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

1

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

2 Winship Cancer Institute | Emory University

Objectives

• Review epidemiology of AML
• Summarize developments on risk stratification of elderly AML
• Discuss recent trials and new agents for elderly AML

3 Winship Cancer Institute | Emory University

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

4 Winship Cancer Institute | Emory University

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

5 Winship Cancer Institute | Emory University

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-RUNX1T1 t(16;16); CBFB-MYH11 Mutated 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-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

“Core binding factor (CBF) AML”

6 Winship Cancer Institute | Emory University

Outcomes in Younger and Older Patients w ith AML Based

• n ELN Risk

Overall Survival (%) Relapse-free Survival (%) Overall Survival (%) Relapse-free Survival (%)

Age > 60 Age < 60

Rollig C, et al. J Clin Oncol. 2011;29(20):2758-2765.

7 Winship Cancer Institute | Emory University

Selected trials for fit older patients w ith AML

El Rassi F, et al. Clin Med Insights Oncol. 2013;7:181-197.

8 Winship Cancer Institute | Emory University

High dose daunorubicin for AML, age > 60

Löwenberg B, et al. N Engl J Med. 2009;361(13):1235-1248.

9 Winship Cancer Institute | Emory University

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.

10 Winship Cancer Institute | Emory University

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.

11 Winship Cancer Institute | Emory University

Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000.

CPX-351 vs. 7+3- Patient Characteristics

12 Winship Cancer Institute | Emory University

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 w ith new ly diagnosed, high risk AML

13 Winship Cancer Institute | Emory University

Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract 7000.

CPX-351 vs 7+3 in older patients w ith new ly diagnosed, high risk AML

14 Winship Cancer Institute | Emory University

CPX-351 vs 7 + 3, follow up on consolidation

Kolitz JE, et al. J Clin Oncol. 2017;35(suppl): Abstract 7036.

15 Winship Cancer Institute | Emory University

What about unfit older patients w ith 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

16 Winship Cancer Institute | Emory University

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

18 Winship Cancer Institute | Emory University

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

19 Winship Cancer Institute | Emory University

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.

20 Winship Cancer Institute | Emory University

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/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.

21 Winship Cancer Institute | Emory University

Targeting BCL BCL2 i in AM n 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.

22 Winship Cancer Institute | Emory University

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.

23 Winship Cancer Institute | Emory University

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

24 Winship Cancer Institute | Emory University

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.

25 Winship Cancer Institute | Emory University

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.

26 Winship Cancer Institute | Emory University

Phase I open at Emory

Main toxicity is cytokine release syndrome

27 Winship Cancer Institute | Emory University

CAR T-cells for AML

8 open studies in clinicaltrials.gov

28 Winship Cancer Institute | Emory University

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.

29 Winship Cancer Institute | Emory University

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