William Blum, MD
The Ohio State University and James
Cancer Hospital

• Low and intermediate-1 risk MDS
• Intermediate-2 and high risk MDS

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)

Overall survival (OS)
1.0
0.8
0.6
0.4
0.2
0.0
0 1
P < .001
< 60 yrs 1.0
0.8
Favorable (n=339)
Intermediate-II (n=156)
0.6
Intermediate-I (n=144)
0.4
0.2
Adverse (n=179)
0.0
5 0 2
Years
3 4
P < .001
Adverse (n=229)
1 2 Years 3
≥ 60 yrs
Favorable (n=145)
Intermediate-II (n=222)
Intermediate-I (n=136)
4 5
ELN classification, slide courtesy Mrozek, K

Levine, ASH education book 2012, from Patel NEJM 2012

Intensified Induction in AML Patients < 60
ECOG E1900
Untreated AML, N=657, median age 47
Induction Post -Remission
DNR 45 mg/m 2 x 3 days
+ Cytarabine
100 mg/m 2 x 7 days
1-2 course to CR
High-dose
Cytarabine x 2
DNR 90 mg/m 2 x 3 days
Sibling Allogeneic
HCT
Observation
Gemtuzumab
Ozogamicin
6 mg/m 2 IV day 1
(DISCONTINUED)
Auto-
HCT
Fernandez HF, et al. N Engl J Med. 2009;361(13):1249-1259.

ECOG E1900: Overall Survival
0.6
0.5
0.4
0.3
1.0
0.9
0.8
0.7
0.2
0.1
0.0
0
Log Rank
P = 0.003
10 20
All Patients
(N = 647)
Induction Treatment
DNR 45 mg/m 2 /day
DNR 90 mg/m 2 /day
50
N = 327
N = 330
60 70 80 30 40
Month
Induction Deaths
DNR 45 DNR 90 P
4.5% 5.5% 0.60
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
Favorable and
Intermediate Cytogenetics
Log Rank
P=0.004
10 20 30
Month
40
N = 178
N = 180
50 60 70
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
Unfavorable Cytogenetics
Log Rank
P = 0.45
10 20 30
Month
40
N = 63
N = 59
50 60
Fernandez HF, et al. N Engl J Med. 2009;361(13):1249-1259.

• 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

CR
2 yr EFS
Death in CR
Death during induction
Relapse
ATRA+ATO
N=75
75 (100)
97%
1
0
2
AIDA
N=79
75 (95)
86.7%
3
4
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

• 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

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

• 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

*including t-AML
Core binding factor (CBF) +
AML
High dose
Ara-c
(HIDAC) x 3
ADE
Non-CBF AML HIDAC/VP chemomob
Bu/VP autologous
PBSCT
(or HIDAC x2)
Kolitz, et al, manuscript in review

• 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

• Eligible if adequate count recovery within 60-90 days of last consolidation/autoPBSCT
• Decitabine 20mg/m 2 /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

Received decitabine, N
CBF AML, N
Non-CBF AML, N
134
46 (34%)
88
73 auto + 15 HIDAC
6.3 Time from induction to maintenance, months
Median age, years 45 (range, 18-60)
Median presenting WBC count, x10 9 /L
13.5 (range, 0.4-221)

Decitabine administration data, N=132
Total number of cycles given, N 770
7 Median number of cycles given/patient, N
Treatment duration
– Patients who received all 8 cycles, %
– Patients who received at least 4 cycles, %
Reasons that < 8 cycles were given
– Relapse, %
– Patient refusal, %
– Adverse events, %
– Other, including unknown, %
46
75
53
25
7
15

Adverse Event Cycle
1 2 3 4 5 6 7 8 U
Grade >3
Neutrophil, N
102
Total cycles
77 65 56 55 40 27 23 11 456/770
59%
Any Grade
Infection, N
Infection with
Grade >3
Neutrophil, N
Grade >3
Platelets, N
28 11 8 11 7 6 4 3 1
12
77
4 1 7 1 1 0 2
38 37 27 26 21 12 9
0
6
79
10%
28
4%
253
33%
N, Number of patients with adverse event in each cycle
U, Unknown cycle number

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

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

• 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…

• 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

• 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): 25.3 ITD+ vs. 19.0 ITD-
– Most common Grade 3-4 toxicities myelosuppression and QTc prolongation
Cortes JE et al. Abstract No. 48

• 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): 23.1 ITD+ vs. 25.6 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

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

• 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%

• 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)

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)

• 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

• 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

• 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

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?