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New concepts in the management of elderly patients with AML
Martha L. Arellano, MDAssociate Professor of Hematology/Oncology
Director, Hematology & Medical Oncology Fellowship ProgramWinship Cancer Institute of Emory University, Atlanta, GA
Sea IslandJuly 27, 2017
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Objectives
• Review epidemiology of AML
• Summarize developments on risk stratification of elderly AML
• Discuss recent trials and new agents for elderly AML
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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
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Tools to Diagnose and Characterize AML
Blasts
Terstappen LW, et al. Leukemia. 1991;5(4):315-321.
Look at the blood/ marrow smear
Flow Cytometry
Chromosomes (cytogenetics)
FISH gene mutations/sequencing
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AML Prognostic Groups: European Leukemia Net (ELN)
Rollig C, et al. J Clin Oncol. 2011;29(20):2758-2765.
ELN genetic risk group Subsets
Favorable t(8;21); inv(16); RUNX1-RUNX1T1t(16;16); CBFB-MYH11Mutated NPM1 without FLT3-ITD (normal karyotype)Mutated CEBPα (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-MLLAbnormalities not classified as favorable or adverse
Adverse inv(3) or t(3;3); RPN1-EVI1t(6;9); DEK-NUP214t(v;11)(v;q23); MLL rearranged-5 or del(5q); -7abnl(17p)complex karyotype
“Core binding factor (CBF) AML”
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Outcomes in Younger and Older Patients with AML Based on ELN Risk
Ove
rall
Surv
ival
(%)
Rela
pse-
free
Sur
viva
l (%
)
Ove
rall
Surv
ival
(%)
Rela
pse-
free
Sur
viva
l (%
)
Age > 60Age < 60
Rollig C, et al. J Clin Oncol. 2011;29(20):2758-2765.
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Selected trials for fit older patients with AML
El Rassi F, et al. Clin Med Insights Oncol. 2013;7:181-197.
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High dose daunorubicin for AML, age > 60
Löwenberg B, et al. N Engl J Med. 2009;361(13):1235-1248.
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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.
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Jeffrey E. Lancet, Geoffrey L. Uy, Jorge E. Cortes, et al. ASCO 2016
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.
11Winship Cancer Institute | Emory UniversityLancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000.
CPX-351 vs. 7+3- Patient Characteristics
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Better CR, less toxicity vs 7+3
Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000.
CPX-351 vs 7+3 in older patients with newly diagnosed, high risk AML
13Winship Cancer Institute | Emory UniversityLancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000.
CPX-351 vs 7+3 in older patients with newly diagnosed, high risk AML
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CPX-351 vs 7 + 3, follow up on consolidation
Kolitz JE, et al. J Clin Oncol. 2017;35(suppl): Abstract 7036.
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What about unfit older patients with AML?
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.
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
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Integrated Genetic Profiling in AML
Patel J, et al. N Engl J Med. 2012;366(10):963-964.
Functional Categories of Genes Commonly Mutated in AML
Signaling
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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
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FLT3 inhibitors and their kinase interactions
ASP2215
CP-868,596
Zarrinkar PP, et al. Blood. 2009;114(14):2984-2992. Fathi AT. Blood. 2013;122(2):239-242.
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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/m2) + 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/m2 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.
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Targeting BCL2 in AML
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.
ABT-199 (venetoclax) plus: decitabine or azacitidine or low dose cytarabine being investigated.
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ABT-199 (venetoclax) plus low dose cytarabine or hypomethylating therapy
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.
• CR + CRi= 60%. Andrew Wei, Stephen Strickland, Gail Roboz, et al. ASH 2016
Venetoclax + low dose Ara-C for newly dx AML age > 65, ineligible for induction.
Wei A, et al. Blood. 2016;128: Abstract 102. Pratz K, et al. Haematologica. 2017;102(Suppl 1): Abstract S472.
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Targeting IDH 1 and 2 in AML
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.
Phase 1/2 study AG-221 -73 pts IDH2 mutation-15/25 (60%) CR, 10 PR
Phase 1 study AG-120 -14 pts IDH1 mutation-7/14 (50%) ORR
Phase III soon to open
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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.
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Advances in immune therapy for AML
CAR = Chimeric Antigen ReceptorTargets surface antigens in an MHC-independent fashion and consist of an ectodomain, hinge domain, transmembranedomain, 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.
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Phase I open at Emory
Main toxicity is cytokine release syndrome
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CAR T-cells for AML8 open studies in clinicaltrials.gov
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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.
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AML Studies at Emory
1. Omacetaxine for Consolidation and Maintenance in fit older AML patients2. (QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in AML Subjects
Who are FLT3-ITD Positive3. 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 soon5. 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 pipeline7. 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