ASBMT Update Acute Leukemia

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1 ASBMT Update Acute Leukemia Tara L. Lin, MD Director, Acute Leukemia Program

2 1. Tara Lin, MD 2. ASBMT Update Acute Leukemia 3. April 22, Financial Disclosure Disclosures I have no financial interest to disclose. 5. Unlabeled/Unapproved Uses disclosure Use of investigational agents on FDA-approved clinical trials will be discussed 6. No relevant financial relationships or affiliations to disclose. 2

3 Overview Transplant for Acute Leukemia Who, when and why Data from ASBMT 2017 SWOG S1203: Induction and Referral Rates in Untreated AML CPX-351 in Older Secondary AML CAR-T therapy for AML Leukemia Program at KUCC AML molecular diagnostics/prognosis Clinical trials Acute Leukemia Hotline 3

4 Overview Transplant for Acute Leukemia Who, when and why Data from ASBMT 2017 SWOG S1203: Induction and Referral Rates in Untreated AML CPX-351 in Older Secondary AML CAR-T therapy for AML Leukemia Program at KUCC AML molecular diagnostics/prognosis Clinical trials Acute Leukemia Hotline 4

5 Transplant for Acute Leukemia 5

6 Transplant for Acute Leukemia TRM GVHD Leukemia biology Disease status Performance Status Co-morbidities Donor Preparative regimen Risk of leukemia relapse 6

7 S = standard of care, well-defined C = standard of care, clinical evidence available N = not generally recommended 7

8 Timing for HCT Consultation Acute Myelogenous Leukemia (AML) - Adult High-resolution HLA typing is recommended at diagnosis for all patients Early after initial diagnosis, all AML patients including: CR1 except favorable risk AML [defined as: t(16;16), inv 16, or t(8;21) without c- KIT mutation; t(15;17); normal cytogenetics with NPM1 or isolated biallelic CEBPA mutation and without FLT3-ITD] Antecedent hematological disease (e.g., myelodysplastic syndrome (MDS)) Treatment-related leukemia Primary induction failure or relapse Presence of minimal residual disease after initial or subsequent therapy CR2 and beyond, if not previously evaluated SOURCE: NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Timing for HCT Consultation Acute lymphoblastic leukemia (ALL) Adult High-resolution HLA typing is recommended at diagnosis for all patients Early after initial diagnosis, all ALL patients including:

9 Timing for HCT Consultation Acute lymphoblastic leukemia (ALL) Adult High-resolution HLA typing is recommended at diagnosis for all patients Early after initial diagnosis, all ALL patients including: CR1 Primary induction failure or relapse Presence of minimal residual disease after initial or subsequent therapy CR2 and beyond, if not previously evaluated SOURCE: NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

11 Optimal Management of Acute Leukemia Improved outcomes large volume, academic centers Interdisciplinary team nurses, pharmacists, SW Increased access to clinical trials Early HLA typing and stem cell transplant referral 11

12 Overview Transplant for Acute Leukemia Who, when and why Data from ASBMT 2017 SWOG S1203: Induction and Referral Rates in Untreated AML CPX-351 in Older Secondary AML CAR-T therapy for AML Leukemia Program at KUCC AML molecular diagnostics/prognosis Clinical trials Acute Leukemia Hotline 12

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14 Why we need to do better FDA approved drugs for AML Year Cytarabine (ara-c) 1969 Daunorubicin 1979 Mitoxantrone 1987 Idarubicin 1990 Gemtuzumab Ozogamicin (Myelotarg) 2000 Clofarabine 2004 Hypomethylating agents Azacitidine, Decitabine 14

15 Feasibility of Allogeneic HCT Among High-Risk AML Patients in First Complete Remission Results of the Transplant Objective from the SWOG (S1203) Randomized Phase III Study of Induction Therapy Using Standard 7+3 Therapy or Idarubicin with High-Dose Cytarabine (IA) versus IA plus Vorinostat Clinical Trials Registry: NCT # John M. Pagel, Megan Othus, Guillermo Garcia-Manero, Min Fang, Gerald P. Radich, David A. Rizzieri, Guido Marcucci, Stephen A. Strickland, Mark R. Litzow, M. Lynn Savoie, Stephen R. Spellman, Dennis L. Confer, Jeffrey W. Chell, Maria Brown, Bruno C. Medeiros, Mikkael A. Sekeres, Tara L. Lin, Geoffrey Uy, Bayard L. Powell, Jonathan E. Kolitz, Richard A. Larson, Richard M. Stone, David Claxton, James Essell, Selina M. Luger, Sanjay R. Mohan, Anna Moseley, Harry P. Erba, Frederick R. Appelbaum

16 Background AML patients with high-risk cytogenetics have a significantly worse survival compared to similarly treated intermediate- or favorable-risk patients Better outcome in high-risk AML patients in CR1 who undergo allogeneic HCT compared with consolidation chemotherapy only 40% of patients proceed to HCT Alternative donors are available for the large majority of highrisk AML patients outcomes after allogeneic HCT from fully MUD are similar to those following MRD transplantation the lack of a matched sibling donor (available in about 33%) should not be a barrier to HCT

17 SWOG 1203 Transplant Objectives To determine if a prospective organized effort could rapidly identify alternative donors to improve the historical 40% allogeneic HCT rate Primary Objective To determine whether it is possible to get 60% or more of adults age 61 with high-risk AML in CR1 to allogeneic HCT Secondary Objective To determine if transplanting significantly more adults with high-risk AML in CR1 would lead to an improved outcome compared with the historical RFS of 22%

18 Patients and Methods Buccal Swab Obtained Untreated AML patients between ages Cytogenetics (results 7-10 days) Standard cytarabine + daunorubicin (7+3; n=261) Idarubicin with highdose cytarabine (IA; n=261) IA with vorinostat (IA+V; n=216) All patients with high-risk cytogenetics underwent expedited HLA-typing Typing to be completed within 6 business days

19 Expedited Donor Identification and HCT Preliminary search results sent to referring physician/hct Center HLA type siblings and activate formal search Matched sibling available? Identify and qualify URD or ducb Yes No Procure URD or ducb HCT HCT

20 Frequency of HCT in CR1 Among High- Risk AML 738 eligible patients median age 49 years (range, 18-60) 159 (22%) had high-risk cytogenetics 60 (38%) (38%) IA 38 (24%) IA+V HCT in 317 of all 738 patients (43%) 107 of 159 high-risk patients achieved CR/CRi (67%) 68 (64%) of the high-risk patients received a HCT in CR1 p<0.001 compared to historical rate of 40% 39 high-risk CR1 patients did not receive a transplant in CR1

21 Reasons for 39 high-risk CR1 patients not receiving a transplant in CR1 Reason Co-morbidities 1 Death 6 No insurance 1 No donor 1 Physician decision 3 Patient decision 3 Relapse 6 Other 10 Unknown 8 N

22 Transplant Data HCT Donor Status N (%) MRD 25 (37%) MUD 31 (45%) Mismatched related donor 3 (4%) Mismatched unrelated donor 8 (12%) UBC 1 (1%) 66 high-risk patients transplanted in CR/CRi have detailed data Median time to HCT from CR1 was 76 days (range, ) 57 patients (86%) received a myeloablative regimen 9 (14%) received reduced-intensity conditioning

23 Overall survival, high risk cohort All high risk patients, N = 159, deaths = 94 Patients achieving CR1, N = 107, deaths = 57 Patients transplanted in CR1, N = 68, deaths = Months since randomization

24 Conclusions In newly diagnosed adults with AML age with early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor CR1 transplant rate of 64% in the high-risk group significant improvement in RFS over historical controls Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing allogeneic HCT in CR1 as soon as possible.

25 Analysis of Transplantation Rate and Overall Treatment Efficacy by Age for Patients Aged With Untreated Secondary Acute Myeloid Leukemia (AML) Given CPX-351 Liposome Injection Versus Conventional Cytarabine and Daunorubicin in a Phase III Trial Jeffrey E. Lancet 1, Geoffrey L. Uy, 2 Jorge E. Cortes, 3 Laura F. Newell, 4 Tara L. Lin, 5 Ellen K. Ritchie, 6 Robert K. Stuart, 7 Stephen A. Strickland, 8 Donna Hogge, 9 Scott R. Solomon, 10 Richard M. Stone, 11 Dale L. Bixby, 12 Jonathan E. Kolitz, 13 Gary J. Schiller, 14 Matthew J. Wieduwilt, 15 Daniel H. Ryan, 16 Antje Hoering, 17 Michael Chiarella, 18 Arthur C. Louie, 18 and Bruno C. Medeiros 19 1 H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 2 Washington University School of Medicine, St Louis, MO; 3 The University of Texas MD Anderson Cancer Center, Houston, TX; 4 Oregon Health & Science University, Portland, OR; 5 University of Kansas Medical Center, Kansas City, KS; 6 Weill Cornell Medical College of Cornell University, New York, NY; 7 Hollings Cancer Center Medical University of South Carolina, Charleston, SC; 8 Vanderbilt-Ingram Cancer Center, Nashville, TN; 9 Gordon and Leslie Diamond Health Care Centre, Vancouver, BC, Canada; 10 BMT Group of Georgia, Atlanta, GA; 11 Dana-Farber Cancer Institute, Boston, MA; 12 Comprehensive Cancer Center, University of Michigan, Grass Lake, MI; 13 Monter Cancer Center, Northwell Health System, Lake Success, NY; 14 David Geffen School of Medicine/UCLA, Los Angeles, CA; 15 University of California, San Diego, San Diego, CA; 16 University of Rochester, Rochester, NY; 17 Cancer Research and Biostatistics, Seattle, WA; 18 Celator Pharmaceuticals, Inc., Ewing, NJ; 19 Stanford University School of Medicine, Stanford, CA 2017 BMT Tandem Meetings, February 22-26, 2017, Orlando, FL

26 Challenges in AML: Elderly Patients and High-risk Subtypes AML patients aged 60 years experience low remission rates to intensive therapy and high rates of induction mortality1-3 o 20% of patients have secondary AML o 7% of patients have therapy-related AML Granfeldt Østgård LS, et al. J Clin Oncol. 2015;33: Appelbaum FR, et al. Blood. 2006;107(9): Juliusson G, et al. Blood. 2009;113(18): Thein MS, et al. Cancer. 2013;119: Estimated 5-year survival Among patients with AML, those with high-risk AML subtypes also have a dismal prognosis1 30% 25% AML Patients (all subtypes) SEER Database, Men 24% 21% Women 20% 15% 10% 7% 5% 9% 2% 1% 0% All ages years years 1% 0% 85 years

CPX-351 CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin designed to achieve synergistic antileukemia activity 5:1 molar ratio of cytarabine:daunorubicin provides synergistic

27 CPX-351 CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin designed to achieve synergistic antileukemia activity 5:1 molar ratio of cytarabine:daunorubicin provides synergistic leukemia cell killing in vitro 1 In patients, CPX-351 preserved delivery of the 5:1 drug ratio for over 24 hours, with drug exposure maintained for 7 days 2 Selective uptake of liposomes by bone marrow leukemia cells in xenograft models 3 1. Tardi P et al. Leuk Res. 2009;33(1): Feldman EJ et al. J Clin Oncol. 2011;29(8): ; 3. Lim WS et al. Leuk Res. 2010;34(9):

CPX-351 Phase III Study Design Randomized, open-label, parallel-arm, standard therapy controlled 1:1 randomization, enrolled from December 2012 to November 2014 Patients with CR or CRi could be

AML AML with history of MDS with and without prior HMA therapy AML with history of CMML De novo AML with MDS karyotype Induction (1 2 cycles) 7+3 (n = 156) 60 69 years 70 75 years Follow-up: Death OR

28 CPX-351 Phase III Study Design Randomized, open-label, parallel-arm, standard therapy controlled 1:1 randomization, enrolled from December 2012 to November 2014 Patients with CR or CRi could be considered for allogeneic HCT, based on institutional criteria Key Eligibility Previously untreated Ages years Able to tolerate intensive therapy ECOG PS 0 2 Stratifications: Therapy-related AML AML with history of MDS with and without prior HMA therapy AML with history of CMML De novo AML with MDS karyotype Induction (1 2 cycles) 7+3 (n = 156) years years Follow-up: Death OR 5 years CPX-351 (n = 153) CPX-351 (n = 73) Patients in CR or CRi: Consolidation (1 2 cycles) 7+3 (n = 52) AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; CR, complete response; CRi, CR with incomplete platelet or neutrophil recovery; ECOG PS, Eastern Cooperative Oncology Group performance status; HMA, hypomethylating agents; MDS, myelodysplastic syndrome. 1. World Health Organization. WHO Classification of Tumours of Haematopoitic and Lymphoid Tissues. Swerdlow S et al (ed). Lyon, IRAC Press,

Aged 60 69 years Hazard ratio = 0.68 (0.49, 0.

29 Overall Survival by Age Subgroup Median OS was significantly longer in the CPX-351 arm versus the 7+3 arm for both stratification age subgroups Aged years Hazard ratio = 0.68 (0.49, 0.95) CI, confidence interval; OS, overall survival. Aged years Hazard ratio = 0.55 (0.36, 0.84) 29

30 Allogeneic Transplantation Rates by Age Subgroup Aged years 40 Aged years Patients (%) Patients (%) Transplantation rate Odds Ratio (95% CI) 1.25 ( ) CPX-351 (n = 36) 7+3 (n = 33) 28.1 Transplantation rate 3.12 ( ) CPX-351 (n = 16) 7+3 (n = 6) Note: Percentages reflect number with endpoint out of column total. Odds ratios are calculated with the 7+3 arm as the reference group. CI, confidence interval; CR, complete response; CRi, complete response with incomplete neutrophil or platelet recovery.

31 Characteristics of Patients Undergoing Transplant Aged years Characteristic, n (%) Sex Male Female Aged years CPX-351 (n = 36) 7+3 (n = 33) CPX-351 (n = 16) 7+3 (n = 6) 21 (58) 15 (42) 18 (55) 15 (45) 12 (75) 4 (25) 5 (83) 1 (17) ECOG PS (94) 2 (6) 31 (94) 2 (6) 14 (87) 2 (13) 6 (100) 0 AML subtype taml MDS with prior HMA MDS without prior HMA CMMoL de novo, MDS karyotype 6 (17) 13 (36) 4 (11) 0 13 (36) 8 (24) 12 (36) 4 (12) 0 9 (27) 5 (31) 1 (6) 3 (19) 3 (19) 4 (25) 1 (17) 2 (33) 1 (17) 0 2 (33) Response status at time of transplant CR CRi No response Relapse 21 (58) 6 (17) 8 (22) 1 (3) 16 (49) 4 (12) 13 (39) 0 8 (50) 4 (25) 4 (25) 0 3 (50) 1 (17) 2 (33) 0 Time from first dose Median days (range) (59-418) 112 (50-311) 105 (57-380) 128 (96-230) CMMoL, chronic myelomonocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; HMA, hypomethylating agent treatment (azacitidine or decitabine); MDS, myelodysplastic syndrome; taml, treatment-related AML. 31

32 Mortality by Day 100 After Transplant Day 100 any cause mortality was 53% lower in the CPX-351 arm CPX-351 (n = 52) 7+3 (n = 39) 5 (9.6) 8 (20.5) Refractory AML 2 (3.8) 3 (7.7) Graft-vs-host disease 2 (3.8) 1 (2.6) Renal 0 1 (2.6) Respiratory 0 1 (2.6) Multi-organ failure 0 1 (2.6) Septic shock 0 1 (2.6) 1 (1.9) 0 Causes of death <100 days, n (%) Any cause Unknown 32

33 Survival Landmarked from Time of Transplant For all transplanted patients, median OS has not been reached in the CPX-351 arm versus months for 7+3 (HR = 0.46; P = ) Hazard ratio = sided P value = Median follow-up in patients who were alive: CPX-351 (n = 34): 531 days (range: ); 7+3 (n = 13): 442 days (range: ). CI, confidence interval; HR, hazard ratio; OS, overall survival. 33

34 Survival Landmarked from Time of Transplant by Age Subgroup CPX-351 was associated with significantly longer median OS after transplant versus 7+3 irrespective of age subgroup Aged years Median OS from date of transplant, months HR (95% CI) P value (1-sided) Aged years CPX-351 (n = 36) 7+3 (n = 33) CPX-351 (n = 16) 7+3 (n = 6) NR (9.20, NR) (6.16, 24.25) NR (7.06, NR) 6.64 (0.85, NR) 0.49 (0.24, 0.98) 0.22 (0.04, 1.23) P = P = Median follow-up for patients who were alive: CPX-351 (n = 34): 531 days (range: ); 7+3 (n = 13): 442 days (range: ). CI, confidence interval; HR, hazard ratio; NR, not yet reached; OS, overall survival. 34

35 Conclusions In this phase III trial, CPX-351 was associated with significantly longer median OS and higher rates of CR+CRi versus 7+3 among patients aged 60 to 75 years with newly diagnosed, high-risk AML A greater proportion of patients treated with CPX-351 versus 7+3 in both stratification age subgroups proceeded to transplant Overall, post-transplant OS was significantly longer in patients treated with CPX-351 versus 7+3, although the difference did not reach statistical significance in the 70 to 75 age subgroup These results suggest that CPX-351 may provide a bridge to successful transplant in a poor-risk subgroup of AML patients Results should be interpreted with caution (exploratory analysis of a non-randomized subgroup) 35

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39 Overview Transplant for Acute Leukemia Who, when and why Data from ASBMT 2017 SWOG S1203: Induction and Referral Rates in Untreated AML CPX-351 in Older Secondary AML CAR-T therapy for AML Leukemia Program at KUCC AML molecular diagnostics/prognosis Clinical trials Acute Leukemia Hotline 39

40 Leukemia Program at KUCC Need to add advanced molecular testing to our diagnostic workup Risk stratification Potential clinical trial selection/referral In 2016, Clinical Molecular Oncology Lab (CMOL) developed and validated 65 gene panel for AML/MDS KUCC Molecular Tumor Board (oncologists from KUMC and CMH, geneticists, pathologists) meets twice monthly to review cases 40

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$or Refractory Acute Myeloid Leukemia SIERRA:$

44 A Multicenter, Pivotal Phase 3 Study of Iomab-B Prior to Allogeneic Hematopoietic Cell Transplantation versus Conventional Care in Older Subjects with Active, Relapsed or Refractory Acute Myeloid Leukemia SIERRA: Study of Iomab-B in Elderly Relapsed or Refractory AML 44

Iomab-B: Targeted Radiation Enabling HCT Iomab-B consists of an anti-cd45 mab (BC8) that targets lymphohematopoietic cells and the βparticle emitting radionuclide 131-I.

45 Iomab-B: Targeted Radiation Enabling HCT Iomab-B consists of an anti-cd45 mab (BC8) that targets lymphohematopoietic cells and the βparticle emitting radionuclide 131-I. Iomab-B selectively ablates bone marrow, killing leukemia & immune system cells Therapy is part of the transplant regimen; must be followed immediately by HCT New marrow grows back after the transplant and blood production resumes 45

46 Iomab-B Prior to Allogeneic Hematopoietic Cell Transplantation versus Conventional Care in Older Subjects with Active, Relapsed or Refractory Acute Myeloid Leukemia R/R or PIF AML CD45 expression on leukemia cells by flow Age 55+ MSD or MUD available 46

47 Iomab-B Prior to Allogeneic Hematopoietic Cell Transplantation versus Conventional Care in Older Subjects with Active, Relapsed or Refractory Acute Myeloid Leukemia 47

48 LLS Consortium Beat AML: Omically Guided Targeted Therapy for Acute Myeloid Leukemia KU invited to join 11 other consortium institutions Goal to integrate advanced genomics into initial therapy decisions Rapid turn-around Central testing Support from pharma to provide drugs for these trials 48

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50 Acute Leukemia Hotline Streamlined access to the on call leukemia physician Facilitate patient transfers Updated information on clinical trials Go Live March 6,

Background CPX-351. Lancet J, et al. J Clin Oncol. 2017;35(suppl): Abstract 7035.

Background CPX-351. Lancet J, et al. J Clin Oncol. 2017;35(suppl): Abstract 7035. Overall Survival (OS) With Versus in Older Adults With Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia (taml): Subgroup Analysis of a Phase 3 Study Abstract 7035 Lancet JE, Rizzieri D, Schiller