Background

A randomized trial of anthracycline dose intensification during induction in younger

patients with acute myeloid leukemia: Results of Eastern Cooperative Oncology

Group study E1900

Hugo F. Fernandez, MD; Zhuoxin Sun, PhD; Mark R. Litzow, MD; Selina M. Luger, MD; Elisabeth M. Paietta,

PhD; Gordon Dewald, PhD; Rhett P. Ketterling, MD; Jacob M. Rowe, MD; Hillard M. Lazarus, MD;

Martin S. Tallman, MD

http://www.ecog.org/

Background

• In younger adults (<60 years old) with newly diagnosed AML:– Daunorubicin 45mg/m2/day CR rates of 50 -75%– Anthracycline dose-intensification during induction

may improve CR:• SWOG daunorubicin 70mg/m2/d

– High CR rates in young group

• CALGB 9621- daunorubicin 90-95mg/m2/d – High CR rates/ tolerable toxicity

– OS improvement not demonstrated in a randomized trial.


E1900: Objectives

Primary Objective:– To compare OS between two induction regimens

daunorubicin 45mg/m2 vs. 90mg/m2/d

Secondary Objectives:– Evaluate impact of allogeneic SCT in AML patients

with unfavorable prognostic factors

– Evaluate impact pre HSCT GO on DFS

Planned accrual goal: 830 patients

Closed November 2008- 657 patients.


Eligibility

• De novo Acute Myeloid Leukemia– Per WHO 2001 criteria

• Age 16-60 years

• No prior treatment

• No MDS > 6 months

• Allogeneic or autologous HSCT candidate


ECOG Protocol E1900:Schema

Gemtuzumab Ozogamicin

6 mg/m2 IV x 1

Daunorubicin45 mg/m2/day x 3

or90 mg/m2/day x 3

+Cytarabine 100 mg/m2/day x 7

Allogeneic HSCT

CR

HighIntermediate

HiDAC x 2;PBSC Harvest

after 2nd course

Autologous SCTBusulfan IV 0.8 mg/kg Every 6 hrs x 16 doses

Cyclophosphamide 60mg/kg/d x 2

FavorableIntermediateIndeterminate

Closed to accrual 10/2007

Risk Allocation

Persistent AML:2nd cycle ofDaunorubicin 45mg/m2/d x3Cytarabine 100mg/m2/d x7


Results

• 657 patients entered

• Age: median 48 (17 to 60 ) years

• Patient demographics similar

• Disease characteristics similar

• Data base closed as of March 1, 2009

• 547 evaluable for response


Disposition of Patients

Entered657

Randomized to 45mg/m2

330Randomized to 90mg/m2

327

Evaluable for Response293

Evaluable for Response289

Complete Remission168 (57.3%)

Complete Remission204 (70.6%)


Results: Toxicity

• Induction deaths were similar– 45mg/m2 : 4.5%; – 90mg/m2 : 5.5%

• Grade 3/4 toxicity similar

• High-dose daunorubicin arm – Cardiac toxicity not increased – Did not impact delivery of HSCT


Post-remission

• Patients allocated to:– Allogeneic: high risk – Autologous : favorable, intermediate

• Recovered from induction toxicity

• 341/657 (51.9%) registered to second step– 49.9% transplanted

• 34 received allogeneic transplant• 136 received autologous transplant


Induction Treatment CNSRFAIL MEDIANTOTAL45 mg/m2/day 330 199 131 15.790 mg/m2/day 327 168 159 23.7

Pro

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Log Rank Test p=0.003

Overall Survival by Induction Treatment-All Patients

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OS by Induction-All Patients


OS by Induction: <55years


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OS by Induction:≥55 Years


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Overall Survival by Treatment -- Age>=55

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Cytogenetic Risk

45mg/m2 90mg/m2 Total p

Favorable (%) 11.6 15.6 13.6 0.40

Intermediate (%) 43.3 39.9 41.1

Indeterminate (%) 27.1 26.1 26.6

Unfavorable (%) 18.0 19.3 18.7


OS by Induction: Favorable and Intermediate


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OS by Induction: Unfavorable


Response by Mutational Analysis


OS by Induction: FLT3 Positive


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Overall Survival by Induction Treatment--FLT3 Positive Patients

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OS by Induction: FLT3 Negative


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Overall Survival by Induction Treatment--FLT3 Negative Patients

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CNSRFAIL MEDIANTOTALFLT3 ITDNegative 241 116 125 28.6Positive 64 39 25 15.2

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Overall Survival by FLT3 at the high dose

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OS Daunorubicin 90mg/m2/d: FLT3 Status


OS by Induction: MLL Positive


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Overall Survival by Induction Treatment--MLL-PTD Positive Patients

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OS by Induction: MLL Negative


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Overall Survival by Induction Treatment--MLL-PTD Negative Patients

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Conclusions

• In AML patients <60 years, induction therapy with daunorubicin 90mg/m2/d: – Is safe– Improves CR rates: 70.6% vs. 57.3%– Improves OS: 23.7 vs. 15.7 mo.– 45mg/m2/d is no longer the standard dose


Future Directions

• Randomized trial of other anthracycline doses – Daunorubicin 60 mg vs. 90 mg/m2/day– Idarubicin 12 mg/m2/day vs. 90 mg/m2/day

• Focus on shortcomings – Patients older than 55 years- P-gp inhibitors- Zosuquidar

– Unfavorable cytogenetics– Mutation abnormalities

• FLT3 positive- CALGB 10603- RATIFY trial• MLL


Acknowledgements

Investigators

• Martin Tallman• Hillard Lazarus• Mark Litzow• Selina Luger• Jacob Rowe• ECOG E1900 PIs

Laboratory• Elisabeth Paietta

• Janis Racevskis

• Rhett Ketterling

• Gordon DeWald

• Gary Hicks

• John Bennett

Data/ Statistics• Zhuoxin Sun

• Julie Mann

• Xiaopan Yao


Documents

Background