TREATMENT UPDATES IN ACUTE LEUKEMIA. Shannon McCurdy, MD University of Pennsylvania

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1 TREATMENT UPDATES IN ACUTE LEUKEMIA Shannon McCurdy, MD University of Pennsylvania

2 TIMELINE FOR FDA APPROVED AGENTS FOR AML Midostuarin Enasidenib Cytarabine + Daunorubicin (7+3) Gemtuzumab Ozogamicin approved Gemtuzumab Gemtuzumab Ozogamicin Ozogamicin withdrawn Liposomal Daunorubicin and Cytarabine

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4 ACUTE MYELOID LEUKEMIA 4

5 MUTATIONAL LANDSCAPE: 200 CASES DE NOVO AML MUTATIONS: 1. FLT3 28% 2. NPM1 27% 3. DNMT3A 26% 4. IDH1 or IDH2 20% N Engl J Med 2013;368:

6 FLT3: MIDOSTAURIN Kinase inhibitor, including inhibition of FLT3 and KIT FDA Approved based on 717 patients with newly diagnosed AML with FLT3 ITD or FLT3 TKD (i.e. D835) Midostaurin 50mg PO BID Days 8-21 In combination with 7+3 induction In combination with HIDAC (ARA-C) consolidation Midostuarin 50mg daily continuous for up to 12 cycles (take with food) Approved as maintenance in Europe, but not in the U.S. 6

7 RATIFY/C10603 SCHEMA FLT3 SCREEN PRE-REGISTER Stratify* FLT3 ITD or TKD R A N D O M I Z E DNR 60 mg/m2 d1-3 ARA-C 200 mg/m2 d1-7 Midostaurin 50 mg BID d8-21 DNR 60 mg/m2 d1-3 ARA-C 200 mg/m2 d1-7 Placebo BID d8-21 CR CR HidAC Midostaurin HidAC Placebo X 4 X 4 Midostaurin MAINTENANCE 12 months Placebo MAINTENANCE 12 months FLT3 WILD TYPE not eligible for enrollment Stratification: TKD; ITD with allelic ratio <0.7 vs 0.7 Screened 3277 Age <60 to find 896 FLT3 mut+ patients; 717 randomized Stone RM, et al. NEJM 2017

8 RATIFY/C10603 MIDOSTAURIN OVERALL SURVIVAL BENEFIT All patients Arm 4-year Survival Transplanted patients MIDOSTAURIN 51.4% (95%CI: 46, 57) MIDOSTAURIN PLACEBO 44.3% (95%CI: 39, 50) PLACEBO SCT in CR1 HR 0.61 SCT, non-cr1 HR 0.98 Hazard Ratio*: sided log-rank p-value*: Stone RM, et al. NEJM 2017

9 Forest Plot of OS by FLT3 status Mido effect on OS was similar across FLT3 subtypes

10 FLT3 Tyrosine Kinase Inhibitors in Development Quizartinib N O N O H Crenolanib O N N H O N H N S O N N O H 3 C CH 3 N OCH 3 Cl F F F Sorafenib O O O N H O N CH 3 Midostaurin N H N H N Gilteritinib

11 NEWER FLT3 INHIBITORS Drug Half life (dosing) D835 activity Selectivity Single agent Relapse/refractory Chemo combinations Quizartinib (AC220) Long (once daily) No Narrow, inhibits KIT Phase 3 enrollment complete Ph 1/2 completed, 1 Ph3 ongoing Crenolanib Short (TID) Yes Narrow, spares KIT N/A (Phase 3 with chemo ongoing) Ph 2 completed 2 Ph3 to open 2018 Gilteritinib (ASP2215) Long (once daily) Yes Narrow spares KIT Phase 3 ongoing Ph 1/2 ongoing 3 1. Altman JK, et al ASH abstracts 2013; Burnett AK, et al ASH abstracts Wang ES, et al. ASH Abstract 2017 # Pratz KW, et al. ASH Abstract 2017 #722

12 GILTERITINIB STUDY DESIGN AND TREATMENT Phase 1 study (NCT ): Patients aged 18 years with newly diagnosed AML Multicenter, open-label, 3+3 design Enrollment began 1/ 2015 Adult patients with newly diagnosed AML Dose-escalation cohorts of 40, 80, and 120 mg/day gilteritinib with 3 6 patients per cohort Dose Escalation Remission induction (1 2 cycles) Cytarabine (100 mg/m 2 ; Days 1 7) + Idarubicin (12 mg/m 2 ; Days 1 3) + Gilteritinib (once daily, Days 1 14 or 4 17*) Consolidation (1 3 cycles) DLT Observation More than 20 patients in the doseexpansion cohort, including 15 FLT3 Mut+ patients Cytarabine (1.5 g/m 2 q12h; Days 1, 3, and 5) + Gilteritinib (once daily, Days 1 14) Maintenance (up to 26 cycles) Gilteritinib (once daily) Pratz et al. ASH 2017

13 GILTERITINIB DOSE-LIMITING TOXICITIES AND TEAES Gilteritinib 40 mg/day Days 1 14, 2 patients had DLT with prolonged neutropenia and thrombocytopenia (n=1) and decreased ejection fraction (n=1) Subsequently modified to Days 4 17 with no further DLTs in 40 or 80mg/day The MTD was not reached Gilteritinib 120 mg/day was chosen as the first expansion dose Dose escalation in the 200 mg/day gilteritinib cohort is ongoing Grade 3 TEAEs in 10%: febrile neutropenia (36.7%), thrombocytopenia (18.4%), neutropenia (16.3%), and decreased platelet count (12.2%) Serious TEAEs: febrile neutropenia (n=8), sepsis (n=2), small intestinal obstruction (n=2), lung infection (n=2), and decreased ejection fraction (n=2), no deaths from TEAEs Pratz et al. ASH 2017

14 ANTILEUKEMIC RESPONSE: FLT3 MUT+ Response Parameter*, n (%) FLT3 Mut+ (n=21) CR 19 (90.5) CRp 1 (4.8) CRi 1 (4.8) PR 0 CRc 21 (100) CR, complete remission; CRc, composite complete remission; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; FLT3, fms-like tyrosine kinase 3; Mut+, mutationpositive; PR, partial remission; WT, wild-type. *Response parameters were defined according to the International Working Group Criteria for AML (Cheson B, et al. J Clin Oncol. 2003;12(24): ). Two patients were excluded from the response analysis population: one patient was excluded due to favorable cytogenetic status and one patient was excluded due to refusal to undergo a bone marrow biopsy and withdrawal of consent. CRc included patients who achieved CR, CRp, and CRi. Pratz et al. ASH 2017

15 IDH2: ENASIDENIB FDA approved for the treatment of adult patients with relapsed or refractory AML with an IDH2 mutation Based on AG221-C-001 (NCT ) Single arm study of 199 adults with relapsed or refractory AML with an IDH2 mutation Enasidenib 100mg PO daily 23% CR/CRh lasting 8.2 months Median time to first response was 1.9 months Median time to best response was 3.7 months Stein EM, Dinardo CD, et. al. Blood % of transfusion-dependent patients became transfusion-independent 76% of transfusion-independent patients maintained transfusion independence Side effects >20%: Nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite 15

16 ENASIDENIB DIFFERENTIATION SYNDROME Differentiation Syndrome occurs in 14% associated with: Respiratory symptoms such as supplemental oxygen requirement (76%) Renal dysfunction (70%) Fever (36%) Lymphadenopathy (33%) Bone pain (27%) Weight gain/edema (21%) Pleural (45%) or pericardial effusion (18%) Onset range: 10 days to 5 months Hyperleukocytosis not necessary to develop differentiation syndrome Treatment: Dexamethasone 10mg BID and hemodynamic monitoring Taper steroids after symptom resolution If severe pulmonary symptoms (requiring intubation) and/or renal dysfunction >48 hours, stop Enasidenib 16

17 IDH1 INHIBITOR: IVOSIDENIB SINGLE-ARM, OPEN-LABEL, PHASE 1 study Dose escalation (n=78) Enrollment complete Patients with midh1+ advanced hematologic malignancies Oral ivosidenib daily in continuous 28-day cycles Doses included 100 mg BID, 300, 500, 800, 1200 mg QD Dose expansion (n=180) Enrollment complete: 500 mg QD in continuous 28-day cycles R/R AML in 2nd+ relapse, relapse after SCT, refractory to induction or reinduction, or relapse within 1 year, n=126 Untreated AML not eligible for SOC, n=25 Other non-aml midh1 R/R advanced hematologic malignancies, n=11 Other R/R AML not eligible for Arm 1, n=18 ClinicalTrials.gov NCT Dinardo et al. Abstract 725 ASH 2017

18 IVOSIDENIB MOST COMMON AES ( 15%) (N=258) All treated patients, N=258 Any grade, n (%) Grade 3, n (%) Any AE 255 (98.8) 200 (77.5) Diarrhea 86 (33.3) 6 (2.3) Leukocytosis 78 (30.2) 17 (6.6) Nausea 76 (29.5) 3 (1.2) Fatigue 74 (28.7) 8 (3.1) Febrile neutropenia 65 (25.2) 64 (24.8) Dyspnea 61 (23.6) 9 (3.5) Anemia 60 (23.3) 49 (19.0) Electrocardiogram QT prolonged 58 (22.5) 23 (8.9) Edema peripheral 56 (21.7) 0 (0.0) Pyrexia 53 (20.5) 4 (1.6) Decreased appetite 51 (19.8) 4 (1.6) Constipation 48 (18.6) 2 (0.8) Cough 48 (18.6) 1 (0.4) Hypokalemia 45 (17.4) 7 (2.7) Vomiting 45 (17.4) 3 (1.2) Arthralgia 41 (15.9) 5 (1.9) Thrombocytopenia 41 (15.9) 35 (13.6) Top 10 Adverse Events: 1. Diarrhea 33% 2. Leukocytosis 30% 3. Nausea 30% 4. Fatigue 29% 5. Neutropenic Fever 25% 6. Dyspnea 24% 7. Anemia 23% 8. QT prolongation 23% 9. Edema 22% 10. Decreased Appetite 20% Dizziness 40 (15.5) 1 (0.4) Epistaxis 39 (15.1) 2 (0.8) Dinardo et al. Abstract 725 ASH 2017

19 IVOSIDENIB AES OF INTEREST Leukocytosis Grade 3 leukocytosis reported in 10/125 patients (8%) Managed with hydroxyurea None were fatal QT prolongation Grade 3 QT prolongation reported in 10/125 patients (8%) Study drug was reduced in 1 patient and held in 5 patients (all grades) None were Grade 4 or fatal IDH-differentiation syndrome (IDH-DS) All grade reported in 12/125 patients (9.6%) 4/12 had co-occurring leukocytosis Managed with corticosteroids and diuretics, and hydroxyurea if accompanied by leukocytosis None were Grade 4 or fatal Best response for the 12 patients with IDH- Differentiation Syndrome: Best Response CR CRh CRi/CRp MLFS SD n= Grade 3 = WBC > 100,000/mm 3 ; Grade 4 = clinical manifestations of leukostasis, urgent intervention indicated Dinardo et al. Abstract 725 ASH 2017

20 IVOSIDENIB RESPONSE IN RELAPSED/REFRACTORY AML (N=125) Primary R/R AML Set (n=125) CR+CRh rate, n (%) [95% CI] 38 (30.4%) [22.5, 39.3] Time to CR/CRh, median (range) months 2.7 (0.9, 5.6) Duration of CR/CRh, median [95% CI] months 8.2 [5.5, 12.0] CR rate, n (%) [95% CI] 27 (21.6%) [14.7, 29.8] Time to CR, median (range) months 2.8 (0.9, 8.3) Duration of CR, median [95% CI] months 9.3 [5.6, 18.3] CRh rate, n (%) 11 (8.8%) Overall Response Rate, n (%) [95% CI] 52 (41.6%) [32.9, 50.8] Time to first response, median (range) months 1.9 (0.8, 4.7) Duration of response, median [95% CI] months 6.5 [4.6, 9.3] CRh = 6 patients with investigator assessed responses of CRi/CRp and 5 with MLFS Dinardo et al. Abstract 725 ASH 2017

21 IVOSIDENIB RESPONSE IN UNTREATED AML AND MDS Characteristic Untreated AML Arm 2 a (n=34) Women / men, n 15 / 19 Age in years, median (range) 76.5 (64 87) ECOG PS at screening, n (%) (23.5) 20 (58.8) Prior MDS, n (%) 18 ( 52.9) Response Overall Response Rate, n (%) [95% CI] 19 (55.9) [37.9, 72.8] MDS Arm 3 b (n=12) 3 / (52 78) 4 (33.3) 6 (50.0) NA 11 (91.7) [61.5, 99.8] Duration of response, median [95% CI] months Duration of CR, median [95% CI] months 9.2 [1.9, NE] NE [5.6, NE] NE [2.3, NE] NE [2.8, NE] a Untreated AML patients not eligible for standard of care therapies in expansion Arm 2 and from dose escalation whose starting dose was 500 mg QD b MDS patients in expansion Arm 3 and from dose escalation whose starting dose was 500 mg QD Dinardo et al. Abstract 725 ASH 2017

22 IDH INHIBITORS WITH AZACITIDINE KEY ELIGIBILITY CRITERIA PHASE 1B (3+3 DESIGN) PHASE 2 (2:1 RANDOMIZATION) Newly diagnosed AML Age 18 Ineligible for intensive chemotherapy Pts with antecedent hematologic disorders allowed but prior HMA excluded midh1 midh2 Dose-finding* Ivosidenib + AZA n=7 Dose-finding* Enasidenib + AZA n=6 Expansion Ivosidenib + AZA n=15 Follow-up midh2 Randomization 2 1 Enasidenib 100mg QD + SC AZA n=66 SC AZA Monotherapy n=33 Follow-up SC AZA 75mg/m 2 /day x 7 days/ 28-day cycle (all study phases) PRIMARY ENDPOINTS: Recommended combination dose (RCD); safety KEY SECONDARY ENDPOINTS: Overall response rate PK/PD QOL outcomes PRIMARY ENDPOINT: PRIMARY ENDPOINT Overall response rate KEY SECONDARY ENDPOINTS: Safety Event-free survival Overall survival *Dose finding for enasidenib or ivosidenib; AZA dose remained constant 4 pts had enrolled in expansion as of data cutoff (1 Sep 2017); enrollment is now closed ClinicalTrials.gov NCT AML, acute myeloid leukemia; AZA, azacitidine; IC, induction chemotherapy; ORR, overall response rate; QOL, quality of life; RCD, recommended combination dose Dinardo et al. Abstract 639 ASH

23 ENASIDENIB + AZACITIDINE: TREATMENT-EMERGENT ADVERSE EVENTS Median enasidenib Tx cycles: 9 (range 1-13) Most common TEAEs (any grade): nausea, hyperbilirubinemia (n=4 each) IDH-differentiation syndrome (IDH-DS) occurred in 1 pt in the enasidenib 200-mg arm Grade 3-4 treatment-emergent adverse events Enasidenib 100 mg + AZA (n=3) Enasidenib 200 mg + AZA (n=3) Enasidenib + AZA Total (N=6) n (%) Hematological Neutropenia 0 2* (67) 2* (33) Thrombocytopenia 0 1* (33) 1* (17) Febrile neutropenia 0 1* (33) 1* (17) Anemia 0 1* (33) 1* (17) Lymphocyte count decreased 0 1 (33) 1 (17) WBC count decreased 0 1 (33) 1 (17) Non-hematological Pneumonia 1 (33) 1 (33) 2 (33) Hyperbilirubinemia 1 (33) 1* (33) 2* (33) Colitis 1 (33) 0 1 (17) Upper respiratory tract infection 1 (33) 0 1 (17) Hypocalcemia 1 (33) 0 1 (17) Hypokalemia 1 (33) 0 1 (17) Hypophosphatemia 1 (33) 0 1 (17) Hemorrhoidal hemorrhage 1 (33) 0 1 (17) Hypoxia 0 1 (33) 1 (17) Embolism 0 1* (33) 1* (17) Dinardo et al. Abstract 639 ASH 2017 *One event considered to be treatment-related 23

24 IVOSIDENIB (IDH1 INHBITOR) + AZACITIDINE Median ivosidenib Tx cycles: 3.0 (1-13) Most common TEAEs (any grade): nausea (n=8), constipation (6), fatigue (5), diarrhea (4) IDH-1 case of differentiation syndrome 1 death on-study d/t pneumonia Grade 3-4 treatment-emergent adverse events Hematological Anemia 2* (18) Febrile neutropenia 2 (18) Neutropenia 1* (9) Thrombocytopenia 1* (9) Non-hematological Pneumonia 2 (18) Constipation 1* (9) Dizziness 1 (9) Atrial fibrillation 1 (9) Blood creatinine increased 1* (9) IDH differentiation syndrome 1* (9) Parainfluenza virus infection 1 (9) Sepsis 1 (9) Cellulitis 1 (9) INR increased 1 (9) Gastrointestinal hemorrhage 1 (9) Ivosidenib 500 mg + AZA (N=11) n (%) 24 *One event was considered to be treatment-related Dinardo et al. Abstract 639 ASH 2017

25 OVERALL RESPONSE RATES FOR IDH INHBITORS + AZACITIDINE Overall response rate (ORR): CR + CRi/CRp + PR + MLFS (IWG 2003) Enasidenib + AZACITIDINE: ORR: 4 of 6 (67%) In the enasidenib 100 mg + AZA arm, 2 pts achieved CR In the enasidenib 200 mg + AZA arm, 1 pt achieved PR and 1 had MLFS Ivosidenib (IDH1 inhibitor) 500 mg + AZACITIDINE: ORR: 8 of 11 (73%) 4 pts achieved CR, 1 achieved CRi, 1 achieved PR, and 2 pts had MLFS CR = morphologic complete remission; CRi = morphologic complete remission with incomplete neutrophil recovery; CRp = morphologic complete remission with incomplete platelet recovery; PR = partial remission; MLFS = morphologic leukemia-free state; SD = stable disease; PD = progressive disease; MR = morphologic relapse after CR/CRi/CRp Dinardo et al. Abstract 639 ASH

26 GEMTUZUMAB OZOGAMICIN (GO) FDA approved for adults with de novo CD33 + AML History: 2000 Granted accelerated approval as a single agent (9mg/m 2 x 2 14 days apart) for patients 60 years+ with relapsed CD33 + AML 2009 SWOG S0106 trial of GO with 7+3 (6mg/m 2 D4) stopped early due to increased induction mortality and VOD 2010 GO pulled from the market 2015 Lower dose of GO with 7+3 submitted based on ALFA-0701 (3mg/m 2 D1, D4, D7 of induction, D1 of consolidation cycles 1 and 2) Castaigne S, et al. Lancet yr EFS & OS 40.8% and 53.2% 2-yr EFS and OS 17.1% and 41.9% Schrama D, et al Nat Rev Drug Dev 2006

27 META-ANALYSIS: VOD RATE BY GO MONOTHERAPY DOSE IN PATIENTS WITH RELAPSED/REFRACTORY AML GO dose N VOD incidence (95% CI) 9 mg/m2 x 2 (10 studies combined) % (3.5, 8.1) 6 mg/m2 x 2 (7 studies combined) % (6.4, 26.4) 3 mg/m2 d1, 4, 7 (3 studies combined) 87 0% (0.0, 1.1) 27

28 GEMTUZUMAB OZOGAMICIN + INTENSIVE CHEMOTHERAPY Age <60, CBF+ Survival benefit Age >60 Survival benefit No benefit, used 6 mg/m2 No benefit, used 6 mg/m2 Age 50-70, Survival benefit Hills R, et al. Lancet Oncol, 2014

29 BENEFIT WITH GO SEEN IN CORE BINDING FACTOR (CBF) LEUKEMIA CBF t(8;21); inv(16) Intermediate Adverse Hills RK, et al. Lancet Oncol

30 SPLICING VARIANT FOR CD33 ASSOCIATED WITH ALTERNATE ISOFORM AND LACK OF BENEFIT FROM GO Eliminates CD33 IgV domain, which is the antibody-binding site for GO Lamba, et al. JCO

31 VYXEOS (CPX-531) Liposome-encapsulated combination of Ara-C and Dauno FDA approved for adults with newly-diagnosed therapy-related AML (t-aml), AML with prior history of MDS, or AML with cytogenetic abnormalities diagnostic for MDS 100 nm bilamellar liposomes 5:1 molar ratio of cytarabine to daunorubicin 1 unit = 1.0 mg cytarabine plus 0.44 mg daunorubicin Lancet et al. ASCO Abstract 2016

32 PHASE 3 STUDY CPX-351 VS STANDARD INDUCTION IN YEAR OLD PATIENTS WITH NEWLY DIAGNOSED TREATMENT RELATED, SECONDARY AML, OR AML-MRC CPX-351 n= unit = 1 mg cytarabine mg daunorubicin n=156 First Induction 100 units/m 2 Days 1, 3 and 5 First Induction Cytarabine: 100 mg/m 2 x 7 d Daunorubicin: 60 mg/m 2 x 3 d Re-induction 100 units/m 2 Days 1 and 3 Re-induction Cytarabine: 100 mg/m 2 x 5 d Daunorubicin: 60 mg/m 2 x 2 d Consolidation 65 units/m 2 Days 1 and 3 Consolidation Cytarabine: 100 mg/m 2 x 5 d Daunorubicin: 60 mg/m 2 x 2 d Lancet et al. ASCO Abstract

33 VYXEOS (CPX-351) IMPROVES OVERALL AND POST-TRANSPLANT SURVIVAL Lancet et al. ASCO Abstract 2016

34 VYXEOS (CPX-351) IMPROVED 30 AND 60 DAY MORTALITY AND CR RATES 60-day mortality CR rates Lancet J, et al. ASCO 2016

35 LONGER DURATION TO NEUTROPHIL AND PLATELET RECOVERY WITH VYEXOS ANC 500/uL Platelets 50,000/uL CPX CPX Patients Receiving 1 Induction n=58 n=34 n=58 n=34 Median (days) Patients Receiving 2 Inductions n=15 n=18 n=15 n=18 Median (days) Lancet et al. ASCO Abstract 2016 Lancet J, et al. ASCO

36 ACUTE LYMPHOBLASTIC LEUKEMIA 36

37 BLINATUMOMAB FDA approved for relapsed or refractory pre-b ALL in adults and children, confirmed clinical benefit after accelerated approval and expanded indication to Ph+ relapse or refractory pre-b ALL TOWER (NCT ) Blinatumomab at 9 mcg/day on days 1-7 and 28mcg/day on days 8-28 and for subsequent cycles Improved OS with median 7.7 months vs. 4.0 months in the SOC arm ALCANTARA (NCT ) Expanded indication to Ph+ with 45 patients with disease resistance or intolerance to second generation TKI and imatinib 36% complete remission rate, duration median 6.7 months Premedication with dexamethasone, very short half-life T cell CD3 BiTE B or pre-b CD19 cell T cell B or pre-b cell 37

38 BLINATUMOMAB TOWER STUDY FOR RELAPSED/REFRACTORY ALL N=189 Response Rate: CR and CRh: 43% of patients within the first 2 cycles 82% of whom were MRD negative 40% bridged to allo SCT, which led to durable remissions.now Being Studied Combined with Induction Chemotherapy in Newly Diagnosed Ph- Pre-B ALL Topp et al; Lancet Oncology, 2014 Toxicities Neurologic (delirium, seizure, other) 58% any grade; 13% Grade 3 or 4 Mostly in Cycle 1 Cytokine Release Syndrome 2% Grade 3 >50% blasts; pre-phase treatment with high dose dexamethasone Stepwise dosing for cycle 1 (9µg/d x 7 days then 28µg/d x 21 days) Pre-treatment 20mg Dexamethasone before D1 and Dose Escalations Fever occurs in 60% Mortality 23 (12%) fatal adverse events (mostly sepsis) No patient in remission died during therapy

39 INOTUZUMAB OZOGAMICIN FDA approved for relapsed/refractory pre-b ALL Dosing 0.8 mg/m2 on Day 1, then 0.5mg/m2 on Days 8 and 15 First cycle days, subsequent cycles 28 days with full dosing if CR not achieved Phase 3 INO-VATE ALL (NCT ) n= 326 Inotuzumab ozogamicin (n=164) vs. investigator s choice chemo (n=162) ITT 35.8% CR for median 8 months (89.7% MRD negative) vs. 17.4% CR for median 4.9 months (31.6% MRD negative) ITT analysis CR/CRi rate was 80.7% (78.4% MRD negative) vs. 29.4% (28.1% MRD negativity) PFS was 5 vs. 1.8 months; OS was 7.7 vs. 6.7 months KANTARJIAN HM ET AL. N ENGL J MED 2016;375:

40 INOTUZUMAB OZOGAMICIN CD22 MoAb bound to calicheamicin Adverse Reactions: Cytopenias Infection Hemorrhage Neutropenic fever/fever Nausea Headache Transaminitis, hyperbilirubinemia Abdominal pain VOD/SOS in 11% May prolong the QT when combined with other QT prolonging agents Thomas X. Blood and Lymphatic Cancer: Targets and Therapy

41 MINI-HYPERCVAD PLUS INOTUZUMAB OZOGAMICIN IN ALL PATIENTS 60 20% 5-yr survival in older patients SEER, 2013 American Cancer Society.: Cancer Facts and Figures, Also being studied in EWALL-INO NCT in a phase 2 in combination with the first two treatment cycles only (vs. 4 used above) Kantarjian et al. The Lancet Oncology Jan The Lancet Oncology DOI: ( /S (18) )

42 TISAGENLECLEUCEL (KYMRIAH) nd or later relapse for ALL age 25 years T cell Approval based on trial of 63 pediatric and young adult patients with an 83% remission rate at 3 months Black box warning for cytokine release syndrome (CRS), which can be treated with Tocilzumab, REMS program required Native TCR CTL019 cell CD19 Dead tumor cell Anti-CD19 CAR construct Black box warning for neurologic symptoms Tumor cell Milone, et al. Mol Ther 2009 Carpenito, et al. PNAS 2009

43 ELIANA: FIRST GLOBAL MULTI-CENTER CAR T CELL TRIAL IN PEDIATRIC ALL 94% of pts received CTL centers across 11 countries (US, EU, Canada, Australia, Japan) CRS manageable with no deaths due to CRS CR/CRi 83% Grupp et al, ASH 2016: Abstract 221

44 THERE IS ALWAYS HOPE 44

45 Slide Contributors: Mark Levis Keith Pratz Courtney Dinardo Alexander Perl Noelle Frey THANK YOU!

46 VENETOCLAX + HMAS PRATZ ET AL. ABSTRACT EHA Patients received DEC or AZA with VEN given as a continuous 400-mg dose versus 800- mg dose for 28 days during cycle 1 Shortened duration of 800-mg dose during subsequent cycles in patients with leukemia clearance to allow for recovery of the absolute neutrophil count (ANC) Arm D1 (n=25) + Arm E1 (n=25) Cycle 1 Ramp-Up Arm D2 (n=25) + Arm E2 (n=25) Cycle 1 Ramp-Up 46

47 PATIENT CHARACTERISTICS Characteristic N=100 Age, median (range), years 72.5 (65 86) 75 years, n (%) 39 (39) Male, n (%) 61 (61) ECOG performance score, n (%)* Baseline bone marrow blast count, n (%) >50 Cytogenetics, n (%) Intermediate Poor 26 (26) 58 (58) 15 (15) 32 (32) 32 (32) 36 (36) 47 (47) 53 (53) Secondary AML, n (%) 22 (22) *Data were missing for 1 patient. Defined in the 2014 NCCN guidelines, version 2. PRATZ ET 47 All AL. data ABSTRACT as of 17-Feb-2017 EHA 2017.

48 RESPONSE RATES BY IWG CRITERIA WITH 2 DOSING SCHEDULES OF VEN IN COMBINATION WITH HMAS 76% 68% 72% 56% 68% CR + CRi Arm VEN + DEC 400 mg n=25 * * * DEC 800 mg n=25 AZA 400 mg n=25 AZA 800 mg n=25 N=100 *One patient each in arms D1, D2, and E1 discontinued before assessment. Also in arm D2, 1 patient was still on active treatment at the time of this analysis and had no response reported. RD = resistant disease MLFS = morphological leukemia-free state PRATZ ET AL. ABSTRACT EHA

49 OS FOR ALL PATIENTS Median time since first dose of study drug: 9 months Survival estimates: 79% (95% CI: 70 86%) at 6 months 70% (95% CI: 59 79%) at 12 months Median OS has not been reached PRATZ ET AL. ABSTRACT EHA

50 CONCLUSIONS: IDH INHIBITORS + AZACITIDINE Enasidenib or Ivosidenib + AZA combinations well tolerated grade 1-2 GI events: indirect bilirubinemia in enasidenib-treated d/t off-target inhibition of UGT1A1 enzym11 pts remained on-study at data cutoff Phase 1b confirms 100 mg enasidenib + AZA and 500 mg ivosidenib + AZA for further study Ongoing studies of midh inhibitors + AZA: Randomized phase 2 portion of the current study of enasidenib + AZA (enrollment complete in the ivosidenib + AZA arm) Phase 3 placebo-controlled AGILE study of ivosidenib + AZA (NCT ) in newly diagnosed AML not suitable for intensive therapy Dinardo et al. Abstract 725 ASH