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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 .

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Aml and mds highlights from 2012

AML and MDS:Highlights from 2012

William Blum, MD

The Ohio State University and James Cancer Hospital


Our agenda highlights from 2012
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*

* International expert panel recommendations on behalf of ELN (Blood 115:453-74, 2010)


Overall survival (OS)

< 60 yrs

≥ 60 yrs

P < .001

P < .001

Favorable (n=339)

Favorable(n=145)

Intermediate-II (n=222)

Intermediate-II (n=156)

Intermediate-I (n=136)

Overall Survival

Intermediate-I (n=144)

Adverse (n=179)

Adverse (n=229)

Years

Years

ELN classification, slide courtesy Mrozek, K



Intensified induction in aml patients 60 ecog e1900
Intensified Induction in AML Patients < 60ECOG 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):1249-1259.


Induction Treatment

DNR 45 mg/m2/day

DNR 90 mg/m2/day

ECOG E1900: Overall Survival

Favorable andIntermediate Cytogenetics

All Patients

(N = 647)

1.0

0.9

0.8

0.7

1.0

0.6

N = 178

Probability

0.5

0.9

0.4

0.3

0.8

N = 180

Log Rank

P=0.004

0.2

0.7

0.1

0.0

0.6

0

10

20

30

40

50

60

70

0.5

Probability

Month

N = 327

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

0

10

20

30

40

50

60

70

80

0.4

N = 63

0.3

Month

Log Rank

P = 0.45

0.2

N = 59

0.1

0.0

0

10

20

30

40

50

60

Month

Fernandez HF, et al. N Engl J Med. 2009;361(13):1249-1259.


Apl ato in induction chemotherapy
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

Plenary abstract

Lo-Coco et al. Abstract No. 6


Lo-Coco et al. Abstract No. 6


  • Median follow up 31 months (0.07-50.4) common in chemotherapy arm

  • 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 common in chemotherapy armDecitabinein 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
Maintenance in AML common in chemotherapy arm

  • 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 DFSbut not OS in older patients; Lowenberg, JCO 1998

  • Gemtuzumabozogamicin, 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 efficaciousbut did not meet survival endpoint; Kolitz, CALGB 19808


Calgb 19808 newly diagnosed untreated aml 60 years

CALGB 10503 common in chemotherapy armnewly diagnosed, untreated *AML<60 years*including t-AML

CALGB 19808newly 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


Primary endpoint
Primary Endpoint common in chemotherapy arm

  • 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
Treatment plan: Decitabine common in chemotherapy arm

  • 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
Patient characteristics, common in chemotherapy armdecitabine


Decitabine administration data n 132
Decitabine administration data, N=132 common in chemotherapy arm

Total number of cycles given, N 770

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, % 53

  • Patient refusal, % 25

  • Adverse events, % 7

  • Other, including unknown, % 15


Myelosuppression and infection per cycle
Myelosuppression common in chemotherapy armand infection, per cycle

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 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 status1
DFS for 10503 (and historical control, 19808), based on CBF status

DFS, 10503 vs. 19808, CBF AML

DFS, 10503 vs. 19808, non-CBF AML


Conclusions
Conclusions status

  • 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
Relapsed/refractory AML – AC220 status

  • 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 ac2201
Relapsed/refractory AML – AC220 status

  • 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
Relapsed/refractory AML status

  • 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

CALGB 100103/BMT CTN 0502 status

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 05021
CALGB 100103/BMT CTN 0502 status

  • 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
CALGB 100103/BMT CTN 0502 statusDemographics

  • 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
CALGB 100103/BMT CTN 0502 statusDisease 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 status

  • Kantarjian, et al--Update on randomized trial placebo vsromiplostim 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 status

  • Garcia-Manero, et al---Extended dosing of oralazacitidine 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
Relapsed/refractory AML/MDS status

  • 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


Conclusions1
Conclusions status

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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