MDS-U• Cytopenia(s)• 1% blasts

• Minimal dysplasia but clonal cytogenetic abnormality considered presumptive evidence of MDS • <5% blasts

Swerdlow SH, Campo E, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Lyon: IARC Press, 2008, page 89 (Section: Brunning RD et al, “Myelodysplastic

syndromes/neoplasms, overview)”.

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World Health Organization MDS Categories (2008) (cont’d)

Name Abbreviation Blood Findings Bone Marrow findings

Refractory anemia with ring sideroblasts and

thrombocytosis RARS-T

• Anemia• No blasts

• ≥15% of erythroid precursors are ring sideroblasts

• Erythroid dysplasia only • <5% blasts •Proliferation of large megakaryocytes

Chronic myelomonocytic leukemia, type 1

CMML-1• >1x109/L monocytes • <5% blasts

• Unilineage or multilineage dysplasia• <10% blasts

Chronic myelomonocytic leukemia, type 2

CMML-2• >1x109/L monocytes • 5%-19% blasts or Auer rods

• Unilineage or multilineage dysplasia• 10%-19% blasts

Atypical chronic myeloid leukemia

aCML

• WBC>13x109/L • Neutrophil precursors >10%• <20% blasts

• Hypercellular • >20% blasts • BCR-ABL-1 negative

Juvenile myelomonocytic

leukemiaJMML

• >1x109/L monocytes •<20% blasts

• Unilineage or multilineage dysplasia• <20% blasts • BCR-ABL-1 negative

MDS-unclassified (‘Overlap Syndrome’)

MDS-U/MPN-U

• Dysplasia with myeloproliferative features• No prior MDS or MPN

• Dysplasia with myeloproliferative features

Swerdlow SH, Campo E, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Lyon: IARC Press, 2008, page 89 (Section: Brunning RD et al, “Myelodysplastic

syndromes/neoplasms, overview)”.

STAGING & RISK STRATIFICATIONHow Severe is your MDS?

International Prognostic Scoring System

Adapted from Greenberg PL, et al. Blood. 1997;89:2079-2088.

Cytogenic Risk Group IPSS Karyotype Abnormalities

Good Normal, -Y, del(5q), del(20q)

Intermediate +8, any other single or double abnormality

Poor Complex with ≥ 3 abnormalities, anomaly of chromosome 7

IPSS Parameter Categories and Associated Scores

Cytogenic Risk GroupGood Intermediate Poor

0 0.5 1

Bone Marrow Blast %≤ 5% 5%-10% 11%-20% 21%-30%

0 0.5 1.5 2

Number of Cytopenias0 or 1 2 or 3

0 0.5

IPSS Risk Group Points % of PatientsMedian survival,

yearsTime to 25% with

AML, years

Low 0 33% 5.7 9.4

Intermediate-1 0.5-1 38% 3.5 3.3

Intermediate-2 1.5-2 22% 1.1 1.1

High ≥ 2.5 7% 0.4 0.2

Cytogenetic Groups in the IPSS-R

Risk groupIncluded karyotypes

(19 categories)

Median survival, months

Proportion of patients in this

group

Very good del(11q), -Y 60.8 2.9%

GoodNormal, del(20q), del(5q) alone or

with 1 other anomaly, del(12p)48.6 65.7%

Intermediate

+8, del(7q), i(17q), +19, +21, any single or double abnormality not listed, two or more independent

clones

26.1 19.2%

Poorder(3q), -7, double with del(7q),

complex with 3 abnormalities15.8 5.4%

Very poor Complex with > 3 abnormalities 5.9 6.8%

Schanz J, et al. J Clin Oncol. 2012;30(11):820-829.

Scoring for the IPSS-RParameter Categories and Associated Scores

Cytogenetic risk group

Very good Good Intermediate Poor Very Poor

0 1 2 3 4

Marrow blast proportion

≤ 2% > 2% - < 5% 5% - 10% > 10%

0 1 2 3

Hemoglobin(g/dL)

≥ 10 8 - < 10 < 8

0 1 1.5

Platelet count(x 109/L)

≥ 100 50 - < 100 < 50

0 0.5 1

Abs. neutrophil count (x 109/L)

≥ 0.8 < 0.8

0 0.5

Possible range of summed scores: 0-10

Greenberg PL, et al. Blood. 1997;89:2079-2088.

Risk Groups for the IPSS-RRisk group Points % of Patients

Median survival, years

Time until 25% of patients develop

AML, years

Very low ≤ 1.5 19 % 8.8 Not reached

Low > 1.5 – 3 38 % 5.3 10.8

Intermediate > 3 – 4.5 20 % 3.0 3.2

High > 4.5 – 6 13 % 1.6 1.4

Very High > 6 10 % 0.8 0.73

100

Overall Survival, years

Pat

ien

ts, %

00 2 4 6 8 10 12

20

40

60

80

Pat

ien

ts, %

Time to AML Evolution, years

0 2 4 6 8 10 12

100

0

20

40

60

80

Very low Low Int High Very high

Greenberg PL, et al. Blood. 1997;89:2079-2088.

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www.ipss-r.com

Age Dependence of the IPSS-R

www.ipss-r.com

Global MDACC Model

Prognostic Category

Prognostic Score Value

1 2 3Performance status

≥ 2

Age, years 60-64 ≥ 65

Platelets, × 109/L 50-199 30-49 < 30

Hemoglobin, g/dL < 12

BM blasts, % 5-10 11-29

WBC, × 109/L > 20

Cytogenetics

Chromosome 7 abnormality, or complex (≥ 3

abnormalities)

Prior transfusion Yes

1. Kantarjian H, et al. Cancer. 2008:113:1351-1361.

BM, bone marrow; Int, intermediate; MDACC, MD Anderson Cancer Center; WBC, white blood cell.

Risk Category

Risk Score

Low 0-4

Int-1 5-6

Int-2 7-8

High ≥ 9

Validation of the MD Anderson Prognostic Risk Model for patients with myelodysplastic syndrome

Komrokji et al, Cancer Sep 2011

Out of 484 patients low/int-1 IPSS risk,

119 (25%) were reclassified as int-2

or high risk by MDAS

Genetic Abnormalities in MDS

Karyotype Array CGHSNP Array

Karyotype/FISH GenotypingSequencing

Translocations/Rearrangements

Uniparental Disomy/ Microdeletions

Copy Number Change

Point Mutations

Rare in MDSRare – often at sites of

point mutationsAbout 50% of cases Most common

t(6;9)

i(17q)

t(1;7)

t(3;?)

t(11;?)

inv(3)

idic(X)(q13)

4q - TET2

7q - EZH2

11q - CBL

17p - TP53

del(5q)-7/del(7q)

del(20q)

del(17p)

del(11q)

+8

-Y

Likely in all cases

~80% of cases have mutations in a known gene

Observed Frequency in MDS

Vardiman JW, et al. Blood. 2009;114(5):937-951; Tiu R, et al. Blood. 2011;117(17):4552-4560; Schanz J, et al. J Clin Oncol. 2011; 29(15):1963-1970; Bejar R, et al. N Engl J Med. 2011;364(26):2496-2506; Bejar R, et al. J

Clin Oncol. 2012;30(27):3376-3382.

What is a mutation?

…TTGAGTC

G….

…TTGAGTAG….

Why should we care about gene mutations in MDS?1. Biology

Mutations give us clues about what went wrong with MDS cells.

2. DiagnosisMutations help us diagnose other bone marrow diseases.(e.g., BCR/ABL = CML; JAK2V617F = Polycythemia vera)

3. PrognosisMutations help us predict outcome in other bone marrow diseases.(e.g., DNMT3AR882H in acute myeloid leukemia)

4. TherapyMutations help us choose the right drugs in other bone marrow diseases.

(e.g., BCR/ABL -> Imatinib)

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RUNX1

ETV6

WT1 PHF6

GATA2

DNMT3AEZH2

ASXL1

IDH1 & 2

UTX

TP53

Transcription FactorsTyrosine Kinase Pathway

Epigenetic Dysregulation

SF3B1

Splicing Factors

JAK2

NRAS

BRAFKRAS

RTKs

PTPN11

NOTCH?MAML?

ZSWIM4?UMODL1?

CBL

NPM1

ATRX

Others

SRSF2

U2AF1ZRSF2

SETBP1

SF1SF3A1

PRPF40BU2AF2

PRPF8

BCOR

TET2

Genes Recurrently Mutated in MDS

37Courtesy of Bejar R.

Bejar R, et al. N Engl J Med. 2011;364(26):2496-2506.

Impact of Mutations by IPSS Group

39

RUNX1

ETV6

EZH2

ASXL1

TP53

39

TP53 Mutations and Complex Karyotypes

Complex Karyotype

TP53 Mutated

The adverse prognostic impact of the complex karyotype is entirely driven by its frequent association with mutations of TP53

Bejar R, et al. N Engl J Med. 2011;364(26):2496-2506; Bejar R, et al. N Engl J Med. 2011;364(26, supp 1):2496-2506.

Response to Azanucleoside Treatment by Mutation Status

What does this mean to you?• Molecular mutations may be used as a tool to confirm

diagnosis.

• Molecular mutations have prognostic value additional to clinical variables.

• Molecular mutations may be used to tailor therapy accordingly.

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CURRENT STANDARD TREATMENT FOR MDS

Therapeutic Objectives for Patients with MDS

MDS Type (IPSS) Treatment Goals

lower-risk

• Achieving RBC-TI

• Hematologic improvement

• Improving QoL

• ? Overall survival and AML transformation

higher-risk

• Overall survival and AML transformation• Altering disease’s natural history (eg,

CR/PR, OS, cytogenetic responses, disease transformation, progression-free survival)

• Improving QoL

TREATMENT OF LOWER RISK MDS

When do we need to treat?• The goal of treatment in lower risk MDS is to improve

blood counts and alleviate related symptoms.

• In asymptomatic patients with adequate counts treatment may not be needed or indicated.

• Majority of patients will need treatment for anemia and to reduce or eliminate red blood cell transfusion.

• Occasionally treatment is directed to improve platelets or neutrophils.

Supportive Care

• RBC transfusions are used for anemic patients who experience fatigue and/or shortness of breath. The frequency varies from patient to patient.

• MDS patients who require periodic red cell transfusions typically receive two units. Most of doctors will transfuse RBC if hemoglobin is less than 8 g/dl.

• There are several concerns related to RBC transfusions• Iron overload• Risk of retaining excess fluid• Transmission of infection

• Despite the concerns, red cell transfusions improve the quality of life for patients with symptomatic anemia.

• Some patients may need platelets transfusion.

Thrombocytopenia in MDS

• Severe thrombocytopenia (< 20-30): 7-15%• Associated with higher WHO subtype or IPSS scores• Independently prognostic for overall survival and predictive

of bleeding• Bleeding as sole cause of death: 10-15%

• Beyond disease-modifying therapies, platelet transfusions are the only treatment for thrombocytopenia in MDS

• Alloimmunization rates to plts: 20-85% for heavily transfused

• Bacterial contamination rate 83 per million

• Aminocaproic acid may be considered for treatment of bleeding episodes refractory to platelets transfusion.

Gonzalez-Porras, et al. J Cancer. 2011;117:5529-37Kantarjian H. Cancer. 2007;109:1705-14.

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Red Blood cells Growth FactorsErythropoietin or EPO (Epogen®, Procrit®) and Darbepoietin (Aranesp®)

• The “recombinant” form of this natural growth factor is used to treat symptoms associated with anemia; it stimulates the bone marrow to produce red blood cells.

• The treatment is most likely to benefit patients whose natural (blood serum) EPO level is below 500 and who do not need frequent transfusions.

• Patients who are unresponsive to EPO alone may derive additional benefit when EPO is combined with other growth factors that stimulate the bone marrow to produce white blood cells.

• Recombinant EPO, epoietin, is available as two different brand-name drugs: Epogen® and Procrit®. Darbepoetin (Aranesp®) is a different form of, erythropoietin that is longer acting.

• Response rate vary from 20-40%, usually an initial trial is given for 6-8 weeks. If patient responds the duration of response averages 12-18 month.

ESA in MDS key points• No difference between epoietin and darbepoietin. (dose

equivalence).• Start with a 6-8 weeks trial, if no response consider

adding G-CSF weekly.• Epoietin starting dose is 40,000 units weekly and may be

escalated to 60,000 weekly.• Among responders average duration of response 12-18

months.• Some studies suggest survival advantage among

responders.

G-CSF/GM-CSF Use in MDS

• Currently there is no evidence to support use of either G-CSF or GM-CSF as single treatment in MDS patients

• G-CSF and GM-CSF can rise the neutrophil counts in MDS patients

• GM-CSF did not affect hemoglobin levels neither the transformation to AML in two randomized clinical trials

• In a randomized trial G-CSF had no effect on survival, transformation to AML, nor hemoglobin levels

Ganser A, Hoelzer D. Semin Hematol. 1996;33:186. Rose C, et al. Leukemia. 1994; 8:1458.Shuster MW. Blood. 1990;76: abstract 318. Shuster MW, et al. 1995;Blood 86 (suppl 1): abstract 338.Greenberg, et al. Blood. 1994;82:suppl: abstract 196.

Deletion 5q31 in MDS

Interstitial chromosome 5q deletion is the most common chromosome abnormality in MDS

Two CDRs: 5q31->q32 (1.5 Mb); 5q33 (5q- syndrome) 5q-Syndrome’ – Van den Berghe 1974

– Isolated 5q deletion– Severe hypoplastic anemia– Mild leukopenia– Normal or elevated platelets– Atypical megakaryocytes– Indolent natural history

From Vardiman JW. ASH Image Bank.

Lai F, et al. Genomics 2001; 71: 235.Jaju RJ, et al. Genes Chrom Cancer 1998; 22:251.

Van den Berghe H, et al. Nature 1974; 251:427.

–<5% blasts

WHO

Primary endpoint: transfusion independenceSecondary endpoints: duration of TI, cytogenetic response, minor erythroid response, pathologic response, safety

Lenalidomide in MDS With 5q Deletion

RESPONSE

REGISTER

Lenalidomide10 mg PO x 21 days

EligibilityIPSS diagnosed low/int-1 MDS

del(5q31)≥ 2 U RBC/8 wksPlatelets > 50,000/µLANC > 500/µL

Yes Continue

No Off study

Wk

Lenalidomide10 mg/day PO

0 4 8 12 16 20 24

List AF, et al. N Engl J Med. 2006;355:1456-1465.

MDS-003: Response to Lenalidomide Therapy


38/85(45%)

62/85(73%)

Res

po

nse

(%

)

0

20

40

70

80

100

Res

po

nse

(%

)

0

20

40

70

80

100Erythroid Response Cytogenetic Response

TI

99/148(67%)

112/148(76%)

TI + Minor CCR CCR + PR

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MDS-003: Response to Lenalidomide Therapy

Erythroid Response

TI

99/148(67%)

112/148(76%)

TI + Minor

Cytogenetic Response


Res

po

nse

(%

)

0

20

40

70

80

100

Res

po

nse

(%

)

0

20

40

70

80

100

CCR CCR + PR

38/85(45%)

62/85(73%)

Median Hb increase was 5.4 g/dLTime to response 4.6 wksDuration of response > 2 yr

MDS-002/003: Treatment-Related Adverse Events

Grade ≥ 3 Adverse Events, % Non-Del(5q) Del(5q)

Thrombocytopenia 20 44

Neutropenia 25 55

Pruritus 1 3

Rash 4 6

Diarrhea 1 3

Fatigue 4 3

List AF, et al. N Engl J Med. 2006;355:1456-1465.Raza A, et al. Blood. 2008;111:86-93.

MDS-002: Response to Lenalidomide Therapy in non del 5 q lower risk MDS

56/214(26%)

93/214(43%)

Res

po

nse

(%

)

0

20

40

70

80

100

Res

po

nse

(%

)

0

20

40

70

80

100Erythroid Response Cytogenetic Response

TI TI + Minor

4/47(9%)

9/47(19%)

CCR CCR + PR

Raza A, et al. Blood. 2008;111:86-93.

Res

po

nse

(%

)

0

20

40

70

80

100

Res

po

nse

(%

)

0

20

40

70

80

100

MDS-002: Response to Lenalidomide Therapy in non deletion 5 q lower risk MDS

CCR CCR + PR

4/47(9%)

9/47(19%)

Erythroid Response Cytogenetic Response

TI TI + Minor

56/214(26%)

93/214(43%)

Median Hb increase was 3.2 g/dLTime to response 4.8 wksMedian duration of response 41 wk

Raza A, et al. Blood. 2008;111:86-93.

• Open-label, single-center study evaluated combined therapy with LEN + EPO in patients with IPSS low/Int-1–risk MDS who failed prior ESA treatment and were RBC-TD

• Treatment consisted of:

• LEN monotherapy (10 or 15 mg daily) for 16 weeks

• After 16 weeks, non-responders could receive LEN (same dose) + EPO (40,000 U/week)

• Toxicity profile was similar in patients treated with LEN monotherapy and LEN + EPO

LEN + EPO Phase 1/2 Study

Rate of HI-E,a % (n/n)LEN Monotherapy

(N = 39)LEN + EPO

(n = 23)

Del(5q) MDS 86 (6/7) 50 (2/4)

Non-del(5q) MDS 25 (8/32) 21 (4/19)

Komrokji RS, et al. Blood. 2012;120:3419-34.

Hypomethylating Agents• Two medications approved by FDA

• Azacitidine: first FDA approved drug for MDS• Decitabine

• Administered subcutaneously or intravenously.• Low dose chemotherapy with unique mechanism of

action. • In general well tolerated.• Response rates 40-50%.

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Hematological Improvement

†† † †† †

≥75 years <75 years

Hematologic Improvement

Komrokji et al, EHA 2010

Any HI = major + minor responses; individual cell lines show major responses only* Ongoing pts with <56 days on-study were excluded† Individual cell line denominators include only pts eligible for improvement

118/194 82/181 51/117 19/98 98/174 76/163 37/101 19/111

Randomized Phase II Study of Alternative Azacitidine Dose Schedules

A. 5-2-2: 75 mg/m2

B. 5-2-5: 50 mg/m2

C. 5: 75 mg/m2

x6 IWG2000 HI

12 CyclesAZA x 5dq4-6 wks

Study Design (N = 151)

Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856.

N = 50

N = 51

N = 50

Eligibility All FAB Cytopenia ECOG PS: 0-3

*IWG 2000 criteria

Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856.

Frequency of Major HI

Lineage HI in Evaluable Pts,* n (%)

5-2-2 (n = 50)

5-2-5 (n = 51)

5d (n = 50)

ErythroidMa 19/43 (44) 19/43 (44) 20/44 (46)

RBC-TI 12/24 (50) 12/22 (55) 15/25 (64)

PlateletMa 12/28 (43) 8/30 (27) 11/22 (50)

Any HI 22/50 (44) 23/51 (45) 28/50 (56)

NeutrophilMa 4/23 (17) 4/23 (17) 9/24 (38)

Heme AEs > Gr 3 33/50 (66) 24/48 (50) 17/50 (34)

AE Tx delay 34/50 (68) 30/48 (63) 17/50 (34)

Age < 60 years*

RA vs other FAB

Karyotype (+8 WT1)[2]

Hypocellular marrow

HLA-DR15 allele*

PNH phenotype

RBC transfusion duration*

Immunosuppressive Therapy (IST) in MDSNHLBI Response Predictive Variables (N=82)[1]

1. Saunthararajah Y, et al. Blood. 2002;100(5):1570-1574.

2. Sloand E, et al. ASH 2004. Abstract 1431.

3. Saunthararajah Y, et al. Blood. 2003;102(8):3025-3027.

Independent Variables AgeDuration transfusion

dependent HLA-DR15

*Multivariate significance[1,3]

Anemia Management Algorithm 2015

Epo > 500 mU/mL≥ 2 U RBC/mo

Del(5q)

Lenalidomide

Epo < 500 mU/mL< 2 U RBC/mo

ESA

Del5q

+ GCSF HMA

Age

> 60 ≤ 60

IST

List AF. Hematology. 2007.

EPO, serum erythropoietin; ESA , erythropoiesis-stimulating agents; GCSF, granulocyte colony-stimulating factor; HMA, hypomethylating agents; IST, immunosuppressive therapy; RBC, red blood cells.

Iron Overload

• One unit of blood contains 200-250 mg of iron.

• After 15-20 units of RBC transfusion patients develop iron overload.

11/20/2015

12

Serum Ferritin Is Predictive of Survival and Risk of AML in MDS

Development of transfusional iron overload is a significant independent prognostic factor for overall survival and evolution to AML

Sanz G, et al. 2008 ASH. Abstract 640.

Pro

bab

ility

0

0.4

1.0

0.6

5

0.8

0.2

Yrs From Diagnosis

0 10 15 20

Ferritin < 1000 mcg/LFerritin ≥ 1000 mcg/L

P < .0001

OS Time Without AML

Pro

bab

ility

0

0.4

1.0

0.6

5

0.8

0.2

Yrs From Diagnosis

0 10 15 20

P < .0001

Iron Chelation Therapy and Survival

Rose C, et al. ASH 2007. Abstract 249.

• OS significantly better for patients who received iron chelation therapy

• Results consistent across all subgroups analyzed (IPSS low and intermediate-1, sex, age)

Median survival: 63 months (whole group)115 vs 51 months (P < .0001)

CT

No CT

Diagnosis to Death Time (Mos)

0 50 100 150 200 2500.00

0.25

0.50

0.75

1.00

Sur

viva

l Dis

trib

utio

n F

unct

ion

Impact of Iron Chelation Therapy on Overall Survival and AML Transformation in Lower Risk MDS

Komrokji, et al. ASH Annual Meeting 2011: Abstract 2776.

In a study comparing patient preferences, patients were more willing to continue taking deferasirox than deferoxamine by end-of-study (84% vs 11%,

respectively; P < .001)[25]

Reducing the number of IV infusions of deferoxamine, by using high-dose deferoxamine administered over 48 hrs every 2-4 wks, was shown to be safe

and effective for reduction of iron overload in sickle cell disease[26]

24. Neufeld EJ. Hematology Am Soc Hematol Educ Program. 2010;2010:451-455. 25. Vichinsky E, et al. Acta Haematol. 2008;119:133-141. 26. Kalpatthi R, et al. Pediatr Blood Cancer. 2010;55:1338-1342.

Table[24] Deferoxamine Deferasirox Deferiprone

Advantages Long-term safety recordHighly effectiveStrongest chelator

Oral administrationDaily dosing

Oral administrationBetter cardiac protection compared to deferoxamineAllows aggressive iron chelation when iron stores are low with minimal excess toxicity

Disadvantages Parenteral administrationLocal skin reactionsMay be inferior to deferiprone for cardiac protectionChallenging patient compliance

GI disturbance limits tolerabilityMany patients have inadequate response at MTDNot yet demonstrated to reduce cardiac siderosis

GI disturbances and joint pain limit tolerabilityRare agranulocytosis and neutropenia

ICT

ICT

• Box warnings

• Noted more often when administered in excess of iron burden

• Deferoxamine: ocular and auditory disturbances, acute renal failure, hepatic dysfunction, adult respiratory distress syndrome, growth retardation in children

• Deferasirox: renal failure, hepatic failure, gastrointestinal hemorrhage

• Deferiprone: agranulocytosis, infection (leading to death)

28. Neufeld EJ. Hematology Am Soc Hematol Educ Program. 2010;2010:451-455.

Table[1] Deferoxamine Deferasirox Deferiprone

Administration SC or IV, continuous infusion 5-7 days/wk

Oral suspension Oral tablet

Common AEs Local skin reaction, hearing loss, late bone problems

Rash, GI disturbances, diarrhea, mild changes in creatinine, proteinuria, transaminases

GI disturbances, joint pain, arthritis

Severe AEs Retinopathy, acute pulmonary distress

Peptic ulcers, liver or renal dysfunction leading to failure, cytopenias

Agranulocytosis, neutropenia

Cost $$ $$$$ $-$$

Adverse Events.System Organ Class classification of related and not related AEs

System Organ Class – Preferred terms

Events

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13

MDS Patients Who Are Likely to Benefit Most From Management Iron Overload

Characteristic NCCN1 MDS Foundation2

Transfusion status

• Received 20-30 packed RBC units

• Continuing transfusions

• Transfusion dependent, requiring 2 units/month for > 1 year

Serum ferritin level

• > 2500 μg/L • 1000 μg/L

MSD risk • IPSS: Low- or Int-1 • IPSS: Low- or Int-1• WHO: RA, RARS and

5q-

Patient profile • Candidates for allografts • Life expectancy > 1 year and no comorbidities that limit progress

• A need to preserve organ function

• Candidates for allografts

1. NCCN Clinical Practice Guidelines in Oncology. 2. Bennett JM. J Hematol. 2008;83:858-861.

TREATMENT OF HIGHER RISK MDS

Defining Higher risk MDS• Higher risk MDS = higher chance of AML transformation

and worse overall survival. • Historically IPSS is the most common tool used to define

higher risk MDS.• 1/3 of MDS patients are classified as int-2 or high risk by

IPSS with expected overall survival < 1.5 years

Utility of New Clinical Risk stratifying Models for Patients with Lower-Risk Myelodysplastic SyndromesN=1196

N (%) Median OS (mo) Median OS (mo) original reports of the prognostic systems

LR-PSS Category

Category 1 261 (23%) 62.4 80.3

Category 2 593 (52%) 51.4 26.6

Category 3 287 (25%) 37.8 14.2

IPSS-R Category

Very Low 195 (17%) 55.4 81.6

Low 519 (46%) 51.8 51.6

Intermediate 327 (29%) 43.5 27.6

High 96 (8%) 18

Very High 3 10.8

Of 291 patients (26%) who survived ≤24 months from diagnosis, only 37% and 45%

were classified as LR-PSS category 3 and IPSS-R categories ≥Intermediate,

respectively (P=0.06).

Zeidan et al, American J Hem. 2015 Aug 11.

Therapeutic Objectives for Patients with MDS

MDS Type (IPSS) Treatment Goals

lower-risk

• Achieving RBC-TI

• Hematologic improvement

• Improving QoL

• ? Overall survival and AML transformation

higher-risk

• Overall survival and AML transformation• Altering disease’s natural history (eg,

CR/PR, OS, cytogenetic responses, disease transformation, progression-free survival)

• Improving QoL

Allogeneic Stem cell transplant is the only curative option

Risk Group, Yrs

Transplantation at Diagnosis

Transplantation at Yr 2

Transplantation at Progression

Low 6.51 6.86 7.21Int-1 4.61 4.74 5.16Int-2 4.93 3.21 2.84

High 3.20 2.75 2.75

Cutler C, et al. Blood. 2004;104:579-585.

Median age: 42 yrs

Data precede all FDA-approved drugs for MDS

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14

Allogeneic Hematopoietic Stem Cell Transplantation remains the only curative option for MDS patients

Koreth J, et al. J Clin Oncol. 2013;31:2662-2671.

AHSCT for Patients ≥50 Years MDS or Secondary AML

ZiYi Lim et al, JCO, 2010

• n= 1333• No data on

IPSS• No data on

RX prior to AHSCT

Allogeneic Hematopoietic Cell Transplant Prognostic Variables for Outcome

• % marrow blasts• Cytogenetic pattern

• t-MDS• IPSS

• BM fibrosis grade• Preparative regimen

• Age• Ferritin

• Platelets < 100,000 cells/mL

• Disease duration

• HLA-compatibility• Co-morbidity index

Procedure-Related MortalityRelapse

Hypomethylating Cytosine Analogs

Santini V, Kantarjian, HM, Issa, JP. Ann Intern Med 2001, Apr 3;134(7):573-86.

N O

NH2

N

N O

NH2

NCH3

N O

NH2

NN

Ribose

N O

NH2

NN

Deoxyribose

5-aza-cytidine(Vidaza™)

5-aza-2′-deoxy-cytidine(Dacogen ™)

5-methyl-cytosineCytosine

DNAspecific

DNA & RNAincorporation

RibonucleotideReductase

DNAspecific

90% RNA, 10% DNAincorporation

Azacitidine + BSC (75 mg/m2/day x 7 days SC q28 days)

Stratified by FAB: RAEB, RAEB-T

IPSS: int-2, high

(n = 179)

(n = 179)

Treatment continued until unacceptable toxicity or AML transformation or disease progression

CCR

RANDOMIZE

Physician choice of 1 of 3 CCRs

1. BSC only

2. LDAC (20 mg/m2/day SC x 14 day q28-42 days)

3. 7 + 3 chemotherapy (induction + 1-2 consolidation cycles)

Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

AZA-001: Trial Design

0

1.0

5 10 15 20 25 30 35 40Time From Randomization (Mos)

00.10.20.30.40.50.60.70.80.9

Pro

po

rtio

n S

urv

ivin

g

CCRAzacitidine

HR: 0.58 (95% CI: 0.43-0.77; log-rank P = .0001)

24.5 mos15 mos


AZA-001 Trial: Azacitidine SignificantlyImproves OS

11/20/2015

15

AZA-001: Grade 3/4 Adverse Events (≥ 2% of Patients)*

Adverse Events, n (%) Azacitidine(n = 175)

BSC Only(n = 102)

Neutropenia 159 (91) 70 (69)

Thrombocytopenia 149 (85) 72 (71)

Leukopenia 26 (15) 1 (1)

Anemia 100 (57) 67 (66)

Febrile neutropenia 22 (13) 7 (7)

Pyrexia 8 (5) 1 (1)

Abdominal pain 7 (4) 0

Dyspnea 6 (3) 2 (2)

Fatigue 6 (3) 2 (2)

Hematuria 4 (2) 1 (1)

Hypertension 2 (1) 2 (2)

*When any grade of the reactions occurs in ≥ 5% of azacitidine-treated patients.


The Treatment Paradigm for Azanucleosides• AZA extends OS and alters the natural history of disease.

• CR is not necessary to extend OS - MDS is NOT AML

• Responding patients received a median of 14 cycles (range, 6-24+)

• Long-term continuation until disease progression optimizes OS potential (i.e., Rx Duration > Response Quality)

• First response may occur up to 9 months with maximal response after up to 11 cycles

What do These Findings Mean for You?

• If your blood counts improve on azacitidine treatment, then it is likely it will extend your prognosis & survival.

• Responding patients should remain on azacitidine as long as it is working.

• If after 6 or more courses of azacitidine your situation has not improved and your features are stable, it is less liklely the treatment with prolong survival.

• A decision to stop and try a new therapy should be addressed with your doctor.

EORTC-06011 Decitabine Phase III Trial: Study Design

• Open-label, multicenter, 1:1 randomized study

• IPSS: int-1, -2, and high-risk MDS; ≥ 60 yrs (n = 223)

• Primary endpoint: survival

Stratification Cytogenics risk

group IPSS

Primary vs secondary

Study center

RANDOMIZE

Decitabine 15 mg/m2 IV x 4 hrs q8h x 3 days q6w(max 8 cycles) (n = 119)

Best Supportive Care(n = 114)

Response assessment q2 cycles; HI, CR, PR, and SD continue for up to 8 cycles;Exception: CR – 2 additional cycles.

Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

20 mg/m2 IV daily recommended in PI

EORTC-06011: Overall Survival with Decitabine Treatment

Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

ADOPT Trial: Study Design• Patients (N = 99) with de novo or secondary MDS of any

FAB subtype and IPSS score ≥ 0.5

• Decitabine 20 mg/m2 IV daily for 5 days• Primary endpoint: ORR by IWG 2006 criteria• Secondary endpoints: cytogenetic response, hematologic

improvement, response duration, survival, safety

Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

11/20/2015

16

ADOPT Trial: Responses

Response (IWG 2006 Criteria), n (%) Patients (N = 99)

Overall complete response rate (CR + mCR) 32 (32)

Overall response rate (CR + mCR + PR) 32 (32)

Overall improvement rate (CR + mCR + PR +HI) 50 (51)

Rate of SD or better (CR +mCR + PR + HI +SD) 74 (75)

CR 17 (17)

mCR 15 (15)

PR 0 (0)

HI 18 (18)

SD 24 (24)

PD 10 (10)

Not assessable 15 (15)


ADOPT: Survival

Patients stratified by FAB subtype


Patients stratified by IPSS score

RA (n = 20)RARS (n = 17)RAEB (n = 45)RAEB-T (n = 6)CMML (n = 11)

Sur

viva

l (%

)

Time (days)

100908070605040302010

0

Sur

viva

l (%

)

Time (days)

100908070605040302010

0

Low ( n = 1)Intermediate 1 (n = 52)Intermediate 2 (n = 23)

High risk (n = 23)

ADOPT: Adverse Events Reported in ≥ 10% of Patients

Event, %Patients

Grade 1-2 Grade ≥ 3

HematologicNeutropenia 1 31

Thrombocytopenia 2 18

Febrile neutropenia 3 14

Anemia 5 12

NonhematologicFatigue 26 5

Nausea 26 1

Pyrexia 17 0

Diarrhea 12 0

Anorexia 12 0

Constipation 11 0

Pneumonia 1 11

Vomiting 10 1

Chills 10 0


Pretransplantation Treatment With AZA and ICT for MDS

Damaj G, et al. J of Clin Oncol. 2012;30:4533-4540.

1.0

0.8

0.6

0.4

0.4

00 200 400 600 800 1000

Days

OS

(Pro

bab

ility

)

AZA alone: HR = 1ICT alone v AZA alone: HR = 1.41

(95% CI: 0.83-2.42; P = NS)ICT-AZA v AZA alone: HR = 3.08

(95% CI: 1.38-6.85; P = .006)

1.0

0.8

0.6

0.4

0.4

00 200 400 600 800 1000

Days

Eve

nt-F

ree

Sur

viva

l(P

rob

abili

ty)



(95% CI: 1.38-5.34; P = .01)

1.0

0.8

0.6

0.4

0.4

00 200 400 600 800 1000

Days

3-Y

ear

Rel

apse

(Pro

bab

ility

)



(95% CI: 0.69-5.06; P = NS)

1.0

0.8

0.6

0.4

0.4

00 200 400 600 800 1000

Days

3-Y

r N

RM

Sur

viva

l(P

rob

abili

ty)


(95% CI: 0.55-2.76);P = NS)ICT-AZA v AZA alone: HR = 2.50

(95% CI: 0.89-7.05; P = .08)

Azacitidine Maintenance after AHSCT

• N= 45, majority AML patients (n=37).• Excluded active disease, active GVHD, active infections.• MTD AZA 32mg/m2 SQ for 5 days SQ X 4 cycles.• Median EFS 18.2 mo (95% CI: 11.9-NR)• One year EFS and OS 58% and 77%

De Lima, et al. Cancer 2010; 116(23)

SCTcandidate

No donor

Allogeneicdonor

Azanucleosides

Investigational

SCTFavorable

Unfavorable

Treatment Algorithm 2013: Higher risk MDS

11/20/2015

17

Outcome After Azanucleoside Failure in MDS and CMML

Institution N AZA Failures, n

AMLProgression,

n (%)

MedianOS, Mos

OS at12 Mos, %

Moffitt[1] 151 59 12 (20.3) 8.4 30

GFM*[2] 435 NR NR 5.6 29

MDACC†[3] NR 87 25 (29) 4.3 28

†Decitabine only.*Includes AZA001, J9950, J0443 studies.

1. Lin K, et al. ASH 2010. Abstract 2913.2. Prebet T, et al. J Clin Oncol. 2011;29:3322-3327.3. Jabbour E, et al. Cancer. 2010;116:3830-3834.

Type of Salvage

N ORR Median OS, Mos

Unknown 165 NA 3.6

Best supportive care

122 NA 4.1

Low-dose chemotherapy

32 0/18 7.3

Intensive chemotherapy

35 3/22 8.9*

Investigational therapy

44 4/36 13.2*†

Allogeneic transplantation

37 13/19 19.5*†

Prébet T, et al. J Clin Oncol. 2011;29:3332-3327.

*Log-rank comparison of BSC vs intensive CT (P = .04), investigational therapy (P < .001), or alloSCT (P < .001). †Comparison of intensive CT vs investigational therapy (P = .05), intensive CT vs ASCT (P = .008), or IT vs ASCT (P = .09).

Salvage Therapy After Azacitidine Failure: GFM and AZA001 Studies

100

75

50

25

00 365 730 1,095 1,460

OS

(%

)

Time Since AZA Failure (Days)

Investigational

Allo-SCT

Management of MDS transformed to AML Response to standard 3+7 Induction chemotherapy

Institution Response Median OS (mo)

Moffitt 9/24 (29%) 3

GFM 3/22 (14%) 8.9

MDACC 3/10 (30%) ?

Jaglal et al. ASH 2011; abstract # 256.

Prébet T, et al. J Clin Oncol. 2011;29:3332-3327.

Jabbour E, et al. Cancer. 2010;116:3830-3834.

CPX-351: Results from Randomized phase II B study

CPX 351 is liposomal formulation of daunorubicin and cytarabine in fixed molar ratio (5:1)

CPX-351 7+3n=84* n=41

CR+CRi 56 (66.7%) 21 (51.2%) p=0.0712**

CR 41 (48.8%) 20 (48.8%)

CRi 15 (17.9%) 1 (2.4%)

Lancet, et al. ASH 2010

Event Free & Overall Survival: sAML

0%

20%

40%

60%

80%

100%

0 3 6 9 12 15 18Months from randomization

0%

20%

40%

60%

80%

100%

0 3 6 9 12 15 18Months from randomization

Logrank p-value = .071.4 (1.1,1.8)17 / 19Arm B: 7+33.8 (1.5,6.1)26 / 32Arm A: CPX-351

Median

in MonthsEvents / N

1.4 (1.1,1.8)17 / 19Arm B: 7+33.8 (1.5,6.1)26 / 32Arm A: CPX-351

Median

in MonthsEvents / N

Logrank p-value= 0.01

0%

20%

40%

60%

80%

100%

0 6 12 18 24Months from randomization

7+3

CPX-351

0%

20%

40%

60%

80%

100%

0 6 12 18 24Months from randomization

7+3

CPX-351

6.1 (1.4, 7.5)14 / 19Arm B: 7+312.1 (9.1, 16.7)17 / 32Arm A: CPX-351Median (mons.)Deaths / N

6.1 (1.4, 7.5)14 / 19Arm B: 7+312.1 (9.1, 16.7)17 / 32Arm A: CPX-351Median (mons.)Deaths / N

Event Free Survival Overall Survival

Logrank p-value= 0.07 Logrank p-value= 0.01

1.4 (1.1, 1.8)17 / 193.8 (1.5, 6.1)26 / 32CPX-351: sAML

Median (mons.)Events / N

7+3: sAML 6.1 (1.4, 7.5)14 / 197+3: sAML12.1 (9.1,16.7)17 / 32CPX-351: sAML

Median (mons.)Deaths / N

Logrank p-value = 0.07 Logrank p-value = 0.01

Lancet, et al. ASH 2010

11/20/2015

18

CLAG-M Induction Regimen Post Azanucleoside Failure

CLAG-M (n=25) 3+7 (n=24) P Value

CR/CRi 14/25 (56%) 9/24 (29%) 0.058

OS 202 days 86 days 0.025

1 year Survival 45% 9%

Jaglal et al. ASH 2011; abstract # 256.

ADVANCES IN MDS TREATMENTWhat is on the Horizon

AGE-RELATEDCLONAL HEMATOPOIESIS

ATTACK OF THE CLONES!

107

Risk of acquiring mutations increases with age

108 109

11/20/2015

19

Non-clonal ICUS

CHIP CCUS LR-MDS HR-MDS

Traditional ICUS MDS by WHO 2008

Clonality

Dysplasia

Cytopenias

Overall Risk

+ – ++ ++ ++

–/+ – – + ++

– + + + ++

Very Low Very Low Low (?) Low High

BM Blast % < 5% < 5% < 5% < 5% 5-19%

Are these two the same?Does morphologic dysplasia matter?

CCUS = clonal cytopenias of undetermined significance; ICUS = idiopathic cytopenias of undetermined significance; CHIP = clonal hematopoiesis of indeterminate potential; LR = lower risk, HR = higher risk

How do we classify these patients?

110

Clinical TrialsWhy participate?

• Patients play an active role in their own health care, they become engaged

• Patients can gain access to new treatments that may not be otherwise available, before formal governmental (FDA) approval

• Patients can help others by contributing to medical research and helping establish new and better treatments for future patients

Clinical TrialsWho can or should participate?

• Patients with a disease where treatment is not curative

• Clinical trials have inclusion and exclusion criteria to

• Protect the safety of the patient from the new treatment being tested

• Help produce reliable results which will make sure the trial really determines if the new treatment is effective

• Inclusion/exclusion criteria include age, type and stage of disease, prior treatment history, organ function (heart, lung, kidneys) to make sure the treatment is safe

Clinical TrialsPhases

• Phase I-designed to determine the best and safest dose and identify side effects

• Phase II-designed to determine the effectiveness of the new treatment

• Phase III-designed to compare the effectiveness of the new treatment to the commonly used treatment

• Phase IV-postmarketing (after FDA approval) trial to further refine the risks and benefits and identify new side effects once the new treatment is widely used

A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat vs. Azacitidine Monotherapy in

Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study

SWOG S1117 [LBA – 5]

Mikkael A. Sekeres, MD, MS, Megan Othus, PhD, Alan F. List, MD, Olatoyosi Odenike, MD, Richard M. Stone, MD., Steven D. Gore, MD, Mark R. Litzow, MD, Rena Buckstein, MD, Mario R. Velasco, MD, Rakesh Gaur, MD, MPH,

Ehab Atallah, MD, Eyal C. Attar, MD, Frederick R. Appelbaum, MD, Harry P. Erba, MD, PhD

SWOG Alliance ECOG NCIC

North American Intergroup Randomized Phase 2 MDS Study S1117: Study Design

AZA (IV/SC)75 mg/m2/d (d1-7)

N=92

AZA (IV/SC) + LEN (PO)75 mg/m2/d (d1-7) + 10mg/d x 21d

N=93

AZA (IV/SC) + Vorin (PO)75 mg/m2/d (d1-7) + 300mg BID (d3-9)

N=91

Higher-risk MDS or CMML

(IPSS >1.5 and/or

blasts >5%)

Groups: SWOG, ECOG,Alliance, NCIC

Total Sample Size: 276

Primary Objective: 20%improvement of ORR (CR/PR/HI) based on

2006 IWG Criteria

Secondary Objectives: OS,RFS, LFS

Power 81%, alpha 0.05 for each combo arm vs. AZA

03/2012 – 06/2014

Sekeres et al. ASH 2014: LBA - 5

11/20/2015

20

Sekeres et al. ASH 2014: LBA - 5

Response Variable

AZA AZA+LEN

(P-value vs. AZA)

AZA+VOR (P-value vs.

AZA)Total n=260

Median Tx Duration

(Wks)25 24 20 23

Overall Response Rate (%)

37 39 (1.0) 24 (.07) 33

CR/PR/HI (%) 24/0/13 18/1/19 (.66) 15/1/7 (.12) 19/1/13

CMML ORR (%) 33 (n=15) 59 (.15) (n=19) 13 (.41) (n=16) 34

Relapse-free Survival (median) 7 months 8 months (.45) 11 months (.29) 7 months

Relapse-free survival, on Tx >6 months (median)

7 months 7.5 months (.74) 13 months (.11) 8.5 months

North American Intergroup Randomized Phase 2 MDS Study S1117: Response

Birinapant/TL32711 • Bivalent Smac mimetic

(Second mitochondria-derived activator of caspases)

• Relieves apoptosis resistance as an IAP & Bcl2 family antagonist

• Antagonizes IAP proteins(cIAP1, cIAP2, ML-IAP, XIAP)

• Suppresses NF-kB activation• In vitro & in vivo synergy with

azacitidine and decitabine• Induces apoptosis in AML

HSCs alone and in combination

• Entering randomized phase 2 with 5Aza

Targeted Inhibition of Apoptosis Resistance & TNF signaling

IAP: Inhibitors of Apoptosis Proteins. TetraLogic Pharmaceuticals

(n = 4)

CI: “combination index” where <1 implies synergy

AZA: azacitidine

Flow cytometric analysis performed in triplicateResults expressed as mean ± standard error of the mean

(n = 7)

Birinapant (TL) + 5-AC x 48 h

Single-agent & Combination Activity of Birinapant with 5-AZA in Primary AML

cells

. TetraLogic Pharmaceuticals

Phase II Study: Novel SQ HypomethylatingAgent SGI-110 in Adults with AML

• SGI-110: dinucleotide of decitabine and deoxyguanosine • Increases in vivo exposure of decitabine by blocking deamination

Kantarjian HM, et al. ASH 2013. Abstract 497.

SGI-110: BED60 mg/m2/day x 5

(n = 43)

Relapsed/refractory AML or treatment-naive elderly AML ≥ 65 yrs of

age with secondary AML, adverse cytogenetics,

preexisting cardiac, or pulmonary

comorbidities, or ECOG performance status 2

(N = 90)

Continued until

unacceptable toxicity or disease

progression*SGI-110: Highest Well-Tolerated Dose90 mg/m2/day x 5

(n = 47)

*International Working Group 2006 AML response criteria.

Primary endpoint: ORR (CR/CRp/CRi)

Secondary endpoints: safety, DOR, OS

Overall survival (OS) and baseline disease characteristics in MDS patients with primary HMA failure in a randomized, controlled, phase III study of rigosertib

• Pierre Fenaux, Aref Al-Kali, Maria R. Baer, Mikkael A. Sekeres, Gail J. Roboz, Gianluca Gaidano, Lewis R. Silverman, Bart L Scott, Peter Greenberg, Uwe Platzbecker, David P. Steensma, Karl A Kreuzer, Lucy A. Godley, Robert Collins, Ehab L. Atallah, Nozar Azarnia, Guillermo Garcia-Manero

• Novel small molecule targets RAS Binding Domain (RBD) of signaling proteins

• Novel MoA: targets pathways including PI-3 Kinase and Polo-Like Kinase

• Initial studies indicate clinical activity in pts with MDS and AML

• Both oral and IV rigosertib available – ONTIME trial used the IV formulation

Divakar et al, AACR Annual Meeting 2014; abst LB-108; Olnes et al, Leuk Res 2012;36:964-5; Chapman et al, Clin Cancer Res 2012;18:1979-91.

Rigosertib (ON 01910.Na)121

RAF signaling is blocked

Cell Membrane

C-RAF

KinaseDomain Rigosertib

Inactive RAF(Closed)

RAS

Rigosertib blocks RAS/RAF interaction

RAS Binding Domain

11/20/2015

21

ONTIME Trial: Study Design• Phase III, randomized, controlled, safety & efficacy study

comparing rigosertib + BSC* vs BSC* alone (2:1)

• Adult pts who had relapsed after, failed to respond to, or progressed during HMA therapy

• 299 pts enrolled at 87 sites in US and Europe

• Rigosertib administered as 1800 mg/24 hr for 72 hrs as a continuous IV ambulatory infusion

• Pts stratified by bone marrow blast count (5-19% vs 20-30%)

• Primary endpoint = overall survival

• Analysis based on 242 events (deaths; ≥ 80% maturity)

• Median follow-up of >18 months

122

*BSC=Best supportive care: RBC & platelets; growth factors; hydroxyurea to manage blastic crises when pts transition to leukemia; pts on the BSC arm also allowed low-dose cytarabine, as medically justified.

ONTIME Trial: Primary Efficacy Results – ITT

123

ONTIME Trial: Median Overall Survival for Pts with Primary HMA Failure – Investigator Assessment

Per Prebet 2011, “Primary HMA Failure” was defined as either no response to or

progression during HMA therapy

ONTIME Trial: Conclusions• Primary endpoint of OS did not reach statistical

significance in the ITT population• 2.3-month improvement in median OS in the ITT population

• Rigosertib treatment-related improvement in OS was noted in the following well-balanced subgroups:• Primary HMA failure (64% of pts: HR = 0.69; p = 0.04)• IPSS-R Very High Risk (45% of pts: HR = 0.56; p = 0.005)• Cytogenetic criteria also important prognostic factors

• Monosomy 7 (HR = 0.24; p = 0.003)• Trisomy 8 (HR = 0.34; p = 0.035)

• Continuous IV infusion with rigosertib had a favorable safety profile in this population of elderly pts with HR MDS

GFM LEN-EPO 2008Study Design

a ≥ 12 consecutive weeks of epoetin alfa/beta ≥ 60,000 U/week or darbepoetin ≥ 250 g/week.b By 2006 and 2000 IWG criteria.

del, deletion; EPO, epoetin beta; ESA, erythropoiesis-stimulating agent; GFM, Groupe Francophone des Myélodysplasies; HI-E, hematologic improvement-erythroid; Int, intermediate;

IPSS, International Prognostic Scoring System; IWG, International Working Group; LEN, lenalidomide; MDS, myelodysplastic syndromes; QoL, quality of life; RBC, red blood cell; TD,

transfusion-dependent; TI, transfusion independence.

• Primary endpoint: erythroid response by IWG 2006 criteria after 4 cycles• Secondary endpoints: safety, major HI-E, minor HI-E, erythroid response duration, time to response,

time to progression, RBC-TI, prognostic factors of response, survival, QoL

Adult patients with lower-risk (IPSS low-/Int-1–risk), non-del(5q) MDS and RBC-TD anemia (≥ 4 RBC transfusions/8 weeks) relapsed from or resistanta to ESA

LEN 10 mg days 1-21 LEN 10 mg days 1-21 + EPO 60,000 U/week

Responseb after 4 cycles

If failure to LEN alone, add EPO at discretion of physician; otherwise discontinue

Continue treatment until relapse

No responseb after 4 cycles

Randomization

Phase 2, Multicenter, Randomized Trial

28-day cycles

Toma A, et al. J Clin Oncol. 2013;31(suppl) [abstract 7002].http://www.clinicaltrials.gov/ct2/show/NCT01718379.

GFM LEN-EPO 2008Responses

Toma A, et al. J Clin Oncol. 2013;31(suppl) [abstract 7002].

ITT PopulationLEN + EPO

(n = 65)LEN

(n = 64)P Value

Erythroid response 40% 23.4% .043

RBC-TI 24.6% 14.1% .13

EPO, epoetin beta; GFM, Groupe Francophone des Myélodysplasies; ITT, intent-to-treat; LEN, lenalidomide; RBC, red blood cell; TI, transfusion independence.

• For all patients or those who received ≥ 4 cycles of therapy,

erythroid response was significantly higher in the LEN + EPO arm

Patients Who Received ≥ 4 Cycles

LEN + EPO(n = 50)

LEN(n = 49)

P Value

Erythroid response 52% 30.6% .03

RBC-TI 32% 18.4% .12

11/20/2015

22

Phase 3 Study of Oral Aza in LR-TD MDS Patients with Thrombocytopenia

YesContinue Tx Until

Progression (24 mos)

Eligibility•IPSS Low/Int-1MDS•RBC>2U/28dx>84d•Hb ≤ 9g/dL prior to

Transfusion• Platelet count≤

50×109/L

Oral azacitidine300mg X 21/28 d + BSC

[n=193 pts]

RANDOMIZE

PlaceboX 21/28 days + BSC

[N=193 pts]

RESPONSE

Week 0 4 12 16 208 24

Double-blind phase

Oral Azacitidine (CC-486)-MDS-003

NoOff Study

Primary Endpoint: RBC-TI for ≥ 84 days

Secondary: HI-P, OS, RBC-TI duration, AML

Novel Strategies to Abrogate Aberrant Innate Immune Activation

X

X

CD33-IgGChimera

EC-Domain

IgG1-Fc

Human IgG1

CD33

S100-Trap (Soluble CD33-R)

Figure adapted from Wei S & List A, J Clin Invest 2013.

X

CD33Targeting MDSC Anti CD33 mAB

XTargeting TLR

OPN-305 (TLR-2 mAB)

Luspatercept Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from the Phase 2 PACE-MDS Study

Uwe Platzbecker, Ulrich Germing, Aristoteles Giagounidis, Katharina Götze, Philipp Kiewe, Karin Mayer, Oliver Ottmann,Markus Radsak, Thomas Wolff, Detlef Haase, Monty Hankin, Dawn Wilson, Xiaosha Zhang, Abderrahmane Laadem,Matthew Sherman, Kenneth Attie

Ineffective Erythropoiesis in MDS

Anemia, a hallmark of MDS, is challenging to treat, particularly after failure of ESAs1

Defects in maturation of erythroid precursors (ineffective erythropoiesis) lead to erythroid hyperplasia and anemia

Ineffective erythropoiesis is driven by excessive Smad2/3 signaling2

1. Fenaux P, et al. Blood. 2013;121:4280

2. Zhou L, et al. Blood 2008;112:3434

High EPO levels drive proliferation

Excessive GDF-induced Smad2/3 signaling inhibits RBC maturation

ReticBaso EBFU-E CFU-E Pro E RBCPoly E Ortho E

131EHA 2015

Luspatercept Activity in MDS

Luspatercept, a modified activin receptor type IIB (ActRIIB) fusion protein,acts as a ligand trap for GDF11 and other ligands of the TGF-β superfamily to suppress Smad2/3 activation and increases Hgb in healthy volunteers1

In a murine model of MDS, RAP-536 (murine analog of luspatercept) corrects ineffective erythropoiesis, reduces erythroid hyperplasia and increases hemoglobin2

1. Attie, K et al. Am J Hematol 2014;89:766

2. Suragani R et al., Nat Med 2014;20:408

High EPO levels drive proliferation

Excessive GDF-induced Smad2/3 signaling inhibits RBC maturation


132EHA 2015

Luspatercept Activity in MDS

Luspatercept, a modified activin receptor type IIB (ActRIIB) fusion protein,acts as a ligand trap for GDF11 and other ligands of the TGF-β superfamily to suppress Smad2/3 activation and increases Hgb in healthy volunteers1

In a murine model of MDS, RAP-536 (murine analog of luspatercept) corrects ineffective erythropoiesis, reduces erythroid hyperplasia and increases hemoglobin2

1. Attie, K et al. Am J Hematol 2014;89:766

2. Suragani R et al., Nat Med 2014;20:408


Luspatercept promotes differentiation and maturation by trapping Smad2/3 activating ligands

133EHA 2015

11/20/2015

23

NCT01749514EudraCT 2012-002523-14

Luspatercept PACE-MDS 3-Month Treatment Study Overview

Phase 2, multicenter, open-label, dose-finding, 3-month treatment study in IPSS low/int-1 MDS

Key eligibility criteria:

Nonresponsive/refractory to ESA or EPO >500 U/L

No prior azacitidine or decitabine

No current lenalidomide, ESA, G-CSF

Primary efficacy endpoints:

Low transfusion burden (LTB, <4U RBC/8 weeks, Hgb <10 g/dL):Hemoglobin increase of ≥ 1.5 g/dL for ≥ 2 weeks

High transfusion burden (HTB, ≥4U RBC/8 weeks):Reduction of ≥4U or ≥50% units transfused over 8 weeks

134EHA 2015

3-Month Treatment Study Enrollment

Dose Escalation Expansion

Dose Level (mg/kg) 0.125 0.25 0.50 0.75 1.0 1.33 1.75 1.0*

No. of patients 3 3 3 6 3 6 3 22

Enrollment in the dose escalation and expansion is complete (N=58)

Dose escalation, N=27, in 7 sequential cohorts, n=3-6 each, luspatercept dose level ranging from 0.125 to 1.75 mg/kg, subcutaneously, every 3 weeks

Expansion, N=31, starting dose 1.0 mg/kg, individual dose titration up to 1.75 mg/kg

Preliminary results for 49 patients (N=27 dose escalation, N=22 expansion)are presented

* Starting dose level; dose level increased to 1.33 mg/kg in 8 patientsand to 1.75 mg/kg in 2 patients

Data as of 17 Apr 2015135EHA 2015

Baseline Characteristics (1 of 2)

N=49

Age, yr, median (range) 71 (27-88)

Sex, male, n (%) 27 (55%)

Prior ESA treatment, n (%) 30 (61%)

Prior lenalidomide treatment, n (%) 9 (18%)

Time since diagnosis, yr, median (range) 2.8 (0.2-13.6)

Hemoglobin, g/dL, LTB patients, median (range)

8.7 (6.8-10.1)(n=17)

Units RBC transfused/8 weeks in patients who received transfusions, median (range)

LTB (n=6) HTB (n=32)2 (2-2) 6 (4-14)


Baseline Characteristics (2 of 2)

Patient SubgroupN = 49n (%)

IPSS

Low 27 (55%)

Int-1 21 (43%)

Int-2 1 (2%)

IPSS-R

Very Low 2 (4%)

Low 30 (61%)

Intermediate 14 (29%)

High 3 (6%)

Ring Sideroblast (RS) N=48

RS positive (≥15% of cells) 40 (83%)

SF3B1 mutation present* 29 (73%)

SF3B1 mutation absent 10 (25%)

RS negative (<15% of cells) 8 (17%)


* One patient was not evaluable for SF3B1

Dose-Dependent Erythroid Response and Transfusion Independence

Response Criteria

0.125-0.5 mg/kgN=9

n (%)

0.75-1.75 mg/kgN=40n (%)

Primary efficacy endpoint 3 (33%) 23 (58%)

IWG HI-E 2 (22%) 19 (48%)

Transfusion independence (TI) 1/7 (14%) 11/30 (37%)

LTB HTB4/6 7/24

Transfusion Independence: Transfusion-free for ≥ 8 weeks on treatment for patients who received at least 2 RBC units pre-treatment

• 10 of the 11 TI patients in the higher dose groups had onset within the first 6 weeks of treatment


Enriched Response in RS+ and mSF3B1Sub-groups in Higher Dose Groups

Patient Population IWG HI-E

All Patients 19/40 (48%)

RS* positive 19/35 (54%)

EPO < 200 14/23 (61%)

EPO ≥ 200 5/12 (42%)

RS negative 0/4 (0%)

SF3B1 mutation* present 16/26 (62%)

SF3B1 mutation absent 3/13 (23%)

RS: Ring sideroblast; positive if ≥15% of erythroid precursors in bone marrowEpo: Serum erythropoietin (mU/mL)

SF3B1: Splicing factor 3B1Higher Dose Groups: 0.75-1.75 mg/kg

* One patient not evaluable Data as of 17 Apr 2015139EHA 2015

11/20/2015

24

Safety Summary for 3-Month Treatment Study

Majority of adverse events (AEs) were grade 1 or 2

Two possibly related serious adverse events (SAEs): grade 3 muscle pain (onset day 90); grade 3 worsening of general condition (onset day 44, recurred day 66, unrelated)

One possibly related non-serious grade 3 AE of blast cell count increase

Preferred Termn (%)

0.125-0.5 mg/kgN=9n (%)

0.75-1.75 mg/kgN=40n (%)

Overall(N=49)

Myalgia 2 (22) 5 (13) 7 (14)

Diarrhea 2 (22) 4 (10) 6 (12)

Nasopharyngitis 1 (11) 5 (13) 6 (12)

Headache 0 5 (13) 5 (10)

Abdominal pain upper 1 (11) 3 (8) 4 (8)

Bone pain 1 (11) 3 (8) 4 (8)

Bronchitis 0 4 (10) 4 (8)

Fatigue 0 4 (10) 4 (8)

Hypertension 0 4 (10) 4 (8)

Muscle spasms 2 (22) 2 (5) 4 (8)

Adverse events (all grades) reported in ≥ 4 patients, regardless of causality


A Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (MDS) and Anemia Requiring Transfusion

Rami Komrokji, Guillermo Garcia-Manero, Lionel Ades, Abderrahmane Laadem, Bond Vo, Thomas Prebet,Aspasia Stamatoullas, Thomas Boyd, Jacques Delaunay, David P. Steensma, Mikkael A. Sekeres, Odile Beyne-Rauzy, Jun Zou,Kenneth M. Attie, Matthew L. Sherman, Pierre Fenaux, Alan F. List

Background• Anemia is a hallmark of MDS that is challenging to

treat, particularly after failure of ESAs1

• Sotatercept (ACE-011):• Is a novel and first-in-class ActRIIA

fusion protein

• Acts on late-stage erythropoiesis to increase maturation and release of erythrocytes into the circulation2–4

• Inhibits SMAD2/3 signaling3

• Acts via a mechanism distinct from EPO

ActRIIA, activin receptor type IIA; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; Ig, immunoglobulin; MDS, myelodysplastic syndromes.

1. Fenaux P, Adès L. Blood. 2013;121:4280-6.2. Iancu-Rubin C, et al. Exp Hematol. 2013;41:155-66.3. Carrancio S, et al. Br J Haematol. 2014;165:870-82.

4. Dussiot M, et al. Nat Med. 2014;20:398-407.

Sotatercept (ACE-011)ActRIIA–Fc fusion protein

Extracellular domain of ActRIIA

Fc domain of IgG1 antibody

Sotatercept Activity in MDS

Baso E, basophilic erythroblast; BFU-E, burst-forming unit erythroid; BMP, bone morphogenetic protein; CFU-E, colony-forming unit erythroid; GDF, growth differentiation factor; Hb, hemoglobin; IL, interleukin; Ortho E, orthochromatic erythroblast; Poly E, polychromatic erythroblast; Pro-E, proerythroblast; RBC, red blood cell; SCF, stem cell factor; TGF-β, transforming growth factor beta.

TGF-β ligands (e.g. GDF15,GDF11, BMP6, activin A) which

negatively regulate late erythropoiesis

Bone marrow microenvironment

Produces

Sotatercept

releases block

Baso E Poly E Ortho E Reticulocyte RBC

SCFIL-3EPO

BFU-E CFU-E Pro-E

EPO-responsive

EPO-dependent

EPO

8–64 cells500 cells

Delayed Hb increase Rapid Hb increase

• Mobilizes cells from precursor pools into blood, leading to rapid RBC effects

• Effect relies on continuous formation of late-stage precursors from earlier progenitors

Eligibility Criteria• Eligible patients had:

• IPSS Low- or Int-1-risk MDS

• Hb ≤ 9.0 g/dL, and requiring transfusion of ≥ 2 units of RBCs in

the 12 weeks prior to enrollment

• No response, loss of response, or low chance of response (serum EPO level > 500 mIU/mL) to ESAs

• Patients classified based on RBC transfusion burden:

• ≥ 4 units/8 weeks: high transfusion burden (HTB)

• < 4 units/8 weeks: low transfusion burden (LTB)

Study Design

a Maximum of 20 evaluable patients enrolled per dose level.q3w, every 3 weeks.

0.1 mg/kg s.c. q3wa

0.3 mg/kg s.c. q3wa

0.5 mg/kg s.c. q3wa

2.0 mg/kg s.c. q3wa

1.0 mg/kg s.c. q3wa

Response:

Continue treatment

q3w

No response:

Discontinue treatment

Assess erythroid response after 5–8 cycles

Progression/ therapeutic

failure:

Discontinue treatment

Assess MDS and overall survival every

6 months, up to

24 months after

treatment

Part 2: Recommended dose (as determined by Steering Committee) in Part 1 carried over into Part 2 with enrollment of 15 additional patients

Part 1: Dose finding

11/20/2015

25

Baseline Patient Characteristics (1 of 2)

CharacteristicSotatercept dose group

Overall(N = 59)0.1 mg/kg

(n = 7)0.3 mg/kg

(n = 6)0.5 mg/kg

(n = 21)1.0 mg/kg

(n = 20)2.0 mg/kg

(n = 5)

Age, median (range), years

65 (58–79)

73 (66–86)

69 (56–82)

74 (60–84)

73 (47–81)

71 (47–86)

Female, n (%) 3 (43) 0 4 (19) 9 (45) 4 (80) 20 (34)

Time since MDS diagnosis, median (range), years

4 (1–6) 8 (4–10) 6 (<1–31) 3 (<1–20) 2 (<1–5) 4 (<1–31)

RBC transfusion burden, median (range), units/8 weeks

9 (4–10) 8 (6–11) 6 (2–16) 6 (0–10) 4 (3–8) 6 (0–16)

RBC transfusion status, n (%)

HTB (≥ 4 units/8 weeks) 7 (100) 6 (100) 18 (86) 15 (75) 4 (80) 50 (85)

LTB (< 4 units/8 weeks) 0 0 3 (14) 5 (25) 1 (20) 9 (15)

IPSS risk, n (%)

Low 4 (57) 4 (67) 5 (24) 7 (35) 0 20 (34)

Int-1 3 (43) 2 (33) 16 (76) 13 (65) 5 (100) 39 (66)Data presented for patients in Part 1 (dose-finding) of the study only.

Baseline Patient Characteristics (2 of 2)Characteristic

Sotatercept dose groupOverall(N = 59)0.1 mg/kg

(n = 7)0.3 mg/kg

(n = 6)0.5 mg/kg

(n = 21)1.0 mg/kg

(n = 20)2.0 mg/kg

(n = 5)

Serum EPO level, n (%)

≤ 500 mIU/mL 4 (57) 4 (67) 10 (48) 11 (55) 3 (60) 32 (54)

> 500 mIU/mL 3 (43) 2 (33) 9 (43) 5 (25) 1 (20) 20 (34)

Missing 0 0 2 (10) 4 (20) 1 (20) 7 (12)

Prior use of ESAs, n (%) 6 (86) 6 (100) 20 (95) 20 (100) 5 (100) 57 (97)

Prior use of hypomethylating agents, n (%)

6 (86) 6 (100) 13 (62) 6 (30) 1 (20) 32 (54)

Prior use of lenalidomide, n (%) 5 (71) 5 (83) 10 (48) 6 (30) 2 (40) 28 (48)

Prior use of other MDS treatments, n (%) 6 (86) 5 (83) 8 (38) 7 (35) 1 (20) 27 (46)

Data presented for patients in Part 1 (dose-finding) of the study only.

Overall Erythroid Response• Of 59 patients enrolled in Part 1 (dose finding) of the

study, 25 (42%) achieved HI-E:

• Sotatercept 0.1 mg/kg: 0 of 7 patients

• Sotatercept 0.3 mg/kg: 4 of 6 patients (67%)





Overall RBC-TI ResponseAchievement of RBC-TI in HTB or RBC-TI with mean Hb increase ≥ 1.5 g/dL in LTB patients over any 8-week period

NA, not applicable.

Pat

ient

s (%

)

33%

NANA

80%

Sotatercept dose group

17%11%

20%

0%

100%

0%

n = 4 n = 1

n = 15 n = 5

n = 18 n = 3

n = 6n = 0

n = 7n = 0

HTB:LTB:


Erythroid Response: HTB Patients• HI-E was achieved in 19 of 50 (38%) HTB patients

• In the 1.0 mg/kg dose group, 6 of 15 (40%) HTB patients achieved HI-E

• Median duration of response was 123 days in the 1.0 mg/kg dose group

CharacteristicSotatercept dose group

Overall(n = 50)0.1 mg/kg

(n = 7)0.3 mg/kg

(n = 6)0.5 mg/kg

(n = 18)1.0 mg/kg

(n = 15)2.0 mg/kg

(n = 4)

HI-E (RBC transfusion burden reduction ≥ 4 units/8 weeks), n (%)

0 4 (67) 8 (44) 6 (40) 1 (25) 19 (38)

Longest period with transfusion burden reduction ≥ 4 units/8

weeks, median (range), daysNA

68 (62–173)

109 (56–601+)

123 (62–360+)

63 (63–63)

104 (56–601+)

RBC-TI ≥ 8 weeks, n (%) 0 1 (17) 2 (11) 3 (20) 0 6 (12)

Duration of RBC-TI ≥ 8 weeks, daysa NA 124

154, 601+

59, 78, 360+

NA59, 78, 124, 154, 360+,

601+

aValues presented for individual patients. Data presented for patients in Part 1 (dose-finding) of the study only.

Erythroid Response: LTB Patients• Of 9 LTB patients, 6 (67%) achieved a mean Hb increase

of ≥ 1.5 g/dL sustained for ≥ 8 weeks in the absence of

transfusions• Median Hb increase 2.8 g/dL (range 1.9–4.6) among responders

• Median duration of RBC-TI: 367+ days (range 76–526+ days)• Patients with Hb > 11.0 g/dL were subject to dose delay per protocol,

which may have impacted assessment of duration of Hb increase


11/20/2015

26

Erythroid Response:Sideroblastic vs Non-Sideroblastic MDS

RSaHI-E by sotatercept dose group and RS status, n/N (%)

0.1 mg/kg 0.3 mg/kg 0.5 mg/kg 1.0 mg/kg 2.0 mg/kg

≥ 15% 0/6 4/4 (100) 7/13 (54) 7/11 (64) 2/3 (67)

< 15% 0/1 0/2 2/6 (33) 1/5 (20) 0/2

• In the combined sotatercept 1.0 mg/kg and 2.0 mg/kg dose groups, HI-E was achieved in 64% of sideroblastic and 14% of non-sideroblastic patients (chi-square test P = 0.03)

a RS status is from baseline, where available; RS status was unknown for 6 patients: 2 and 4 patients from the sotatercept 0.5 and 1.0 mg/kg groups, respectively.


Common Treatment-Emergent AEsCharacteristic, n (%)

Sotatercept dose groupOverall(N = 59)0.1 mg/kg

(n = 7)0.3 mg/kg

(n = 6)0.5 mg/kg

(n = 21)1.0 mg/kg

(n = 20)2.0 mg/kg

(n = 5)

Patients with ≥ 1 TEAE (any grade) 4 (57) 3 (50) 16 (76) 17 (85) 3 (60) 43 (73)TEAEs (any grade) in ≥ 10% patients

Fatigue/astheniaa 0 1 (17) 9 (43) 12 (60) 1 (20) 23 (39)

Peripheral edema 2 (29) 2 (33) 4 (19) 4 (20) 0 12 (20)

Diarrhea 0 2 (33) 5 (24) 3 (15) 2 (40) 12 (20)

Nausea 0 1 (17) 3 (14) 4 (20) 1 (20) 9 (15)

Constipation 0 1 (17) 6 (29) 2 (10) 0 9 (15)

Vomiting 0 1 (17) 2 (10) 3 (15) 0 6 (10)

Decreased appetite 0 0 3 (14) 3 (15) 1 (20) 7 (12)

Pain in extremity 0 1 (17) 2 (10) 3 (15) 1 (20) 7 (12)

Headache 3 (43) 1 (17) 2 (10) 2 (10) 1 (20) 9 (15)

Dizziness 1 (14) 2 (33) 1 (5) 1 (5) 1 (20) 6 (10)

Cough 1 (14) 1 (17) 2 (10) 5 (25) 0 9 (15)

Dyspnea 0 1 (17) 4 (19) 2 (10) 1 (20) 8 (14)

Hypertension 0 1 (17) 2 (10) 2 (10) 1 (20) 6 (10)

Grade 3–4 TEAEsb 1 (14) 1 (17) 10 (48) 6 (30) 1 (20) 19 (32)a Pooled incidence of fatigue and asthenia. b Suspected treatment-related grade 3–4 AEs were reported in 3 patients: 1 patient with grade 3 pain in extremity, 1 patient with grade 3 hypertension, and 1 patient with grade 4 acute myeloid leukemia.

TEAE, treatment-emergent AE (AEs newly acquired or worsening during or after administration of first dose of study treatment). Data presented for patients in Part 1 (dose-finding) of the study only.

A Multi-Institution Phase I Trial of Ruxolitinib in Chronic Myelomonocytic Leukemia (CMML)

Eric Padron, Amy Elizabeth Dezern, Kris Vaddi, Peggy A Scherle, Qing Zhang, Yan Ma, Maria Balasis, Sara Tinsley, Hanadi Ramadan, Casandra Zimmerman, David P. Steensma, Gail J. Roboz, Jeffrey E. Lancet, Alan F. List, Mikkael A. Sekeres, Rami S. Komrokji

Introduction• CMML is a life threatening hematologic malignancy with no

clear disease modifying therapy available.

• GM-CSF hypersensitivity is a feature of CMML that can be successfully targeted by JAK2 inhibitors in vitro.

• Ruxolitinib is and FDA approved JAK1/JAK2 inhibitor for the treatment of DIPSS intermediate-2 and high risk myelofibrosis

Study design

• Key inclusion criteria included a confirmed WHO diagnosis of CMML without regard to previous therapies given.

• Key exclusion criteria included an ANC<0.25x103 c/dL and a platelet count<35x103c/dL.

• The use of GM-CSF analogs was prohibited but G-CSF was allowed.

11/20/2015

27

Conclusions• Ruxolitinib is well tolerated in CMML with no DLT identified.

• Broad activity of ruxolitinib in CMML to include hematologic, spleen, and preliminary symptom responses identified.

• No change in mutational burden but down regulation of inflammatory cytokines and pSTAT5 levels after therapy identified.

• Phase 2 study to incorporate MPN-SAF is ongoing.

SCREENING

RANDOMIZATION

INTERIM

BM

BIOPSY

BM

BIOPSY

Week 1 Week 26 Week 30 Week 58

Romiplostim 750 mcg weekly (N = 160)

Romiplostim in MDS. Study Design

LTFU

AND

EOS

No IP

Week 54

No IP

• IPSS low/int-1 MDS on supportive care only, with PLTs 1) ≤20x109/L or 2) ≤50x109/L with a history of bleeding. Stratified by baseline IPSS (low, int-1) and PLT count (<20,

20-50x109/L).• Enrollment: July 2008 to March 2011; 250 pts. IP dose adjusted by PLT count.• After completing Rx, pts moved to long-term follow-up (LTFU) for 5 years.

26-Week Treatment Period 24-Week Treatment Continuation

Placebo weekly (N = 80)

Romiplostim750 mcg weekly +

standard of care (N = 160)

Placebo weekly + standard of care (N = 80)

Kantarjian et al. ASH 2012

Romiplostim Clinical Efficacy in Selected Groups

Platelet Count (x109/L)

Clinically Relevant Endpoints in Practice Results in this study

20-50 Platelet Transfusions not routine: Bleeding Reduction

CSBE reduced RR = 0.35 (95% CI: 0.21, 0.59) p<0.0001, n = 120, 48%

<20 Patients Transfused Routinely: Platelet Transfusion Reduction

PTE reduced RR = 0.71 (95% CI: 0.61, 0.82) p<0.0001, n = 130, 52%

<10 Worst group refractory to platelet transfusions:Platelet Count Improvement

HI-P improved responses7% vs. 30%Diff = 23% (95% CI: -6%, 46%)p = 0.23, n = 34, 14%

CSBE = clinically significant bleeding events, PTE= protocol-defined Tx events


Romiplostim Placebo HR 95% CI

Deaths 38.1% (64) 37.8% (31) 1.08 0.70, 1.67

AML 8.9% (15) 8.5% (7) 1.15 0.47, 2.85

AML-free survival 39.3% (66) 39.0% (32) 1.09 0.71, 1.68

(x) = x patients

Time (months)

Ove

rall

Su

rviv

al P

rob

abili

ty

0 6 12 18 24 30 360.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

82 77 70 57 50 41 37 30 24 15 8 4PlaceboRomiplostim

Patients at Risk:

Overall Survival

HR 1.08 (95% CI: 0.70, 1.67)

PlaceboRomiplostim

64168 155 144 123 108 83 62 47 29 19 13 2133

Time (months)

AM

L-F

ree

Su

rviv

al P

rob

abili

ty

0 6 12 18 24 30 360.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

82 76 70 55 49 40 36 29 22 15 8 4PlaceboRomiplostim

Patients at Risk:

AML-Free Survival

HR 1.09 (95% CI: 0.71, 1.68)

PlaceboRomiplostim

63168 153 141 119 105 80 60 44 28 19 13 2129


11/20/2015

28

Eltrombopag in Low- or Intermediate- 1 Risk MDS• Phase II , national, multicentre, prospective,

randomized, single blind study

Patients (N = 69)

Eltrombopag + Standard care

(n = 46)Placebo

+ Standard care(n = 23)

Wk 24

Randomization 2:1

Eltrombopag + Standard care

Standard Care

CR and R

Dose start: 50 mg with increases every 2 weeks up to 300 mg daily. Oliva et al. ASH 2012, Abstract # 923

Response EltrombopagN= 9

PlaceboN=5

R, n 3 0

CR, n 5 0

NR 1 5

Total, n (%) 8 (89) 0 (0)

WHO bleeding grade ≥ 2 0 8

Platelet responses at 16 weeks:

Time to Response:•In 4 cases, early responses after 1 week;•In 2 cases by 8 weeks and in 2 cases by 12 weeks.Median daily eltrombopag dose at response: 75 mg (IQR 50-175)

Oliva et al. ASH 2012, Abstract # 923

Summary of TPO Agonist Studies • Use of TPO stimulants in MDS remains investigational

• Romiplostim and Eltrombopag were effective single agents in reducing bleeding events and platelet transfusions in some patients

• Safety of TPO stimulants need further assessment.–with longer follow up of Romiplostim study the risk of

AML was not increased– preliminary data with Eltrombopag did not show

increase risk.

• Ongoing studies are exploring potential combination of these agents with disease-modifying therapies

Which clinical studies to consider in MDS

• Lower risk MDS• Combination studies of current available therapy with

investigational agents.

• New investigational agents alone.

• Higher risk MDS• Combination studies of azacitidine/decitabine with new drugs• After azacitidine/decitabine failure

MDS program at Moffitt Clinical investigators

Rami Komrokji, MDJeffrey Lancet, MD

Basic-ScientistsSheng Wei, Ph.D

PK Burnette, Ph.DVasco Oliveira, Ph.DGary Reuther, Ph.D

Physician-ScientistsAlan List, MD

Eric Padron, MDEpidemiology

Dana Rollison, Ph.DDepartment of

Bone Marrow Transplantation

Hematopathology

Supportive ServicesInfection Disease

Pain servicePsychosocial Services

Palliative Care

Experimental Therapeutics Clinical Research UnitQuality patient care

11/20/2015 normal blood and bone marrow … is mds.pdf · •one of the most common hematological...

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