Kevin Kelly, MD, Phd Acute Myeloid and Lymphoid Leukemias

Kevin Kelly, MD, Phd Acute Myeloid and Lymphoid Leukemias Relevant financial relationships in the past twelve months by presenter or spouse/partner. Speakers bureau: Novartis, Janssen, Gilead, Bayer The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational. 14 th Annual California Cancer Conference Consortium August 1-12, 218

Agenda Management of Younger Patients With AML Management of Older Patients With AML Management of Relapsed AML Management of Newly Diagnosed ALL Management of Relapsed ALL

RATIFY: First-line Chemotherapy ± Midostaurin in FLT3-Mutated AML Randomized phase III study Induction* (1-2 cycles) Consolidation (up to 4 cycles) Maintenance (12 cycles) Stratified by ITD/TKD Pts with ND FLT3- positive AML, aged 18-59 yrs, and stratified according to FLT3 subtype (TKD or ITD high or low) (N = 717) Daunorubicin 6 mg/m 2 IVP D1-3 + Cytarabine 2 mg/m 2 /d IVCI D1-7 + Midostaurin 5 mg PO BID D8-21 (n= 36) Daunorubicin 6 mg/m 2 IVP D1-3 + Cytarabine 2 mg/m 2 /d IVCI D1-7+ Placebo D8-21 (n = 357) CR CR Cytarabine 3 g/m 2 over 3h q12h D1,3,5 + Midostaurin 5 mg PO BID D8-21 (n = 231) Cytarabine 3 g/m 2 over 3h q12h D1,3,5 + Placebo D8-21 (n = 21) Midostaurin 5 mg PO BID D1-28 (n = 12) Placebo D1-28 (n = 85) Stone RM, et al. N Engl J Med. 217;377:454-464. *Hydroxyurea allowed for 5 days prior to induction therapy.

Probability of Survival (%) RATIFY: Overall Survival 1 9 8 7 6 5 4 3 2 1 Pts at Risk, n Midostaurin Placebo mos, Mos (95% CI) CR 59% CR 54% 12 24 36 48 6 72 849 Mos 36 357 Midostaurin Placebo 269 221 28 163 74.7 (31.5-NR) 25.6 (18.6-42.9) 1-sided P =.9 by stratified log-rank test 181 147 151 129 97 8 37 3 1 1 Overall ITD (high) ITD (low) TKD Pts 717 214 341 162 HR (95% CI).4.6.8 1. 1.2 Midostaurin Better.78 (.63-.96).8 (.57-1.12).81 (.6-1.11).65 (.39-1.8) Placebo Better P Value.9 (1 sided).19 (2 sided).19 (2 sided).1 (2 sided) Stone RM, et al. N Engl J Med. 217;377:454-464.

OS (%) RFS (%) Standard of Care Induction Chemotherapy ± Gemtuzumab Ozogamicin Gemtuzumab ozogamicin 3 mg/m 2 on Days 1, 4, 7 of induction and Day 1 of each consolidation cycle 1 OS 1 RFS 8 6 4 8 6 4 Pts at Risk, n Control Gemtuzumab ozogamicin 2 6 12 18 24 3 36 42 48 Mos 139 139 Log-rank P =.368 117 118 82 98 45 66 26 43 Castaigne S, et al. Lancet. 212;379:158-1516. 16 25 6 16 4 Pts at Risk, n Control Gemtuzumab ozogamicin 2 6 12 18 24 3 36 Mos 14 113 Log-rank P =.3 83 11 39 68 19 41 6 29 3 16 1 8

OS (%) OS (%) AML15: Addition of Gemtuzumab Ozogamicin to Cytarabine-Based Induction Therapies in AML OS: All Pts OS: Favorable Karyotype AML 1 75 No gemtuzumab ozogamicin Gemtuzumab ozogamicin 1 75 No gemtuzumab ozogamicin Gemtuzumab ozogamicin 79% 5 25 2P =.3 Pts, n No gemtuzumab ozogamicin 557 Gemtuzumab ozogamicin 556 1 2 3 4 5 Yrs Events, n Obs. Exp. 315 32.4 297 39.6 43% 41% 5 25 2P =.3 No gemtuzumab ozogamicin Gemtuzumab ozogamicin Pts, n 65 72 Events, n Obs. Exp. 3 18.2 13 24.8 1 2 3 4 5 Yrs 51% Burnett AK, et al. J Clin Oncol. 211;29:369-377.

RR (Probability) RR (Probability) CD33 Splicing Polymorphisms in Pediatric AML Following Gemtuzumab Ozogamicin 1. rs12459419 = CC 1. rs12459419 = CT.75 P <.1.75 P <.975.5 No-GO (n = 145).5 No-GO (n = 11).25 GO (n = 154).25 GO (n = 125) 2 4 6 8 2 4 6 8 Yrs From End of Induction 1 Yrs From End of Induction 1 Lamba JK, et al. J Clin Oncol. 217;35:2674-2682.

Older Patients

OS Outcomes in Older Adults With AML (Aged 65-93 Yrs) 1. OS by Leukemia Therapy, Stratified by Charlson Comorbidity Index (CCI).8.6.4.2 6 12 18 24 3 36 42 48 54 6 Treated, CCI = Treated, CCI = 2 Untreated, CCI = 1 Mos After Diagnosis Treated, CCI = 1 Untreated, CCI = Untreated, CC1 = 2 Oran B, et al. Haematologica. 212;97:1916-1924.

Number of Driver Mutations Increase With Age in Pts With AML No. Mutated Genes per Pt, by Age Category P <.1 P =.6 1..8.6.4 No. Mutated Genes 1 2 3 4 5.2 < 4 Yrs 4-59 Yrs 6 Yrs Metzeler KH, et al. Blood. 216;128:686-698.

Proportional Surviving Mutations in Older Pts With AML Variables* Pts With Alteration, % All Older Younger P Value FLT3/ITD 22.5 22.6 22.5 >.999 FLT3/TKD 6.5 6.8 6.3.848 NRAS 12.1 13. 11.6.662 KRAS 3.2 2.3 3.9.426 PTPN11 3.9 6.2 2.5.5 KIT 3.2 2.3 3.9.426 JAK2.6.6.7 >.999 WTI 6.9 3.4 9.1.23 NPM1 22.3 28.2 18.6.21 CEBPA 14.3 1.2 16.8.55 RUNX1 13.4 19.8 9.5.2 MLL/PTD 5.8 6.8 5.3.543 ASXL1 1.9 17.6 6.7 <.1 IDH1 5.8 6.8 5.3.543 IDH2 11.9 14.7 1.2.183 *For all variables except Cohesin, n = 462; for Cohesin, n = 411. Tsai CH, et al. Leukemia. 216;3:1485-1492. Variables* Pts With Alteration, % All Older Younger P Value TET2 14.3 24.3 8.1 <.1 DNMT3A 15.2 2.9 11.6.8 TP53 7.6 13. 4.2.1 Cohesin 1. 9.6 1.2 >.999 1..8.6.4.2 P =.42 No adverse genetic alterations (n = 37) At least 1 adverse genetic alteration (n = 32) 5 1 15 2 OS (Mos)

AML Ontogeny Can Be Mutationally Defined Gene Color Specificity > 95% for sec. AML > 95% for de novo AML < 95% for sec. AML < 95% for de novo AML SRSF2 ZRSR2 SF3B1 ASXL1 BCOR EZH2 U2AF1 STAG2 NF1 RUNX1 CBL NRAS TET2 GATA2 TP53 KRAS PTPN11 IDH1 IDH2 SMC1A RAD21 FLT3 DNMT3A SMC3 CEBPA NPM1 11q23-rearranged CBF-rearranged Lindsley RC, et al. Blood. 215;125:1367-1376. Secondary AML De Novo AML Mutated cases, n (%) 19 (2) 7 (8) 1 (11) 3 (32) 7 (8) 8 (9) 15 (16) 13 (14) 6 (6) 29 (31) 5 (5) 21 (23) 19 (2) 2 (2) 14 (15) 7 (8) 5 (5) 1 (11) 1 (11) 3 (3) 2 (2) 18 (19) 18 (1) 2 (2) 3 (3) 5 (5).1.1.1 1 1 1 1 Odds Ratio 1 (1) 1 (1) 5 (3) 2 (2) 3 (2) 8 (4) 3 (2) 7 (4) 19 (11) 3 (2) 15 (8) 17 (9) 2 (1) 16 (9) 8 (4) 9 (5) 2 (11) 19 (11) 7 (4) 5 (3) 5 (28) 51 (28) 7 (4) 13 (7) 54 (3) 11 (6) 19 (9) P Value.1.5.1 <.1.35.9.2.7.5 <.1.13.2.14.6.15.4 1 1 1 1 1.14.14.7.28 <.1.2 <.1

Pts Achieving CR After Intensive Induction CT (%) Event-Free Survival (%) Differential Outcomes in Pts With de novo AML Based on Mutational Profile Clinically defined de novo AML, age 6 yrs 1 75 5 25 No CR CR 1 5 Clinically defined de novo AML, age 6 yrs De novo/pan-aml Secondary-type TP53 mutated 6 12 18 Mos Lindsley RC, et al. Blood. 215;125:1367-1376.

Older Age Remains Independent Prognostic Factor in AML Variable Age 6 yrs Female sex AML category De novo AML Secondary AML Therapy-related AML ECOG performance status -1 2 WBC count (5,/μL increase) MRC cytogenetic risk category Intermediate Favorable Adverse HR for Death (95% CI) 2.14 (1.6-2.87).82 (.66-1.1) 1 1.21 (.85-1.71) 2.24 (1.48-3.39) 1 1.38 (1.1-1.73) 1.1 (1.3-1.17) 1.41 (.25-.66) 1.65 (1.24-2.19) P Value <.1.59.29 <.1.5.4 <.1 <.1 Metzeler KH, et al. Blood. 216;128:686-698. Slide credit: clinicaloptions.com

CPX-351 1-nm bilamellar liposomes 5:1 molar ratio of cytarabine to daunorubicin 1 unit = 1.-mg cytarabine plus.44-mg daunorubicin Lancet JE, et al. ASCO 216. Abstract 7.

Prevalence of Synergy or Antagonism (% of Cell Screened) First-line CPX-351 in Newly Diagnosed Elderly AML: Phase II Study 24 CPX-351: liposomal formulation [1] Cytarabine + daunorubicin in 5:1 fixed molar ratio Taken up by cells, with preference for bone marrow Phase II study in elderly AML [2] Aged 6-75 yrs, fit for chemo 2:1 randomization to CPX-351 (1 U/m 2 IV Days 1, 3, 5) vs 7 + 3 CR/CRi rate superior with CPX-351 (P =.7) CPX-351: 67%; 7 + 3: 51% 7 6 5 4 3 2 1 Percent synergistic Percent antagonistic 1:1 1:5 1:1 5:1 1:1 CYT:DN Molar Ratios 1. Tardi P, et al. Leuk Res. 29;33:129-139. 2. Lancet JE, et al. Blood. 214;123:3239-3246.

First-line CPX-351 in High-Risk AML: Phase III Study Design Stratified by age (6-69 yrs vs 7-75 yrs), disease characteristics* Consolidation 1-2 cycles in pts with CR or CRi Pts with previously untreated high-risk AML,* 6-75 yrs of age, ECOG PS -2, ability to tolerate intensive therapy (N = 39) CPX-351 Induction, 1-2 cycles 1 units/m 2 C1: Days 1, 3, 5; C2: Days 1,3 (n = 153) 7+3 Induction, 1-2 Cycles Cytarabine: 1 mg/m 2 /day Daunorubicin: 6 mg/m 2 C1: Ara-C, 7 days; Daun, 3 days C2: Ara-C, 5 days; Daun, 2 days (n = 156) Until death or 5-yr follow-up Primary endpoint: OS *Therapy-related AML; AML with history of MDS ± prior HMA therapy or CMML; de novo AML with MDS karyotype. CPX-351 arm: 65 units/m 2, Days 1, 3; 7 + 3 arm: same dosing as reinduction (C2). Secondary endpoints: event-free survival, CR + CRi, 6-day mortality Lancet JE, et al. ASCO 216. Abstract 7.

Survival (%) First-line CPX-351 in High-Risk AML: OS 1 8 6 ITT Analysis Population CPX-351 7 + 3 Events, n/n 14/153 132/156 HR:.69 P =.5 Median Survival, Mos (95% CI) 9.56 (6.6-11.86) 5.95 (4.99-7.75) 4 2 3 6 9 12 15 18 21 24 27 3 33 36 Mos From Randomization Lancet JE, et al. ASCO 216. Abstract 7.

OS (%) First-Line CPX-351: Survival Landmarked From Time of Transplant 1 8 Kaplan-Meier Curve for OS Landmarked at Time of Stem Cell Transplant CPX-351 7 + 3 Events, n/n 18/52 26/39 mos (95% CI) Not reached 1.25 (6.21-16.69) HR:.46; log-rank P =.46 6 4 2 CPX-351 7 + 3 CPX-351 7 + 3 52 39 46 31 4 27 34 2 27 15 2 7 15 4 3 6 9 12 15 18 21 24 27 3 33 36 Mos From Stem Cell Transplant 9 1 6 1 3 Lancet JE, et al. ASH 216. Abstract 96.

CPX-351: Toxicity Considerations Grade 3-5 Nonhematologic AE, n (%) CPX-351 (n = 153) 7 + 3 (n = 151) All Pts (N = 34) Febrile neutropenia 14 (68) 17 (71) 211 (69) Pneumonia 3 (2) 22 (15) 52 (17) Hypoxia 2 (13) 23 (15) 43 (14) Sepsis 14 (9) 11 (7) 25 (8) Hypertension 16 (1) 8 (5) 24 (8) Respiratory failure 11 (7) 1 (7) 21 (7) Complete Recovery Counts for Pts With CR/CRi Pts receiving 1 induction, n Median, days Pts receiving 2 inductions, n Median, days ANC 5/µL CPX- 351 58 35 15 35 7 + 3 34 29 18 28 Plts 5,/µL CPX- 351 58 36.5 15 35 7 + 3 34 29 18 24 Fatigue 11 (7) 9 (6) 2 (7) Bacteremia 15 (1) 3 (2) 18 (6) Ejection fraction dec. 8 (5) 8 (5) 16 (5) Lancet JE, et al. ASCO 216. Abstract 7.

OS Outcomes With Various Treatment Approaches in Pts Aged > 7 Yrs With AML Pts at Risk, n HMA High intensity Supportive care Low intensity Dhulipala VC, et al. ASH 215. Abstract 255. 1..9.8.7.6.5.4.3.2.1 6 12 18 24 3 36 42 48 54 6 Mos 11 238 187 67 9 14 47 32 56 93 29 19 39 54 13 11 19 37 6 8 12 27 4 7 8 17 4 6 3 15 2 3 2 9 2 1 2 8 2 1 1 4 2 1 HMA High intensity Supportive care Low intensity Censored Slide credit: clinicaloptions.com

Probability of Survival Survival Outcomes in Pts With TP53-Mutated AML 1..8.6 TP53 wt; not complex karyotype TP53 mut; not complex karyotype TP53 wt; complex karyotype TP53 mut; complex karyotype.4.2 2 4 6 8 1 Yrs Papaemmanuil E, et al. N Engl J Med. 216;374:229-2221. Slide credit: clinicaloptions.com

Variant Allele Frequency Survival (%) Extended (1-Day) Decitabine in TP53-Mutated AML Clearance Rate of TP53 Mutations Survival After SCT, by TP53 Mutation Status 1 1 8 6 4 8 6 4 Transplantation and TP53 mutation Transplantation and wild-type TP53 2 2 P =.99 Pts at Risk, n TP53 mutation Wild-type TP53 2 4 6 8 1 Days 7 24 7 24 4 16 3 1 2 5 Welch JS, et al. N Engl J Med. 216;375:223-236.

Ivosidenib (AG-12) Somatic IDH1 and IDH2 mutations result in accumulation of oncometabolite 2-HG [1] Epigenetic changes, impaired cellular differentiation midh identified in multiple solid and hematologic tumors [1,2] Mutation Frequency, % midh1 midh2 Pts With AML [2] 7-14 8-19 Ivosidenib (AG-12): first-in-class, oral, potent, reversible, selective inhibitor of midh1 enzyme [3] 1. Mondesir J, et al. J Blood Med. 216;7:171-18. 2. Medeiros BC, et al. Leukemia. 217;31:272-281. 3. DiNardo CD, et al. ASH 217. Abstract 725.

Ivosidenib (AG-12) vs Enasidenib (AG-221) Efficacy/toxicity profile of midh1 and midh2 inhibitor appears similar Parameter midh1 Inhibitor: Ivosidenib [1] Disease(s) evaluated (N = 258) R/R AML, other hematologic malignancies Testing of combination therapies ongoing midh2 Inhibitor: Enasidenib [2] (N = 239) R/R AML, MDS CR/CRh at RP2D, % 3.4 26.6 CR duration, mos 9.3 8.8 Differentiation syndrome, % 11.2 7. DNA methyltransferase inhibitors: synergistic effect on release of differentiation block in midh/leukemia models in vitro [3] 1. DiNardo CD, et al. ASH 217. Abstract 725. 2. Stein EM, et al. Blood. 217;13:722-731. 3. DiNardo CD, et al. ASH 217. Abstract 639.

Venetoclax With Decitabine or Azacitidine for AML: Background AML diagnosed at median age of 68 yrs, [1] yet elderly patients often ineligible or refractory to intensive induction CT [2] BCL-2: antiapoptotic protein expressed at high levels in AML, associated with poor outcomes and CT resistance [3] Venetoclax: oral BCL-2 inhibitor associated with in vitro antileukemic activity synergistic with hypomethylating agents (ie, azacitidine) [4] Venetoclax may serve as efficacious, low-intensity treatment for AML in elderly patients ineligible for standard induction CT Current report assessed safety, efficacy of venetoclax in combination with azacitidine or decitabine in elderly patients with previously untreated AML ineligible for standard induction chemotherapy [5] 1. NIH. Cancer stat facts: leukemia - acute myeloid leukemia (AML). 2. Kantarjian H, et al. Blood. 21;116:4422-4429. 3. Pan R, et al. Blood. 215;126:363-372. 4. Bogenberger JM, et al. Leuk Lymphoma. 215;56:226-229. 5. DiNardo CD, et al. ASCO 218. Abstract 71. Slide credit: clinicaloptions.com

Venetoclax With Decitabine or Azacitidine for AML: Study Design Multicenter, open-label phase Ib dose-escalation and dose-expansion trial (data cutoff: July 7, 217) Patients with untreated AML; aged 65 yrs; ineligible for standard induction; ECOG PS -2; no prior HMA/CT for antecedent hematologic disorder, CAR T-cell tx, other experimental tx; no favorable-risk cytogenetics*; no active CNS involvement; WBC count 25 x 1 9 /L; no HIV, HBV, HCV infection (N = 145) Dose Escalation Venetoclax ramped up to 4, 8, or 12 mg QD + Decitabine 2 mg/m 2 on Days 1-5 or Azacitidine 75 mg/m 2 on Days 1-7 in 28-day cycles Dose Expansion Venetoclax ramped up to 4 or 8 QD + Decitabine 2 mg/m 2 on Days 1-5 or Azacitidine 75 mg/m 2 on Days 1-7 in 28-day cycles *Core binding factor: inv(16), t(16;16), t(8;21), or t(15;17). Venetoclax ramped up during cycle 1: Day 1, 1 mg; Day 2, 2 mg; Day 3, 4 mg; Day 4, 8 mg; Day 5, 12 mg (11 patients). On reaching assigned dose level of 4, 8, or 12 mg QD, that dose was continued for rest of cycle. Primary endpoint: safety Secondary endpoints: CR, CRi, DoR, OS DiNardo CD, et al. ASCO 218. Abstract 71. Exploratory endpoint: MRD (< 1-3 leukemic cells at any measurement as detected by multicolor flow cytometry) Slide credit: clinicaloptions.com

Venetoclax With Decitabine or Azacitidine for AML: Baseline Characteristics Median follow-up of 15.6 mos Characteristic, n (%) Median age, yrs (range) 75 yrs, n (%) All Patients (N = 145) 74 (65-86) 62 (43) Male 81 (56) ECOG PS 1 2 BL bone marrow blasts 3% 31% to 5% > 5% 32 (22) 9 (62) 23 (16) 44 (3) 48 (33) 53 (37) Median mos on study (range) 8.9 (.2-31.7) DiNardo CD, et al. ASCO 218. Abstract 71. Characteristic, n (%) All Patients (N = 145) BL hydroxyurea use 14 (1) Cytogenetics Intermediate risk Favorable 74 (51) 71 (49) Secondary AML 36 (25) Slide credit: clinicaloptions.com

Venetoclax With Decitabine or Azacitidine for AML: Response and Survival Outcome CR + CRi, % CR CRi MRD negativity in patients with CR/CRi, n/n (%) Median DoR in patients with CR/CRi, mos (95% CI) Intermediate risk Poor risk de novo AML Secondary AML All Patients* (N = 145) 67 37 3 Venetoclax 4 mg Venetoclax 8 mg Azacitidine (n = 29) Decitabine (n = 31) Azacitidine (n = 37) Decitabine (n = 37) 76 38 38 CR/CRi rates in subgroups: intermediate-risk cytogenetics, 74%; poor-risk cytogenetics, 59%; de novo AML, 67%; secondary AML, 67%; aged < 75 yrs, 69%; aged 75 yrs, 64% 71 45 26 28/97 (29) 1/22 (45) 7/22 (32) 7/21 (33) 3/27 (11) -- 12.9 (11.-NR) 6.7 (4.1-9.4) 9.4 (7.2-11.7) NR (12.5-NR) NR (5.6-NR) -- -- -- -- 12.5 (5.1-NR) -- -- -- -- 57 3 27 11.7 (4.6-12.9) -- -- -- -- Median OS, mos (95% CI) 17.5 (12.3-NR) NR (11.-NR) 17.5 (1.3-NR) *Including 11 patients who received venetoclax at 12 mg. DiNardo CD, et al. ASCO 218. Abstract 71. 73 38 35 9.2 (5.9-NR) -- -- -- -- Slide credit: clinicaloptions.com

Venetoclax With Decitabine or Azacitidine for AML: Conclusions In this phase Ib dose-escalation and dose-expansion trial, venetoclax plus decitabine or azacitidine was well tolerated with deep, durable responses in elderly patients with previously untreated AML CR/CRi rate in all patients: 67% Promising CR/CRi rates observed in high-risk subgroups: poor-risk cytogenetics (59%), secondary AML (67%), and 75 yrs of age (64%) After median follow-up of 15.6 mos, median OS was 17.5 mos in all patients (1-yr survival rate ~ 5%) MRD negativity observed in 45% of patients who received venetoclax 4 mg + azacitidine Investigators suggested that venetoclax at 4 mg QD in combination with decitabine or azacitidine offers optimal risk benefit profile DiNardo CD, et al. ASCO 218. Abstract 71. Slide credit: clinicaloptions.com

Acute Lymphoblastic Leukemia