ANCO 2015: Treatment advances in acute leukemia

Transcription

1 ANCO 2015: Treatment advances in acute leukemia Michaela Liedtke, MD Stanford, CA September 12, 2015!" Disclosures Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Steering Committee Celgene, Novartis, Millennium, Pfizer, Onyx/Amgen, Prothena None Pfizer, Amgen, Millennium None None None 1

2 Learning Objectives # Summarize current treatment approaches for ALL and AML # Review new targeted agents and immuno-therapies for acute leukemia Outline 1. Acute lymphoblastic leukemia: 1. Current treatments 2. Novel targeted therapies for ALL 2. Acute myeloblastic leukemia: 1. Current treatments 2. Updates on FLT3 inhibitors for AML 3. Other new targeted agents for AML 2

3 Acute Lymphoblastic Leukemia ASH image bank Current ALL Treatment Approach Risk Stratification Induction Post-Remission Ph+ AYA (15-39) Pedi-ALL multiagent chemo protocol plus TKI Allo-HCT -/+ TKI Consol/Maint + TKI (if no donor) Ph+ Adult (40+) Multiagent chemo protocol plus TKI Allo-HCT -/+ TKI Consol/Maint + TKI (if no donor) Diagnosis of ALL Ph- AYA (15-39) Pedi-ALL multiagent chemo protocol Consolidation Maintenance Allo-HCT (high risk) Ph- Adult (40+) Multiagent chemo protocol Consolidation Maintenance Allo-HCT (high risk) NCCN Guidelines, ALL, v

4 Outcomes for newly diagnosed patients with ALL Group n age Ph+ % T- cell % CR % DFS % MRC/ECOG (15-65) at 5 y CALGB (16-80) at 5 y GIMEMA (12-60) at 9 y GMALL 05/ (15-65) at 5 y HyperCVAD (15-92) at 5 y LALA (15-55) at 5 y UCSF (16-59) at 5y Adapted from Pui et al, NEJM, 2006 Pediatric regimens for adolescents and young adults DFCI Adult ALL Consortium Protocol De Angelo D et al. Leukemia

5 Poor survival for relapsed ALL Survival Probability Kantarjian H et al. Cancer Total Events Median (months) CR duration Overall survival ALL Risk Stratification # Age # Ph Status # WBC count # Other cytogenetic features: Hypodiploidy t(v;11q23): MLL rearranged Complex karyotype ( 5) # MRD after induction # Ph-like ALL NCCN Guidelines, ALL, v

6 Ph-like ALL GEP similar to Ph Alteration of lymphoid transcription factor genes Poor outcome 10% children 27% adults Roberts, NEJM 2014 Novel targeted therapies for ALL 6

7 Inotuzumab: Conjugated anti-cd22 Ab JF devries, Leukemia Inotuzumab: Conjugated anti-cd22 Ab MD Anderson Comparison Single-dose inotuzumab from 1.3 to 1.8 mg/m 2 IV every 3 to 4 weeks vs Weekly inotuzumab (total 1.8 mg/ m 2 /course) Phase III trial: B Weekly inotuzumab compared to investigator s choice SOC chemotherapy Study met first primary objective of improved CR/Cri rate Weekly dose schedule was equally effective and less toxic than a singledose schedule Cancer. 2013, 199:

8 SWOG1312: Inotuzumab + CVP Bispecific T-cell Engagers (BiTE) V H V L α-cd3 antibody CD3 T Cell Blinatumomab BiTE α-cd19 antibody V H VL Target antigen CD19 Tumor Cell Redirected lysis Bargou R., et al. Science 2008;321(5891):

9 Blinatumomab for relapsed/refractory B-ALL Blinatumomab 9 mcg/day days 1-7 then 28mcg/day days day cycles up to 5 total 79% of responders achieved CR/CRh in C1 Topp et al, Lancet Onc, Blinatumomab for relapsed/refractory B-ALL Med RFS 5.9 mo (95% CI ) Med OS 6.1mo (95% CI ) Topp et al, Lancet Onc,

10 Cytokine Release Syndrome Lee et al, Blood, Blinatumomab for B-ALL in MRD+ complete remission Phase 2 study in minimal residual disease (MRD)-positive B-precursor acute lymphoblastic leukemia (ALL) Blinatumomab (15 µg/m 2 /d) was well tolerated Blinatumomab induced an 80% MRD response in evaluable patients Topp et al, JCO

11 E1910: Blinatumomab for B-ALL in CR1 Chimeric Antigen Receptor (CAR) T-cells ~2-4 weeks from apheresis to patient Maude et al, Hematology, Jacobson et al, Blood,

12 CD19 CAR-T Cells are highly active in R/R ALL Grupp et al, NEJM, Acute Myeloid Leukemia 12

13 Current AML Treatment Approach New AML Age < 60 Induction High Intensity (e.g. 7+3 ) Consolidation High-dose AraC Autologous HCT Allogeneic HCT *Clinical Trials are Recommended for ALL Patients Age 60 High Intensity Low-intensity Hospice/BSC Ara-C based Low-intensity RIC allo-hct Relapsed or Refractory High Intensity Low-intensity Hospice/BSC Salvage Allogeneic HCT (MA or RIC) Decision-Making Tool for Older AML Induction # # Variables: Age Temperature Hemoglobin Platelets Fibrinogen LDH de novo vs secondary AML Cytogenetics/Molecular Krug et al, Lancet,

14 AML Risk Stratification Age, Cytogenetics and mutational status of FLT3, NPM1 and CEBPA. Age Age > 60 Mrozek et al, JCO, Prognostic Score for Intermediate Risk AML # PINA OS and PINA RFS Score # # Variables: NPM1 FLT3-ITD bicebpa WBC Age ECOG PS Pastore et al, JCO,

15 Clonal Heterogeneity in AML Mutation 1, 2, 3, 4, 5, 10 Mutation 1, 2, 3, 4, 5, 9 Mutation 1, 2, 3, 4, 5, 8 Leukemia Mutation 1, 2, 3, 6, 7 Mutation 1, 2, 3, 4, 5 Pre-Leukemic HSC Mutation 1, 2, 3, 6 Mutation 1, 2, 3, 4 Mutation 1, 2, 3 Mutation 1, 2 Mutation 1 Normal HSC No Mutations Jan et al, Oncogene, Model of Relapse in AML Presentation Treatment Relapse Leukemic clones Leukemia C B A Pre-leukemic HSC clones Normal HSC HSC Jan et al, Oncogene, D A: Dominant Presenting Clone B: Minor Presenting Clone C: Further Leukemic Clonal Evolution D: Further Pre-Leukemic Clonal Evolution 15

16 FLT3 Inhibitors for AML ASH education book FLT3 Inhibitors for AML Patrick P. Zarrinkar et al. Blood 2009;114:

17 Azacitidine in combination with Sorafenib Sorafenib 400mg BID daily 28 Day cycles Days: Azacitidine 75mg/m2 IV/SC Ravandi et al. Blood, Azacitidine in combination with Sorafenib Med Dur CR: 2.3 mo (1-14.3) Ravandi et al. Blood,

18 SORAML Study AML age patients FLT3-ITD+ 17% R 1:1 *HCT in CR Int Risk (MRD), High risk (MRD, MURD) Rollig et al, ASH 2014 Abstract# 6. SORAML Outcomes Placebo Sorafenib CR rate 59% 60% Med RFS 23mo NR 3yr RFS 38% 56%* p=0.017 Med OS NR NR 3yr OS 56% 63% p=0.382 Median 36mo Observation FLT-ITD+: no difference EFS, trend for OS and RFS improvement in Soraf arm G3+ AE: fever (40%), infections (22%), bleeding (2%), HFS (all higher in Soraf arm) 9.2mo 20.5mo Rollig et al, ASH 2014 Abstract# 6. 18

19 Targeting Mutated IDH Cimmino, Cell Stem Cell review, AG-221 Targets IDH2 AG-221: oral, potent, reversible, selective inhibitor of mutant IDH2, triggers blast differentiation Phase 1 study: Advanced IDH2 mutant heme malignancies (R140Q and R172K) BID and QD dosing with dose-escalation 48 patients dosed, no MTD, 9 deaths within 28 days AG-221 N 48 Evaluable 32 CR/CRi/ CRp 12 PR 8 SD 5 PD 7 Durable response (up to 8 cycles), 5 bridged to Allo-HCT Stein et al, ASH 2014 Abstract#

20 Targeting Bcl-2 # Apoptosis is dysregulated in AML # ABT-199 is a selective oral inhibitor of Bcl-2 # Preclinical activity in AML Nature reviews, 2014 ABT-199 Targets Bcl-2 ABT-199/GDC-199: selective, oral, potent Bcl-2 inhibitor Phase 2 study in R/R AML or front-line for unfit pts Intra-patient dose escalation from 20mg to 1200mg Patients ABT-199 N 32 Med Age 71 (19-84) R/R 30 saml Prior Rx 14 IDH1 mut 2 IDH 2 mut 9 FLT3-ITD+ 6 Response/AE ABT-199 CR/CRi 5 (15.5%) 50% blast reduction 6 (19%) PD 10 Febrile neutropenia 8 Anemia 3 Pneumonia 3 TLS 0 3 of CR/CRi had IDH mutations (2 MRD- IDH2 and 1 MRD+ IDH1) Konopleva et al, ASH 2014 Abstract#

21 Targeting BTK in AML Rushworth et al, Blood, Targeting BTK in AML Rushworth et al, Blood,

22 CD33 and CD123 CAR T-Cells in AML Pilot clinical trials in AML have shown modest anti-aml activity with anti-aml CAR T-cells. Kenderian et al, Leukemia, Summary # Current treatment approaches for acute leukemias use age- and disease-based risk stratification to determine choice of therapy # A variety of novel targeted agents are in development for both ALL and AML # Immunotherapy may revolutionize the way we treat leukemias and other malignancies # Participation in clinical trials is crucial to allow timely and cost-effective use of novel therapies 22

23 Stanford Acute Leukemia Research - Bruno Medeiros Michaela Liedtke Steve Coutre New Patient Coordinator: Tony Polk