AML IN OLDER PATIENTS Whenever possible, intensive induction therapy should be considered

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1 AML IN OLDER PATIENTS Whenever possible, intensive induction therapy should be considered Charles A. Schiffer, M.D. Karmanos Cancer Institute Wayne State University School of Medicine Detroit, MI

2 WHY ARE MOST SUBTYPES OF AML SO DRUG RESISTANT? Hematopoietic precursors are designed to survive repeated exposure to multiple types of natural toxins Most resistance mechanisms have been shown to be amplified in undifferentiated precursors They can survive exposure to huge doses of chemotherapeutic agents in vitro (marrow purging ) Therefore, It is not surprising that leukemias which derive from hematopoietic stem cells are particularly resistant (eg - Ph chromosome pos diseases, MDS, MPD, FAB M0)

3 HOW TO DEFINE AML and WHO IS BEING TREATED ON THESE TRIALS?

4 OLDER ELDERLY REAL AML WHO MDS/AML

5 MRC LOW DOSE ARA-C vs. SUPPORTIVE CARE MEDICALLY UNFIT PATIENTS ~ 15% CR Burnett et al, Cancer 109:1114, 2007

6 S0432: Overall Survival by Tipifarnib Regimen Erba et al Blood 2007; 110: 136a (abstract 440)

7 THE ISSUE OF UNFIT FOR INTENSIVE THERAPY Very subjective and difficult to define PS, comorbidities, karyotype Implications for clinical trials Critical in making recommendations for individual patients Implications for new drug assessment/approval Control arm?

8 Azacitidine Treatment Prolongs Overall Survival in Higher-Risk MDS Patients Compared with Conventional Care Regimens: Results of the AZA-001 Phase III Study P Fenaux, MD, GJ Mufti, MD, V Santini, MD, C Finelli, MD, A Giagounidis, MD, R Schoch, MD,A List, MD, S Gore, MD, J Seymour, MD, E Hellstrom-Lindberg, MD, J Bennett, MD, J Byrd, MD, J Backstrom, MD, L Zimmerman, BSN, D McKenzie, MS, CL Beach, PharmD and L Silverman, MD on behalf of the International Vidaza High-Risk MDS Survival Study Group

9 Azacitidine Survival Study Screening/Central Pathology Review AZA 75 mg/m 2 /d x 7 d q28 d Investigator CCR Tx Selection Randomization CCR Best Supportive Care (BSC) only Low Dose Ara-C (LDAC, 20 mg/m 2 /d x 14 d q28-42 d) d Std Chemo (7 + 3) BSC was included with each arm Tx continued until unacceptable toxicity or AML transformation or disease progression

10 Baseline Clinical Characteristics N = 358 Parameter Age (yrs) Median Pts 65 (%) FAB (%) RAEB RAEB-T CMML IPSS (%) INT-1 INT-2 High AZA N= CCR N= CCR Regimens BSC Only N=105 LDAC N=49 Std Chemo N=

11 Proportion Surviving Overall Survival: Azacitidine vs CCR ITT Population months Log-Rank p= HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 Difference: 9.4 months 50.8% 24.4 months 26.2% 0.1 And some do OK without treatment Time (months) from Randomization CCR AZA

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13 SHOULD OLDER/ELDERLY PATIENTS BE TREATED? Not at all - supportive care With standard anthracycline/cytarabine With experimental therapy since it is hard to do worse focus on noncytotoxics

14 Age, Performance Status and Early Death in AML N = 437 Performance Status Death within 30 days % 13% 9% 1 0% 14% 21% 2 38% 19% 42% 3 17% 24% 62% SWOG - Appelbaum

15 Age, Performance Status and Complete Response Rate in AML Performance Complete Response Status % 40% 50% 1 60% 49% 38% 2 25% 38% 27% 3 50% 41% 29% N = 437 SWOG - Appelbaum

16 THE MAJOR ADVANCE IN AML THERAPY IN THE PAST YEARS: ZOFRAN AZOLES FOR PREVENTION/TREATMENT OF INFECTIONS WITH MOLDS LEUCOCYTE DEPLETION TO PREVENT ALLOIMMUNIZATION

17 RELAPSE FREE SURVIVAL CALGB 8923 AGE > 60 YEARS CONVENTIONAL DOSE ARA-C X 4 vs HIDAC/MITOXANTRONE X 2

18 THE DECISION FROM HELL: MDS PATIENT WITH WORSENING CYTOPENIAS AND INCREASING BLASTS AML induction therapy 7 & 3 Decitabine or azacytidine` Azacytidine + GO GO Clofarabine Low dose Ara-C Clinical trials Supportive care

19 WHAT TO DO TOMORROW FOR POST REMISSION THERAPY FOR PATIENTS NOT ON A CLINICAL TRIAL Assess patient s goals Individualize Conventional dose Ara-C HIDAC for the occasional patient with favorable cytogenetics or NPM1 mutated No maintenance Don t rush into reinduction treatment Consider clinical trials of nonmyeloablative allogeneic transplantation

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21 A CRITICAL CHALLENGE: THE DEVELOPMENT OF METHODOLOGY TO EFFICIENTLY EVALUATE NEW NONCYTOTOXIC THERAPIES Angiogenesis inhibitors Tyrosine kinase inhibitors - FLT3 Farnesyl transferase inhibitors Modulators of apoptosis Other signal transduction inhibitors Immunologic manipulations Histone deacetylase inhibitors Et al

22 WHAT TO DO NEXT? patients = 1-2 monster phase III studies or. 30 phase II exploratory trials - dose/schedule - biologic correlates whenever possible focus on responders