Best of ASH: Acute leukemia. Frédéric Baron

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1 Best of ASH: Acute leukemia Frédéric Baron

2 I Acute Myeloid Leukemia Flt3 inhibitors (ratify, sorafenib after HCT) 5 other important abstracts (in brief)

3 Mutated genes in AML FLT3: The Cancer Genome Atlas Research Networ, NEJM

4 Fms-like tyrosine kinase (FLT3) FLT3 - Class 3 RTK (such as c-kit, PDGFR) - Promotes survival and proliferation of HSC - Only expressed by HSC Mutations FLT3-ITD: +/- 20% of AML; => autophosphorylation of FLT3. FLT3-TKD: +/- 5% of AML (mostly point mutation in codon D835 or deletions of codon 1836) => gain function mutation.

5 FLT3 mutations: Most frequent mutations: - FLT3-ITD ( ~ 20% of AML) - FLT3-TKD ( ~ 5% of AML) FLT3-mutated AML ~50% ~20% EFS O N Number of patients at risk : FLT FLT FLT3-TKD+ FLT3-ITD+ (years) FLT3-TK D+ FL T3-ITD+ From EORTC AML-12; Willemze et al., JC ND

6 FLT3 inhibitors First generation Sunitinib, Sorafenib, Midostaurin, Lestaurtinib - Low selectivity. - Low potency (IC 50 ~ 400 nm). Little efficacy as single agent but FLT3 inhibition was associated with efficacy Second generation Quizartinib (AC220), Crenolanib - Higher selectivity - High potency (IC 50 =19 nm (AC=220) or =2.7 nm (crenolanib). Efficacy as single agent with some CR achieved! 6

7 Kinase interaction maps for FLT3 inhibitors (red circles indicate kinase bound) Quizar nib Lestaur nib Midostaurin Zarrinkar et al., Blood 2009 Quizar nib Lestaur nib Zarrinkar Zarrinkar et al., Blood 2009

8 Abstr# 6: The Multi-Kinase Inhibitor Midostaurin Prolongs Survival Compared with Placebo in Combination with Daunorubicin /Cytarabine Induction, High-Dose Ara-C Consolidation, and As Maintenance Therapy in Newly Diagnosed AML pts age with FLT3 Mutations : An International Prospective Randomized P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) Richard Stone et al.

9 RATIFY: study design, n= yrs of age with FLT3-mutated (non-apl) AML (N = 717) Stratified by ITD/TKD; randomized Induction* (1-2 cycles) Daunorubicin 60 mg/m 2 IVP D1-3 + Cytarabine 200 mg/m 2 /d IVCI D1-7 + Midostaurin 50 mg PO BID D8-21 (n= 360) Daunorubicin 60 mg/m 2 IVP D1-3 + Cytarabine 200 mg/m 2 /d IVCI D1-7 + Placebo D8-21 (n = 357) Double-blind, placebo-controlled, randomized phase III study Primary endpoint: OS (not censored for SCT) Secondary endpoint: EFS CR CR Consolidation (up to 4 cycles) Cytarabine 3 g/m 2 over 3h q12h D1,3,5 + Midostaurin 50 mg PO BID D8-21 (n = 231) Cytarabine 3 g/m 2 over 3h q12h D1,3,5 + Placebo D8-21 (n = 210) *Hydroxyurea allowed for 5 days prior to induction therapy. Maintenance (12 cycles) Midostaurin 50 mg PO BID D1-28 (n = 120) Placebo D1-28 (n = 85) Stone RM, et al. ASH Abstract 6.

10 Baseline characteristics 3279 patients were screened -> 717 randomized Characteristic Midostaurin + Chemo (n = 360) Placebo + Chemo (n = 357) Median age, yrs (range) 47.1 ( ) 48.6 ( ) Female, n (%) 187 (52) 212 (59) FLT3 stratification groups, n (%) FLT3 TKD (no ITD) ITD allelic ratio < 0.7 ± FLT3 TKD ITD allelic ratio 0.7 ± FLT3 TKD 81 (23) 171 (48) 108 (30) 81 (23) 170 (48) 106 (30) 402/717 (57%) pts received an allogeneic SCT Stone RM, et al. ASH Abstract 6.

11 RATIFY OS HR 0.77 (95%CI; 0.63, 0.95) P=0.007 Stone RM, et al. ASH Abstract 6.

12 RATIFY EFS HR 0.80 (95%CI; 0.67, 0.95) P=0.004 Stone RM, et al. ASH Abstract 6.

13 Stone RM, et al. ASH Abstract 6. RATIFY OS : FLT3 mutation

14 Midostaurin added to standard chemo in pts with newly diagnosed FLT3-mutated AML Improved OS and EFS, regardless of ITD/TKD stratification group and despite high SCT rate (57%), vs placebo Safety/tolerability similar in midostaurin and placebo arms Study investigators suggest midostaurin addition to current standard chemo with 1-yr subsequent maintenance as a new standard of care for these pts Benefit caused by FLT3 inhibition? Midostaurin in older patients? RATIFY Conclusions

15 Abstr# 864: Hematopoietic Cell Transplantation with or without Sorafenib Maintenance for Patients with FLT3-ITD AML in CR1 Andrew Brunner et al.

16 Sorafenib after allo-hct 80 consecutive pts at 2 institutions in Boston transplanted for FLT3-ITD AML in CR1. Pts given sorafenib in CR after HCT were in the sorafenib group, and others were the control group. Median date of sorafenib initiation: day 68, landmark analysis including only controls alive without relapse at that day. Sorafenib, N=26 Controls, N=41 Brunner, et al. ASH Abstract 864.

17 Survival Probability Abst 453: Final Results from a Phase 2 Study of Pracinostat in Combination with Azacitidine in Elderly Patients with Acute Myeloid Leukemia (AML) # Design Results 453 Phase II Elderly unfit first line: Vidaza + Pracinostat (oral HDAC inhibitor) OS by Cytogenetic Risk CR/Cri: 42% 1-yr OS 57% Censored High Risk Intermediate Risk N= P = Mos Garcia-Manero G, et al. ASH Abstract 453.

18 Pts (%) Pts (%) # Design Results 218 First line young non-favorable AML, ALFA-0702/Clara: 3 HiDAC (cytar. 3g/m2/12h, d1/3/5) vs 3 CLARA (cytar. 1g/m 2 /12h, d1-/5, clofa 30 mg/m 2 d2-6) (n=468); Phase III 2-y RFS: 52 vs 31%; P=.04 2-y OS: 50 vs 68%; P=.18 DFS: Censored for SCT DFS: Not Censored CLARA: 52.1% HDAC: 30.5% HDAC vs CLARA HR: 1.61 (95% CI: ; P =.042) N=107 CLARA HDAC CLARA: 57.8% HDAC: 45.6% HDAC vs CLARA HR:1.34 (95% CI: ; P =.122) CLARA HDAC N= Mos Mos Thomas X, et al. ASH Abstract 218.

19 Other top abstracts in brief # Design Results 221 UKNCRI AML17: 2 vs 1 courses of High Dose Cytarabine As consolidation in Younger AML patients (n=1017) 458 Guadecitabine (SGI-110) in 103 unfit pts first line AML (5d vs 10d) 1306 Phase I study IDH1 inhibitor AG-120 (dose escalation, n=66) Relapse: HR=0.8, P=.04 0S: HR=0.9, P=.4 HR=0.8, P=.04 in FLT3- WT patients CR/CRi: 57 vs 48% OS (median) 11 vs 9 mo OR: 36% CR/CR1: 18%

20 II Acute Lymphoblastic Leukemia Rituximab Blinatumomab CARs

21 Abstr # 1: Addition of Rituximab Improves the Outcome of Adult Patients with CD20- Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study Sébastien Maury

22 GRAALL-R: Study Design Multicenter, randomized, phase III study from [1] CD20 expressed in 30% to 40% of B-cell precursor ALL pts, associated with worse outcomes [2,3] CD20+ Ph- tx-naïve BCP-ALL pts yrs of age 20% CD20+ blasts no other current/recent malignancies Allogeneic SCT offered in first CR to pts with 1 high-risk criteria Primary endpoint: EFS Pediatric inspired standard Chemo (GRAALL 2005) + Rituximab IV 375 mg/m infusions (n = 105) Pediatric inspired standard Chemo (GRAALL) 2005 w/out Rituximab (n = 104) Secondary endpoints: relapse/death in first CR, safety, EFS after censoring pts given allogeneic SCT in first CR 209 pts in mitt analysis (n = 11 excluded for noneligibility criteria) 1. Maury S, et al. ASH Abstract Thomas DA, et al. Blood. 2009;113: Maury S, et al. Haematologica. 2010;95:

23 Results: Outcomes Rituximab (n=105) Control (n=104) CR 92% 91% MRD<10-4 after 3 consolidation blocks 91% 82%.31 Allo-SCT in CR1 34% 20%.03 2-yr CIR 18% 31%.02 2-yr NRM 12% 12% 2-yr EFS 65% 52% yr OS 71% 64% yr OS HCT) 74% 63%.018 P

24 65% 52% Rituximab Control

25 GRAALL-R Efficacy (MVA) *Adjusted for SCT during CR1. Cumulative incidence of relapse. Rituximab vs No Rituximab Outcome Probability, % HR (95% CI) Adjusted HR* (95% CI) EFS 65 vs ( ) P =.038 OS 71 vs ( ) P =.095 Relapse 18 vs ( ) P = ( ) P = ( ) P = ( ) P =.018 EFS impacted by age, CNS involvement, WBC at diagnosis Maury S, et al. ASH Abstract 1.

26 Conclusions Rituximab added to chemotherapy demonstrated clinical benefit vs chemotherapy alone in adult pts with CD20+, Ph- BCP-ALL Improved EFS (P =.038) Prolonged OS in pts not receiving SCT during CR1 (P =.018) Well-tolerated safety profile in the rituximab group vs standard chemo alone The investigators conclude that adding rituximab to standard chemotherapy should become a standard of care for patients with CD20+, Ph- BCP-ALL They note that further study required to determine optimal rituximab dosing Maury S, et al. ASH Abstract 1.

27 Bispecific T-cell engager (BiTE ) antibody that directs cytotoxic T cells to CD19-positive target cells, resulting in serial lysis 1 Blinatumomab: Mechanism of Anti-CD3ε Antibody V H V L Action BiTE Antibody Construct scfv scfv Redirected Lysis V L Anti-TAA Antibody V H CD19 is a highly specific B- cell marker expressed throughout B-cell development and in > 90% of B-cell lineage malignancies 2 Cytotoxic T Cell T-Cell Proliferation CD25 CD69 CD3ε TAA Tumor Cell Serial Lysis Apoptosis T-Cell Activation References: 1. Bargou R, et al. Science. 2008;321: Raponi S, et al. Leuk Lymphoma. 2011;52:

28 Abstr #679: Complete Molecular and Hematologic Response in Adult Patients With Relapsed/Refractory (R/R) Ph+ B-Precursor ALL Following Treatment With Blinatumomab: Results From a Phase 2 Single-Arm, Multicenter Study (ALCANTARA) Giovanni Martinelli et al.

29 Introduction Phase 2 study of single-agent blinatumomab in adult patients with Phi-neg R/R B-precursor ALL 1 CR/CRh rate was 43% MRD response rate among patients with CR/CRh was 82% Ph+ is the most common single cytogenetic abnormality in B- precursor ALL - ~25% of adult ALL is Ph+ and frequency of Ph+ disease increases with age Ph+ ALL historically has a poor prognosis 1. Topp MS, et al. Lancet Oncol 2015;16:57 66.

30 Key Inclusion Criteria Eligibility Adults ( 18 years) with Ph+ B-precursor ALL - Relapsed or refractory to at least one 2+ generation TKI or - Intolerant to 2+ generation TKI and intolerant/refractory to imatinib > 5% bone marrow blasts ECOG performance status 2 Key Exclusion Criteria Allogeneic HSCT within 12 weeks prior to start of blinatumomab Active acute or active chronic (grade 2 4) GvHD, or systemic treatment for GvHD within 2 weeks before treatment start History or presence of clinically relevant CNS pathology (epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson s disease, cerebellar disease, organic brain syndrome, psychosis) CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; GvHD, graft-versus-host disease

31 Screening / Pre-phase 30-day Safety Follow-up Follow-up (up to 18 months) Open-Label, Single-Arm, Multicenter Phase 2 Study in R/R Ph+ ALL Blinatumomab 9 to 28 μg/day* civ infusion 4 weeks on, 2 weeks off Up to 2 cycles Primary endpoint assessment Blinatumomab 28 μg/day civ infusion 4 weeks on, 2 weeks off Up to 3 cycles Consolidation Study Endpoints Primary CR/CRh during the first 2 cycles Key Secondary Minimal residual disease response by PCR of BCR-ABL during the first 2 cycles CR, CRh, and duration Relapse-free survival Overall survival HSCT realization Incidence of adverse events and antibody formation * Only cycle 1, days 1 to 7: 9 μg/day CR, complete remission; CRh, complete remission with partial hematological recovery of peripheral blood counts (platelets > 50,000/μL and ANC > 500/μL); civ, continuous intravenous; HSCT, hematopoietic stem cell transplantation Martelli G, et al. ASH Abstract 679.

32 Results CR/CRi in 16/45 pts (36%) 1.0 Survival Probability HSCT after blinatumomab CR: 4/16 patients Patients at Risk 45 Study Month NE, not estimable Martelli G, et al. ASH Abstract 679. Median follow-up: 8.8 months

33 Neurologic Events and Cytokine Release Syndrome (Regardless of Causality) All patients (N = 45) Any grade Grade 3 Grade 4 Neurologic events, n (%) 21 (47) 3 (7) 0 (0) Preferred terms with 5% frequency Paraesthesia 6 (13) 0 (0) 0 (0) Confusional state 5 (11) 0 (0) 0 (0) Dizziness 5 (11) 0 (0) 0 (0) Tremor 4 (9) 0 (0) 0 (0) Cytokine release syndrome, n (%) 4 (9) 0 (0) 0 (0) Martelli G, et al. ASH Abstract 679.

34 Conclusions The present study showed single-agent antileukemia activity of blinatumomab in patients with R/R Ph+ ALL who had failed 2+ generation TKI therapy, with a CR/CRh rate of 36% (95% CI, 22 51) Hematologic and molecular responses were independent of mutational status, including presence of the T315I mutation Among responders, 88% (14/16) achieved complete MRD response Median OS of 7.1 months was observed in this poor prognostic Ph+ patient population Adverse events were consistent with previous blinatumomab treatment experience in the setting of R/R Ph-negative ALL Martelli G, et al. ASH Abstract 679.

35 Abstr #680: Long-Term Outcomes After Blinatumomab Treatment: Follow-up of a Phase 2 Study in Pts With MRD+ B-cell Precursor ALL Gökbuget et al.

36 MRD in ALL Assessment of MRD by quantitative measurement of individual T-cell receptor (TCR) and immunoglobulin (Ig) rearrangements is possible in >90% of ALL pts MRD evaluation allows standardised, sensitive (0.01%) and individual response evaluation Persistent MRD (molecular CR) after standard induction and consolidation or recurrent MRD (molecular failure) after prior MRD negativity is a strong prognostic factor for relapse and overall survival Nearly all pts with persistent or recurrent MRD relapse despite continued chemotherapy Outcome of Adult ALL According to Molecular Remission Status After Induction and Consolidation I (GMALL Trial 07/2003) 1 Remission Duration in MRD>10-3 (excluding SCT) N=24 Median: 4.9 mo Reference: 1. Gökbuget N, et al. Blood. 2012;120: Time [years]

37 Inclusion / exclusion criteria Adult patients with CD19+ B-precursor ALL in hematological CR (first or later) were eligible if they had: MRD, defined as a level of 10-3 (molecular failure or molecular relapse) in an assay with a minimum sensitivity of 10-4 ANC (neutrophils) 1,000/μL Platelets 50,000/μL Hemoglobin level 9 g/dl Exclusion criteria included: Circulating blasts or extra-medullary ALL involvement A history of CNS pathology, including CNS involvement by ALL Prior allo SCT Prior chemotherapy (within 2 weeks) or radiotherapy (within 4 weeks) Gökbuget N, et al. ASH Abstract 680.

38 Treatment Overview Cycle 1 Blinatumomab 15 µg/m 2 /day Primary endpoint assessment Patients ineligible for allo SCT Up to three additional cycles Patients eligible for allo SCT Up to three additional cycles AlloSCT when donor is available 100-day allo SCT-related mortality assessment 2-year follow-up for efficacy Survival follow-up Blinatumomab was given by continuous IV infusion, 15 μg/m 2 /d x 28 days per cycle, for 4 weeks on/2 weeks off (one cycle) for a maximum of up to four cycles Allo SCT was offered for eligible patients at any time after cycle 1 A protocol amendment dated July, 2012, permitted restarting blinatumomab treatment at 5 μg/m 2 /day following treatment interruption due to a grade 3 neurologic adverse event Intrathecal prophylaxis was given during screening and in each treatment interval Gökbuget N, et al. ASH Abstract 680.

39 Complete MRD Response after Cycle 1 by Clinical Characteristics Primary Endpoint Efficacy Set n/n % (95% Exact CI) Overall Gender Female Male Age /103 35/43 47/60 29/32 25/35 17/23 11/13 80 (71-87) 81 (67-92) 78 (66-88) 91 (75-98) 71 (54-85) 74 (52-90) 85 (55-98) Complete MRD response (Primary endpoint FAS): 80% (82/103) MRD Level at Baseline 10-3 to < to <10 ( 0.1% to < 1%) -2-1 ( 1% to < 10%) 10-1 to <1 ( 10% to < 1) 40/51 36/43 6/9 78 (65-89) 84 (69-93) 67 (30-93) Remission Status CR2/3 CR1 Treatment Interruptions During Cycle 1 No Yes Neurologic Events Grade 2 During Cycle 1 No Yes 27/37 55/66 45/58 37/44 59/73 23/30 78 (60-90) 83 (72-91) 78 (65-87) 84 (70-93) 81 (70-89) 77 (58-90) Complete MRD response: MRD neg with sensitivity of 10-4 (1:10.000) Complete MRD Response Rate (95% CI) Gökbuget N, et al. ASH Abstract 680.

40 Survival Probability OS (not censoring at HSCT or post-blina. CT) Kaplan-Meier estimate of median OS = 36.5 (95% CI: 19.8, NR) months Number of Subjects at Risk: Study Month Gökbuget N, et al. ASH Abstract 680.

41 Survival Probability OS according to MRD cycle : 2: Number of Subjects at Risk: P = 0.002* Gökbuget N, et al. ASH Abstract 680. Study Month (Landmark Analysis Beginning at Study Day 45) 1: MRD complete responder at cycle 1 (N = 85) Median 95% CI 38.9 (33.7, NR) 2: MRD incomplete responder at cycle 1 (N = 22) Median 95% CI 12.5 (3.2, NR)

42 Probability of RFS Probability of RFS Role of SCT in Patients with Complete MRD Response Transplant realization rate: 72% First remission (N = 60) Simon-Makuch Plot of RFS (Landmark 45 days) Second or later remission (N = 25) 1.0 Allo SCT No Allo SCT 1.0 Allo SCT No Allo SCT Allo SCT prior to relapse or censoring: Yes: 15 (60%) No: 10 (20%) Allo SCT prior to relapse or censoring: Yes: 46 (77%) No: 14 (23%) Gökbuget N, et al. ASH Abstract 680. Study Month (Landmark Analysis Beginning at Study Day 45)

43 Summary Blinatumomab induced a high complete MRD response rate (80%). 67% of the pts were able to receive SCT in CR after blinatumomab. Blinatumomab may contribute to prolonged RFS and OS in pts with MRD-positive ALL. MRD response was associated with improved OS, RFS. Pts treated in CR1 had improved RFS and RD compared to those treated in subsequent remission. Among pts who experienced neurologic events on study, most had a worst event grade of 2. 10% of pts interrupted or discontinued treatment due to grade 3 neurologic events. The role of subsequent SCT cannot be determined by this study.

44 Abstr# 681: Durable Remissions in Children with Relapsed/Refractory ALL Treated with T Cells Engineered with a CD19-Targeted Chimeric Antigen Receptor (CTL019) Stephan Grupp et al.

45 Chimeric Antigen Receptor (CAR) Targeting antibody Intracellular signaling domain

46 Methods T cells collected in the patients (even when after allo- HCT) T cells lentivirally transduced with a CAR composed of anti-cd19 scfv/4-1bb/cd3ζ. Ex-vivo expansion with anti-cd3/anti-cd28 beads. Lymphodepleting chemotherapy. Infusion ( cells/kg with a transduction efficiency of %). 53 children / young adults with CD19+ ALL 41/53 patients had detectable ALL Grupp S, et al. ASH Abstract 681.

47 Results 90% of pts grade 1-4 cytokine release syndrome at peak T cell expansion (28% of patients required IL-6 receptor antagonist tocilizumab +/- steroids). 50/53 patients -> CR after infusion. 20 patients relapsed, including 13 patients with CD19 neg blasts at relapse. 1-yr RFS & OS: 44% and 78%. CARs persisted with B cell aplasia persisting 3-39 months after infusion in patients with response Grupp S, et al. ASH Abstract 681.

48 Other important abstracts # Design Results 682 CD19-Targeted 19-28z CAR Modified T Cells in Adult Patients with R/R B-cell ALL 83 Mini-HCVD* + Inotuzumab (anti CD22) ozogamicin phase II elderly ALL patients *Cyclophosphamide, Dexamethasone, MTX, Cytarabine, rituximab 29/44 patients-> MRD neg CR 2-yr OS 64%

49 Take home messages AML Midostaurin combined with 3+7 SOC in young FLT3-mutated patients. AZA+ Pracinostat promising in elderly unfit patients. Interest of clofarabine for post-remission therapy in younger AML (IR/HR) patients who cannot benefit from allo-hct ALL the addition of rituximab to the pediatric-inspired GRAALL improves EFS (OS) in adults with CD20-positive, Ph-negative, BCP-ALL. Blinatumomab induces a high complete MRD response rate (80%) in patients with MRD+. Blinatumomab & CD19 CARs effective in patients with R/R CD19+ ALL.