CARE at ASH 2014 Leukemia. Julie Bergeron, MD Maisonneuve-Rosemont Hospital

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1 CARE at ASH 2014 Leukemia Julie Bergeron, MD Maisonneuve-Rosemont Hospital

2 Acute Leukemias Dr. Julie Bergeron Hôpital Maisonneuve-Rosemont, Montréal

3 Disclosures Advisory boards in 2014: AMGEN EUSA pharma Industry-sponsored clinical trials: Boehringer-Ingelheim Celgene Roche Novartis Amgen

4 Educational sessions this year in A.L. Insights from Pediatric Hematologic Malignancies: Focus on Acute Lymphocytic Leukemia Molecular / genetic landscape Risk assignment criteria Late tx effects AML in the elderly patient Fitness assessment Treatment strategies Tools and risk factors for BMT Biologically Based Acute Leukemia Therapy: 2014 and Beyond Molecular classificaton of intermediate-risk AML Immunotherapeutics Role of epigenetics in AML and it s treatment MRD: CML and ALL Different techniques CML milestones MRD in ALL practically Transplantation : adoptive T-cell strategies Optimise GVL effect T-cell treatment ex : EBV CAR T cells Patients ask about it Immediate / daily clinical relevance The future is now. Adult littérature lagging behind pediatric trying to catch up!

5 Top A.L. abstracts this year: 2 Abstracts in plenary session! [1] T-Lymphoblastic Leukemia (T-ALL) Shows Excellent Outcome, Lack of Significance of the Early Thymic Precursor (ETP) Immunophenotype, and Validation of the Prognostic Value of End-Induction Minimal Residual Disease (MRD) in Children s Oncology Group (COG) Study AALL0434 [6] Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated in the Randomized Placebo-Controlled SAL-Soraml Trial

6 Plenary session

7 [1] T-Lymphoblastic Leukemia (T-ALL) Shows Excellent Outcome, Lack of Significance of the Early Thymic Precursor (ETP) Immunophenotype, and Validation of the Prognostic Value of End- Induction Minimal Residual Disease (MRD) in Children s Oncology Group (COG) Study AALL0434 What is ETP ALL? EARLY T-CELL PRECURSOR LEUKEMIA: A SUBTYPE OF VERY HIGH-RISK ACUTE LYMPHOBLASTIC LEUKEMIA IDENTIFIED IN TWO INDEPENDENT COHORTS (St-Jude and AEIOP ALL-2000) ETP characteristics: CD1a, CD8 (-) CD5 weak One or more stem cell / myeloid marker (>25%): CD117, CD34, HLA-DR, CD13, CD33, CD11b, and/or CD65 St-Jude s AALL0434 opened in 2006 (?) Because of (unsalvagable) relapse Coustan-Smith, Lancet Oncol February ; 10(2): doi: /s (08)

8 [1] T-Lymphoblastic Leukemia (T-ALL) Shows Excellent Outcome, Lack of Significance of the Early Thymic Precursor (ETP) Immunophenotype, and Validation of the Prognostic Value of End- Induction Minimal Residual Disease (MRD) in Children s Oncology Group (COG) Study AALL0434 Largest study of T-ALL (n=1144) ETP not prognostic in this contemporary cohort Why? More intense chemo for high risk? Nelarabine? WBC >200: inferior EFS and OS * Px cutoff value for day 29 MRD = 1% * More ETP cases where MRD (+) For B-ALL «usual» cutoff for d29 MRD more around 0.01% (10-4 ) * Significant only for non-etp but smaller numbers of ETP with these characteristics

9 [6] Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated in the Randomized Placebo-Controlled SAL-Soraml Trial Sorafenib = multi kinase inhibitor (ex: FLT3, VEGF, PDGFR, RAF) N = 276, YO, newly dx AML Tx: 7-3 (dauno 60) 3 HDAC consol +/- Sorafenib and in maintenance CR identical 17% FLT3-ITD (no clearly increased differential benefit?) EFS: OS: Median not reached neither arm OS at 3 yrs 56 vs 63 % but (yet?) NS

10 [6] Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated in the Randomized Placebo-Controlled SAL-Soraml Trial AEs: Fever, bleeding, infection and hand-foot syndrome increased in Sora arm (not numbered in abstract) Could change practice if: OS differences emerged with longer follow up Toxicity does not counterbalances lower relapse rates

11 Abstract sessions: Which one My selection for it s clinical relevance: 615 Saturday, December 6, 2014: 12:00 PM-1:30 PM South Building, Esplanade (Moscone Center) Updated APL0406 LoCoco NEJM2013 ATRA + ATO in low/int-risk APL patients Dasatinib in CBF kit-mutated - CALGB Small numbers but Dasa + chemo «abrogates» the negative px impact of KIT mutation Kit-mutated CBF AML will always be small numbers don t expect larger randomised series soon Dauno 60 vs 90mg/m 2 in UKNCRI AML17 60=90 with higher early mortality in the 90mg/m 2 arm No subgroup benefits UKMRC uses double induction with 3 doses of 50mg/m 2 dauno in induction 2

12 Individual Abstracts with a je ne sais quoi [796] Favorable Outcomes for Older Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL): Early Results of U.S. Intergroup Trial C10403Clinically Relevant Abstract AYA Alliance AYA YO, STD arm of COGAALL0232 Med age 24 2yr EFS 66% MRD neg d28 (38%) = 100% EFS Induction Consolidation Maintenance Delayed Intensification * * * HDMTX * * Ph-like signature (28%) and WBC>30 = adverse Maintenance Total Peg Asp: 5 doses = 12500UI/m2 Tuesday, December 9, 2014: 8:15 AM West Building, (Moscone Center)

13 Ph-like signature? Ph-like ALL: 27% among young adults Poor outcome Roberts KG,

14 [379] BLAST: A Confirmatory, Single-Arm, Phase 2 Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE ) Antibody Construct, in Patients with Minimal Residual Disease B-Precursor Acute Lymphoblastic Leukemia (ALL) Previous report (Blood 2012) on 20 patients This time n=116 Molecular disease 10-3 after 3 chemo 78% CMolR (<10-4 ) after 1 cycle Other BiTE antibodies in development: AMG 330 : CD3 CD33 h8f4bite : CD3- PR1/HLA-A2 REGN1979: CD3-CD20 Topp MS, : Monday, December 8, 2014: 10:30 AM West Building, (Moscone Center)

15 [115] AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the IDH2 Mutant Metabolic Enzyme, Induces Durable Remissions in a Phase I Study in Patients with IDH2 Mutation Positive Advanced Hematologic Malignancies AML : Inhibition of IDH2 (AG-221) Mutations in IDH1 and IDH2 in +/-15% of adult AML (enriched in NK- AML) IDH1/2 = enzymes. Mutations confer gain of function Accumulation of 2-HG Epigenetic changes. (IDH2 R172 (~ 2% of AML) dismal prognosis) Abstract [115]: Phase 1, dose escalation of AG-221, oral agent «Advanced IDH2-mutated hematologic malignancies» 32 pts evaluable for efficacy : 12 have CR (8), CRp or Cri IDH2 mutations also described in ETP ALL and adverse px Well tolerated (MTD not reached, AE gr 1-2) Sunday, December 7, 2014: 4:30 PM West Building, (Moscone Center)

16 [70] Molecular Detection of Minimal Residual Disease Provides the Most Powerful Independent Prognostic Factor Irrespective of Clonal Architecture in Nucleophosmin (NPM1) Mutant Acute Myeloid Leukemia Residual disease known to be adverse px feature Why has it not translated into clinic already : Threshold and timing of measurements for decision making not standardised A step forward with these AML17 data: 367 (NPM1mut) patients on the UKNCRI AML17 trial MRD(+) in blood (15% of cases) after course 2: RR 77 vs 28% OS 25 vs 77% UK MRC uses 2ble induction MRD = Ze most significant px fx in multivariate (HR 4,5) -- Overrides FLT3 Clinical utility: identify the so-called ELN «favorable» (NPM1mut- FLT3nonITD) that is likely to relapse. Sunday, December 7, 2014: 12:45 PM Yerba Buena Ballroom Salon 9 (San Francisco Marriott Marquis)

17 New Agents Vosaroxin [385] Quinolone-derived Topo-II inhibitor Anti-CXCR4 Ab Ulocuplumab [386] AI-10-49: inhibitor of fusion protein CBFB-SMMHC (inv(16)) [390] EPZ5676: inhibitor of DOT1L1 [387] Histone methyltransferase recruited by MLL fusion proteins Monday, December 8, 2014: 10:30 AM-12:00 PM South Building, Gateway Ballroom 103 (Moscone Center)

18 Thank you! Enjoy San Francisco and ASH 2014