2. 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
3. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Acute Myeloid Leukemia
4. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Cytogenetic and Molecular Subsets in Younger AML
patients
4
Grimwade, et al. Blood 2016;127: 29-41
5. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
6. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
FLT3 Structure and Activating
Mutations
5-10%
Litzow MR. Blood. 2005;106:3331-3332.
7. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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.
8. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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%)
9. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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)
10. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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.
11. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
12. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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)
13. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Kaplan Meier Curve: Overall Survival
Censored at time of transplant
NE: not estimable
* controlled for FLT3 subtype (TKD, ITD-Low, ITD-High)
14. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
KM survival Curves for Overall Survival
post-transplant
All Transplants SCT in/outside of CR1
NE: not estimable
15. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
16. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
17. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
18. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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)
19. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 19
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
20. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
21. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
22. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
23. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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)
24. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 24
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)
25. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
26. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
27. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
28. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Acute Lymphocytic Leukemia
29. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Immune therapy in ALL
30. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
31. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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)
32. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
33. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
34. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
35. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
36. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
37. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
38. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
39. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
40. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
41. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
42. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Myelodysplastic Syndrome
43. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
44. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
45. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
46. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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.
47. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
48. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
49. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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.
50. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
51. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
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52. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
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.
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53. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Questions?
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