New concepts in the management of elderly patients with AML Martha L. Arellano, MD Associate Professor of Hematology/Oncology Director, Hematology & Medical Oncology Fellowship Program Winship Cancer Institute of Emory University, Atlanta, GA Sea Island July 27, 2017 1
Objectives Review epidemiology of AML Summarize developments on risk stratification of elderly AML Discuss recent trials and new agents for elderly AML 2
Incidence of AML 4 /100,000 people per year are diagnosed with AML. 1.3% of all new cancer cases 1.8 % of all cancer deaths Estimated New cases/deaths: 21,380/10,590 (2017, USA). Median age at AML diagnosis: 69 years Therapy-related AML is increasing SEER 2017 3
Tools to Diagnose and Characterize AML Look at the blood/ marrow smear Chromosomes (cytogenetics) Flow Cytometry FISH gene mutations/sequencing Blasts Terstappen LW, et al. Leukemia. 1991;5(4):315-321. 4
AML Prognostic Groups: European Leukemia Net (ELN) ELN genetic risk group Favorable Intermediate-I Intermediate-II Adverse Rollig C, et al. J Clin Oncol. 2011;29(20):2758-2765. Subsets t(8;21); inv(16); RUNX1-RUNX1T1 t(16;16); CBFB-MYH11 Mutated NPM1 without FLT3-ITD (normal karyotype) Mutated CEBPα (normal karyotype) FLT3-ITD +, NPM1 +/- (normal karyotype) Wild-type NPM1 and no FLT3-ITD (normal karyotype) t(9;11)(p22;q23); MLLT3-MLL Abnormalities not classified as favorable or adverse inv(3) or t(3;3); RPN1-EVI1 t(6;9); DEK-NUP214 t(v;11)(v;q23); MLL rearranged -5 or del(5q); -7 abnl(17p) complex karyotype Core binding factor (CBF) AML 5
Outcomes in Younger and Older Patients with AML Based on ELN Risk Age < 60 Age > 60 Overall Survival (%) Relapse-free Survival (%) Overall Survival (%) Relapse-free Survival (%) Rollig C, et al. J Clin Oncol. 2011;29(20):2758-2765. 6
Selected trials for fit older patients with AML El Rassi F, et al. Clin Med Insights Oncol. 2013;7:181-197. 7
High dose daunorubicin for AML, age > 60 Löwenberg B, et al. N Engl J Med. 2009;361(13):1235-1248. 8
High dose daunorubicin for AML, age > 60 Younger and favorable risk CTG groups may benefit. Löwenberg B, et al. N Engl J Med. 2009;361(13):1235-1248. 9
CPX-351 vs. 7+3 in older patients with newly diagnosed, high risk AML Jeffrey E. Lancet, Geoffrey L. Uy, Jorge E. Cortes, et al. ASCO 2016 Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000. 10
CPX-351 vs. 7+3- Patient Characteristics Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000. 11
CPX-351 vs 7+3 in older patients with newly diagnosed, high risk AML Better CR, less toxicity vs 7+3 Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000. 12
CPX-351 vs 7+3 in older patients with newly diagnosed, high risk AML Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000. 13
CPX-351 vs 7 + 3, follow up on consolidation Kolitz JE, et al. J Clin Oncol. 2017;35(suppl): Abstract 7036. 14
What about unfit older patients with AML? Closed chromatin: transcriptional repression Open chromatin: transcriptional activation Decitabine and Azacitidine: ORR (CR/CRp/CRi) in 15-47%, largely replacing low dose Ara-C as the comparator arm for older AML studies. Pracinostat: ORR (CR +CRi +MLFS) in 27/50 patients (54%), incl. 21/50 (42%) CR. Ph III planned Johnstone RW. Nat Rev Drug Discov. 2002;1(4):287-299. Topp MS, et al. Blood. 2012;120(26):5185-5187. Garcia-Manero G, et al. Blood. 2015;126: Abstract 453. Blum W, et al. Proc Natl Acad Sci U S A. 2010;107(16):7473-7478. Kantarjian H, et al. J Clin Oncol. 2012;30(21):2670-2677. Thepot S, et al. Am J Hematol. 2014;89(4):410-416. Fenaux P, et al. J Clin Oncol. 2010;28(4):562-569. W. Burnett AK, et al. Cancer. 2007;109(6):1114-1124. 15
Integrated Genetic Profiling in AML Patel J, et al. N Engl J Med. 2012;366(10):963-964. 16
Functional Categories of Genes Commonly Mutated in AML Signaling
Molecular markers and targets in AML https://www.sulm.ch/pdf/sml/donnerstag_16-06-2016/16-06-2016_haferlach_haematol-diagnostik_ultra-deep-sequencing_swissmedlab2016.pdf 18
FLT3 inhibitors and their kinase interactions CP-868,596 ASP2215 Zarrinkar PP, et al. Blood. 2009;114(14):2984-2992. Fathi AT. Blood. 2013;122(2):239-242. 19
Addition of Sorafenib to Chemotherapy Improves the Overall Survival of Older Adults with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) (Alliance C11001) Phase II of induction and sorafenib in newly dx AML age > 60, with FLT ITD or TKD. Induction: 3+7 (dauno 60 mg/m 2 ) + sorafenib 400 mg po bid on d1-7. 2nd cycle of cytarabine and daunorubicin (5+2) + sorafenib, if no marrow aplasia CR: cytarabine 2 g/m 2 on d 1-5 with sorafenib 400 mg bid on days 1-28 x 2 cycles Maintenance: sorafenib 400 mg bid for 12 months Primary endpoint: 1-yr OS N= 54 ( FLT3 ITD= 39; FLT 3 TKD = 15); median follow-up = 28 mos. CR/CRi 1 year OS 30-60 day death Median DFS Median OS 57 (69%) 62% (45-78; P=0.0001) 9% 12.5 mos. 15 mos. 2 year OS and DFS, 28% and 27% Toxicity: Gr 1 diarrhea, fatigue, transaminitis; Gr2 palmar-plantar erythrodyesthesia Uy GL, et al. Blood. 2015;126: Abstract 319. 20
Targeting BCL2 in AML ABT-199 (venetoclax) plus: decitabine or azacitidine or low dose cytarabine being investigated. Thomas DA, et al. Blood. 2004;103(12):4396-4407. DiNardo C, et al. Blood. 2015;126: Abstract 327. Pollyea DA, et al. J Clin Oncol. 2016;34(suppl): Abstract 7009. 21
ABT-199 (venetoclax) plus low dose cytarabine or hypomethylating therapy Venetoclax + low dose Ara-C for newly dx AML age > 65, ineligible for induction. Venetoclax + Decitabine or Azacitidine for newly dx AML age > 65, ineligible for induction. 100 pts were enrolled in the expansion stage. Treatment-emergent AEs (TEAEs; in 30% of pts): nausea (59%), diarrhea (42%), constipation (39%), fatigue (31%), and decreased WBC (31%). Most frequent grade 3/4 TEAE and serious AE (SAE) was febrile neutropenia (41% gr ¾; and 29% SAE). No TLS was observed. Andrew Wei, Stephen Strickland, Gail Roboz, et al. ASH 2016 CR + CRi= 60%. Wei A, et al. Blood. 2016;128: Abstract 102. Pratz K, et al. Haematologica. 2017;102(Suppl 1): Abstract S472. 22
Targeting IDH 1 and 2 in AML Phase 1 study AG-120-14 pts IDH1 mutation -7/14 (50%) ORR Phase 1/2 study AG-221-73 pts IDH2 mutation -15/25 (60%) CR, 10 PR Phase III soon to open Prensner JR, et al. Nat Med. 2011;17(3):291-293. Pollyea D, et al. Presented at: American Association for Cancer Research Annual Meeting. April 5-9, 2014. San Diego, California, United States. Abstract 1LBA. Dinardo C, et al. Blood. 2015;126: Abstract 1306. C. Dinardo et al. AASH 2015. Stein E, et al. Blood. 2015;126: Abstract 323. 23
SGN-CD33A Phase I, N= 53 (49 evaluable), median age 75 -ORR 76%, CR/CRi in 35 subjects (71%) -MRD achieved in 19 (42%) CR pts and 5/15 (33 percent) CRi pts. Phase III trial halted due to toxicity concerns Kung Sutherland MS, et al. Blood. 2013;122(8):1455-1463. Fathi A, et al. Haematologica. 2016;102(Suppl 1): Abstract S503. 24
Advances in immune therapy for AML CAR = Chimeric Antigen Receptor Targets surface antigens in an MHC-independent fashion and consist of an ectodomain, hinge domain, transmembrane domain, and endodomain. Laszlo GS, et al. Blood. 2014;123(4):554-561. Chichili GR, et al. Sci Transl Med. 2015;7(289):289ra82. Mardiros A, et al. Blood. 2013;122(18):3138-3148. 25
Phase I open at Emory Main toxicity is cytokine release syndrome 26
CAR T-cells for AML 8 open studies in clinicaltrials.gov 27
In summary, Fit older AML- induction + targeted agent if available consider transplant in remission Unfit older AML- hypomethylating agent + targeted agent if available All older AML patients are candidates for clinical trails. 28
AML Studies at Emory 1. Omacetaxine for Consolidation and Maintenance in fit older AML patients 2. (QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in AML Subjects Who are FLT3-ITD Positive 3. Safety Study of MGD006 in Relapsed/Refractory AML (MGD006-01) 4. Study of Orally Administered AG-120 in Subjects with Advanced Hematologic Malignancies with an IDH1 Mutation, EAP opening soon 5. Study of ADCT-301 in Patients With Relapsed/Refractory CD25-positive Acute Myeloid Leukemia (AML) or CD25- positive Acute Lymphoblastic Leukemia (ALL) 6. A Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy, in the pipeline 7. Expanded access program of gemtuzumab ozogamicin for R/R AML, opening soon. 8. PRevention Of BLeeding in hematological Malignancies With Antifibrinolytic (Epsilon Aminocaproic Acid) (PROBLEMA) 9. Symptom-directed transfusion of PRBCs in patients with anemia 29