11/20/2015 1 MYELODYSPLASTIC SYNDROMES Rami Komrokji, MD Professor of Oncologic Sciences Clinical Director Malignant Hematology Moffitt Cancer Center Tampa, 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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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
• 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
• 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,
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
List AF, et al. N Engl J Med. 2006;355:1456-1465.
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
List AF, et al. N Engl J Med. 2006;355:1456-1465.
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
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
AZA-001 Trial: Azacitidine SignificantlyImproves OS
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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.
Fenaux P, et al. Lancet Oncol. 2009;10:223-232.
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
• 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
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Outcome After Azanucleoside Failure in MDS and CMML
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)
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
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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
• 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
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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,
• 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
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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
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
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
ReticBaso EBFU-E CFU-E Pro E RBCPoly E Ortho E
Luspatercept promotes differentiation and maturation by trapping Smad2/3 activating ligands
133EHA 2015
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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
* One patient not evaluable Data as of 17 Apr 2015139EHA 2015
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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
Data as of 17 Apr 2015140EHA 2015
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
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
Data presented for patients in Part 1 (dose-finding) of the study only.
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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.
Data presented for patients in Part 1 (dose-finding) of the study only.
Common Treatment-Emergent AEsCharacteristic, n (%)
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.
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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
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