Acute Myeloid Leukemia

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1 Acute Myeloid Leukemia Upfront Therapy in Newly Diagnosed Elderly AML Patients: Is Decitabine (DAC) the new standard? Raoul Tibes, MD, PhD Senior Associate Consultant, Mayo Clinic Arizona Associate Director, Acute and Chronic Leukemia Program Assistant Professor, Mayo College of Medicine Mayo Clinic in Arizona Disclosures/Conflict of Interest No disclosure relevant to this talk OFF LABEL USE: TOUCH ON LABORATORY USE OF FDA APPROVED DRUGS AND THEIR USE IN CLINCIAL TRIALS 1

2 Survival by Decade 1970s to 2000s has not improved in AML patients > 60 years old < 60 years > 60 years Kantarjian, Cancer 2009 AML one of the deadliest cancers: 9,0409 will die each year = 75 % of newly dx 6 th and 7 th leading cause of cancer deaths in men and women Few other cancers have higher mortality rate (i.e. pancreatic cancer) American Cancer Society Facts and Figures 2010 > 70 years Kantarjian, Blood 2010 Overview of Discussion 1. How can we improve therapy for AML patients 1. Does Adding Drugs to Induction Therapy or Increasing Dose Improve Outcome, if not what are alternative approaches 2 LowerIntensity Regimens in Newly Dx Elderly AML 2. Lower Intensity Regimens in Newly Dx Elderly AML Patients 2

3 Meta Analysis of Randomized Controlled Trials in AML Patients Age > 60 Years Adding an Additional Agent to Standard Therapy 65 RCTs, n=15,110 patients, 64 direct comparisons of induction treatments, median age 68 years, Primary Outcome: CR Comparator/reference induction treatment: Daunorubicin (30 60 mg/m 2 x3 days) and Cytarabine (100 mg/m 2 x7 10 days) Only 14 of 65 showed significant differences in CR after random effects meta analyses Overall CR rate ~50% Significantly higher CR rates: ATRA (CR: 42%) or Lomustine (CR:67%) added to Ida/AraC (OR = 1.93 [ ] and 1.76 [ ]) Also good: Time sequential ential induction with HDanthracycline/anthracenedione + HiDAC (CR: 78%); Ida/medium AraC (CR: 80%); Significantly lower CR rates: no treatment, clofarabine, daunorubicin plus topotecan, gemtuzumab ozogamicin (2 schedules 1, 3, 5 and 1, 8 days) (OR = 0.01 [ ], 0.15 [ ], 0.03 [ ], 0.06 [ ], and 0.05 [ ] Survival not different Ziogas DC et al, Clin Ther Mar;33(3): High dose Daunorubicin 45 vs. 90 mg/m 2 2 Studies: < 60 years age and > 60 years age Newly diagnosed AML Both studies 45 vs. 90 mg/m2 Daunorubicin x 3 days < 60 years (n=330 vs. 327) AraC 100mg/m2 IV x 7 days Fernandez et al, NEJM 2009 > 60 years (n=411 vs. 402) AraC 200mg/m2 IV x7 days Löwenberg et al, NEJM

4 High dose Daunorubicin Newly Dx AML < 60 years Age Fernandez et al, NEJM 2009 Daunorubicin dose 45 mg/m 2 90mg/m 2 Significance CR (overall) 57% 71% p<0.001 CR Post 1 st cycle of all patients achieving CR 72% 83% Survival months 15.7 ms 23.7 ms p=0.003 Survival < 50 y/o 19 ms 34 ms p=0.004 Survival > 50 y/o 12 ms 17 ms p=0.2 High dose Daunorubicin AML > 60 years Age Modified: all patients Löwenberg et al, NEJM 2009 Overall no advantage 90mg vs. 45mg EFS and OS only better: y/o patients CBF leukemias (inv16, t8;21) years > 65 years CBF 4

5 45 vs. 90 mg/m2 Daunorubicin: Conclusion Across Both Studies Improved overall survival 90mg vs. 45mg mainly in favorable and possible in intermediate cytogenetics no benefit in unfavorable cytogenetics BUT higher CR rates allo BMT the younger the patient the better response and OS (in both studies: < 50 y/o in Fernandez and y/o in Lowenberg) Core binding factor (CBF) leukemias did better (in Lowenberg 200mg Cytarabine, does it make a difference?) FLT3(+) )patientsdid worse despite90mg, nosignificant OS benefit No significant higher toxicities similar induction death rate and grade 3 5 cardiac toxicities but higher death rate in CR in older patients (Lowenberg) Neutropenic enteritis/perforation, 2 nd malignancy, complication after allo BMT Outcome of AML Patients > Age 60( 65) Years with Standard Induction has Remained Dismal > 60 years > 70 years 5

6 Lower Intensity Regimens in Newly Diagnosed Elderly AML Patients 1. Decitabine (Phase III Trial, Phase II Data) 2. 5 Azacytidine (AZA 001) 3. High dose Lenalidomide in AML Induction 4. 5 Azacytidine +/ Lenalidomide in Upfront AML treatment Similar Outcome using Low Intensity vs. Induction Regimens in Elderly AML 298 AML, > 60 years age AraC+anthracycline+/ VP16 LD AraC +/ ATO; Tipifarnib median OS Low Intensity: 5.0 ms Induction: day mortality similar From Roboz G. et al, Leuk Res Apr;36(4): Epub 2012 Feb 8. 6

7 Phase 3: Decitabine vs. Supportive Care (SC) or s.c. Cytarabine in Newly Diagnosed AML > 65 years Open label (randomized) phase III trial in 485 patients Median age 73 years Decitabine 20mg/m2 2 x 5 days vs. Treatment tchoice [mostly Low dose AraC 20mg/m2 x10 days] Response, % Decitabine (n = 242) Treatment Choice (n = 243) Low-Dose Cytarabine (n = 215) Supportive Care (n = 28) CR + CRp 17.8* 78* 7.8* *P =.001; OR: 2.5 (95% CI ). > 50% of pts with treatment related grade 3/4 adverse event; rates similar between decitabine and cytarabine treatment (low with SC) Thomas XG, et al. ASCO Abstract Decitabine vs. SC or LD ara C in Elderly AML: Survival after 446 Deaths From Thomas XG, et al. ASCO Abstract

8 Phase 3: Decitabine vs. Supportive Care (SC) or s.c. Cytarabine in Newly Diagnosed AML > 65 years median overall survival (OS) not statistically longer with decitabine: 7.7 vs 5.0 mos; (HR: 0.85; 95% CI: ; P =0.108) Decitabine with significant OS benefit in pts > 75 years, de novo AML diagnosis, bone marrow blast > 30% intermediate risk cytogenetics ECOG PS 2 Caution: OS not broken down by supportive care vs. s.c. Cytarabine arms! Thomas XG, et al. ASCO Abstract Phase 2 Multicenter German Study Decitabine (DAC): Newly Dx AML > 60 years n=227, median age 72 years DAC 135mg/m2total dose (15mg/m2) IV over 72 hours every 6 weeks All trans retinoic acid allowed in cycle 2, n=100 pts Responding pts eligible for DAC maintenance 20mg/m(2) x3 days for maximum of 12 months 51% had 2 nd AML (i.e. prior MDS) Median 2 cycles DAC (range 1 4), 88/227 pts had 4 cycles Lubbert M et al, Haematologica Dec 1 8

9 Phase 2 Multicenter German Study Decitabine (DAC): Newly Dx AML > 60 years CR PR ALE SD 13% 13% 26% 25% ALE = anti leukemic effect: >25% marrow blast decrease 6 week death rate 12.8 % (29 patient) Median OS5 5.5months 1 year survival 28%, 2 year survival 13% Lubbert M et al, Haematologica Dec 1 5 Azacytidine in AML with 20 30% Blasts: Data from the MDS/AML Approval Trial AZA=001 AZA 001 = 358 pts, of these 113 met criteria for AML, 20 30% blasts median age 70 years randomly assigned to 5 Aza vs. conventional care regimens (CCR) [47% BSC, 34% Low dose AraC (LDAC), 19% Induction Chemo (IC)] Response, % 5-Aza Intensive Rx LD-AraC CR 10/55 (18%) 6/11 (55%) 3/20 (15%) Fenaux P. et al, JCO 2010: 28:

10 5 Azacytidine in AML with 20 30% Blasts: Data from the MDS/AML Approval Trial AZA=001 5 Aza CCR Median OS 24.5 ms 16 ms HR 0.47; 95%CI , p= year OS 50% 16% p=0.001 Fenaux P. et al, JCO 2010: 28: Azacytidine In Newly Dx AML: Retrospective Review including 35 AML Patients Retrospective analysis of 82 pts; 35 pts with de novo AML n=17/35 (48%) overall response [vs. 19% pretreated] n=11/35 (31%) CR/CRi [vs. 11% pretreated] Response rate significantly higher in untreated pts (P =.006) and WBC <10 10(9)/L (P =.006). Median overall survival 9 months [vs. 7 months pretreated] Projected overall survival at median f/uof 12 months was 35% [vs. 18% pretreated] Patients that were untreated and had response: median overall response duration 13 months with overall survival rates of 58% at 1 year; 24% at 2 years Maurillo L et al, Cancer Jul

11 High Dose (50mg) Lenalidomide in Elderly Newly Dx AML 50mg daily x28 days for 2 cycle 10mg/day maintenance Newly dx AML, age > 60 years, median age = 71 years Overall CR/CRi rate = 30%, which was 53% in patients completing 2 full cycles Better response if low (< 1000/L) circulating blast count median time to response 30 days median time of response = 10 months (1 to > 17 months) Toxicity: anemia, neutropenia, thrombocytopenia, infection Fehniger et al, Blood 2011 High Dose (50mg) Lenalidomide (Len) + 5 Azacytidine (25, 50, 75mg/m 2 ) AML > 60 Years 2 cycles induction (28 days) of Len 50 mg PO days 1 28, 5 AZA escalating cohorts 25, 50, 75 mg/m2 IV days 1 5 Maintenance cycles (every 28 days) with Len 10mgPO days 1 28and 5 AZA 75 mg/m2 days 1 5 max 12 cycles Median age was 74 (range 63 81) median duration of therapy 2 months (range months). 11 (73.3%) patients completed 1and 7 (46.7%) completed 2 induction cycles; 5 (30%) patients went to maintenance DLT: grade 3/4 non DLT hematological toxicity in 6/11 (54.1%); neutropenic fever seen in 5/11 (45.4%). RESPONSE: Overall 7 of 11 (63.6%) evaluable patients responded CR/CRi in 3 (27.3%), partial remission (PR) in 4 (36.4%) median duration of response 3 months (range months) Giridharan Ramsingh et al, ASH 2011, #

12 Is Decitabine the New Standard in Elderly AML? Personal Opinion: May be or may be 5 Azacytidine For AML > 70 years lower intensity option should be strongly considered Are Lower Intensity Approaches thenew Standard in Elderly AML? Which Patient to Treat with Lower Intensity Therapy: some suggestions When and in Whom Older: most/all > years (may be > years) Unfavorable cytogenetics, 2 nd AML, previous MDS Intermediate cytogenetics: poor molecular markers (i.e. FLT3 mutated) not a allo BMT candidate not wanting induction Monosomal/complex/ 5/ 7 karyotype: does not negatively affect OS or response rate in most lower intensity trials vs. standard induction 12

13 Which Patient to Treat with Intensive Rx/Induction: some suggestions Age < 60 intensive induction 60 70years: consider all options including patient preference and curative potential with allo BMT Standard Induction Therapy Consider always Rx on a trial, dose of Daunorubicin year old (? > 60 90mg/m2) if CR matters Potential allo BMT candidates type and refer early for BMT Consult Otherwise novel regimens and/or treat on trial if possible (i.e. trial, IA + SAHA, ECOG2906, SWOG 117) Conclusion To date most trials adding a 3 rd agent and most new combinations have not improved outcome of AML induction, especially elderly and poor cytogenetic risk AML Elderly pts tolerate and can benefit from standard induction Lower intensity therapy, i.e. 5 Aza and DAC are options for AML pts > (70) years age, especially with poor risk disease features and/or not allo BMT candidates Consider allo BMT for all eligible and appropriate pts Up to age 70+ years (at Mayo) Maintenance lower intensity therapy is adopted in AML now s.c. low dose AraC can achieved remission (i.e % CR), mostly if not unfavorable cytogenetic risk group (Burnett AK, Cancer 2007, 109:1114 ) 13

14 THANK YOU! Questions? Call for clinical trials, AML/MDS consult or 2 nd opinion Mayo