Acute Leukemia. Richard M. Stone, MD Harvard Medical School Boston, Massachusetts

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1 Acute Leukemia Richard M. Stone, MD Harvard Medical School Boston, Massachusetts

2 Outline 1. Mutationally Targeted Therapies AML A. FLT3 inhibition Upfront with 3+7 chemotherapy: Ancillary data from C10603/RATIFY trial Upfront with 3+7chemotherapy: Crenolanib and gilteritinib Upfront with HMA: Quizartinib B. IDH inhibition: IDH1 and IDH inhibitor, in R/R AML, untreated AML, with HMA, with Immune-based therapies in AML A. CAR T-cell B. Targeted therapy with antibodies/antibody-like molecules C. Checkpoint inhibition 3. Other novel therapies in AML A. Promoting apoptosis B. E-selectin inhibitor 4. ALL: Antibodies, TKIs ( in PH+) and CAR-T cells AML, Acute myeloid Leukemia; HMA, hypomethylating agent; IDH, isocitrate dehydrogenase; R/R, relapsed or refractory; CAR, chimeric antigen receptor; TKI, tyrosine kinase inhibitor

3 AML Therapy for Patients Age <60 Standard induction chemotherapy: 3+7 Daunorubicin 60 mg/m 2 /d 90 mg/m 2 /d x 3 Or idarubicin 12 mg/m 2 d x 3 Cytarabine 100 mg/m 2 /d 200 mg/m 2 /d x 7 continuous infusion Ida plus high-dose ara-c (IA) inferior to standard 3+7 (SWOG 1203 study) Midostaurin 50 mg bid daily 8 21 days for mutation FLT3? Add GO 3 mg/m 2 /d 1, 4, and 7 Postremission (consolidation) therapy If ELN adverse or CR2: Allogeneic SCT Maybe even DUCB or haploidentical SCT If ELN favorable: (CBF) cytogenetics, or normal cytogenetics with biallelic CEBPa, or NPM1 mutation and FLT3 ITD wildtype (or low burden): 4 cycles HiDAC; add midostaurin 50 mg bid daily 8 21 for mutation FLT3 If ELN intermediate: Allogeneic SCT if sibling or MUD, otherwise HiDAC If mutant FLT3, add midostaurin in days 8 through 21 of a consolidation cycle IA, intra-arterial; SWOG, South West Oncology Group; GO, gemtuzumab ozogamicin; ara-c, cytarabine; Ida, intermediate-dose ara-c; SCT, stem cell transplantation; DUCB, double umbilical cord blood; CBF, core binding factor; MUD, matched unrelated donor; HiDAC, high dose ara-c

4 Therapy of Older Patients With AML Induction Fit, de novo, likely to benefit: Daunorubicin 60 mg/m 2 /d 90 mg/m 2 /d x 3d + cytosine arabinoside 100 mg/m 2 /d 200 mg/m 2 /d by IVCI for 7 days Add midostaurin days 8 through 21 if FLT3 mutation? Add GO 3 mg/m 2 /d 1, 4, and 7 Fit, secondary (s/p MDS or with MDS-type cytogenetics): CPX-351 Unfit (age >70 75, PS >2, comorbid double strand) Hypomethylating agent Consider 10d decitabine in TP53 mutation Consider fractionated GO as single agent Postremission therapy RIC allogeneic SCT if feasible? Repeat induction for others IVCI, intravenous continuous infusion; MDS, myelodysplastic syndrome; s/p, status post; PS, performance status; RIC, reduced-intensity conditioning

5 CPX-351 in High-Risk AML Background CPX-351: Liposomal formulation of cytarabine and daunorubicin packaged at 5:1 molar ratio 1 unit = 1.0 mg cytarabine plus 0.44 mg daunorubicin Liposomal encapsulation avoids fluctuating drug ratios Preferential uptake & intracellular release in leukemic blasts Improved efficacy compared to free drug

6 CPX-351 in High-Risk AML CPX-351 Clinical Experience Phase I (relapsed / refractory AML): MTD 100 U/m 2 Phase 2: Newly diagnosed older AML Randomized 2:1 CPX-351 or 7+3 Planned analysis: Secondary AML subset: improved RR (57.6% vs 31.6%, P =.06), EFS and OS Phase 3: Untreated high-risk AML years 309 patients randomized to CPX U/m 2 days 1, 3 & 5 (n=153) v 7+3 (n=156) CPX-351 vs 3+7: CR+CRi (47.7% vs. 33.3%; P=0.016), OS (P=0.005), EFS (P=0.021) 60-day mortality favored CPX-351 (13.7 vs 21.2%) Lancet JE, et al. Blood. 2014;123(21): Lancet JE, et al. J Clin Oncol. 2016;34(15 suppl): Abstract 7000.

7 Phase III Study of Chemotherapy + Midostaurin (PKC412) or Placebo in Newly Diagnosed Patients 60 Years of Age With FLT3-Mutated Acute Myeloid Leukemia (RATIFY) Patients with newly diagnosed AML 18 to <60 years with activating FLT3 mutations Screening within 48 hours Stratification by TKD and ITD (ratio <0.7 vs 0.7) (n = 717) R Induction (1 2 cycles) Midostaurin (50 mg bid, days 8-21) Daunorubicin (60 mg/m 2 /d, days 1-3) Cytarabine (200 mg/m 2 /d, days 1-7) Placebo (bid, days 8-21) Daunorubicin (60 mg/m 2 /day, days 1-3) Cytarabine (200 mg/m 2 /d, days 1-7) CR Consolidation* (up to 4 cycles) Midostaurin (50 mg bid, days 8-21) High-dose cytarabine (3 g/m 2 /d, q 12 h, days 1, 3, and 5) Placebo (bid, days 8-21) High-dose cytarabine (3 g/m 2 /day q 12 h, days 1, 3, and 5) CR Maintenance (up to 12 cycles) Midostaurin (50 mg bid, days 1-28) Placebo (bid, days 1-28) * Patients with an HLA-compatible family donor may proceed to allogeneic HCT ClinicalTrials.gov NCT Primary endpoint: OS Key secondary endpoint: EFS TKD, tyrosine kinase domain; ITD, internal tandem duplication; OS, overall survival; EFS, event-free survival Stone R, et al. N Engl J Med. 2017;377(5):

8 Kaplan-Meier Analysis of Overall Survival (Not Censored for Transplantation) in RATIFY Showed a 22% Reduction in Risk of Death With Midostaurin Plus Chemotherapy vs Placebo + Chemotherapy Stone R, et al. N Engl J Med. 2017;377(5):

9 Prognostic Impact of NPM1/FLT3-ITD Genotypes From Randomized Patients With Acute Myeloid Leukemia (AML) Treated Within the International RATIFY Study Abstract 467 Döhner, K, Thiede C, Larson RA, Prior TW, Marcucci G, Jones D, Krauter J, Heuser M, Lo- Coco F, Ottone T, Nomdedeu J, Mandrekar SJ, Sanford BL, Laumann K, Geyer SM, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte TM, Jansen JH, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Cheng Y, Pallaud C, Stone RM, Hartmut D, Bloomfield CD

10 Overall Survival According to ELN Subgroups Survival Probability Log-rank, + Censored P =.001 Logrank p= NPM1 mut /FLT3-ITD low NPM1 mut /FLT3-ITD high NPM1 wt /FLT3-ITD low NPM1 wt /FLT3-ITD high Time, Months Noncensored at HCT HCT, hematopoietic-cell transplantation Konstanze D, et al. Blood. 2017;130: Abstract 467.

11 Overall Survival According to ELN Subgroups and Midostaurin Versus Placebo Subgroup Forest Plot of Hazard Ratios by Patient Subgroups for OS non-censored at SCT No.of Patients Hazard Ratio (95% CI ) Hazard Ratio 95% CI P Value Overall ( ).014(one-sided) NPM1-MT/ITD-High ( ).128(two-sided) NPM1-MT/ITD-Low ( ).091(two-sided) NPM1-WT/ITD-High ( ).025(two-sided) NPM1-WT/ITD-Low ( ).894(two-sided) HR CI95 PValue_side <-Midostaurin Better- -Placebo Better-> Konstanze D, et al. Blood. 2017;130: Abstract 467.

12 Multivariate Analysis for Overall Survival Two-Sided P value ELN subgroups (NPM1/FLT3-ITD) <.001 Treatment (midostaurin vs placebo).012 Allogeneic HCT <.001 WBC ( vs <50 x10 9 /L).028 Age (difference of 10 years).335 Sex.689 ELN, European LeukemiaNet; HCT, hematopoietic-cell transplantation; WBC, white blood cell count Konstanze D, et al. Blood. 2017;130: Abstract 467.

13 Clonal Evolution of FLT3-ITD Positive AML in Patients Treated With Midostaurin in Combination With Chemotherapy Within the Ratify (CALGB 10603) and AMLSG Trials Abstract 182 Schmalbrock LK, Cocciardi S, Dolnik A, Agrawal M, Theis F, Jahn N, Blätte TJ, Gaidzik VI, Paschka P, Panina E, Fiedler W, Salih HR, Wulf G, Germing U, Lubbert M, Thol F, Heuser M, Larson RA, Ganser A, Schlenk RF, Stone RM, Döhner H, Konstanze D, Bullinger L

14 Presence of FLT-ITD Clones at Diagnosis and Relapse D, diagnosis; R, relapse; *Higher allelic ration Schmalbrock LK, et al. Blood. 2017;130: Abstract 182.

15 Low Relapse Rate in Younger Patients 60 Years Old With Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML) Treated With Crenolanib and Cytarabine/Anthracycline Chemotherapy Abstract 566 Wang ES, Tallman MS, Stone RM, Walter RB, Karanes C, Jain V, Collins RH

16 Crenolanib is a Highly Selective Type I Tyrosine Kinase Inhibitor of FLT3 Kinase-binding region Crenolanib Binds at the Adenosine ring Type I inhibitor: Active against both active and inactive conformations phosphate group mimic binding region of FLT3 mutations Nonbinding region Metabolism only Pan-FLT3 Inhibitor: Active against novel variant FLT3 mutations Overcomes resistance conferring FLT3 mutations, eg. FLT3-D835 High selectivity: No KIT inhibition at clinically achievable levels (which permits count recovery and no hair depigmentation) Highly selective for FLT3: No KIT inhibition Crenolanib inhibits FLT3 D835 activating mutations: May overcome resistance to type II TKIs Crenolanib is a pan-flt3 TKI: Inhibits FLT3 variants at low nm concentration Ramachandran et al., AACR, 2012 Wang ES, et al. Blood. 2017;130: Abstract 566. Smith et al., Leukemia, 2015 FLT3 Mutation FLT3 Phosphorylation IC 50 (nm) E573D 1.3 L576R 1.4 Juxta V592A 6.7 -membrane F594C 6.4 domain F594Y 6.7 Y599C 2.1 M664I 2.1 Kinase 1 N676K 15.9 A680V 1.3 Kinase 2 D835Y 2.4 (activation D839E 3.2 loop) N841I 2.5 Tarlock et al., EHA, 2017

17 Phase II Trial of Crenolanib in Newly Diagnosed FLT3-Mutant AML Goal: To assess the tolerability and efficacy of crenolanib when administered sequentially with standard induction chemotherapy in patients with newly diagnosed FLT3-mutant AML Induction (1-2 cycles) Consolidation (up to 4 cycles) Maintenance (up to 12 cycles) Newly diagnosed AML with activating FLT3 mutations Total 44 patients 60 years old: 29 patients Crenolanib HiDAC + Crenolanib HSCT Crenolanib Key Features: FLT3-ITD or FLT3-TKD Any FLT3 allelic burden Physician s choice of anthracycline High doses of daunorubicin (90 mg/m 2 ) allowed in younger patients Wang ES, et al. Blood. 2017;130: Abstract 566. Induction Cytarabine 100 mg/m 2 /CIV, d1- d7 Dnr 90 mg/m 2 (<60y) or Ida 12 mg/m 2, d1-d3 Crenolanib 100 mg tid starting d9 Consolidation Cytarabine 3 g/m 2 (<60y) or 1 g/m 2 (60y), q12h, 6 doses Crenolanib 100 mg tid starting d7 Maintenance Crenolanib 100 mg tid continuously

18 High Overall Response Rate Induction regimen CR/CRi After Induction 1 Overall Complete Response Cytarabine + daunorubicin + crenolanib n = 16 11/16 (69%) 13/16 (81%) Cytarabine + idarubicin + crenolanib n = 13 11/13 (85%) 12/13 (92%) Total N = 29 22/29 (76%) 24/29 (83%) Wang ES, et al. Blood. 2017;130: Abstract 566.

19 91% CR/CRi Patients Achieved FLT3-Negative Status After Treatment FLT3 Status After Treatment Status Available (n = 23) FLT3 negative 21 (91%) FLT3 positive 2 (9%) 24 patients achieved CR/CRi after standard treatment combined with crenolanib. FLT3 analysis was performed after induction or consolidation, and FLT3 data were available in 23 patients. FLT3 mutation clearance was seen in 21/23 patients, including patients who had variant FLT3 mutations Wang ES, et al. Blood. 2017;130: Abstract 566.

20 Overall Survival of Patients 100 Median Age of 51 Years Median Age of 47 Years 80 79% Survival Overall probability Survival (%) Median follow-up: 17.6 months (range 4.4 months 29.6 months) Months Number at risk Total of six deaths: Two refractory (including 1 with complex cytogenetics and mutant TP53) Two relapsed (both received <1 week of maintenance) Two in remission (1 history of cirrhosis with portal hypertension, 1 post HSCT complication) Wang ES, et al. Blood. 2017;130: Abstract 566. Estimated 1 year OS in Mido arm: ~75% Estimated 2 year OS in Mido arm: ~60%

21 Preliminary Results From a Phase 1 Study of Gilteritinib in Combination With Induction and Consolidation Chemotherapy in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML) Abstract 722 Pratz K, Cherry M, Altman JK, Cooper BW, Cruz JC, Jurcic JG, Levis MJ, Lin TL, Perl AE, Podoltsev NA, Schiller G, Liu C, Bahceci E

22 Antileukemic Response to 80 mg/d Gilteritinib in FLT3 mut+ Patients by Mutation Type and TKI Status Proportion of Patients Achieving Response,% Response Rates By FLT3 Mutation Type CR CRp CRi PR ORR = 55% CRc = 43% ORR = 62% CRc = 54% ORR = 17% CRc = 8% 0 0 FLT3-ITD FLT3-ITD and FLT3-D835 TKI Naive Prior TKI Therapy only FLT3-D835 only N = 45 N = 124 N = 141 N = 13 N = 12 CRc included patients who achieved complete remission, complete remission with incomplete hematologic recovery, and complete remission with incomplete platelet recovery, ORR included patients in CRc plus patients who achieved PR CR, complete remission; CRc, composite remission (CRc = CR+CRi+CRp;); CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; ORR, overall response rate (ORR=CRc+PR); PR, partial remission Pratz K, et al. Blood. 2017;130: Abstract 722. Proportion of Patients Achieving Response, % Response Rates By TKI Status CR CRp CRi PR ORR = 56% CRc = 44% ORR = 42% CRc = 31%

23 Study Design and Treatment Phase I study (NCT ): Multicenter, open-label, 3+3 design Enrollment began in January 2015 and is ongoing Adult patients aged 18 years with newly diagnosed AML were enrolled Dose-escalation cohorts of 40, 80, and 120 mg/day gilteritinib with 3 6 patients per cohort More than 20 patients in the dose-expansion cohort, including 15 FLT3 Mut+ patients Dose Escalation Patients aged 18 years with newly diagnosed AML Remission induction (1 2 cycles) Cytarabine (100 mg/m 2,d 1 7) + Idarubicin (12 mg/m2, d 1 3) + Gilteritinib (once daily, d 1 14 or 4 17*) Consolidation (1 3 cycles) Cytarabine (1.5 g/m 2 q 12 h, d 1, 3, and 5) + Gilteritinib (once daily, d 1 14) Maintenance (up to 26 cycles) DLT Observation *Gilteritinib was initially administered on days 1 14, but the schedule was later changed to administration on days 4 17 due to DLTs in the 40 mg/day dose cohort. Pratz K, et al. Blood. 2017;130: Abstract 722. Gilteritinib (once daily)

24 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+, mutation-positive; PR, partial remission; WT, wildtype *Response parameters were defined according to the International Working Group Criteria for AML (Cheson B, et al. J Clin Oncol. 2003;21(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 K, et al. Blood. 2017;130: Abstract 722.

25 Antileukemic Response: FLT3 WT Response Parameter*, n (%) FLT3 WT n = 23 CR 9 (39.1) CRp 0 CRi 5 (21.7) PR 3 (13.0) CRc 14 (60.9) *Response parameters were defined according to the International Working Group Criteria for AML (Cheson B, et al. J Clin Oncol. 2003;21(24): ). Two patients with favorable cytogenetic status were excluded from the response analysis population. Pratz K, et al. Blood. 2017;130: Abstract 722.

26 The Combination of Quizartinib With Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) With FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial Abstract 723 Swaminathan M, Kantarjian HM, Daver N, Borthakur G, Ohanian M, Kadia T, DiNardo CD, Jain N, Estrov Z, Ferrajoli A, Garcia-Manero G, Konopleva M, Andreeff M, Pemmaraju N, Jabbour EJ, Wierda WG, Ravandi F, Pinsoy MR, Cortes JE

27 Quizartinib (AC220) Second-generation class II RTK inhibitor Principal target organs in animal studies were bone marrow and lymphoid organs DLT: QTcF prolongation In phase I and II studies, composite complete response rate (CRc) ~50% among patients with FLT3-ITD Dose-finding study (30 mg v 60 mg): Similar CRc Higher ORR (71% v 61%), remission duration (20 wk v 4 wk) and OS (25.4 wks v 20.7 wks) with 60 mg Swaminathan M, et al. Blood. 2017;130: Abstract 723.

28 Quizartinib + Azacitidine or Low-Dose Cytarabine Study Design MDS, CMML, or AML FLT3-ITD and one of the following: Age 60 years with previously untreated disease Age 18 years with refractory or relapsed disease with 1 prior treatment regimen (ie, 1 st salvage) Any age who received HMA and progressed to AML N = 61 Physician s Choice Quizartinib + AZA N = 37 Quizartinib + LDAC N = 24 (CR+CRi+PR+HI) Secondary endpoints: CRc (CR+CRp+CRi); overall survival and relapse-free survival Swaminathan M, et al. Blood. 2017;130: Abstract 723.

29 Quizartinib + Azacitidine or Low-Dose Cytarabine Response to Therapy Best Response N (%) Q+AZA Q+LDAC Total CR 8 (22) 2 (8) 10 (16) CRp 2 (5) 5 (21) 7 (12) Cri 15 (41) 7 (29) 22 (36) CRc (CR+CRp+Cri) 25 (68) 14 (58) 39 (64) OR (CRc+HI+PR) 26 (70) 16 (67) 42 (69) NR 9 (24) 8 (33) 17 (28) 60-day mortality 2 (5) 0 (0) 2 (3) Swaminathan M, et al. Blood. 2017;130: Abstract 723.

30 AML: FLT3i Conclusion Understand role of FLT3i + low-dose chemotherapy: SWOG unfit, older: azacytidine vs aza/midostaurin vs aza/nivolumab (phase II/III) (FLT3 mut or WT) Understand role of specific v nonspecific TKI + chemo in upfront patients Chemo + mido vs chemo + crenolanib in upfront mutant FLT3 AML Understand role of specific FLT3i single-agent rx in advanced mutant FLT3 AML Results of dealer s choice vs quizartinib and dealer s choice vs gilteritinib trials awaited Swaminathan M, et al. Blood. 2017;130: Abstract 723.

31 ARO-021: Phase III Comparison of Crenolanib With Midostaurin in Combination With Chemotherapy Eligibility N = 510 Cytarabine/ Daunorubicin + Crenolanib Consolidation + Crenolanib Crenolanib maintenance Newly diagnosed FLT3-mutated AML R 1:1 Cytarabine/ Daunorubicin + Midostaurin Consolidation + Midostaurin Midostaurin Maintenance Primary Endpoint Event-free survival Secondary Endpoints Overall survival Relapse-free survival Composite complete remission rate Duration of response Swaminathan M, et al. Blood. 2017;130: Abstract 723.

32 IDH1 and IDH2 MUTATIONS IDH mutations occur in ~20% of patients with AML Most (~85%) occur in diploid or +8 de novo AML Higher prevalence with increased patient age Enriched in certain molecularly and karyotypically defined populations (eg, normal karyotype, mutant-npm1 AML) Hot-Spot mutations in enzymatic active site IDH1-R132, IDH2-R140 or IDH2-R172 Often considered founder mutations IDH mutations are ancestral in 20% of IDH1 cases and 35% of IDH2 cases Can be acquired at time of progression 10% - 15% of AML from MDS 20% - 25% of AML from MPN Dang L, et al. Trends Mol Med. 2010;16(9): Chou WC, et al. Leukemia. 2011;25(2): Molenaar RJ, et al. Leukemia. 2015;29(11): Swaminathan M, et al. Blood. 2017;130: Abstract 723.

33 Enasidenib Monotherapy is Effective and Well-Tolerated in Patients with Previously Untreated Mutant-IDH2 (midh2) Acute Myeloid Leukemia (AML) Abstract 638 Pollyea DA, Tallman MS, De Botton S, DiNardo CD, Kantarjian HM, Collins RH, Stein AS, Xu Q, Tosolini A, Gupta I, Agresta VS, Stein EM

34 Older Patients With Previously Untreated IDH2-Positive AML Were Eligible to Enroll in Phase I of the Pivotal Study A subgroup of older patients with previously untreated midh2 AML received enasidenib monotherapy in the phase I portions of the AG221-C-001 study* Patients: Untreated midh2 AML ECOG PS 0-2 Not candidates for standard treatment Enasidenib dosing: Dose-escalation: 50 mg/day 650 mg/day Expansion phase: 100 mg qd Continuous 28-day treatment cycles Pollyea DA, et al. Blood. 2017;130: Abstract 638. All Patients in AG221-C-001 N = 345 Previously Untreated AML N = 38 R/R AML: n = 281 MDS: n = 17 Other: n = 9 *NCT Data cutoff: 1 Sept 2017 ECOG PS, Eastern Cooperative Oncology Group performance status

35 Response Median number of enasidenib treatment cycles: 6.5 (range 1-35) Previously Untreated midh2 AML N = 38 Overall response (CR, CRi/CRp, PR, MLFS), n (%) 12 (32) ORR 95%CI 17.5%, 48.7% Best response, n (%) CR 7 (18) CRi/CRp 1 (3) PR 2 (5) MLFS 2 (5) Stable Disease*, n (%) 18 (47) Disease Progression, n (%) 1 (3) Not evaluable, n (%) 7 (18) *Failure to achieve a response but not meeting criteria for progressive disease for a period of 8 weeks Data cutoff: 1 Sept 2017 CRi/CRp, CR with incomplete neutrophil or platelet recovery; MLFS, morphologic leukemia-free state; ORR, overall response rate Pollyea DA, et al. Blood. 2017;130: Abstract 638.

36 Individual Patients PD AEPDPD PD Death Other WC AE PD WC WC WC Death ID Treatment Duration, Response and Disposition Transplant PD AE DeathPD ID PD Transplant PD PD PD PV ID AE Death PD PD PD Other Patient decision Ongoing Ongoing Ongoing CR Non-CR response SD PD NE Previously Untreated midh2 AML N = 38 Follow-up time, median months (range) 8.6 ( ) Time to first response, median months (range) 1.9 ( ) Time to best response, median months (range) 3.7 ( ) Time to CR, median months (range) 5.6 ( ) Duration of response, median months [95%CI] 12.2 [7.4, NR] Duration of CR, median months [95%CI] NR [3.7, NR] Treatment duration (months) Data cutoff: 1 Sept 2017 AE, adverse event; ID, investigator decision; NE, not evaluable; NR, not reached; PD, progressive disease; PV, protocol violation; SD, stable disease; WC, withdrew consent Pollyea DA, et al. Blood. 2017;130: Abstract 638.

37 Overall Survival Overall Survival Overall Survival: Responders Survival Median OS 11.3 months [95%CI 5.7, 17.0] Survival Median OS NR [95%CI 10.4 months, NR] Months Months Data cutoff: 1 Sept 2017 Pollyea DA, et al. Blood. 2017;130: Abstract 638.

38 Ivosidenib (AG-120) in Mutant IDH1 AML and Advanced Hematologic Malignancies: Results of a Phase 1 Dose Escalation and Expansion Study Abstract 725 DiNardo CD, De Botton S, Stein EM, Roboz GJ, Mims AS, Pollyea DA, Swords R, Altman JK, Collins RH, Mannis GN, Uy GL, Donnellan W, Pigneux A, Fathi AT, Stein AS, Erba HP, Prince GT, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Yen K, Kapsalis SM, Liu H, Goldwasser M, Agresta S, Attar EC, Tallman MS, Stone RM, Kantarjian HM

39 Single-Arm, Open-Label, Phase I, Multicenter Trial Study Dose escalation (n = 78) Enrollment complete Study Design and Objectives Dose expansion (n = 180) Enrollment complete: 500 mg qd in continuous 28-day cycles 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 R/R AML in 2 nd + 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 Study objectives Primary Secondary Safety and tolerability, MTD and/or RP2D, clinical activity midh1 R/R AML enrolled in expansion arm 1 DLTs, pharmacokinetics and pharmacodynamics (including 2-HG), preliminary clinical activity in advanced hematologic malignancies Exploratory DiNardo CD, et al. Blood. 2017;130: Abstract 725. Determination of comutations and midh1 variant allele frequency (VAF) ClinicalTrials.gov NCT DLTs, dose limiting toxicities; MTD, maximum tolerated dose; RP2D, recommended phase II dose

40 Response in R/R AML 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] Best response CR, n (%) 27 (21.6) CRi or CRp, n (%) 16 (12.8) MLFS, n (%) 9 (7.2) SD, n (%) 44 (35.2) PD, n (%) 13 (10.4) NA, n (%) 16 (12.8) CRh = 6 patients with investigator-assessed responses of CRi/CRp and 5 with MLFS Data cutoff: 12May2017. CRh, CR with partial hematologic recovery; CRp, CR with incomplete platelet recovery; CRi, CR with incomplete hematologic recovery; NA, not assessed; ORR, objective response rate; PD, progressivbe DiNardo CD, et al. Blood. 2017;130: Abstract 725.

41 Transfusion Independence in Primary R/R AML Set Patients Who Were Dependent at Baseline CR Post-baseline transfusion independence, % CRh Non-CR/CRh responders Non-responders Overall 0 Platelet RBC (n=69) (n=68) Post-baseline transfusion independence defined as no transfusion for at least one 56-day period. DiNardo CD, et al. Blood. 2017;130: Abstract

42 Genetic Profiling and Deep IDH1 Mutation Clearance to 0.04% in Ivosidenib (AG-120)-Treated Patients With Mutant IDH1 Relapsed or Refractory and Untreated AML Abstract 2684 Stone RM, Choe S, Zhang V, Marteyn B, Penard-Lacronique V, Wang V, DiNardo CD, Stein EM, Fathi AT, Tallman MS, Kantarjian HM, Attar EC, Wu B, de Botton S

43 Ivosidenib Induces Deep Molecular Remissions in AML Patients with Best Overall Response of CR or CRh (BMMCs) R/R AML (n = 73) Untreated AML (n = 23) No Mutation Clearance No Mutation Clearance n (%) Best Response (n) n Mutation Clearance n (%) n (%) Best Response (n) n Mutation Clearance n (%) CR+CRh 34 7 (21) 27 (79) CR+CRh 9 5 (56) 4 (44) CR 25 7 (28) 18 (72) CR 5 3 (60) 2 (40) CRh (100) CRh 4 2 (50) 2 (50) Others (100) Others (100) Non-CR+CRh responders a (100) Non-CR+CRh responders a (100) Nonresponders (100) Nonresponders (100) P value b.003 P value b.004 Data cutoff: May 12, 2017 a Defined as patients with best overall response of CRi, CRp, MLFS, or PR who do not meet criteria for CR or CRh. b p-value is based on Fisher s exact test comparing IDH1 mutation clearance in patients with best overall response of CR+CRh to patients with Other (non-cr+crh responders and non-responders) Stone RM, et al. Blood. 2017;130: Abstract 2684.

44 By-Subject VAF of Known/Likely Co-Occurring Mutations at Baseline by Response to Ivosidenib Treatment (R/R AML at 500 mg QD (Bone Marrow, N = 142, NGS) 2 1 Stone RM, et al. Blood. 2017;130: Abstract P.001 by Fisher s exact test; (Sung - Lists all RTK pathway genes that are assayed in BWH) 2 All detected FLT3 mutations were FLT3-TKD

45 Mutant Isocitrate Dehydrogenase (midh) Inhibitors, Enasidenib or Ivosidenib, in Combination With Azacitidine (AZA): Preliminary Results of a Phase 1b/2 Study in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) Abstract 639 DiNardo CD, Stein AS, Fathi AT, Montesinos P, Odenike O, Kantarjian HM, Stone RM, Koralek DO, Oostendorp J, Gong J, Gupta I, Vyas P

46 Overall Response Rates Overall response rate (ORR): CR + CRi/CRp + PR + MLFS (IWG 2003) Enasidenib + AZA: ORR: 4 of 6 In the enasidenib 100 mg + AZA arm, the best responses on-study were 2 CRs; 1 pt had PD In the enasidenib 200 mg + AZA arm, 1 pt achieved PR, 1 had MLFS, and 1 maintained SD Ivosidenib 500 mg + AZA: ORR: 8 of 11 4 pts achieved CR 1 pt achieved CRi, 1 pt achieved PR, 2 pts had MLFS, and 3 pts maintained SD Data cutoff: Sep 1, 2017 MR, morphologic relapse after CR/CRi/CRp DiNardo CD, et al. Blood. 2017;130: Abstract 639.

47 Ivosidenib or Enasidenib Combined With Standard Induction Chemotherapy Is Well Tolerated and Active in Patients With Newly Diagnosed AML With an IDH1 or IDH2 Mutation: Initial Results From a Phase I Trial Abstract 726 Stein EM, DiNardo CD, Mims AS, Savona MR, Pratz K, Stein AS, Fathi AT, Stone RM, Pollyea DA, Odenike O, Löwenberg B, Döhner H, Schiller G, Gupta IV, Nabhan S, Zhang V, Almon C, Cooper M, Tallman MS

48 Best Overall Response Summary Ivosidenib (AG-120) + CT Enasidenib (AG-221) + CT Response, n (%) All n = 30 De Novo n = 21 saml n = 9 All n = 50 De novo n = 27 saml n = 23 CR+CRi/CRp 23 (77) 19 (91) 4 (44) 31 (62) 18 (67) 13 (57) CR 19 (63) 15 (71) 4 (44) 25 (50) 16 (59) 9 (39) CRi/CRp 4 (13) 4 (19) - 6 (12) 2 (7) 4 (17) MLFS 1 (3) - 1 (11) 10 (20) 4 (15) 6 (26) PR 2 (7) 1 (5) 1 (11) Persistent disease 2 (7) 1 (5) 1 (11) 5 (10) 2 (7) 3 (13) NE 2 (7) - 2 (22) 4 (8) 3 (11) 1 (4) Best response from any time on study is shown Data cut 01AUG2017 Persistent disease, stable disease + disease progression Stein EM, et al. Blood. 2017;130: Abstract 726.

49 IDH1 Inhibitors: Conclusions 1. Enasidenib is approved for R/R IDH2-mutant AML 2. Ivosidenib likely will be approved for R/R IDH1-mutant AML 3. Possible role for these differentiating agents as single agents in chemotherapy unfit mutant-idh AML 4. The drugs can be given safely with AZA in chemotherapy-unfit IDHmutant AML: Phase II/III HMA +/- IDHi trials underway 5. The drugs can be given safely with 3+7 in chemo in chemotherapy-fit IDH-mutant AML: Phase III trial planned Stein EM, et al. Blood. 2017;130: Abstract 726.

50 Phase I Trial of CD123-Specific CAR-T Cells in AML and BPDCN (#811) Patients with relapsed/refractory AML or blastic plasmacytoid dendritic cell neoplasm (BPDCN) were eligible Exclusion criteria included active CNS disease, active infections, active GVHD post-allosct In six patients with AML with 4-7 prior lines of therapy and prior allsct, there were 2 CR/CRi, 1 MLFS, 2 SD, and 1 PD at day 28 of treatment A CR was attained in the patient with BPDCN Grade 1/2 CRS (n = 4) and grade 1/2 neurotoxicity (dizziness [n = 3], headache [n = 7], somnolence [n = 3]) were observed Stein EM, et al. Blood. 2017;130: Abstract 726.

51 Flotetuzumab: CD123 x CD3 Bispecific DART Protein (#637) DART bispecific platform Multiple applications across different diseases Predictable manufacturability Long-term stability Optimal variable light and heavy chain pairing allows for tighter conformation and closer proximity between effector (CD3+) cells and target (CD123+) cells Ability to tailor half-life and valency Flotetuzumab (MGD006/S80880) mode of action: redirected T-cell killing of CD123+ Cells Target Cell Killing Tumor Cell Anti-CD123 CD123 x CD3 DART Tumor Cell T Cell Anti-CD3 Activation Cytokine release Expansion Differentiation Stein EM, et al. Blood. 2017;130: Abstract 726.

52 Antileukemic Activity at Threshold Dose 500 ng/kg TF TF TF TF Treatment Group Cohort 2: ng/kg/day Cohort 2a: ng/kg/day Cohort 3: ng/kg/day Cohort 7: ng/kg/day Cohort 8: ng/kg/day 4 Days On/ 3 Days Off 7 Days On Rapid responses after single cycle of therapy in majority of patients who respond (cycles 2) TF AML AML MDS AML AML TF AML Antileukemic activity observed in 8/14 patients (57%) AML AML AML AML AML AML AML SD/OB SD/OB PR AML MLF 1 CRi 1 CRi 2 CR 3 CRm 4 Objective response rate (CR/CRi/MLF/PR): 6/14 patients (43%) CR/CRi Rate: 4/14 (28%) CRm, molecular CR;SD/OB,stable disease/other anti-leukemic benefit Stein EM, et al. Blood. 2017;130: Abstract 726.

53 Phase 2 Study of Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy of Patients With Newly Diagnosed Acute Myeloid Leukemia Abstract 815 Ravandi F, Daver N, Garcia-Manero G, Benton CB, Thompson PA, Borthakur G, Kadia T, Boddu PC, Alvarado Y, Jabbour EJ, Konopleva M, Takahashi K, Kornblau S, DiNardo CD, Estrov Z, Flores W, Basu S, Allison J, Sharma P, Pierce S, Brandt M, Pike A, Cortes JE, Kantarjian HM

54 Phase II Study of Nivolumab + IA in Patients With Newly Diagnosed AML Key Eligibility Criteria Regimen AML by WHO criteria (APL excluded), high-risk MDS ( 10% blasts) Ages (Patients over 60 who are very fit may be enrolled) Ps 0, 1, 2 Patients received cytarabine and idarubicin as induction/consolidation Nivolumab 3 mg/kg, q2w, was started on day 24, and continued for a total of one year. Adequate cardiac, renal, and hepatic function Ravandi F, et al. Blood. 2017;130: Abstract 815.

55 Phase II Study of Nivolumab + IA in Patients With Newly Diagnosed AML Characteristics N = 35 Median age 54 years (range, 26-65) -7/7q-/-5/complex 14 (40%) Risk Favorable Intermediate Poor 5 (14%) 16 (46%) 14 (40%) Efficacy N = 35 CR CRp/Cri PR NR Median OS Median EFS Median RFS (in CR) 21 (62%) 5 (14%) 1 (3%) 4 (11%) 15.8 months 8.3 months 17.3 months Suspected iraes N = 35 Rash 2 (6%) Colitis 2 (6%) Pancreatitis 1 (3%) Cholecystitis 1 (3%) Ravandi F, et al. Blood. 2017;130: Abstract 815 In Nonresponders, CD4 + T effector cells exhibited an exhausted phenotype (PD1 + TIM3 + )

56 IA + Nivolumab Comparison to IA Overall Survival Event-Free Survival Remission Duration* Ravandi F, et al. Blood. 2017;130: Abstract 815. * Censored for death in CR

57 Nivolumab (Nivo) With Azacytidine (AZA) in Patients (pts) With Relapsed Acute Myeloid Leukemia (AML) or Frontline Elderly AML Abstract 1345 Daver N, Garcia-Manero G, Basu S, Cortes JE, Farhad Ravandi F, Jabbour EJ, Assi R, Brandt M, Pierce S, Gordon T, Pemmaraju N, Andreeff M, Ning J, Kornblau S, Kadia T, Flores W, Matthews J, DiNardo CD, Borthakur G, Konopleva M, Allison J, Sharma P, Kantarjian HM

58 Nivolumab (Anti-PD1 mab) With 5-Azacytidine for Relapsed AML and Front-Line Elderly AML Phase I/II, open-label, single-arm study AML or Biphenotypic or Bilineage: Refractory or relapsed AML post-mds/cmml: Progressing after MDS/CMML therapy Regardless prior AML therapy Daver N, et al. Blood. 2017;130: Abstract Phase I (3+3 design) N = day Cycles: 5-Aza: IV/SC D mg/m 2 Nivolumab: IV on D1 & D mg/kg Patients at MTD Phase II Relapse (N = 70) 28 day Cycles: 5-Aza: RP2D mg/m 2 IV/SC D1-7 Nivolumab: RP2D mg/kg IV on D1 & D15 X4 cycles or until CR then D1 once Relapsed (N = 70/70) Front line (N = 15/40) Phase I Primary Objective: MTD & RP2D Secondary objectives: Safety Phase II Primary Objective: ORR (CR, CRi, PR, HI & morphologic LFS) per IWG 2003 criteria Secondary objectives: DOR, DFS & OS

59 Phase Ib/II Trial of Nivolumab Plus Azacitidine in Patients With AML Relapsed/Refractory N = 70 Median age 70 years (range, 22-90) In relapsed/refractory AML ORR, 33% CR/CRi/PR, 16 (23%) Median OS, 10.6 months -7/-5/complex cytogenetics 24 (34%) Prior therapies Prior regimens HMA-based HiDAC-based Int-dose cytarabine-based Targeted therapy Daver N, et al. Blood. 2017;130: Abstract (range, 1-7) Grade 2-4 iraes in 15 patients: Pneumonitis (N = 11) Nephritis (n = 6) Skin rash (n = 3) Transaminitis (n = 2) 2 cases of irae-related death Efficacy in frontline AML (>65) Evaluable = 12 CR/CRi/PR in 8 /12(66%) Enrollment ongoing

60 AZA+Nivo in Relapsed AML OS (censored for SCT) by response (N = 70) OS AZA+Nivo versus historical HMA-combo censored for SCT (Salvage 1, N = 32) p <.001 p <.001 Daver N, et al. Blood. 2017;130: Abstract Salvage 1 Median Age: 72 years Secondary AML: 42% Adverse cytogenetics: 35%

61 Phase 1/2 Study of Venetoclax With Low-Dose Cytarabine in Treatment-Naive, Elderly Patients With Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes Abstract 890 Wei A, Strickland SA, Roboz GJ, Hou J-Z, Fiedler W, Lin TL, Walter RB, Enjeti A, Chyla B, Popovic R, Fakouhi K, Shah P, Dunbar M, Xu T, Mabry M, Hayslip J

62 Phase I/II: VEN + LDAC in Elderly Patients With AML PRIMARY OBJECTIVES: safety, PK, MTD, ORR, TTP, and RP2D SECONDARY OBJECTIVES: response rates (CR, CRi, PR, and MLFS), DOR, and OS VEN 600 mg PO QD on days 1 28* LDAC 20 mg/m 2 SC QD on days 1 10 (28-day cycles) Phase I: RP2D 1-year outcomes presented: VEN 600 mg + LDAC *VEN dosed from D2 28 on cycle 1. ClinicalTrials.gov ID number: NCT N = 61: phase I (n = 8) + phase II (n = 53) DOR, duration of response; MTD, maximum tolerated dose; PK, pharmacokinetics; SC, subcutaneously; TTP, time to progression; VEN, venetoclax Wei A, et al. Blood. 2017;130: Abstract 890.

63 AML Response Rates 100% 62% 76% 47% 66% 53% 52% CR + CRi 90% 3% 80% 70% 2% 2% Median time to response 60% 50% 41% 34% 1 month (range: <1 month 9.5 months) 40% 30% 20% 10% 0% 36% 26% 35% 32% 16% 32% 41% 12% 41% 11% Median time to best response 2.6 months (range: <1 month 14.4 months) VEN 600 mg (N = 61) Intermediate (n = 37) Adverse (n = 19) No prior HMA (n = 44) Prior HMA (n = 17) 2 AML (n = 27) Wei A, et al. Blood. 2017;130: Abstract 890. CR CRi PR Data cutoff date: 15 AUG 2017

64 Outcomes According to Molecular Drivers of AML Cytogenetics Intermediate risk n = 37 ORR (CR + CRi) Median OS, mo 28 (76%) OS in Patients NPM1 Adverse risk n = 19 9 (47%) CEBPA biallelic Molecular Subgroups NPM1 n = 7* 7 (100%) NR Surviving Chromatin-spliceosome CEBPA biallelic n = 3 Chromatinspliceosome n = 22 TP53-aneuploidy n = 20 3 (100%) NR 15 (68%) (50%) Censored observation TP53-aneuploidy OS, months *Four of the 7 NPM1 patients have FLT3 mutations (3: ITD, 1: TKD). Wei A, et al. Blood. 2017;130: Abstract 890. Data cutoff date: 15 AUG 2017.

65 GMI-1271 Improves Efficacy and Safety of Chemotherapy in R/R and Newly Diagnosed Older Patients with AML: Results of a Phase 1/2 Study Abstract 894 DeAngelo DJ, Jonas BA, Liesveld JL, Bixby DL, Advani AS, Marlton P, O'Dwyer M, Magnani JL, Thackray HM, Becker PS

66 GMI-1271, an E-Selectin Antagonist, Disrupts the Relationship Between Tumor Cells and Bone Marrow Microenvironment E-selectin: Constitutively expressed in the bone marrow microvasculature Binds to the E-selectin ligand on AML cells Promotes cell-adhesion-mediated drug resistance (CAMDR) of leukemic cell DeAngelo DJ, et al. Blood. 2017;130: Abstract 894. GMI-1271, an E-selectin antagonist: Inhibits activation of cancer survival pathways (eg, NF-KB), disrupting CAMDR within bone marrow microenvironment Protects normal HSCs by enhancing quiescence and ability for self renewal Reduces chemotherapy-associated mucositis

67 Phase I/II Study Schema MEC Induction: mitoxantrone (10 mg/m 2 /d IV), etoposide (100 mg/m 2 /d IV), cytarabine (1000 mg/m 2 /d IV over 60 mins) for 5 days MEC Consolidation: same, for 4 days 7+3 Induction: cytarabine (200 mg/m 2 continuous infusion x 7d), idarubicin (12 mg/m 2 x 3d). Day 15 optional reinduction of 5+2 of same IDAC Consolidation: cytarabine (2 g/m 2 /d IV over 3 hrs QD for 5d), OR cytarabine (1.5 g/m 2 /dose IV over 3 hrs, BID QOD for 6 doses) GMI-1271: 5, 10, or 20 mg/kg q 12 hrs in phase I. RP2D was 10 mg/kg ClinicalTrials.gov identifier: NCT DeAngelo DJ, et al. Blood. 2017;130: Abstract 894.

68 Demographics Older Newly Diagnosed Patients N = 25 Age, median (range) 67 (60-79) Newly diagnosed, All de novo 12 (48) Secondary AML 13 (52) ELN Risk Category Favorable 3 (12) Intermediate 7 (28) Adverse 12 (48) Unknown 3 (12) DeAngelo DJ, et al. Blood. 2017;130: Abstract 894.

69 Overall Survival and Remission Duration Older Newly Diagnosed Patients Overall Survival, % Duration of Remission, % Censored at last known follow-up Median follow-up is 10.5 months 10/25 (40%) have proceeded to HSCT Median EFS is 11.3 months DeAngelo DJ, et al. Blood. 2017;130: Abstract 894

70 ALL: Current Approach PH-Negative - Younger Pediatric-like prescription or HyperCVAD Add rituximab in CD20 Testing addition of blina or ino early in prescription PH-Negative - Older: Larson or hypercvad Ph-Positive - Younger: Ph-Positive - Older TKI plus steroids Options for Relapse: ino, blina, CAR TKI plus chemotherapy (eg, ponat +hypercvad) DeAngelo DJ, et al. Blood. 2017;130: Abstract 894

71 Steroid + Ponatinib monotherapy in Ph-Positive ALL. Overall Results at w36 ( 9 mths) Parameter N (%) CHR* 38/42** (90) CKR 17/19 (90) Deep CMR 11/19 (57) Deep CMR*** at least one time (undetectable) 20/24 Martinelli et al, ASH 2017

72 Inotuzumab Ozogamicin in Combination With Bosutinib for Patients With Relapsed or Refractory Ph+ ALL or CML in Lymphoid Blast Phase Abstract 143 Jain N, Cortes JE, Ravandi F, Konopleva M, Alvarado Y, Kadia T, Wierda, WG, Borthakur G, Naqvi K, Pemmaraju N, DiNardo CD, Daver N, Yilmaz M, Patel K, Linderman DB, Garris R, Jabbour EJ, Kantarjian HM

73 Treatment Schema Cycle 1 D1: 0.8 mg/m 2 D8: 0.5 mg/m 2 D15: 0.5 mg/m 2 Cycle 2-6* D1: 0.5 mg/m 2 D8: 0.5 mg/m 2 D15: 0.5 mg/m 2 *After CR / CCyR / MRD neg: 1.0 mg/m 2 q4 wks Bosutinib continuously daily starting C1D1 until PD or toxicity Inotuzumab Each cycle is 4 weeks Bosutinib daily (3 dose levels) DL1: 300 mg DL2: 400 mg DL3: 500 mg Jain N, et al. Blood. 2017;130: Abstract 143.

74 Overall Responses (N = 16) Parameter N (%) ORR 13/16 (81) CR 8/16 (50) CRp 3/16 (19) CRi 2/16 (12) CCyR 12/13 (92) MMR 11/13 (85) CMR 8/13 (62) Flow neg 9/13 (69) Jain N, et al. Blood. 2017;130: Abstract 143.

75 Role of Remission Status and Prior Transplant in Optimizing Survival Outcomes Following Allogeneic Hematopoietic Stem Transplantation in Patients who Received Inotuzumab Ozogamicin for Relapsed / Refractory Acute Lymphoblastic Leukemia Abstract 886 Kebriaei P. Stelljes M, DeAngelo DJ, Goekbuget N, Kantarjian HM, Advani AS, Merchant A, Stock W, Wang T, Zhang H, Loberiza F, Vandendries E, Marks D

76 Methods: Patient Population Study 1010 Phase I/II trial (NCT ) Aug 2011 Jan 2016 N = 72 Study 1022 (INO-VATE) Phase III trial (NCT ) Aug 2012 Jan 2017 N = 164 Patients R/R ALL patients enrolled in either study and treated with inotuzumab Proceeded to allogeneic HSCT Study 1010: 24 patients included Study 1022: 77 patients included Analysis included 101 patients treated with inotuzumab ozogamicin who then proceeded to HSCT ALL, acute lymphoblastic leukemia; HSCT, hematopoietic stem cell transplant; R/R ALL, relapsed/refractory acute lymphoblastic leukemia Kebriaei P, et al. Blood. 2017;130: Abstract 886.

77 Post-Transplant OS: All HSCT Survival Probability No. of Risk INO ST mo Probability (95% CI) mo Probability (95% CI) INO 45.1 (35.2,54.5) 41.4 (31.5,51.0) ST 64.8 (44.1,79.4) 34.1 (15.3,54.0) Time, Months ** * * + + Censored INO (n = 101, Events = 58) Median OS 9.2 (95% CI 5.1, -) ST (n = 31, Events = 17) Median OS 14.2 (95% CI 11.4, 25.0) HR (unstratified) INO vs ST: (95% CI 0.664, 2.295) P =.7767 (one-sided, unstratified) CI, confidence interval; HR, hazard ratio; INO, inotuzumab ozogamicin; OS, overall survival; ST, standard therapy Kebriaei P, et al. Blood. 2017;130: Abstract 886.

78 Safety Outcomes: VOD 19 (18.8%) patients in the inotuzumab group experienced venoocclusive disease (VOD) post-transplant; 5 of these cases were fatal 1 cycle: 7% 2 cycles: 20% 3 cycles: 19% 4 6 cycles: 24% 2 vs 3 cycles: 16% vs 21% Median time from follow-up SCT to VOD was 15.0 days (range, 3 57 days) No difference was seen in median time from last dose to transplant between patients who experienced VOD and those who did not ALL, acute lymphoblastic leukemia; SCT, stem cell transplant Kebriaei P, et al. Blood. 2017;130: Abstract 886.

79 Chimeric Antigen Receptor (CAR) Abbreviations: CAR, chimeric antigen receptor; GMP, good manufacturing practice; TCR, T-cell receptor

80 Global, Multicenter ELIANA Trial: ALL Registration Study ELIANA is a single-arm global study with centralized manufacturing of tisagenlecleucel 25 sites in 11 countries across North America, Europe, Australia, and Asia FPFV=8 APR 2015 Data cutoff: 23 NOV 2016 Buechner J, at al. Haematologica. 2017;102(s2): Abstract S476.

81 ELIANA: Primary Efficacy Analysis Parameter Efficacy Analysis Set a n = 63 Primary endpoint % (n/n) 95% CI P Overall remission rate (CR + CRi) within 3 months 83 (52/63) (71-91) <.001 d Best overall response, % b CR 63 CRi 19 Secondary endpoint Best overall response of CR or CRi within 3 months with MRD-negative c BM 83 (71-91) <.001 d Primary efficacy analysis consistent with interim analysis where primary endpoint was met a Patients infused with CTL019 3 months prior to data cutoff. b The response was unknown in 6 patients. c MRD negative = MRD <0.01%. d Nominal P value presented to test null hypothesis of overall remission rate <20% for comparison with historical control. Buechner J, at al. Haematologica. 2017;102(s2): Abstract S476.

82 CTL019: Efficacy Outcomes in ALL Studies Duration of Response in B2202 and B2101J RFS 12 mo: 60% (95% CI, 48-75) 24 mo: 53% (95% CI, 39-70) 24 patients in continuous remission 1 year, 19 without further therapy 7 patients proceeded to HSCT, 1 to DLI 2 relapses after SCT Buechner J, at al. Haematologica. 2017;102(s2): Abstract S476.

83 Other CAR-T Cell Constructs in ALL: KTE-C19 and JCAR017 KTE-C19: anti-cd19 CAR T cell therapy; tested in phase I ZUMA-3 and ZUMA-4 trials in adult and pediatric relapsed/refractory ALL 1 82% (9/11) achieved CR/CRi 100% responders tested negative for MRD 38% (5/13) of patients experienced grade 3 CRS JCAR017 explored in a phase I study for pediatric and young adult patients with relapsed/refractory CD19-positive ALL (N = 45) 2 MRD-negative CR rate was 93% Severe CRS: 23% 1. Shah BD, et al. Blood. 2017;130: Abstract Gardner R, et al. Blood. 2016;128: Abstract 219.

84 Phase 1 Results of ZUMA-3: KTE-C19, an Anti- CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL) Abstract 888 Shah BD, Stock W, Wierda WG, Oluwole O, Holmes H, Schiller GJ, Topp MS, Kersten MJ, Houot R, Boissel N, Mojadidi M, Xue A, Mardiros A, Jiang Y, Shen T, Aycock JS, Stout S, Wiezorek JS, Jain R

85 Background Approximately 50% of new ALL cases occur in adults aged 20 y 1 Although 50% of adult ALL patients may achieve longterm survival, 2 outcomes for patients with R/R ALL are poor 3,4 The KTE-C19 CAR construct demonstrated an ORR of 82% and a CR rate of 54% in patients with refractory large B-cell lymphomas after a single infusion of CAR-T cells 5 Promising early efficacy and manageable toxicity were also reported with KTE-C19 in adult patients with R/R ALL 6 Here, we report updated safety and efficacy data from patients with R/R ALL in the ZUMA-3 trial (NCT ) Shah BD, et al. Blood. 2017;130: Abstract

86 ZUMA-3 Treatment Schema KTE-C19 Infusion Leukapheresis Bridging Therapy a Conditioning Chemotherapy First Disease Assessment b Day 4 Day 0 Day 28 Shah BD, et al. Blood. 2017;130: Abstract

87 Summary of Treatment-Emergent and KTE-C19 Related AEs TEAE, a n (%) Dose Dose Dose Overall Group Group Group N = 29 n = 6 n = 14 n = 9 Any TEAE 6 (100) 14 (100) 9 (100) 29 (100) Grade 3 1 (17) 5 (36) 2 (22) 8 (28) Grade 4 4 (67) 9 (64) 5 (56) 18 (62) Grade 5 1 (17) 0 (0) 1 (11) 2 (7) Any KTE- C19 related 6 (100) 14 (100) 9 (100) 29 (100) TEAE Grade 3 2 (33) 6 (43) 4 (44) 12 (41) Grade 4 2 (33) 7 (50) 3 (33) 12 (41) Grade 5 1 (17) 0 (0) 0 (0) 1 (3) 2 patients who received KTE-C19 died during the study due to AEs 1 due to multiorgan failure secondary to CRS on study Day 6, as previously reported 1 1 due to cerebrovascular accident not related to KTE- C19 treatment on study Day 48 No cases of cerebral edema Shah BD, et al. Blood. 2017;130: Abstract

88 Best Overall Response With 8 Weeks of Follow-Up Dose Group n = Dose Group n = Dose Group n = 4 Overall N = 24 CR Rate (CR + CRi), n (%) 4 (67) 10 (71) 3 (75) 17 (71) CR 3 (50) 10 (71) 3 (75) 16 (67) CRi 1 (17) (4) Blast-free hypoplastic/aplastic BM, n (%) 0 2 (14) 0 2 (8) 88% (21/24) of all patients treated had undetectable MRD a - 100% of CR/CRi/blast-free hypoplastic/aplastic BM - 2 patients with unconfirmed CR/CRi were also MRD- 67% (2/3) CR rate for patients with Ph+ disease 4 patients have relapsed, with a time to relapse ranging from 130 to 234 days: 1 CD19- a MRD negativity was defined as <0.01% B lymphoblasts in BM by multicolor flow cytometry. BM, bone marrow; CR, complete remission; CRi, CR with incomplete blood count recovery; MRD, minimal residual disease; ORR, objective response rate; Ph+, Philadelphiachromosome positive Shah BD, et al. Blood. 2017;130: Abstract 888.

89 Autologous vs Allogeneic CAR-T Cell Therapy Various approaches to CAR-T Cell Therapy ASH 2017: Phase I results of UCART19 in adults with CD19+ R/R B-ALL Benjamin R, et al. ASH 2017, Abstract 887

90 Conclusions New drugs approved in AML Midostaurin: w/induction chemo, FLT3 mutant upfront 2. Enasidenib: single agent, R/R IDH2 mutant 3. CPX-351: upfront in secondary AML 4. Gemtuzumab: w/chemo, CD33+ upfront or single-agent relapsed CD33+ 5.? 2018, Ivosidenib: single agent, R/R IDH1 mutant Drugs to watch in AML include venetoclax, GMI-1271, ICPI ALL: Use of BITE, ADC, and CART changing the approach

91 Acknowledgements Clinical Team at DFCI: Dan DeAngelo, Martha Wadleigh, David Steensma, Jackie Garcia, Goyo Abel, Eric Winer, Marlise Luskin Ilene Galinsky, NP Andrian Penicaud, PA, Kat Edmonds, NP, Sarah Cahill, PA, Mary Girard, PA, Sioban Creedon, NP BMT Team: Alyea, Antin, Armand, Cutler, Ho, Koreth, Soiffer DFHCC Team: Avigan, Rosenblatt, Amrein, Fathi, Brunner, Hobbs Scientific Team at Dana-Farber/Harvard Cancer Center Ben Ebert; Andy Lane, Coleman Lindsley,Jim Griffin; Tony Letai, David Weinstock, David Frank, Kim Stegmeir, Donna Neuberg, Tom Look, S Armstrong, T Graubet Worldwide Collaborators Alliance: R Larson, G Marcucci, W Blum, G Uy, G Roboz, S. Mandrekar Worldwide:,C Schiffer, T Fischer, H Dohner, K Dohner, C Thiede, R Schlenk, and others. Slides Daver, E Stein, C Dinardo, B Medeiros, E Wang, D Pollyea, A Wei, C Rollig, K Dohner, J Cortes D DeAngelo, M Davids, K Pratz, D Steensma