1. AML and MDS: Highlights from 2012
William Blum, MD
The Ohio State University and James Cancer Hospital

2. Our agenda- Highlights from 2012
Risk stratification and treatment decisions in AML
Novel treatment strategies for AML
Low and intermediate-1 risk MDS
Intermediate-2 and high risk MDS

3. France talk ELN 10-15 final shortened
4/15/2017 5:16 AM
ELN Standardized Reporting System for correlation of cytogenetic and molecular genetic data with clinical data in AML*
Genetic Group
Subsets
Favorable
t(8;21)(q22;q22); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD (normal karyotype)
Mutated CEBPA (normal karyotype)
Intermediate-I
Mutated NPM1 and FLT3-ITD (normal karyotype)
Wild-type NPM1 and FLT3-ITD (normal karyotype)
Wild-type NPM1 without FLT3-ITD (normal karyotype)
Intermediate-II
t(9;11)(p22;q23); MLLT3-MLL; Cytogenetic abnormalities not classified as favorable or adverse
Adverse
inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 t(6;9)(p23;q34); DEK-NUP214
t(v;11q23); MLL rearranged –5 or del(5q); –7; abn(17p); complex karyotype (≥3 abn)
* International expert panel recommendations on behalf of ELN (Blood 115:453-74, 2010)

4. France talk ELN 10-15 final shortened
4/15/2017 5:16 AM
Overall survival (OS)
Favorable (n=339)
Intermediate-II (n=156)
< 60 yrs
Intermediate-I (n=144)
Adverse (n=179)
Overall Survival
Years
P < .001
≥ 60 yrs
Intermediate-II (n=222)
Intermediate-I (n=136)
Adverse (n=229)
Years
Favorable (n=145)
P < .001
ELN classification, slide courtesy Mrozek, K

5. Levine, ASH education book 2012, from Patel NEJM 2012

6. Intensified Induction in AML Patients < 60 ECOG E1900
Untreated AML, N=657, median age 47
Induction
Post -Remission
DNR 45 mg/m2
x 3 days
Observation
1-2 course
to CR
High-dose
Cytarabine
x 2
+ Cytarabine
100 mg/m2 x 7 days
Auto-
HCT
DNR 90 mg/m2
x 3 days
Gemtuzumab
Ozogamicin
6 mg/m2 IV day 1
(DISCONTINUED)
Sibling Allogeneic
HCT
Fernandez HF, et al. N Engl J Med. 2009;361(13):

7. ECOG E1900: Overall Survival
Favorable and Intermediate Cytogenetics
All Patients
(N = 647)
1.0
0.9
0.8
0.7
1.0
0.6
N = 178
Probability
0.5
0.9
Induction Treatment
DNR 45 mg/m2/day
DNR 90 mg/m2/day
0.4
0.8
0.3
0.2
Log Rank
P=0.004
N = 180
0.7
0.1
0.6
0.0 10 20 30 40 50 60 70
Probability
0.5
N = 327
Month
0.4
Unfavorable Cytogenetics
0.3
1.0
0.9
0.2
N = 330
0.8
Log Rank
P = 0.003
0.1
0.7
0.6
0.0
Probability
0.5 10 20 30 40 50 60 70 80
0.4
Month
0.3
N = 63
0.2
Log Rank
P = 0.45
N = 59
DNR 45
DNR 90 P
Induction Deaths
4.5%
5.5%
0.60
0.1
0.0 10 20 30 40 50 60
Month
Fernandez HF, et al. N Engl J Med. 2009;361(13):

8. APL: ATO in induction chemotherapy
Randomized, Phase III trial comparing ATRA+ arsenic trioxide (ATO) vs. ATRA+ standard chemotherapy in non-high risk APL (WBC <10K)
Primary objective: EFS at 2 years; non-inferiority trial (at least 80% of pts alive and free from events at 2 years)
ATRA+ATO vs. AIDA
Lo-Coco et al. Abstract No. 6
Plenary abstract

9. Death during induction 4 Relapse 2 5
ATRA+ATO
N=75
AIDA
N=79 CR
75 (100)
75 (95)
2 yr EFS
97%
86.7%
Death in CR 1 3
Death during induction 4
Relapse 2 5
Fevers, prolonged neutropenia, and thrombocytopenia more common in chemotherapy arm
Hyperleukocytosis more frequent in ATO arm
Other events such as differentiation syndrome and increased LFTs similar in both arms
One patient in ATO arm discontinued therapy due to prolonged QTc
Lo-Coco et al. Abstract No. 6

10. Median follow up 31 months (0.07-50.4)
For patients with newly diagnosed, non-high risk APL, ATO+ATRA induction was at least not inferior for 2 year EFS when compared to standard chemotherapy based regimen
Lo-Coco et al. Abstract No. 6

11. on behalf of the Alliance for Clinical Trials in Oncology
Maintenance Therapy with Decitabine in Younger Adults with Acute Myeloid Leukemia (AML) in First Remission: a Phase II Cancer and Leukemia Group B Study (Alliance 10503)
William Blum, Ben Sanford, Rebecca Klisovic, Daniel J. DeAngelo, Geoffrey Uy, Bayard L. Powell, Wendy Stock, Maria R. Baer, Jonathan E. Kolitz, Meir Wetzler, Eva Hoke, Clara D. Bloomfield, Susan Geyer, Guido Marcucci, Richard M. Stone, and Richard A. Larson
on behalf of the Alliance for Clinical Trials in Oncology

12. Maintenance in AML No compelling data for cytotoxic chemotherapy
Not better than intensive therapy; Cassileth, Blood 1992
Studied, but abandoned; Mayer, NEJM 1994
Low dose ara-c q6 weeks showed modest benefit for DFS but not OS in older patients; Lowenberg, JCO 1998
Gemtuzumab ozogamicin, no benefit
3 courses ineffective in younger patients; Petersdorf, ASH 2009 (S0106)
Ineffective in older patients; Lowenberg, Blood 2010
Immunotherapy
Allogeneic transplantation…
Vaccine therapy (WT1, PR1, hTERT, CD168, etc) promising?
IL-2/ histamine dihydrochloride improved LFS compared to observation; Brune, Blood 2006
IL-2 efficacious but did not meet survival endpoint; Kolitz, CALGB 19808

13. CALGB 19808 newly diagnosed, untreated AML<60 years
CALGB newly diagnosed, untreated *AML<60 years *including t-AML
CALGB newly diagnosed, untreated AML<60 years
IL-2 maintenance randomization
Decitabine maintenance therapy
Core binding factor (CBF) + AML
High dose Ara-c (HIDAC) x 3
ADE
Bu/VP autologous PBSCT
(or HIDAC x2)
Non-CBF AML
HIDAC/VP chemomob
Kolitz, et al, manuscript in review

14. Primary Endpoint
Decitabine given for 1 year following intensive induction and consolidation
DFS
Feasibility, tolerability/ toxicities
Detect DFS difference of 15% (at one year) in non-CBF patients
Historical control of previous CALGB trials, identical induction and risk-adapted consolidation therapies

15. Treatment plan: Decitabine
Eligible if adequate count recovery within days of last consolidation/autoPBSCT
Decitabine 20mg/m2/day IV over 1 hour for 5 days *
Cycles repeated every 6 weeks
Total of 8 cycles (≈1 year post-consolidation)
* Dose modifications based on hematologic toxicity

16. Patient characteristics, decitabine
Received decitabine, N
134
CBF AML, N
46 (34%)
Non-CBF AML, N 88
73 auto + 15 HIDAC
Time from induction to maintenance, months
6.3
Median age, years
45 (range, 18-60)
Median presenting WBC count, x109/L
13.5 (range, )

17. Decitabine administration data, N=132
Total number of cycles given, N
Median number of cycles given/patient, N 7
Treatment duration
Patients who received all 8 cycles, % 46
Patients who received at least 4 cycles, % 75
Reasons that < 8 cycles were given
Relapse, %
Patient refusal, %
Adverse events, % 7
Other, including unknown, % 15

18. Myelosuppression and infection, per cycle
Adverse Event
Cycle 1 2 3 4 5 6 7 8 U
Total cycles
Grade >3 Neutrophil, N
102 77 65 56 55 40 27 23 11
456/770
59%
Any Grade Infection, N 28 1 79
10%
Infection with Grade >3 Neutrophil, N 12 4%
Grade >3 Platelets, N 38 37 26 21 9
253
33%
N, Number of patients with adverse event in each cycle
U, Unknown cycle number

19. DFS for 10503 (and historical control, 19808), based on CBF status
DFS, vs , CBF AML
DFS, vs , non-CBF AML

20. DFS for 10503 (and historical control, 19808), based on CBF status
DFS, vs , CBF AML
DFS, vs , non-CBF AML
10503
Historical control, observation/IL-2
1 year OS, % 96
3 year OS, % 66
61/68
1 year DFS, % 80
3 year DFS, % 53
45/56

21. Conclusions
For younger patients in CR after induction and consolidation, decitabine maintenance did not improve clinical outcome relative to the historical control
For your practice
Maintenance therapy with azanucleosides remains investigational…

22. Relapsed/refractory AML – AC220
Single agent quizartinib (AC220) Phase 2 trials
FLT3 inhibitor
Age >60 years with AML relapsed in <1 yr or refractory to induction chemotherapy (n=134)
Age >18 years with AML relapsed or refractory after salvage chemotherapy or HSCT (n=137)
Both trials included FLT3-ITD positive and negative patients

23. Relapsed/refractory AML – AC220
Age >60 years with AML relapsed in <1 yr or refractory to induction chemotherapy (n=134)
Single agent
CR/CRi/CRp: 54% ITD+ vs. 32% ITD-
Median OS (weeks): ITD+ vs ITD-
Most common Grade 3-4 toxicities myelosuppression and QTc prolongation
Cortes JE et al. Abstract No. 48

24. Relapsed/refractory AML
Age >18 years with AML relapsed or refractory after salvage chemotherapy or HSCT (n=137)
Single agent
CR/CRi/CRp: 44% ITD+ vs. 34% ITD-
Median OS (weeks): ITD+ vs ITD-
Primary Grade 3-4 toxicities myelosuppression and QTc prolongation
* FLT3 D835 mutations resistant to AC220; new inhibitor, crenolanib, appears to have activity in vitro (Smith CC et al. Abstract No. 141)
Levis MJ et al. Abstract No. 673

25. CALGB /BMT CTN 0502
A Phase II Study of Allogeneic Transplant for Older Patients with AML in First Morphologic Complete Remission Using a Reduced Intensity Preparative Regimen
Steven M. Devine, Kouros Owzar, William Blum, Daniel DeAngelo, Richard M. Stone, Jack W Hsu, Richard E. Champlin, Yi-Bin A. Chen, Ravi Vij, James L Slack, Robert J. Soiffer, Richard A. Larson, Thomas C. Shea, Vera Hars, Elizabeth Bennett, Sada Spangle, Sergio A Giralt, Shelly L Carter, Mary M. Horowitz, Charles Linker, and Edwin P Alyea III on behalf of The Alliance and Blood and Marrow Transplant Clinical Trials Network

26. CALGB 100103/BMT CTN 0502 AML CR1, age 60-74
Primary objective 2-year DFS > 35%
90% power to exclude historical DFS < 20% (based on CALGB and multiple cooperative group trials)
Stopping rules for TRM
Assume true TRM 20%
Unacceptable TRM 40%

27. CALGB 100103/BMT CTN 0502 Demographics
Related: N=58; Unrelated N=65
Median age 65yrs (60-74); related: 64.5; unrelated: 66
M/F-- 76/47
Cytogenetic risk (CALGB criteria)
Favorable: 1
Intermediate: 83
Adverse: 25
Missing: 14
Donor age (median; range)
Related: 63yrs (43-81); Unrelated: 30 (19-55)

28. CALGB 100103/BMT CTN 0502 Disease free/Overall Survival
DFS at 2 yrs: 39%
(95% CI: 30-50%)
OS at 2 yrs: 46%
(95% CI: 36-57%)
Median follow up: 3.3 yrs (related: 3.9 yrs; unrelated: 2.9 yrs)

29. MDS
Kantarjian, et al--Update on randomized trial placebo vs romiplostim in low/ int-1 risk MDS
Trial had been closed prematurely due to DSM concern of increased transformation to AML in romiplostim arm
Updated data show statistically similar rates of OS and transformation to AML (median f/u 18mo)
Romiplostim showed some evidence of (very modest) efficacy in terms of reducing bleeding complications
Kantarjian HM et al. Abstract No. 421

30. MDS
Garcia-Manero, et al---Extended dosing of oral azacitidine appears to be safe and effective in lower risk MDS
Response rates 39 or 30% in 14 or 21 day dosing (respectively)
Transfusion independence achieved in 47 or 33%
Garcia-Manero et al. Abstract No. 424

31. Relapsed/refractory AML/MDS
SGI-110 (n=78 included AML and higher risk MDS)
Single agent, dinucleotide of decitabine/guanosine
designed to provide extended exposure with subcutaneous administration
Phase 1-2 PK/PD guided dose-escalation study
Two regimens: daily x 5 doses OR weekly x 3; both with 28 day courses
AML responses (n=44): 2 CRs, 1 CRp, 1 CRi
Dose related hypomethylation observed
Decitabine exposure increased in dose-proportional manner
Kantarjian HM et al. Abstract No. 414

32. Conclusions
Advances in biology for both AML and MDS, most that are not (yet) clinically relevant for day-to-day clinical practice, will be the cornerstone for novel therapies in the next decade.
What about your practice today?
For non-high risk APL, ATO-based induction viable option
Albeit an expensive one
Maintenance decitabine does not appear to improve outcomes in younger AML patients in CR1
Many promising early phase clinical studies in AML and/or MDS, next year?