Incorporating Molecular Data into Risk Stratification for AML Steven Devine M.D. The Ohio State University Comprehensive Cancer Center

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Current State of AML Therapy Excluding the roughly 20-30% of good risk patients, 40-90% of younger patients (age 18-59) achieving remission are destined to relapse

Current State of AML Therapy Excluding the roughly 20-30% of good risk patients, 40-90% of younger patients (age 18-59) achieving remission are destined to relapse All but a very select subset of older AML patients (> 60) will die due to relapsed or refractory disease

Prognostic/predictive factors in AML FactorComment AgeMajor impact at diagnosis WBCContinuous variable Prior therapy or MDS?Karyotype may be more important Extramedullary diseaseVariable Day 14 blast countHigher percentage worse # cycles of inductionOne better than two Cytogenetic/molecular profileMajor Impact at diagnosis Gene expression profileCan further subdivide patients MicroRNA expressionNeeds validation by other groups Gene sequencingFuture application MRD detection at CR??; seems like it should be useful

Prognostic/predictive factors in AML FactorCommentBasis for Transplant recommendation? AgeMajor impact at diagnosisYes WBCContinuous variableNot solely Prior therapy?Karyotype may be more important Not solely Extramedullary diseaseVariableNot solely Day 14 blast countHigher percentage worseRarely # cycles of inductionOne better than twoRarely Cytogenetic/molecular profile Major Impact at diagnosisYes Gene expression profileCan further subdivide patientsNot yet MicroRNA expressionNeeds validation by other groups Not yet Gene sequencingFuture applicationNot yet MRD detection at CR??; seems like it should be useful Possibly for cytogenetics/FISH

Döhner K, et al. Haematologica 2008;93: Reproduced with permission. Major cytogenetic subgroups of acute myeloid leukemia (AML) (excluding acute promyelocytic leukemia) and associated gene mutations

Byrd JC, et al. Blood 2002;100: This research was originally published in Blood. © 2002 the American Society of Hematology. CALGB Database: Outcomes in AML Patients < 60 years of Age based on Karyotype at Diagnosis

BMT versus Conventional therapy for AML with poor risk cytogenetics SWOG/ECOG Trial Slovak ML, et al. Blood 2000;96: This research was originally published in Blood. © 2000 the American Society of Hematology.

BMT versus Conventional therapy for AML with poor risk cytogenetics EORTC-LG/GIMEMA Suciu S, et al. Blood. 2003;102: This research was originally published in Blood. © 2003 the American Society of Hematology.

Current Role of Allografts for AML Patients <60 years in CR1 Adverse risk cytogenetics –Most agree allograft appropriate consolidation at least up to years of age

Current Role of Allografts for AML Patients <60 years in CR1 Adverse risk cytogenetics –Most agree allograft appropriate consolidation at least up to years of age Favorable risk cytogenetics –No role in general

Current Role of Allografts for AML Patients <60 years in CR1 Adverse risk cytogenetics –Most agree allograft appropriate consolidation at least up to years of age Favorable risk cytogenetics –No role in general Intermediate risk cytogenetics –This is where it gets complicated –Recent meta-analyses suggest benefit Cornellison et al, Blood, 2007 Koreth at al, JAMA, 2009

Molecular Profiles of Cytogenetically Normal AML Döhner H, et al. Blood Oct 30. [Epub ahead of print]. This research was originally published in Blood. © 2009 the American Society of Hematology.

Heterogeneity within Cytogenetically Normal AML Category Gene MutationPrognostic Impact NPM1Favorable in absence of Flt3 ITD Flt3 ITD/allele ratioUnfavorable Flt3 TKDControversial CEBPAFavorable MLL PTDUnfavorable RasNeutral WT-1Controversial Runx1Unfavorable

Impact of Gene Expression in Cytogenetically Normal AML Category GeneImpact of Overexpression BAALCUnfavorable ERGUnfavorable MN1Unfavorable Mir181Favorable

Metzeler K H, et al. J Clin Oncol. 2009;27: Reprinted with permission. © 2009 American Society of Clinical Oncology. All rights reserved High expression of BAALC, ERG, or MN1 predicts shorter overall survival in cytogenetically normal acute myeloid leukemia

Risk Stratifying AML Based on Cytogenetic/Molecular Profile 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;11)(v;q23); MLL rearranged -5 or del(5q); -7; abnl(17p); complex karyotype; monosomal karyotype Döhner H, et al. Blood Oct 30. [Epub ahead of print] This research was originally published in Blood. © 2009 the American Society of Hematology.

BMT versus Conventional therapy for AML with normal cytogenetics Schlenk RF, et al. New Engl J Med. 2008;358: Reprinted with permission © 2009 Massachusetts Medical Society.

Koreth J, et al. JAMA 2009;301: Reproduced with permission. Overall Survival Benefit of Allogeneic SCT for AML in First Complete Remission

Current State of AML Therapy Allogeneic HCT is the single most effective therapy currently available for the prevention of relapse Allogeneic HCT is still a potentially risky therapy and many treating physicians remain reluctant to recommend in CR1 until mortality rates can be substantially lowered

Which patients with AML less than 60 years of age can reasonably be considered for allograting in first remission? Most decisions would be made based on cytogenetic/molecular risk group –Adverse risk karyotype: most would agree –Other intermediate risk cytogenetic abnormalities: choices likely individualized –Cytogenetically normal Decision based on molecular risk? Should all Flt3 ITD patients be allografted?

What recommendations should be made for Flt3 ITD group? Should all of these patients be referred for allograft? On what basis? What about patients already entered on clinic trial (e.g. CALGB 10603/Intergroup)? Should these patients be taken off a clinical trial of TKI for a standard of care allograft?

A call for prospective, multi-center allograft trials in first remission AML based on risk for relapse This can now be accomplished based on studies suggesting no significant difference in overall survival comparing matched sibling to matched unrelated donor transplants

Similar Outcomes in AML regardless of Donor Source Schetelig J, et al. J Clin Oncol. 2008;26: Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved

Log-rank p-value < n=1735 n=2621 n=2184 n=2234

A call for prospective, multi-center allograft trials in first remission AML based on risk for relapse This can now be accomplished based on studies suggesting no significant difference in overall survival comparing matched sibling to matched unrelated donor transplants What would be the possible study designs? –Randomization to transplant or conventional treatment after donor identified? –Up front design to transplant all unfavorable risk patients in first remission if donor identified?

Possible prospective AML Transplant trial designs Randomization to transplant or conventional treatment after donor identified –Would require substantial proportion of patients having a donor identified –What type of conditioning and GVHD prophylaxis? Is there really a standard approach? –How much heterogeneity in transplant approach could be tolerated? –What would be the best endpoint, considering the impact of chronic GVHD on survival and QOL?

Possible prospective AML Transplant trial designs Up front design to transplant all unfavorable risk patients in first remission if donor identified –Would it require Herculean effort to get patients risk stratified, HLA-typed, and donors identified in a timely fashion? –What proportion of patients would have to make it to transplant to be considered successful? –Should all patients have one type of transplant approach or be randomized (Ph 2) to two or more promising strategies? –What would be the study endpoint? DFS, overall survival, GVHD free/relapse free survival composite?

What defines a “suitable donor” allograft for a high risk AML patient in first remission? Matched sibling: Yes Matched unrelated donor: Yes Mismatched unrelated donor (KIR mismatched?) –Cooley et al, Blood, 2009 Mismatched umbilical cord blood? –Gutman et al, BBMT, 2009 Haploidentical related? –Perugia approach (ex vivo T-cell depletion) –Hopkins approach (in vivo alloreactive T-cell depletion)

Cooley S, et al. Blood 2009;113: This research was originally published in Blood. © 2009 the American Society of Hematology. Transplantation using donors with KIR B haplotypes improves overall survival

Ciceri F, et al. Blood 2008;112: This research was originally published in Blood. © 2008 the American Society of Hematology. EBMT Analysis: Leukemia Free Survival for AML Patients Receiving Haploidenitcal Transplantation according to disease stage

Outcomes of myeloablative umbilical cord blood transplants for Acute leukemia in CR compared to unrelated donors Gutman JA, et al. Biol Blood Marrow Transplant. 2009;15: Reproduced with permission.

Major issues with allografting in AML GVHD –opportunistic infection Regimen related organ toxicity –Prohibits use in older patients and/or those with co-morbidities –Should reduced intensity regimens be used in younger patients? RELAPSE

Tackling the major issues in allografting for AML Preventing graft versus host disease –Sirolimus based approaches (currently subject of BMT CTN randomized trial 0402) –Ex vivo T-cell depletion Just completed BMT CTN Phase 2 study in AML CR1/2 Other selective T-cell depletion trials –Post Transplant cyclophosphamide Hopkins, Seattle, MDACC consortium studying –Polyclonal and monoclonal antibodies ATG, Campath, others –Many others

Relapse rate and survival after T-cell depletion in AML CR1 Aversa F, et al. J Clin Oncol. 1999;17: Reprinted with permission. © 1999 American Society of Clinical Oncology. All rights reserved MSKCC published and unpublished

BMT CTN 0303: Multi-Center Trial for AML in CR1 or CR2 Age Conditioning regimen: –Hyperfractionated TBI (TBI) 125 cGy/fx at 8- 20cGy/minute: total dose 1375 cGy over 4 days (-9 through –6) –Thiotepa 5 mg/kg for two days (-5 and –4) –ATG at 2.5 mg/kg on day –4 –Cytoxan at 60 mg/kg on days –3 and –2 –CD34 selected G-CSF mobilized PB on day 0 –No pharmacological GVHD prophylaxis

BMT CTN 0303: Patient Characteristics 47 patients enrolled; 44 transplanted 3 patients withdrew consent (2) or progressed (1) prior to transplant Age: mean 46 (21-59) Gender; M=16; F=28 KPS –100%: 17 –90%: 17 –80%: 8 –70% 2 Remission status: CR1: 37; CR2: 7 Poor risk karyotype/molecular profile: 14/37 CR1 (38%) Devine SM, et al. ASH Abstract 655.

Outcomes of AML patients aged 60 or greater entered on CALGB Trials Farag S, et al. Blood. 2006;108: This research was originally published in Blood. © 2006 the American Society of Hematology.

CALGB Background Results in best group are still poor (n = 276) CR1 Age Receive first consolidation on randomized trial 2-year DFS 24% 3-year DFS 17% Initial results suggest that RIC allografts are feasible in older patients with AML –Hegenbart at al, JCO 2006 –Wong et al, Blood, 2005 –Many other groups But…..virtually all of the published studies are retrospective, highly heterogeneous, or lack a standardized approach. Few if any have asked a specific question in a specific patient population

CALGB Trial in AML CR1 Age >60 The fludarabine/busulfan regimen was chosen in 2003 based on the scant amount of available data at the time

CALGB Initial Statistical Design Primary Endpoint: 2 year DFS Aim for improvement from 20 to 40% Trial would require 36 patients Initial estimate: should take ~36 months to complete enrollment

Poor Initial Accrual to CALGB : Why? Trial Activation Date: 1/15/04

Modifications to CALGB Made note that SWOG trial in this patient population was closed due to poor accrual Formed Protocol team with BMT CTN and joined officially by CTN in June 2006 (Became CALGB /CTN 0502) Protocol Team Decisions: –Added volunteer unrelated donors (10/10) –Added rabbit ATG (for all patients) –Removed DLI from protocol –Lowered DFS goal to 35% at 2 years –Increased target accrual goal to 61 patients

Accrual to CALGB /BMT CTN 0502 as of 12/29/08 55 of 68 total patients enrolled in 2007 and 2008! Trial has just been reactivated to increase # unrelated donor recipients

Beyond /0502 What is ongoing currently in this population of patients? –EBMT randomized trial between Flu/TBI 200 and Std consolidation –Stanford/COH trial (TLI/ATG) –MDACC (Azacytidine post) –Swedish multi-center trial Current proposals –CALGB (dose adjusted bu+ post AZA) –ECOG 2906 –others

Conclusions Allogeneic transplantation remains of vital therapy for younger AML patients in CR1 at high risk for relapse Who exactly should be recommended for transplant in CR1 and what allografts are suitable in this setting remains in flux Patients in CR1 and 60 or older should be transplanted on clinical trials only; single centers cannot address this question Cooperative groups/consortia must work together to get prospective AML focused allograft trials completed There is no standard allograft approach since everything we do can and should be improved

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