Ohio State's 2016 ASH Review - ASH Review 2015Acute Leukemias and MDS

ASH Review 2015
Acute Leukemias and
MDS
Alice Mims, MD, MSCR
January 22, 2016

The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Objectives
 Acute Myeloid Leukemia
 Novel targeted therapeutics
 Acute Lymphocytic Leukemia
 Updates on Immunotherapies
 Myelodysplastic Sydrome
 Improvement of cytopenias with new treatments in
low-risk disease
2

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Acute Myeloid Leukemia

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Cytogenetic and Molecular Subsets in Younger AML
patients
4
Grimwade, et al. Blood 2016;127: 29-41

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A Phase III Randomized Double-blinded Study Of Chemotherapy +/-
Midostaurin (PKC412)
In Newly Diagnosed Adults age 18-60 with FLT3 Mutated Acute Myeloid
Leukemia (AML)
Participants: AMLSG, SAL, OSHO, CALGB/ALLIANCE, GIMEMA, SWOG, EGOG,
PETHEMA, CETLAM, EORTC, NCIC
CTEP sponsored, Novartis provided drug and sponsored outside North America, and
Alliance (formerly CALGB) chaired study, collected data and performed analysis
Richard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze
Dohner, Christian Thiede, Guido Marcucci, Francesco Lo Coco, Rebecca B. Klisovic, Andrew Wei,
Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederic
R. Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold
Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson, and Hartmut Dohner
Plenary Abstract # 6

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FLT3 Structure and Activating
Mutations
5-10%
Litzow MR. Blood. 2005;106:3331-3332.

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RATIFY: Study Design
7
 Double-blind, placebo-controlled, randomized phase III study
– Primary endpoint: OS (not censored for SCT)
– Secondary endpoint: EFS
18-60 yrs of
age with
FLT3-mutated
(non-APL)
AML
(N = 717)
Daunorubicin
60 mg/m2 IVP D1-3 +
Cytarabine
200 mg/m2/d IVCI D1-7 +
Midostaurin
50 mg PO BID D8-21
(n= 360)
Daunorubicin
60 mg/m2 IVP D1-3 +
Cytarabine
200 mg/m2/d IVCI D1-7 +
Placebo
D8-21
(n = 357)
Cytarabine
3 g/m2 over 3h q12h
D1,3,5 +
Midostaurin
50 mg PO BID D8-21
(n = 231)
Cytarabine
3 g/m2 over 3h q12h
D1,3,5 +
Placebo
D8-21
(n = 210)
Midostaurin
50 mg PO BID D1-28
(n = 120)
Placebo
D1-28
(n = 85)
Stratified by
ITD/TKD;
randomized
Induction*
(1-2 cycles)
Consolidation
(up to 4 cycles)
Maintenance
(12 cycles)
CR
CR
*Hydroxyurea allowed for ≤ 5 days prior to induction therapy.

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Patient Characteristics
MIDO
(N=360)
PBO
(N=357) p value
Age (years), median (range)
47.1
(19.0-100.2)
48.6
(18.0-60.9)
0.27
Gender 0.045
Female 187 (51.9%) 212 (59.4%)
Male 173 (48.1%) 145 (40.6%)
FLT3 Stratification Group 0.995
FLT3 TKD (No ITD) 81 (22.5%) 81 (22.7%)
ITD Allelic ratio <0.7 (+/- FLT3 TKD) 171 (47.5%) 170 (47.6%)
ITD Allelic ratio ≥0.7 (+/- FLT3 TKD) 108 (30.0%) 106 (29.7%)

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RATIFY: Safety
Grade 3/4 Nonhematologic AEs (≥ 10% Pts), %
Midostaurin
+ Chemo
(n = 360)
Placebo
+ Chemo
(n = 357)
P Value
Febrile neutropenia 81 82 .92
Infection 40 38 .49
Diarrhea 15 16 1.00
Hypokalemia 13 17 .17
Pain 13 13 .91
Rash/desquamation 13 8 .02
ALT/SGPT 12 9 .23
Fatigue (asthenia, lethargy, malaise) 9 11 .53
 Deaths: 5% (18/360) in midostaurin arm vs 5.3% (19/357) in placebo; leading
causes: infection (4 midostaurin, 7 placebo), pneumonitis (3 midostaurin, 0
placebo), hemorrhage, CNS (1 midostaurin, 2 placebo)

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RATIFY: Efficacy
Characteristic
Midostaurin +
Chemo
(n = 360)
Placebo +
Chemo
(n = 357)
P Value
Median OS, mos (range) 74.7 (31.7-NE) 25.6 (18.6-42.9)
4-yr OS, % (95% CI)
 Uncensored*
 Censored for SCT†
51.4 (46.0-57.0)
63.8 (56.0-71.0)
44.2 (39.0-50.0)
55.7 (47.0-63.0)
.0074
.04
SCT, n (%)
 Any time
 CR1 only
212 (59)
100 (28)
196 (55)
79 (22)
.28
.08
CR, n (%)
 By Day 60
 In induction/consolidation
212 (59)
239 (66)
191 (53)
211 (59)
.15
.045
Median EFS, mos (range)
 By day 60
 In induction/consolidation
8.0 (5.1-10.6)
11.3 (8.4-15.1)
3.0 (1.9-5.9)
6.1 (4.7-7.5)
.0025
.0002
DFS, mos (range) 25.9 (19.4-NE) 14.4 (11.0-22.2) .002
*HR: 0.77.
†HR: 0.75.

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RATIFY: Outcomes by FLT3 Status
 Longer OS shown in midostaurin arm in all FLT3
cohorts
 FLT3-ITD high, HR: 0.80 (95% CI: 0.57-1.12; P = .09)
 FLT3-ITD low, HR: 0.80 (95% CI, 0.59-1.10; P = .08)
 FLT3-TKD, HR: 0.65 (95% CI: 0.39-1.08; P = .05)
 4-yr EFS rate was 28% with midostaurin vs 20% in
placebo, regardless of FLT3 status

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Kaplan Meier Curve: Overall Survival
(Primary ITT Analysis)
• Median follow-up time for survivors: 56.7 mo (range: 0.1, 79.2)
NE: not estimable
* controlled for FLT3 subtype (TKD, ITD-Low, ITD-High)

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Kaplan Meier Curve: Overall Survival
Censored at time of transplant
NE: not estimable
* controlled for FLT3 subtype (TKD, ITD-Low, ITD-High)

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KM survival Curves for Overall Survival
post-transplant
All Transplants SCT in/outside of CR1
NE: not estimable

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CALGB 10603: Conclusions
 An International academic-industry collaborative AML
study based on genotype at dx is feasible
 Grade 3-5 adverse events were similar in each arm
 Midostaurin, a multi-targeted kinase inhibitor improves
OS and EFS when added to standard chemo with one
year maintenance in newly diagnosed pts aged 18-60
with ITD and TKD FLT3 mutant AML
 There was a high SCT rate but OS and EFS benefit was
consistent in uncensored as well as censored analyses
 Study investigators suggest midostaurin addition to
current standard chemo with 1-yr subsequent
maintenance as a new standard of care for these pts

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Safety and Efficacy of AG-221, a Potent Inhibitor of
Mutant IDH2 That Promotes Differentiation of Myeloid
Cells in Patients with Advanced Hematologic
Malignancies: Results of a Phase I/II Trial
16
Eytan M. Stein, Courtney DiNardo, Jessica K. Altman, Robert Collins,
Daniel J. DeAngelo, Hagop M. Kantarjian, Mikkael A. Sekeres, Amir T. Fathi,
Ian W. Flinn, Arthur E. Frankel, Ross L. Levine, Bruno C. Medeiros,
Manish R. Patel, Daniel Pollyea, Gail J. Roboz, Richard M. Stone, Ronan T. Swords,
Martin S. Tallman, Katharine Yen, Eyal C. Attar, Qiang Xu, Alessandra Tosolini,
Jay M. Mei, Anjan Thakurta, Robert D. Knight, and Stéphane De Botton
Oral Abstract # 323

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 IDH is an enzyme of the
citric acid cycle
 Mutant IDH2 produces
2-hydroxyglutarate (2-
HG), which alters DNA
methylation and leads
to a block in cellular
differentiation
 AG-221 (CC-90007) is a
selective, oral, potent
inhibitor of the mutant
IDH2 (mIDH2) enzyme
Isocitrate Dehydrogenase (IDH) Mutations
as a Target in AML
Tumor Cell

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Phase 1/2 Study Design
18
Key Endpoints:
• Safety, tolerability, MTD, DLTs
• Response rates as assessed by local investigator per IWG criteria
• Assessment of clinical activity
AG-221
100 mg PO QD
RR-AML
(N ≈ 125)
Phase 2
Ongoing
Advanced heme
malignancies with IDH2
mutation
Continuous 28 day cycles
Cumulative daily doses of
50-650 mg
Dose Escalation
Completed
RR-AML age ≥60, or any age if
relapsed post-BMT
RR-AML age <60, excluding pts
relapsed post-BMT
Untreated AML pts age ≥60 who
decline standard of care
Any hematologic malignancy ineligible
for other arms
Expansion Phase I
completed (n=25 pts per arm)

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Most Frequent Treatment Emergent
Adverse Events (≥15% of patients)
Any Grade Grade ≥3
Preferred Term %
Nausea 32 2
Diarrhea 28 3
Fatigue 28 6
Hyperbilirubinemia 27 10
Decreased appetite 27 3
Febrile neutropenia 27 26
Dyspnea 23 5
Pyrexia 23 4
Cough 22 0
Vomiting 20 1
Constipation 19 <1
Anemia 18 12
Peripheral edema 18 2
Thrombocytopenia 16 12

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Dose-escalation and Serious Adverse Events
Dose-escalation
 Highest daily AG-221 dose: 650 mg
 Dose-escalation ended; MTD not reached
Treatment Related Serious Adverse Events
 23% of patients had treatment-related SAEs; most frequent were
differentiation syndrome (4%), leukocytosis (4%), and nausea (2%)
 Drug-related grade 5 SAEs:
 atrial flutter (1)
 cardiac tamponade (1)
 pericardial effusion (1)
 respiratory failure (1)
20

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Differentiation Syndrome
21
• 21 days of AG-221 at 100 mg daily
• Fever, oxygen requirement
• Normal BAL
Courtesy Dr. Stephane De Botton
• Dexamethasone 10 mg BID for 15 days
• Resolution of clinical symptoms
• Patient achieves a complete remission

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Response
22
RR-AML
(n = 159)
Untreated
AML
(n = 24)
MDS
(n = 14)
All
(N = 209)
Overall Response
(CR, CRp, CRi, mCR, PR)
59 (37%)
[95%CI: 30%, 45%]
10 (42%)
[22%, 63%]
7 (50%)
[23%, 77%]
79 (38%)
[31%, 45%]
CR 29 (18%)
[95%CI: 13%, 25%]
4 (17%)
[5%, 37%]
3 (21%)
[5%, 51%]
37 (18%)
[13%, 24%]
CRp 1 (1%) 1 (4%) 1 (7%) 3 (1%)
CRi 3 (2%) 0 0 3 (1%)
mCR 9 (6%) 1 (4%) 3 (21%) 14 (7%)
PR 17 (11%) 4 (17%) 0 22 (11%)
SD 72 (45%) 9 (38%) 6 (43%) 96 (46%)
PD 10 (6%) 1 (4%) 0 11 (5%)
Not evaluable 18 (11%) 4 (17%) 1 (7%) 23 (11%)
• Overall response by IDH mutation type: R140Q 36% / R172K 42%
CR, complete response; CRp, CR with incomplete platelet recovery; CRi, CR with incomplete hematologic recovery; mCR, marrow
CR; PR, partial response; SD, stable disease; PD, progressive disease

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Duration of Response: RR-AML
23
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16
Time (months)
SurvivalProbability
Censored
Median response duration:
6.9 months (95%CI 4.9, 9.7)
Responders: n=59
Median Tx duration: 6.8 months
(range: 1.8-18.0)

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Treatment Durations
0 2 4 6 8 10 12 14 16 18 20
CR
CRp
CRi
mCR
PR
SD
PD
NE/Missing
Treatment Duration (months)

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Hematologic Improvement in a Subset of
Patients with Stable Disease
25
RR-AML (N=159)
Overall Response
37% (n=59)
Stable Disease
45% (n=72)
ANC Increase >1K*
42% (30/72)
Platelet Increase >25K*
63% (19/30)
Platelet Increase >50K*
30% (9/30)
*Absolute increase regardless of baseline counts for ANC and platelets

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Conclusions
 AG-221 is generally well-tolerated
 Most frequent TEAEs were gastrointestinal events
 <10% of patients discontinued due to an adverse event
 Differentiation syndrome observed in a small subset of patients;
appears to be easily managed with steroids
 Induces durable responses in patients with RR-AML:
 Overall response rate 37%
 Median duration of response to-date 6.9 months
 Improvement in ANC and platelets was observed in a
subset of RR-AML patients with stable disease
 Randomized phase 3 study of AG-221 vs conventional
care regimens initiated (IDHENTIFY trial; NCT02577406)
26

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 OSU 14169: Pacritinib and Induction chemotherapy
in newly diagnosed AML with FLT3 mutations or
pacritinib with decitabine with newly diagnosed unfit
or relapsed/refractory AML
 PI: Dr. Tina Bhatnagar
 OSU 14239: AG-120 (IDH1 inhibitor)
 PI: Dr. Alice Mims
 OSU 14143: AG-221 (IDH2 inhibitor) in
relapsed/refractory AML
 PI: Dr. Alice Mims
 Upcoming: AG-120 or AG-221 combined with
Induction in Newly diagnosed AML
Ongoing clinical trials at OSU
27

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Acute Lymphocytic Leukemia

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Immune therapy in ALL

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Addition of Rituximab Improves the Outcome of Adult
Patients with CD20-Positive, Ph-Negative, B-Cell
Precursor Acute Lymphoblastic Leukemia (BCP-ALL):
Results of the Randomized Graall-R 2005 Study
Sébastien Maury, Sylvie Chevret, Xavier Thomas, Dominik Heim, Thibaut Leguay,
Françoise Huguet, Patrice Chevallier, Mathilde Hunault, Nicolas Boissel, Martine
Escoffre-Barbe, Urs Hess, Norbert Vey, Thorsten Braun, Jean-Pierre Marolleau,
Yves Chalandon, Véronique Lhéritier, Kheira Beldjord, Marie-Christine Béné, Norbert
Ifrah, and Hervé Dombret
Plenary Abstract # 1

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GRAALL-R: Study Design
 Multicenter, randomized, phase III study from 2005-2014
 CD20 expressed in 30% to 40% of B-cell precursor ALL pts, associated with
worse outcomes
 Allogeneic SCT offered in first CR to pts with ≥ 1 high-risk criteria
 Primary endpoint: EFS
 Secondary endpoints: relapse/death in first CR, safety, EFS after censoring pts given
allogeneic SCT in first CR
 209 pts in mITT analysis (n = 11 excluded for noneligibility criteria)
CD20+ Ph- tx-naïve
BCP-ALL pts
18-59 yrs of age with ≥ 20%
CD20+ blasts and no other
current/recent malignancies
(N = 220)
Standard Chemo + Rituximab
IV 375 mg/m2 16-18 infusions
(n = 105)
Standard Chemo w/out Rituximab
(n = 104)

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GRAALL-R: Baseline Characteristics
Characteristic
All
(N = 209)
Rituximab
(n = 105)
No
Rituximab
(n = 104)
P Value
Median age, yrs 40.2 39.9 41.5 .90
ECOG PS ≥ 2, n (%) 27 (13) 9 (9) 18 (18) .06
WBC ≥ 30 x 109/L, n (%) 44 (21) 21 (20) 23 (22) .74
CNS involvement, n (%) 13 (6) 7 (7) 6 (6) .99
Poor PB blast clearance, n (%) 34 (16) 20 (19) 14 (13) .27
Poor BM blast clearance, n (%) 87 (42) 46 (44) 41 (39) .58
High-risk ALL, n (%) 140 (67) 73 (70) 67 (64) .46
Allogeneic SCT in CR1, n (%) 57 (27) 36 (34) 21 (20) .03
Median CD20 positivity, % (range) 66 (0-100) 61 (0-100) 69 (1-100) .24

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GRAALL-R: Response Rates
Response, n (%)
Rituximab
(n = 105)
No Rituximab
(n = 104)
P Value
CR in 1 induction course 95 (91) 91 (88) .52
CR 97 (92) 94 (90) .63
Resistant disease 1 (1) 1 (1) .99
Induction deaths 7 (7) 9 (9) .61
Postinduction MRD < 10-4 32/49 (65) 22/36 (61) .82
Postconsolidation MRD < 10-4 42/46 (91) 28/34 (82) .31

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GRAALL-R: Efficacy
Rituximab vs No Rituximab
Outcome Probability, % HR (95% CI) Adjusted HR* (95% CI)
EFS
(2 year)
65 vs 52 0.66 (0.45-0.98)
P = .038
0.59 (0.37-0.93)
P = .021
OS
(2 year)
71 vs 64 0.70 (0.46-1.07)
P = .095
0.55 (0.34-0.91)
P = .018
Cumulative
Incidence
of Relapse
18 vs 32 0.52 (0.31-0.89)
P = .017
0.49 (0.27-0.89)
P = .018

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GRAALL-R: Conclusions
 Rituximab added to chemotherapy demonstrated clinical benefit
vs chemotherapy alone in adult pts with CD20+, Ph- BCP-ALL
 Improved EFS (P = .038)
 Prolonged OS in pts not receiving SCT during CR1 (P = .018)
 Well-tolerated safety profile in the rituximab group vs standard
chemo alone
 The investigators conclude that adding rituximab to standard
chemotherapy should become a standard of care for patients
with CD20+, Ph- BCP-ALL
 They note that further study required to determine optimal
rituximab dosing

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Complete Molecular and Hematologic Response in
Adult Patients with Relapsed/Refractory Philadelphia
Chromosome-Positive B-Precursor Acute
Lymphoblastic Leukemia Following Treatment with
Blinatumomab: Results from a Phase 2 Single-Arm,
Multi-Center Study
36
Giovanni Martinelli, Hervé Dombret, Patrice Chevallier, Oliver G. Ottmann, Nicola
Goekburger, Max S. Topp, Adele K. Fielding, Lulu Ren Sterling, Jonathan Benjamin,
and Anthony Selwyn Stein
Oral Abstract # 679

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ALCANTARA: Background
 Blinatumomab, a bispecific T-cell engaging antibody
construct, has shown antileukemic activity in Ph- ALL
 43% of pts achieved CR/CRh in first 2 cycles of
blinatumomab monotherapy
 Pts with R/R Ph+ ALL have a poor overall prognosis
despite improved outcomes from TKI therapy
 ALCANTARA evaluated efficacy and safety of
blinatumomab in pts with R/R Ph+ ALL resistant to
TKI

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ALCANTARA: Study Design
 Phase II single arm study
 Primary endpoint: CR/CRh during first 2 cycles
 Secondary endpoints: best CR, MRD, RFS, OS, allogeneic HSCT rate,
and safety
Adults with R/R
Ph+ B-precursor
ALL; ECOG PS
0-2; > 5% BM
blasts; failed TKI
(N = 45)
Blinatumomab IV
9 µg/day x 1wk
28 µg/day x 3 wks (cycle 1)
28 µg/day x 4 wks (cycle 2)
(4 wks on, 2 wks off)
Consolidation:
Blinatumomab IV
28 µg/day x 4 wks
≤ 3 cycles
(4 wks on, 2 wks off)
Follow-up at
30 days and
≤ 18 mos
Primary Endpoint Assessed
During First 2 Cycles

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ALCANTARA: Efficacy
 Median RFS: 6.7 mos (95% CI: 4.4-NE)
 Median OS: 7.1 mos (95% CI: 5.6-NE)
Parameter Response, %
Primary endpoint
CR/CRh (first 2 cycles)
T315l mutation
≥ 2 prior 2+ gen TKI
Prior ponatinib treatment
36
40
41
35
Secondary endpoints
Best response (first 2 cycles)
CR
CRh
CRi (not including CRh)
31
4
4
Complete MRD response*
MRD response in pts with ABL-kinase mutations
88
100
Proceeded to allogeneic HSCT 25

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ALCANTARA: Conclusions
 Blinatumomab achieved antileukemic activity in Ph+ R/R
ALL pts with poor prognosis and previous failure of TKI
therapy
 CR/CRh rate: 36%
 Response to therapy was independent of T315l mutation
 100% of responders with ABL-kinase domain mutations had
complete MRD response
 Median OS: 7.1 mos
 Safety profile consistent with blinatumomab treatment of
pts with Ph- R/R ALL

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 ECOG E1910: Randomized Trial Incorporating
Blinatumomab in Upfront Therapy for Ph- B Adult
ALL (Ages 30-70)
 PI: Dr. Rebecca Klisovic
 SWOG S1318: Upfront Therapy Blinatumomab with
POMP for Ph- Adult ALL or Blinatumomab with
Dasatinib/Prednisone for Ph+ Adult ALL (Ages ≥ 65)
 PI: Dr. Rebecca Klisovic
Ongoing clinical trials at OSU
41

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Myelodysplastic Syndrome

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Eltrombopag for the Treatment of Thrombocytopenia
of Low and Intermediate-1 IPSS Risk Myelodysplastic
Syndromes: Interim Results on Efficacy, Safety, and
Quality of Life of an International, Multicenter
Prospective, Randomized, Trial
43
Esther Natalie Olivia, Valeria Santini, Caterina Alanti, Antonella Poloni, Alfredo
Molteni, Pasquale Niscola, Grazia Sanpaolo, Flavia Salvi, Giuseppe A. Palumbo,
Enrico Balleari, Stefana Impera, Agostino Cortelezzi, Anna Marina Liberati, Paolo
Avanzini, Paolo Di Bartolomeo, Christian Rose, Odile Beyne-Rauzy, Francesco
Buccisano, Monica Bocchia, Fortunato Morabito, Aspasia Stamatoullas, Francesca
Ronco, Gina Zini, Maria Grazia D’Errigo, Natale Ranieri, Patrizia Cufari, Irene
Santacanterina, Pierre Fenaux, and Roberto Latagliata
Oral Abstract # 91

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EQoL-MDS: Background
 Severe thrombocytopenia occurs in approximately 10% of lower-risk
pts with MDS
 PLT transfusions given for lower IPSS risk pts with bleeding (occurs in
~ 25% pts with low, int-1 risk MDS)
 Thrombopoetin receptor agonists in MDS
 Romiplostim: ↑ PLT responses and ↓ PLT transfusion events vs placebo in
pts with low/int-1 risk MDS, but ↑ peripheral blast cell counts led to study
closure
 OS and AML-free survival similar to placebo
 Eltrombopag: thrombopoetin receptor agonist
 Antiproliferative effects against many AML cell lines but not against
normal cells
 Reduces intracellular iron and induction of differentiation

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EQoL-MDS: Study Design
 Interim results from an international, multicenter, prospective, randomized phase I/II study
 Primary endpoints: phase I—CR or R, safety, and tolerability; phase II—duration of PLT
response, long-term safety, and tolerability
 Secondary endpoints: changes in QoL scores, PLT transfusion frequency, duration of PLT
transfusion independence, TTR, bleeding incidence/severity, OS, leukemia-free survival
Low or int-1 IPSS risk
MDS, relapsed or
refractory to other
treatment options,
PLT < 30 Gi/L
(N = 174)
Eltrombopag*
+ standard care
(n = 116)
Placebo
+ standard care
(n = 58)
Randomized 2:1
Wk 24
CR, R
CR, R
*Eltrombopag started at 50 mg, increasing every 2 wks up to 300 mg/day.
Eltrombopag
+ standard care
Standard care

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EQoL-MDS: Baseline Characteristics
Characteristic Eltrombopag (n = 46*) Placebo (n = 24*)
Mean age, yrs (SD) 69 (11) 66 (16)
Female, % 41 54
Median MDS duration, mos (IQR) 9 (2-39) 9 (2-18)
IPSS risk, %
 Low
 Int-1
26
74
42
58
WHO bleeding score ≥ 2, % 11 12
PLT transfusion dependent, n (%) 33 33
Mean PLT, x 109 (SD) 17.4 (8.1) 16.3 (8.6)
RBC transfusion dependent, % 33 37
Mean Hb, g/dL (SD) 9.9 (2.6) 11 (2.2)
Cytogenetics normal, n
 del20q
36
6
16
3
*Of 70 pts randomized, 24 remain in eltrombopag arm (1 death, 3 each persistent, AML evolution, MDS progression) and
11 in placebo arm (1 each of AML evolution, MDS progression); 1 pt ongoing in each arm.

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EQoL-MDS: Response
8 Wks 24 Wks
Response, n Eltrombopag
(n = 41)
Placebo
(n = 17)
Eltrombopag
(n = 24)
Placebo
(n = 11)
Total responses 21 0 13 3
R 12 0 5 3
CR 9 0 8 0
NR 20 17 11 8
WHO bleeding grade ≥ 2, events 1 2 3 1

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50,000
EQoL-MDS: Mean Change in PLT Counts
8 wks
250,000
200,000
150,000
100,000
0
P < .0001 P < .004
24 wks
50,000
250,000
200,000
150,000
100,000
0
Placebo Eltrombopag Placebo Eltrombopag
26
69
25

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EQoL-MDS: Hematologic Responses
 CRs observed in 2 pts on eltrombopag at 3 mos and in 4 additional pts on
eltrombopag at 6 mos
 Differences between treatment arms in grade 3 bone marrow fibrosis, MDS
progression, and AML evolution were not significant
 Variables significantly associated with platelet response: eltrombopag arm
(P = .002) and baseline hemoglobin levels (P = .008)
8 Wks 24 Wks
Response, n Eltrombopag
(n = 41)
Placebo
(n = 17)
Eltrombopa
g
(n = 24)
Placebo
(n = 11)
Erythroid response 4* 0 4 0
Neutrophil response 4† 1 1 1
*2 stable, 1 MDS progression, 1 liver toxicity.
†1 stable, 1 MDS progression, 1 AML evolution, 1 retrieved consent.

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EQoL-MDS: Conclusions
 Eltrombopag in pts with low/intermediate-1 risk MDS and
severe thrombocytopenia:
 Interim results reveal increased platelet counts, durable PLT
responses vs placebo
 May induce hematological remission in some pts
 Associated with manageable toxicity
 No association with MDS progression or AML evolution
 Pts who responded to eltrombopag reported improved QoL
from baseline
 Trial will continue to evaluate long-term safety, impact on
survival

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Key Points
 AML
 FLT3 inhibition with midostaurin plus standard induction will
likely become the standard of care for newly diagnosed younger
adult AML patients with FLT3 mutated disease
 Small molecular inhibitors that target recurrent molecular
mutations in AML appear to show clinical response and may
allow some patients with relapsed/refractory disease to bridge to
transplantation
 ALL
 The role of immunotherapy in ALL continues to evolve and will
likely soon become part of the standard of care in both upfront
and the relapsed/refractory setting
 MDS
 Targeting the thrombopoietin receptor with eltrombopag in
low/int-1 risk disease appears to improve clinically significant
thrombocytopenia without increasing risk of disease progression
with early findings
51

Research Institute
Acknowledgements
 Thanks to Drs. Richard Stone (midostaurin) and
Eytan Stein (AG-221) for providing me with their
ASH presentation slides for this ASH review.
 I have modified some of the slides due to our time
constraints. This material is unpublished and these
slides should not be reproduced without the consent
of the authors.
52

Research Institute
 Questions?
53

Ohio State's 2016 ASH Review - ASH Review 2015 Acute Leukemias and MDS

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