2/10/2017. Updates in Acute Leukemia Therapy Blood Cancer Incidence in the United States, Leukemia Incidence in the Unites States, 2016

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1 Updates in Acute Leukemia Therapy 2017 Aaron Logan, MD, PhD UCSF Division of Malignant Hematology and Blood and Marrow Blood Cancer Incidence in the United States, 2016 Myeloma (30,330) Leukemia (60,140) Other (6,420) ALL (6,590) CML (8,220) Lymphoma (81,080) AML (19,950) CLL (18,960) Cancer Facts & Figures, American Cancer Society Leukemia Incidence in the Unites States, 2016 Cancer Facts & Figures, American Cancer Society

2 4 AML Risk Stratification AML Mutational Landscape Chen et al., Nature Genetics 2013, 45:

3 AML Front-Line Treatment Algorithms De Novo or Secondary AML Considerations: age, comorbidities, performance status Induction Chemotherapy Low-Intensity Therapy Supportive Care 7+3 HDAC-based or Clinical trial LoDAC HMA or Clinical trial SWOG 1203 Phase III RCT Induction Trial Age De novo or secondary (non-apl) AML Treatment naïve Eligible to receive induction chemo, including anthracycline 7+3 Daunorubicin (90mg/m 2 ) + continuous infusion cytarabine (100mg/m 2 ) IA Idarubicin (12mg/m 2 ) + high-dose cytarabine (1.5g/m2 daily x 4) IA+V Idarubicin + high-dose cytarabine + Vorinostat (500mg TID x 3d) Garcia-Manero et al., ASH 2016, #901 SWOG 1203 Phase III RCT Induction Trial Garcia-Manero et al., ASH 2016, #901 3

4 Percent 2/10/2017 SWOG 1203 Phase III RCT Induction Trial Garcia-Manero et al., ASH 2016, #901 SWOG 1203 Phase III RCT Induction Trial Garcia-Manero et al., ASH 2016, #901 Years SWOG 1203 Phase III RCT Induction Trial Garcia-Manero et al., ASH 2016, #901 4

5 Midostaurin CALGB10603 RATIFY study Stone et al., ASH 2015, #6 Midostaurin CALGB10603 RATIFY study MIDO 74.7 (31.7-not estimable); PBO 25.6 ( ) months Stone et al., ASH 2015, #6 5

6 CPX-351 Liposomal Cytarabine + Daunorubicin Liposomal formulation of cytarabine and daunorubicin 5:1 molar ratio of cytarabine:daunorubicin Fixed molar ratio maintained in human plasma >= 24hours after final dose Drug exposure maintained for 7 days Selective uptake by leukemia cells vs normal cells in bone marrow demonstrated in animal studies 100nm bilamellar liposome CPX-351 Phase III Study Design Medeiros et al., ASH 2016, #902 CPX-351 Phase III Study Response Rates by Age 6

7 CPX-351 Phase III Study OS by Age Medeiros et al., ASH 2016, #902 CPX-351 Phase III Study Early Mortality Rates Medeiros et al., ASH 2016, #902 CPX-351 Phase III Study Survival After HCT Lancet et al., ASH 2016, #902 7

8 Gilteritinib Phase I/II Study for R/R AML Perl et al., ASH 2016, #1069 Gilteritinib Phase I/II Study for R/R AML Perl et al., ASH 2016, #1069 Gilteritinib Phase I/II Study for R/R AML Perl et al., ASH 2016, #1069 8

9 IDH inhibitors in AML Levis. Blood 2013, 122: IDH inhibitors in AML Levis. Blood 2013, 122: Montalban-Bravo & Garcia-Manerao. Eur Onc Haem 2016;12:13 IDH mutations in AML ID mutations are present in ~20% 6-10% IDH1 9-15% IDH2-R140 or IDH2-R172 Associate with NPM1 and FLT mutations Paschka P, et al. J Clin Oncol. 2010;28:

10 AG-221 (Enasidenib) for IDH2 Mutated AML Overall Response (CR, CRp, Cri, mcr, PR) RR-AML (n=159) 59 (37%) CR 29 (18%) The FDA has granted fast track review and possible approval for orphan indicatoin CRp 1 (1%) CRi 3 (2%) mcr 9 (6%) PR 17 (11%) SD 72 (45%) PD 10 (6%) Not evaluable 18 (11%) Stein et al., ASH 2015, #323 AG-120 for IDH1 Mutated AML AG-120 for IDH1 Mutated AML 10

11 Venetoclax (ABT-199) in AML Wei et al., ASH 2016, #102 Venetoclax (ABT-199) in AML Wei et al., ASH 2016, #102 Venetoclax (ABT-199) in AML Wei et al., ASH 2016, #102 11

12 Vadastuximab talirine (SGN-CD33A) SGN-CD33A + HMA for Frontline Therapy in Elderly AML FDA placed several Vadastuximab trials on hold in December 2016 due to concerns regarding fatal hepatotoxicity and VOD in patients proceeding to allogeneic hematopoietic cell transplant Fathi et al., ASH 2016, #591 Whither Checkpoint Inhibition in AML? 12

13 Nivolumab + HMA for Frontline Therapy in Elderly AML Daver et al., ASH 2016, #763 Nivolumab + HMA for Frontline Therapy in Elderly AML Daver et al., ASH 2016, #763 Conclusions The incidence of AML is rising, but so are the treatment options Increasing understanding of the molecular landscape of AML is leading the way to relevant targeted therapies Inhibitors of FLT3, IDH, and bcl-2 are poised to achieve regulatory approval for use in frontline AML therapy soon Cytotoxic chemotherapy, either conventional 7+3 or new formulations (CPX-531) are unlikely to be entirely supplanted by targeted therapies The fate of immunotherapy in AML remains uncertain We appear to be on the brink of precision medicine treatment options for AML 13

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