New concepts in the management of elderly patients w ith AML - PowerPoint PPT Presentation

New concepts in the management of elderly patients w ith 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 Winship Cancer Institute | Emory University 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 Winship Cancer Institute | Emory University 3

Tools to Diagnose and Characterize AML Chromosomes (cytogenetics) Look at the blood/ marrow smear Flow Cytometry gene mutations/sequencing FISH Blasts Terstappen LW, et al. Leukemia . 1991;5(4):315-321. Winship Cancer Institute | Emory University 4

AML Prognostic Groups: European Leukemia Net (ELN) ELN genetic risk group Subsets Favorable t(8;21); inv(16); RUNX1-RUNX1T1 “Core binding factor (CBF) AML” t(16;16); CBFB-MYH11 Mutated NPM1 without FLT3-ITD (normal karyotype) Mutated CEBP α (normal karyotype) Intermediate-I FLT3-ITD + , NPM1 +/- (normal karyotype) Wild-type NPM1 and no FLT3-ITD (normal karyotype) Intermediate-II t(9;11)(p22;q23); MLLT3-MLL Abnormalities not classified as favorable or adverse 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 Rollig C, et al. J Clin Oncol. 2011;29(20):2758-2765. Winship Cancer Institute | Emory University 5

Outcomes in Younger and Older Patients w ith AML Based on ELN Risk Age > 60 Age < 60 Relapse-free Survival (%) Relapse-free Survival (%) Overall Survival (%) Overall Survival (%) Rollig C, et al. J Clin Oncol. 2011;29(20):2758-2765. Winship Cancer Institute | Emory University 6

Selected trials for fit older patients w ith AML El Rassi F, et al. Clin Med Insights Oncol. 2013;7:181-197. Winship Cancer Institute | Emory University 7

High dose daunorubicin for AML, age > 60 Löwenberg B, et al. N Engl J Med. 2009;361(13):1235-1248. Winship Cancer Institute | Emory University 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. Winship Cancer Institute | Emory University 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. Winship Cancer Institute | Emory University 10

CPX-351 vs. 7+3- Patient Characteristics Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000. Winship Cancer Institute | Emory University 11

CPX-351 vs 7+3 in older patients w ith new ly diagnosed, high risk AML Better CR, less toxicity vs 7+3 Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000. Winship Cancer Institute | Emory University 12

CPX-351 vs 7+3 in older patients w ith new ly diagnosed, high risk AML Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000. Winship Cancer Institute | Emory University 13

CPX-351 vs 7 + 3, follow up on consolidation Kolitz JE, et al. J Clin Oncol. 2017;35(suppl): Abstract 7036. Winship Cancer Institute | Emory University 14

What about unfit older patients w ith 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. Winship Cancer Institute | Emory University 15

Integrated Genetic Profiling in AML Patel J, et al. N Engl J Med. 2012;366(10):963-964. Winship Cancer Institute | Emory University 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 Winship Cancer Institute | Emory University 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. Winship Cancer Institute | Emory University 19

Addition of Sorafenib to Chemotherapy Improves the Overall Survival of Older Adults w ith 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. Winship Cancer Institute | Emory University 20

Targeting BCL BCL2 i in AM n 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. Winship Cancer Institute | Emory University 21

ABT-199 (venetoclax) plus low dose cytarabine or hypomethylating therapy Venetoclax + Decitabine or Azacitidine for newly dx Venetoclax + low dose Ara-C for newly dx AML age AML age > 65, ineligible for induction. > 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. Winship Cancer Institute | Emory University 22

Targeting IDH 1 and 2 in AML Phase 1 study AG-120 Phase 1/2 study AG-221 -14 pts IDH1 mutation -73 pts IDH2 mutation -7/14 (50%) ORR -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. Winship Cancer Institute | Emory University 23

SGN-CD33A D33A 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. Winship Cancer Institute | Emory University 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. Winship Cancer Institute | Emory University 25

Phase I open at Emory Main toxicity is cytokine release syndrome Winship Cancer Institute | Emory University 26

CAR T-cells for AML 8 open studies in clinicaltrials.gov Winship Cancer Institute | Emory University 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. Winship Cancer Institute | Emory University 28