Treatment Breakthroughs In AML Martin S. Tallman, M.D. Chief, Leukemia Service Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY Hong Kong 212
Outline Introduction Overview of current therapy Breakthroughs Future Directions
Introduction Median age of AML: 72 years New patients/deaths in 211: 13,4/9, De novo or therapy-related or evolved from MDS or MPN Outcome varies by prognostic factors Heterogeneity in genetics and clinical manifestations Ca for Clinicians, 29; Juliusson Blood, 29
Overview of Current Therapy
Survival of Newly Diagnosed AML Consecutive ECOG Frontline Trials Age 55 1. P r o b a bi lit y.8.6 22-28.4.2 5 n=2,441 199-1999 1 15 1984-199 1973-1982 2 25 Age > 55 P r o b a bi lit y 1..8.6.4 22-28.2 5 n=1,528 199-1999 1984-199 1973-1982 1 15 2 25 Year Year Tallman, Gilliland, Rowe et al. Blood, 25 and update
AML in Older Adults (>6) Overall Survival with Unfavorable Cytogenetics 1 O v e r al l S u rv iv al ( % ) 75 5 25 1 2 3 Years GAMLCG Data HAM-HAM TAD-HAM n=253 4 5 Buchner et al. J Clin Oncol, 26
Breakthroughs Gene discovery/prognostic factors Acute promyelocytic leukemia (ATRA/ATO) Drug development Induction/postremission Minimal residual disease Less intense treatment of older adults Transplantation/alternative donors
Gene Discovery/Prognostic Factors
Distribution of Cytogenetically and Molecularly Defined Risk Groups in AML 14% Other 5% MLL- adverse 3% PTD inv(3)/t(3;3)/evi-1 ADVERSE 34% 12% FLT- ITD/ NPM1 wt INTERMEDIATE 21% t(15;17)/pml-rara 11% t(8;21)/runx1- RUNX1-T1 8% Inv(16)/t(16;16)/ CBFB-MYH11 5% FAVORABLE 45% NPM1 mut/ FLT3- ITD neg/wt1 wt 18% CEBPA mut (biallelic)/ FLT3-ITD neg 3% Grimwade Hematology Am Soc Hematol Educ Program,
Mutation Frequencies 398 Patients on ECOG Protocol E19 For Younger de novo AML Mutation Frequency IDH1 6% IDH2 8% TET2 1% ASXL1 4% FLT3 37%* NPM1 24% KIT 14% CEBP 9% WT1 1% KRAS 2.5% NRAS 1% *ITD 3%,TKD 7% Patel et al. N Engl J Med 212 (in press)
Mutation Mutation Frequencies in Normal Karyotype AML Frequency NPM1 53% (fav) FLT3-ITD 31% FLT3-TKD 11% CEBP 15% (fav) MLL-PTD 8% NRAS 13% IDH1/2 1/3% Schlenk et al N Engl J Med, 28; Boissel et al. J Clin Oncol, 21
Abbas et al. Blood, 21; Ley et al. N Engl J Med, 21; Nibourel et al. Blood, 21; Chou et al. Blood, 21; Patel et al. ASH, 21 Novel Mutations in AML Mutation Freq Associations Outcome IDH1/2 6%/8% Older age, NK, NPM1+ Decreased OS in FLT3-/NPM1- DNMT3A 22% TET2 1% Enriched in intermedrisk, absent in fav-risk May be assoc. with NPM1+ Decreased OS Decreased OS in intermed-risk, FLT3- ASXL1 4% Older age, RUNX1, trisomy 8 and not complex cyto, FLT3, NMP1, WT1; CEBP Decreased OS in intermed-risk, FLT3-
TET2 and ASXL1 Mutations Associated With Adverse Outcom in Intermediate-Risk, FLT3-ITD WT AML Intermediate Risk, FLT3-ITD WT AML 15 P e 1 r c e 5 n t s 5 1 15 2 25 u r OS v (Days) Intermediate Risk, FLT3-ITD WT AML i v 15 ap le 1 r c e n t s u r 5 5 1 OS 15 2 TET2 WT TET2 Mutant P<.1 ASXL1WT ASXL1Mutant P=.1 25!!!!! Patel et al. N Engl J Med, 212 (in press)
IDH/NPM1 Mutations Define Favorable Outcome in FLT3-Neg, Intermediate-Risk AML 1..8 NPM1/IDH double mutant NPM1-mutant, IDH-WT.6.4.2 P<.1. 2 4 6 8 IDH/NPM1-mutant pts, but not NPM1-mutant/IDH-WT pts have a favorable outcome Patel et al. N Engl J Med, 212 (in press)
Inducton/Postremission
Dauno Dose Intensification E19 AML < 6 yrs Induction DNR 45 mg/m2 x 3 days Post -Remission Observation AML + Cytarabine 1mg/m2 x 7 days 1-2 course to CR High-dose Cytarabine x 2 Auto HCT DNR 9 mg/m2 x 3 days Sibling Allogeneic HCT Gemtuzumab Ozogamicin Fernandez et al. N Engl J Med, 29
Intensified Induction in AML ECOG E19 657 patients CR Dauno 45-57% Dauno 9-71% p=<.1 Induction deaths Dauno 45-2.4% Dauno 9-4% p=.28 Fernandez et al. N Engl J Med, 29
Dauno Dose Intensification: E19 Overall Survival P r o b a b i l i t y 1..9.8.7.6.5.4.3.2.1. Log Rank Test p=.3 1 2 All Patients 3 4 Month Induction Treatment 45 mg/m2/day 9 mg/m2/day N=33 5 N=327 6 7 8 Pr ob ab ilit y Pr ob ab ilit y 1..9.8.7.6.5.4.3.2.1 Favorable and Intermediate Cytogenetics Log Rank Test p=.4. 1 2 3 4 5 6 7 1..9.8.7.6.5.4.3.2.1. Log Rank Test p=.45 Month Unfavorable Cytogenetics 1 2 3 4 5 6 Month N=178 N=18 N=63 N=59 Fernandez et al. N Engl J Med,
DNMT Mutational Status Does Not Affect Outcome in E19 Cohort 1.. 8 DNMT- MT DNMT- WT. 6. 4. 2 P=.15 4 2 4 6 8 Patel et al. N Engl J Med, 212 (in press)
High Dose Daunorubicin Improves Outcome in DNMT3A Mutant Patients, But Not DNMT-WT patients 1..8.6 DNMT3A-WT pts 1..8.6 DNMT3A-MT pts Standard Dose High Dose.4.4.2 P=.152.2 P=.4 2 4 6 8 1 2 3 4 5 6 7 Patel et al. N Engl J Med, 212 (in
High Dose Daunorubicin Improves Outcome in Patients With DNMT3A Mutations, MLL Fusions, or NPM1 Mutations 1.. 8. 6. 4. 2 At Risk1 7 1 8 DNMT3A/MLL/NPM1-WT pts P=.67 4 2 5 1 5 1 4 2 3 2 5 6 3 6 8 Std Dose High Dose 1.. 8. 6. 4. 2 DNMT3A, MLL, NPM1 mutant Standard Dose High Dose P=. 1 1 2 3 At Risk8 3 8 8 2 4 4 6 1 4 2 6 3 9 Std Dose High Dose Patel et al. N Engl J Med, 212 (in press) 4 5 6 7
Gemtuzumab Ozogamicin Structure Humanized anti-cd33 antibody linked to calicheamicin History Induces CR/CRp ~ 3% Approved for adults > 6 in first relapse in 2 (dose 9 mg/m2 twice) Rare VOD/SOS Withdrawn from market in 21
Variable Results From Randomized Trials of Gemtuzumab Ozogamicin in AML (age <6) MRC AML15 (3 mg/m2/dose/cycle) No increase in induction mortality Survival benefit in fav-risk Trend for survival benefit in intermed-risk SWOG S16 (6 mg/m2/dose/cycle) Increased induction mortality Trend for survival benefit in fav-risk Burnett et al. J Clin Oncol, 211; Petersdorf et al. Blood, 29 (abstr)
Fractionated Gemtuzumab Ozogamicin + Chemotherapy in De Novo AML ALFA 71 Patients aged 5-7 yrs with de novo AML (N = 278) Induction GO 3 mg/m2/day on Days 1, 4, and 7 + Dauno/ Cytarabine (n = 139) Dauno/ Cytarabine Consolidation (2 courses) GO 3 mg/m2/day on Day 1 + Dauno/ Cytarabine Dauno/ Cytarabine Castaigne et al. ASH 211 (abstr)
ALFA 71 EFS E F S p r o b a b ili t y 1..8.6.4.2. 6 GO + Daunorubicin/Cytarabine Daunorubicin/Cytarabine D/C GO + D/C 12 18 24 3 36 EFS P =.18 D/C (n=139) Events 14 76 GO + D/C (n=139) Median 11.9 mo 19.6 mo 2-year 16.5% 41.1% months Castaigne et al. ASH 211 (abstr)
ALFA 71 GO + dauno/cytarabine improved EFS, OS, RFS in AML aged 5-7 (fav and interm cyto) Safety profile of GO acceptable despite increase in hematologic and liver toxicity Castaigne et al. ASH 211 (abstr)
mtuzumab Ozogamicin (GO) In Induction C AML15 Induction Consolidation DA GO vs ADE GO vs FLAG-Ida GO MACE-MiDAC GO vs HiDAC GO (3. vs 1.5 mg/m2) Burnett et al. Blood, 29 (abstr)
MRC AML15 Post-remission Outcomes 5-yr death in CR 5-yr relapse rate 5-yr RFS 5-yr OS Ara-C 1% 53% 42% 54% MRC 15% 51% 42% 52% Ara-C 1.5 gm 9% 58% 38% 54% Ara-C 3 gm 14% 51% 43% 52% 5 courses % 58% 42% 6% 4 courses 1% 53% 46% 58% Burnett et al. Blood, 29 (abstr)
MRC AML 15 Ara-C dose % S ti ll A li v e 1 8 6 4 2 AraC 3g AraC 1.5g 1 Overall Survival from Consolidation N 31 131 4 Events 1 51 3 2 3 4 Years from entry 2P =.7 54 % 52 % 5 % S ti ll A li v e 1 8 6 4 2 AraC 3g AraC 1.5g 1 N 31 31 4 Relapse-Free Survival from Consolidation Events 14 615 6 2 3 4 Years from entry 2P =.5 42 % 38 % 5 % S ti ll A li v e 1 8 6 4 2 AraC 3g AraC 1.5g 1 Relapse Risk from Consolidation N Events 31 31 4 12 314 3 2 3 4 Years from entry 2P =.2 59 % 51 % 5 % S ti ll A li v e 1 8 6 4 2 AraC 3g AraC 1.5g 1 Death in CR from Consolidation N Events 2P = 2 31 3.1 31 31 4 2 3 4 Years from entry 14 % 8% Burnett et al. Blood, 29 (abstr) 5
OS of CR Patients Randomized to Receive Consolidation Therapy 1. 1. P r o b a bi lit y.8.6.4.2 P=.7 9 1 2 3 High-dose Ara-C arm Conventional standard-dose arm 4 5 6 7 P.8 r.6 o Conventional standard-dose b.4 arm a.2 bi P=.7 lit 1 y 1 2 3 4 5 6 7 Years High-dose Ara-C arm Conventional standard-dose=2 mg/m2 D1-5 x 4 High-dose Ara-C= 2. gm/m2 q12h D1-5 x 3 Ohtake et al. Blood, 211
Induction and Postremission Strategies High-dose daunorubicin appears better for younger patients in induction GO may benefit CBF AML/fav-risk Lower doses of ara-c appear as good as standard HiDAC for consolidation and potentially less toxic HiDAC in consolidation may not benefit intermedand high-risk patients
Drug Development
New Agents in AML Agent Mechanism Comments CPX-351 DOT1L inhibitor Liposomal fixed ratio of dauno/ara-c Histone H3K79 methyltransferase High response rate and reduced mortality Preclinical data against MLL Sorafenib/AC22 Multikinase inhib CRs w/single agent Clofarabine Nucleoside analog Effective in older adults with unfav. prog. factors Sapacitabine Nucleoside analog CRs w/single agent Elacytarabine Eliadic ester of ara-c Modest remission in adv disease Bayne J Pharm Sci, 28; Pollock ASH, 21; Metzelder Blood, 29; Cortes Blood, 29 (abstr); Erba J Clin Oncol, 21; Kantarjian Blood, 29 (abstr); O Brien Blood, 29 (abstr)
CPX-351 A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed Ratio DSPC DSP Cholesterol Cytarabine Daunorubicin G 1 nm bilamellar liposomes 5:1 molar ratio of cytarabine to daunorubicin 1 unit = 1. mg cytarabine plus.44 mg daunorubicin Specifically designed drug delivery vehicle enables specific drug ratios to be maintained Feldman et al. J Clin Oncol, 211
CPX-351 vs 7 + 3 Remission Rates CPX-351 7+3 n=84 n=41 CR+CRi 56 (66.7%) 21 (51.2%) p=.712** CR 41 (48.8%) 2 (48.8%) CRi 15 (17.9%) 1 (2.4%) **one-sided Fisher s Exact test Lancet et al. ASH,
CPX-351 vs 7 + 3 Early Deaths (all causes) CPX-351 7+3 n=85 n=41 3-Day Mortality 3 (3.5%) 3 (7.3%) p=.35 6-Day Mortality 4 (4.7%) 6 (14.6%) p=.53 All early deaths occurred in the high risk group Lancet et al. ASH, 21
CPX-351 vs 7 + 3 Event-Free and Overall Survival Event Free Survival Overall Survival 1% 8% 6% Logrank p-value =.11 CPX-351 1% 8% 6% 7+3 Logrank p-value =.61 CPX-351 4% 7+3 4% 2% 2% % % 3 6 9 12 15 18 6 12 18 24 Months from randomization Months from randomization Lancet et al. ASH, 21
CPX-351 vs 7 + 3 Event Free and Overall Survival Secondary AML Event-Free Survival Overall Survival 1% 8% 6% 4% 2% 7+ 3 Logrank p-value =.7 CPX- 351 1% 8% 6% 4% 2% % % 3 6 9 12 15 18 6 12 18 24 Months from randomization 7+ 3 Logrank p-value =.1 CPX- 351 Months from randomization Lancet et al. ASH, 21
Quizartinib Monotherapy in Relapsed/ Refractory FLT3-ITD Positive AML Quizartinib (AC22), a selective oral FLT3 TKI active in FLT3-ITD pos AML Nonrandomized phase II trial of quizartinib monotherapy ongoing 2 patient cohorts enrolled Cohort 1 Relapsed/refractory to frontline chemo Age 6 years Cohort 2 Relapsed/refractory to second-line chemo or HSCT Age 18 years Cortes et al. ASH, 211 (abstr)
Quizartinib in Relapsed/Refractory FLT3-ITD Positive AML Efficacy Best Response, % CRc (CR + CRp + CRi) Cohort 1 (n = 26) Cohort 2 (n = 36) 46 36 4 Total (N = 62)! CR 4 2! CRp 4 2! CRi 39 36 37 PR 15 22 19 NR 23 22 23 Unknown 15 19 18 Cortes et al. ASH 211, (abstr)
Early Detection of MRD as a Potential Tool For Risk-Stratification in AML Flow cytometry San Miguel et al. Blood 1997 1 MRD post-induction 1 RQ-PCR (WT1) Cilloni et al. J Clin Oncol 29 <2 log reduction >= log reduction % i n C R 75 5 25 < 5x1-3 (n=24) 5x1-3 (n=18) p=. 1 R e l a p si n g % 75 5 25 n=35 n=56 p=.4 75% 4% 1 2 3 4 5 6 7 Months 1 2 Years 3 4 5
Treatment of Older Adults
Treatment of Older Adults Agent N Med Age CR Mortality OS 5-azacitidine 55 7 18% NA 25 mo Decitabine 55 74 24% 7% 7.7 mo Lenalidomide* 33 71 3%** 24% 4 mo Clofarabine 112 71 38% 1% 1 mo *5 mg/m2 for up to two 28-day cycles **53% CR+CRi aux et al. J Clin Oncol, 29; Cashen et al. J Clin Oncol, 21; Fehniger et al. Blood, 21; tarjian et al. Clin Oncol, 21
Overall Survival in Patients Receiving Azacitidine or Conventional Care Regimens P at ie nt S u rv iv al ( p r o p o rti o n ) 1..9.8.7.6.5.4.3.2.1 5% 24.5 mo 16. mo Azacitidine 16% CCR 5 1 15 2 25 3 35 4 Time Since Random Assignment (months) Fenaux et al. J Clin Oncol, 29
Treatment of Older Adults Prognostic factor models exist to predict induction mortality, CR and OS Novel strategies exist with potentially less toxicity and unique mechanisms of action Further studies will define optimal dose and schedule and combinations Important shift away for conventional chemotherapy toward novel strategies-new standard of care
Transplantation/Alternative Donors
Advances in Transplantation Equivalent outcomes MSD and MUD Haploidentical transplantation Umbilical cord Reduced-intensity conditioning Outcome of t-aml
Leukemia-Free Survival by Donor Type For Patients With Heme Malignancy in CR 1,2 or 3 C u m ul at iv e P r o p o rti o n 1.. 8. 6. 4. 2. MM URD (n=52) DUCB (n=128) SIB (n=24) P =.19 MUD (n=152) 1 2 3 4 5 Years post-transplantation Brunstein et al. Blood,
Probability of Overall Survival After Allogeneic HCT for Therapy-Related AML and MDS by Risk Factors 1 Prob at 5 yrs p<.1 P r o b a b ili t y, % 8 6 4 2 4 risk factors 4% (N=25) 1 2 3 4 5 Risk Factors 1. Age >35 2. Poor-risk cytogenetics 3. t-aml not in CR or adv MDS 4. Donor other than MDS or well-matched MUD Year s risk factors 5% (N=82) 1 risk factor 25% (N=293) 2 risk factors 19% (n=29 3 risk factors 12%(N=178) Litzow et al. Blood, 21
Transplantation For AML in CR1 Alternative donor sources expand pool of patients who may benefit Outcome for MUD transplants appears to approach that of MRD Umbilical cord transplantation increasing Identify pts with t-aml who may or may not benefit from transplant
Future Directions in AML Gene expression profiling for signatures characteristic of specific genetic subtypes, identify cooperating mutations and perturbed pathways and predict treatment response Risk-stratify therapy with specific targeted strategies Characterize mechanisms of action and off-target effects of putative molecularly targeted therapies Identify molecular markers of residual disease
Acknowledgments ECOG Leukemia Committee North American Intergroup Colleagues European LeukemiaNet Colleagues Leukemia Service Memorial Sloan-Kettering Cancer Center