AML - Imedex

Report
AML and MDS:
Highlights from 2012
William Blum, MD
The Ohio State University and James
Cancer Hospital
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
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
< 60 yrs
P < .001
0.8
0.8
Favorable (n=145)
Overall Survival
Favorable (n=339)
0.6
Intermediate-II (n=222)
Intermediate-I (n=136)
0.6
Intermediate-II (n=156)
0.4
Intermediate-I (n=144)
0.2
≥ 60 yrs
P < .001
1.0
0.4
0.2
Adverse (n=229)
Adverse (n=179)
0.0
0.0
0
1
2
3
4
Years
ELN classification, slide courtesy Mrozek, K
5
0
1
2
Years 3
4
5
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/m2
x 3 days
Observation
1-2 course
to CR
+ Cytarabine
100 mg/m2 x 7 days
High-dose
Cytarabine
x2
DNR 90 mg/m2
x 3 days
AutoHCT
Gemtuzumab
Ozogamicin
Sibling Allogeneic
HCT
Fernandez HF, et al. N Engl J Med. 2009;361(13):1249-1259.
6 mg/m2 IV day 1
(DISCONTINUED)
ECOG E1900: Overall Survival
All Patients
(N = 647)
Probability
1.0
1.0
0.9
Induction Treatment
0.8
DNR 45 mg/m2/day
DNR 90 mg/m2/day
Probability
0.7
Favorable and
Intermediate Cytogenetics
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
N = 178
Log Rank
P=0.004
N = 180
0.0
0.6
0
10
20
30
0.5
N = 327
0.4
40
50
60
70
Month
Unfavorable Cytogenetics
1.0
0.3
0.9
0.2
0.0
0
10
20
30
40
50
60
70
80
Month
Probability
0.1
0.8
N = 330
Log Rank
P = 0.003
0.7
0.6
0.5
0.4
0.3
0.1
Induction Deaths
DNR 45
DNR 90
P
4.5%
5.5%
0.60
Fernandez HF, et al. N Engl J Med. 2009;361(13):1249-1259.
N = 63
Log Rank
P = 0.45
0.2
N = 59
0.0
0
10
20
30
Month
40
50
60
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
ATRA+ATO
N=75
AIDA
N=79
75 (100)
75 (95)
97%
86.7%
Death in CR
1
3
Death during induction
0
4
Relapse
2
5
CR
2 yr EFS
• 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
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
CALGB 19808
10503
CALGB
newlydiagnosed,
diagnosed, untreated
*AML<60
years
newly
untreated
AML<60
years
*including t-AML
Core binding
factor (CBF) +
AML
High dose
Ara-c
(HIDAC) x 3
Decitabine
IL-2
maintenance
randomization
therapy
ADE
Bu/VP
autologous
PBSCT
Non-CBF AML
HIDAC/VP
chemomob
(or HIDAC x2)
Kolitz, et al, manuscript in review
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
Treatment plan: Decitabine
• Eligible if adequate count recovery within 60-90
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
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, 0.4-221)
Decitabine administration data, N=132
Total number of cycles given, N
770
Median number of cycles given/patient, N
7
Treatment duration
– Patients who received all 8 cycles, %
– Patients who received at least 4 cycles, %
46
75
Reasons that < 8 cycles were given
–
–
–
–
Relapse, %
Patient refusal, %
Adverse events, %
Other, including unknown, %
53
25
7
15
Myelosuppression and infection, per cycle
Adverse Event Cycle
1
2
Grade >3
Neutrophil, N
Any Grade
Infection, N
102
77 65 56 55 40 27 23 11 456/770
59%
11 8 11 7 6 4 3 1
79
10%
Infection with
Grade >3
Neutrophil, N
Grade >3
Platelets, N
12
4
2
0
28
4%
77
38 37 27 26 21 12 9
6
253
33%
28
3
1
4
7
5
1
6
1
7
0
8
U
N, Number of patients with adverse event in each cycle
U, Unknown cycle number
Total
cycles
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
10503
1 year OS, %
96
3 year OS, %
66
DFS, 10503 vs. 19808, non-CBF AML
Historical control,
observation/IL-2
61/68
1 year DFS, % 80
3 year DFS, % 53
45/56
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…
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
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): 25.3 ITD+ vs. 19.0 ITD– Most common Grade 3-4 toxicities
myelosuppression and QTc prolongation
Cortes JE et al. Abstract No. 48
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): 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
CALGB 100103/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
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%
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)
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)
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
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
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
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?

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