Meet-the-Expert: AML Treating older patients with AML Sergio Amadori Tor Vergata University Hospital Rome Istanbul 2012
AML in older patients Poor prognosis Minority treated with intensive Cx Treatment less successful Outcome has not changed over the last 40 years Burnett et al, JCO 2011 Kantarjian, ASCO 2011
Reasons for lack of progress Poor tolerance for intensive Cx Poor PS and comorbidities Therapeutic nihilism Lack of accrual to clinical trials Inherent drug resistance Adverse biology
Available options Low-Int Rx Supp care Intensive Rx Investigational Rx
Intensive Rx: treatment of choice EORTC AML-7 (age 65+) (Lowenberg et al, JCO 1989) ECOG SWOG MDACC 6,283 pts Target: CR Prerequisite for better OS and QOL Lesser responses: limited benefit Walters et al, JCO 2010
Older adults are not all the same FIT Low risk UNFIT FIT Poor risk Candidate for intensive Cx? YES NO What is best strategy? What are alternatives?
Candidates for intensive Rx? Prognostic Risk Models
Intensive Rx Standard approach: DNR + Ara-C (3+7 regimen) for induction Ara-C-based consolidation (1-2 courses) CR, DFS and OS rates inferior to younger pts Age, y CR% ED % RR% Cure % <60 75 <10 50 45 >60 50 ~20 85 <15 Better therapies needed
New strategies Focus on Treatment Intensification Induction Postremiss DNR dose Add new agents RIC-SCT
HOVON/SAKK AML-43 Induction cycle I DNR 45 mg/m 2 x3 Ara-C 200 mg/m 2 x7 Induction cycle II Ara-C 1 g/m 2 q12 hrs x 6 days Post induction none R DNR 90 mg/m 2 x3 Ara-C 200 mg/m 2 x7 Lowenberg et al, NEJM 2009 Ara-C 1 g/m 2 q12 hrs x 6 days R RIC-SCT (optional) GO 6 mg/m 2 q 4 weeks x 3
Induction outcome N=813, age 60-83y DNR 45 DNR 90 P value % CR 54 64 0.002 % CR @course1 35 52 < 0.001 % CR age 60-65y 51 73 0.02 % CR CBF 74 93 % 30-d mortality 12 11 NS
Survival
Addi5on of gemtuzumab (GO) ALFA 0701 E/G AML 17 3 RCT NCRI AML 16
ALFA 0701 study Induction Day 15 additional treatment* for persistent marrow blasts Consolidation (2 courses) Patients aged 50-70 yrs with de novo AML (N = 278) GO 3 mg/m 2 /day on Days 1, 4, and 7 + Daunorubicin 60 mg/m 2 on Days 1-3 + Cytarabine 200 mg/m 2 on Days 1-7 (n = 139) Daunorubicin 60 mg/m 2 on Days 1-3 + Cytarabine 200 mg/m 2 on Days 1-7 (n = 139) CR/CRp GO 3 mg/m 2 /day on Day 1 + Daunorubicin 60 mg/m 2 on Day 1 (first course) or Day 1-2 (2nd course) + Cytarabine 1 g/m 2 /12 hrs on Days 1-4 Daunorubicin 60 mg/m 2 on Day 1 (first course) or Day 1-2 (2nd course) + Cytarabine 1 g/m 2 /12 hrs on Days 1-4 *Patients with persistent marrow blasts > 10% at Day 15 received additional daunorubicin 35 mg/m 2 on Days 1-2 + cytarabine 1 g/m 2 /12 hrs on Days 1-3. Castaigne et al, ASH 2011
Outcomes
OS by cytogenetics Fav/Int K Unfav K Benefit only in patients with fav/interm CG
NCRI AML16 study Age >60 Treatment Schedules DA 3+10 Dauno 50 mg/m 2 d1,3,5; Cytarabine 100 mg/m 2 d1-10 every 12h DA 3+8 Dauno 50 mg/m 2 d1,3,5; Cytarabine 100 mg/m 2 d1-8 every 12h DA 2+5 Dauno 50 mg/m 2 d1,3; Cytarabine 100 mg/m 2 d1-5 every 12h DClo Dauno 50 mg/m 2 d1,3,5; Clofarabine 20 mg/m 2 d1-5 Mylotarg Mylotarg 3mg/m 2 d1 of course 1. Azacytidine Azacytidine 75mg/m 2 daily for 5 days repeated every 6 weeks for 9 courses Burnett et al, ASH 2011
Outcomes CIR Surv from CR OS
OS by baseline features Patients with adverse CG or other poor-risk features unlikely to benefit
EORTC/GIMEMA AML-17 study R GOx2 MICE CR/CRp GO+ ICEx2 MICE CR/CRp ICEx2 Treatment Schedules MICE Mito 7 mg/m 2 d1,3,5; Ara- C 100 mg/m 2 d1-7; Eto 100 mg/m 2 d1-3 GO induc5on 6 mg/m 2 d 1, 15 GO consolid 3 mg/m 2 d 0 ICE Ida 8 mg/m 2 d1,3,5; Ara- C 100 mg/m 2 d1-5; Eto 100 mg/m 2 d1-3 Amadori et al, EHA 2012
Induction results by age 60 50 Age 61-69 Age 70-75 Pa5ents % 40 30 20 10 0 No GO GO No GO GO CR+CRp (%) 47,4 52,3 52,4 32,5 No resp (%) 40,8 29,4 29,8 31,3 Ind death (%) 9,9 11,8 15,5 26,5 Inev/unkn (%) 2 6,6 2,4 9,6 P=0.01
Survival 100 90 80 70 60 50 40 30 20 10 OS (all pts) Logrank test: p=0.07 0 (years) 0 1 2 3 4 5 6 O N Number of patients at risk : Treatment 204 236 102 61 42 30 13 No GO 210 236 78 41 32 27 17 GO 100 90 80 70 60 50 40 30 20 10 OS (age 70-75y) Logrank test: p=0.002 0 (years) 0 1 2 3 4 5 6 O N Number of patients at risk : Treatment 76 84 35 21 15 9 2 No GO 77 83 16 5 5 4 2 GO saml 61-69y 100 90 80 70 60 50 40 30 20 10 OS Logrank test: p=0.02 0 (years) 0 1 2 3 4 5 6 O N Number of patients at risk : Treatment 33 34 12 4 1 1 0 No GO 36 44 21 14 10 8 7 GO
Postremission therapy Group Study PRT Outcome MRC AML-11 1 vs 4 cycles HOVON AML-43 GO vs obs ALFA 9803 6 non-int vs 1 int cycle No diff No diff Better DFS and OS at 2y No proven value All large studies included PRT Poor compliance <50% of pts in CR proceeded to PRT No clear benefit Survival benefit restricted to pts with favorable CG (GOELAMS, retrosp study)* Focus on AlloSCT Goldstone et al, Blood 2001 Lowenberg et al, Blood 2010 Gardin et al, Blood 2007 * Prebet et al, JCO 2009
RIC-AlloSCT in elderly AML CIBMTR (1080 pts age 40-79) N=545 AML in CR1 Viable option for patients up to age 75-80 years TRM comparable to pts age 40-60 Prospective studies needed McClune et al, JCO 2010
Not candidates for intensive Rx Frail PS>2, comorbid Poor risk Multiple risk factors Toxicity Chemo resistance Low intensity Rx Supportive care Investigational Rx
Frail: LDAC > HU (NCRI AML 14) LDAC (N=103) HU (N=99) Early death 26% 26% CR 18% 1% Fav/Int CG Poor CG Burnett et al, Cancer 2007
Poor risk: Novel agents to watch CPX-351 Laromustine Clofarabine Decitabine HD-LEN CR/CRi 67% CR/CRp 32% CR/CRp 46% CR/CRi 64% CR/CRi 30% ED 3% ED 14% ED 10% ED 2% ED 24% Myelosuppressive regimens Responses in all poor risk groups Randomized trials (vs 3+7) Lancet et al, ASH 2010; Schiller et al, JCO 2010; Kantarjian et al, JCO 2010; Blum et al, PNAS 2010; Fehninger et al, Blood 2010
Treating elderly AML in 2012 Fit (Low Risk) Intensive Rx (even at high age) Define optimal therapy, consider RIC-SCT Fit (Poor Risk) Investigational Rx Consider RIC-SCT Unfit/Frail Less intensive Rx (LDAC) Supportive care (HU)
The road to progress Define who should have intensive or non-intensive treatment Novel treatments New approach to trial design Avoid therapeutic nihilism