Leukemia. Andre C. Schuh. Princess Margaret Cancer Centre Toronto

Transcription

1 Leukemia Andre C. Schuh Princess Margaret Cancer Centre Toronto

2 AGENDA Ø Overview Ø Key News This Year Ø Key News out of ASH 2016 Sessions Abstracts Ø Canadian Perspective

3 Ø Overview Stone, R. et al.; RATIFY Study; 3+7 plus Midostaurin in AML; EFS/OS Rollig, C. et al.; 3+7 plus Sorafenib in AML; RFS Wong, T. et al.; Early p53 mutations in taml LoCoco, F. et al.; ATRA/ATO in low/int risk APL; EFS/OS Castaigne, S. et al., 3+7 plus GO; EFS/OS

4 Ø Overview No home-run presentations in acute leukemia or CML at ASH 2016 Numerous exciting and valuable, incremental reports, however

5 ØKey News This Year AML Better understanding of molecular profiling in AML MRD for NPM1 +ve AML Drugs- FLT3 inhibitors, IDH1/2 inhibitors, venetoclax, vadastuximab talirine etc. etc. used up front and in R/R disease

6 N Engl J Med 2016; 374:

7 Integrated Genetic Analysis performed 111 gene NGS on pre-treatment samples from 1540 patients on 3 successive German intensive therapy trials identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more identified in 86% of patients were able to divide the cohort into 11 genetically defined classes, each with distinct clinical features and clinical outcomes Papaemmanuil, E. et al. N Engl J Med 2016;374:

8 Papaemmanuil, E. et al. N Engl J Med 2016;374:

9 Papaemmanuil, E. et al. N Engl J Med 2016;374:

10 the prognostic effects of individual mutations were often altered significantly by the presence or absence of other driver mutations such gene-gene interactions, are especially pronounced in NPM1 mutated AML Papaemmanuil, E. et al. N Engl J Med 2016;374:

11 Papaemmanuil, E. et al. N Engl J Med 2016;374:

12 N Engl J Med 2016; 374:

13 346 NPM1 mutated patients in UK NCRI (MRC) 17 trial All patients also underwent comprehensive molecular profiling at diagnosis with 51 gene NGS panel NPM1 RT-qPCR was performed at counts recovery after each cycle of treatment, and then q3 months until 24 months after consolidation therapy Ivey, A. et al. N Engl J Med 2016; 374:

14 * *after 2 cycles chemo Ivey, A. et al. N Engl J Med 2016; 374:

15 MRD is more predictive than is molecular profile? Outcomes also not related to allosct Ivey, A. et al. N Engl J Med 2016; 374:

16 SOC in UK and Germany Molecular RT-qPCR MRD in CBF, APL, Ph+ NPM1 RT-qPCR in NPM1 mutated cases MFC-MRD in the remaining cases Flow cytometry and molecular approaches are complementary in MRD analysis

17 ØKey News This Year ALL Immunotherapy BiTEs- Blinatumomab Conjugated mabs- Inotuzumab CAR-T cell approaches

18 N Engl J Med 2016; 375:

19 ØKey News out of ASH 2016 AML New Drugs -Single agents -In combination Old drugs in new settings AML in The Elderly -Treatment philosophy -Drug combinations

20 AML- New Drugs- Monotherapy: Final Results of the Chrysalis Trial: A First-in-Human Phase 1/2 Dose-Escalation, Dose-Expansion Study of Gilteritinib (ASP2215) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) Session: 616 Number: 1069 ORR >50% Vadastuximab Talirine Monotherapy in Older Patients with Treatment Naive CD33-Positive Acute Myeloid Leukemia (AML) Session: 613 Number: % CR/CRi Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated with CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial Session: 616 Number: 906 superior OS of elderly high risk AML with CPX-351 continues after allosct

21 AML- New Drugs- In Combination: SWOG S1203: A Randomized Phase III Study of Standard Cytarabine Plus Daunorubicin (7+3) Therapy Versus Idarubicin with High Dose Cytarabine (IA) with or without Vorinostat (IA+V) in Younger Patients with Previously Untreated Acute Myeloid Leukemia (AML) Session: 616 Number: 901 -ve study IA no better than 7+3 in younger pts with AML (actually worse in good risk) IA +/- vorinostat the same Safety and Efficacy of Venetoclax Plus Low-Dose Cytarabine in Treatment-Naive Patients Aged 65 Years with Acute Myeloid Leukemia Session: 616 Number: % CR/Cri Results of a Clinical Study of Pevonedistat (Pev), a First-in-Class NEDD8-Activating Enzyme (NAE) Inhibitor, Combined with Azacitidine (Aza) in Older Patients (Pts) with Acute Myeloid Leukemia (AML) Session: 616 Number: 98 CR/Cri 44%

22 Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML) Session: 613 Number: 591 CR/Cri 73% A Phase 2 Study of Pracinostat and Azacitidine in Elderly Patients with Acute Myeloid Leukemia (AML) Not Eligible for Induction Chemotherapy: Response and Long-Term Survival Benefit Session: 616 Number: 100 CR/Cri 46%; medan OS 19.1 months

23 AML- Old Drugs In New Settings: The Use of Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML): Clinical Outcomes and Their Predictors in a Large InternationalPatient Cohort Session: 615 Number: R/R with 1->3 prior lines of therapy CR 11.7% with median OS 25.6 m

24 AML- Elderly: Intensive Versus Non-Intensive Induction Therapy for Patients (Pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) Using Two Different Novel Prognostic Models Session: 613 Number: 216 validate Swedish leukemia registry data intensive therapy could be considered for most pts, up to the age of 80 years, regardless of their comorbidity burden

25 ØKey News out of ASH 2016 ALL Immunotherapy -BiTEs -Conjugated mabs -CAR-T cells Ph-like ALL New Drug Combinations

26 Immunotherapy: BiTESs and Conjugated mabs- Health-Related Quality of Life (HRQoL) of Blinatumomab Versus Standard of Care (SOC) Chemotherapy in Patients with Relaspsed or Refractory Philadelphia Negative B-Cell Precursor Acute Lymphoblastic Leukemia in a Randomized, Open-LabelPhase 3 Study (TOWER) Session: 614 Number: 222 TOWER Study; all QOL metrics superior with blinatumomab vs. SOC Patient-Reported Outcomes from a Global Phase 3 Randomized Controlled Trial of Inotuzumab Ozogamicin Versus Standard of Care Chemotherapy for Relapsed /Refractory Acute Lymphoblastic Leukemia Session: 612 Number: 1599 INOVATE Study; all QOL metrics superior with inotuzumab vs. SOC

27 Immunotherapy: CAR-T Cells- Many abstracts!!! Analysis of a Global Registration Trial of the Efficacy and Safety of CTL019 in Pediatric and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) Session: 614 Number: 221 in earlier single centre study, CR rate >90% Now, 57 patients in multi-centre study Feasible, safe, CR 83%, all MRD -ve

28 Ph-like ALL: High-Risk Subtype of Ph-like Acute Lymphoblastic Leukemia (ALL) in Adults: Dismal Outcomes of CRLF2+ ALL Patients Treated with Intensive Chemotherapy Session: 618 Number: sequential B-ALLs seen at MDACC 49 Ph-like (age 33.5, 15-71); 46 Ph+ve (age 49, 22-84); 53 Other B-ALL (age 38, 15-79) CR rates similar MRD negativity, EFS, OS much worse in Ph-like group 5 year OS, 23% vs 59%

29 New Drug Combinations: Phase II Study of Hyper-CVAD Plus Nelarabine in Previously Untreated Adult T-Cell Acute Lymphoblastic Leukemia and T-Lymphoblastic Lymphoma Session: 614 Number: 177 safe, effective, durable Phase II Study of the Frontline Hyper-CVAD in Combination with Ponatinib for Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Session: 612 Number: patients (53 untreated) Cardiovascular events necessitated dose reductions CCyR, MMR, and CMR rates 100%, 96%, and 79%, respectively The 3-year CR duration and OS rates 82% and 80%, respectively Landmark analysis at 4 months by allosct showed no difference in 3-year CR duration (no allosct, 79%; allosct, 88%; p=0.48), and 3-year OS (no allosct, 92%; allosct, 79%; p=0.31).

30 CML: Expanded Phase 1 Study of ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Reveals Significant and Durable Responses in Patients with CML-Chronic Phase with Failure of Prior TKI Therapy Session: 632 Number: 625 Non-ATP-competitive BCR-ABL activity with activity against all mutations conferring TKI resistance 101 CML and Ph+ ALL TKI failures 46% MMR within 12 m; majority maintained

31 Questions? Comments?