Effective hematopoiesis AML: MPN current and emerging treatments Deaths each year: ~10,500. New cases each year: ~21,000

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1 AML: numbers Ineffective hematopoiesis ffective hematopoiesis AML: Understanding your diagnosis and New cases each year: ~21,000 /MPN MPN current and emerging treatments Deaths each year: ~10,500 Myeloid lineage Lymphoid lineage Tim Graubert, MD Aplastic Anemia & International Foundation Patient and Family Conference March 24, 2018 Median age: ~67 AML MPAL B-ALL T-ALL Ineffective hematopoiesis ffective hematopoiesis Challenges in /AML diagnosis Genetics 101 Low-grade High-grade Myeloid lineage AML /MPN MPAL MPN B-ALL T-ALL Lymphoid lineage Non-neoplastic causes of cytopenia --Other neoplasms --Inherited --xtrinsic factors Does the patient have a neoplasm? Should the patient be treated for or should another diagnosis be sought? isk-adapted therapy according to prognosis AML Should the patient receive induction or other intensive chemotherapy with a goal of remission? 1

2 AML with recurrent genetic abnormalities What is a mutation? Common mutations in AML t(8;21) inv(16) or t(16;16) UNX1-UNX1T1 CBFB-MYH11 t(15;17) PML-AA TTGAGTCG. TTGAGTAG. LN Molecular isk Groups Conventional chemotherapy for AML Induction Various regimens (IA, 7+3, AcDVP16, etc) Cytarabine (continuous infusion or bolus) Anthracycline Typicallydaunorubicin or idarubicin Day 14 marrow (e.g. 7+3 chemotherapy) If aplasia (marrow < 5% cellularity), wait for recovery If residual leukemia, re-treat. Mrozek K et al, JCO 2012 C rate 75% (includes those needing 2 courses) 2

3 Survival (%) 3/22/2018 Consolidation ecent developments CPX-351 ( Vyxeos ) Most common: High dose cytarabine (HiDAc) Mayer: 3g/m2 IV BID Days 1,3,5 for 3-4 cycles Several alternates (e.g., 1.5 g IV q12 x 6 days) Allogeneic stem cell transplant Liposomal chemotherapy Antibody-drug conjugates FLT3 inhibitors IDH1/IDH2 inhibitors 100nm bilamellar liposomes 5:1 molar ratio of cytarabine to daunorubicin 1 unit = 1.0 mg cytarabine plus 0.44 mg daunorubicin Treatment schedule and dose Vyxeos approval Gemtuzumab ( Mylotarg ) CPX unit = 1 mg cytarabine mg daunorubicin 100 units/m 2 First Induction Days 1, 3 and 5 First Induction Cytarabine: 100 mg/m 2 x 7 d Daunorubicin: 60 mg/m 2 x 3 d Kaplan-Meier Curve for Overall Survival ITT Analysis Population vents/n Median Surv. (95% CI) CPX / (6.60, 11.86) / (4.99, 7.75) Hazard atio = 0.69 p-value = Humanized IgG4 Anti-CD33 mab hp Anti-CD33 antibody conjugated to calicheamicin e-induction Consolidation 100 units/m 2 Days 1 and 3 65 units/m 2 Days 1 and 3 e-induction Consolidation Cytarabine: 100 mg/m 2 x 5 d Daunorubicin: 60 mg/m 2 x 2 d Cytarabine: 100 mg/m 2 x 5 d1 6 Daunorubicin: 60 mg/m 2 x 2 d Approved 8/3/17 for the treatment of adults with: newly diagnosed therapy-related AML (t-aml), or AML with myelodysplasia-related changes (AML-MC) Calicheamicin hydrolyzed in lysosome after internalization Initially approved 2000 in / AML Hepatotoxicity/VOD issues 3

4 Gemtuzumab results FLT3 FLT3 inhibitors Favorable Intermediate Unfavorable ITD: 25-30% High relapse, poor prognosis IC 50 (medium) a IC 50 (plasma) b Lestaurtinib 2 nm 700 nm 6 nm ~1000 nm Sorafenib 3 nm ~265 nm Quizartinib 1 nm 18 nm Approved 9/1/17 for the treatment of adults with: newly diagnosed or / CD33+ AML Lestaurtinib (CP-701) (PKC-412) Sorafenib Quizartinib (AC220) atify Trial atify: Schema atify: Main findings A Phase III andomized Double-blinded Study Of Chemotherapy +/- (PKC412) In Newly Diagnosed Adults aged with FLT3 Mutated Acute Myeloid Leukemia (AML) ichard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze Dohner, Christian Thiede, Guido Marcucci, Francesco Lo-Coco, ebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick. Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, ichard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard hninger, Sergio Amadori, ichard A. Larson, and Hartmut Dohner P F L T - 3 S G I S T C N Stratify* FLT3 ITD or TKD A N D O M I Z FLT3 WILD TYP not eligible for enrollment DN AA-C DN AA-C Placebo C C HidAC HidAC Placebo X 4 X 4 MAINTNANC 12 months Placebo MAINTNANC 12 months Approved 4/28/17 for the treatment of adults with newly diagnosed FLT3m AML Arm 4-year Survival MIDO 51.4% (95%CI: 46, 57) PBO 44.2% (95%CI: 39, 50) 4

5 Mitochondrion IDH2 Citrate Isocitrate KG IDH2m IDH as a therapeutic target cell Citrate Isocitrate IDH1 pigenetic changes Impaired cellular differentiation KG 2-HG IDH1m IDH mutations occur in a spectrum of solid and hematologic tumors IDH1m: IDH2m: ~3% of 3 6% of Mardis, et al, NJM, 2009; Dang, et al, Nature, 2009 IDH inhibitor trials (NCT ): Phase I multicenter study of AG-120 in patients with IDH1 mutant advanced hematologic malignancies (NCT ): Phase I multicenter study of AG-221 in patients with IDH2 mutant advanced hematologic malignancies AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the IDH2 Mutant nzyme, Induces Durable eponses in a Phase 1 Study of IDH2 Mutation Positive Advanced Hematologic Malignancies ytan M Stein1, Jessica K Altman2, obert Collins3, Courtney DiNardo4, Daniel J DeAngelo5, Amir T Fathi6, Ian Flinn7, Arthur Frankel3, oss L Levine1, Bruno C Medeiros8, Manish Patel9, Daniel A Pollyea10, Gail J oboz11, ichard M Stone4, onan T Swords12, Martin S Tallman1, Sam Agresta13, Caroline Almon13, Bin Fan13, Meredith Goldwasser13, Hua Yang13, Katharine Yen 13, Stéphane de Botton14 1Memorial Sloan Kettering Cancer Center, New York, NY; 2obert H. Lurie Comprehensive Cancer Center, Chicago, IL; 3University of Texas Southwestern, Dallas, TX; 4University of Texas MD Anderson Cancer Center, TX; 5Dana-Farber Cancer Institute, Boston, MA; 6Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; 7Sarah Cannon esearch Institute, Nashville, TN; 8Stanford Comprehensive Cancer Center, Stanford University, Stanford, CA; 9Florida Cancer Specialists/SCI, Sarasota, FL; 10University of Colorado Cancer Center, Aurora, CO; 11Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY; 12Sylvester Comprehensive Cancer Center, University of Miami Hospitals, Miami, FL; 13Agios Pharmaceuticals, Cambridge, MA; 14Institut Gustave oussy, Villejuif, France IDH2 inhibitor trial design Ongoing, first-in-human, dose escalation study: AG-221: First-in-class, oral, potent, reversible, selective inhibitor of mutated IDH2 IDH2 mutation-positive hematologic malignancies, including relapsed or refractory AML,, or untreated AML AG-221 in continuous oral dosing QD or BID daily, 28-day cycles Key outcome measures: Safety and tolerability, DLTs MTD and recommended phase 2 dose Overall esponse (C, Cp, Ci, mc, P) IDH2i preliminary results -AML (n = 159) 59 (37%) [95%CI: 30%, 45%] C 29 (18%) [95%CI: 13%, 25%] Untreated AML (n = 24) 10 (42%) [22%, 63%] 4 (17%) [5%, 37%] (n = 14) 7 (50%) [23%, 77%] 3 (21%) [5%, 51%] Approved 8/1/17 for the treatment of adults with / IDH2m AML All (N = 209) 79 (38%) [31%, 45%] 37 (18%) [13%, 24%] Cp 1 (1%) 1 (4%) 1 (7%) 3 (1%) Ci 3 (2%) (1%) mc 9 (6%) 1 (4%) 3 (21%) 14 (7%) P 17 (11%) 4 (17%) 0 22 (11%) SD 72 (45%) 9 (38%) 6 (43%) 96 (46%) PD 10 (6%) 1 (4%) 0 11 (5%) Not evaluable 18 (11%) 4 (17%) 1 (7%) 23 (11%) Benefit does not require C stimate Duration of esponse: 3-month 90% 5

6 xperts at Mass General Leukemia Center Amir Fathi Phil Amrein Gaby Hobbs yal Attar Tim Graubert Hanno Hock Andy Brunner BMT Center YiBin Chen Steve McAfee Tom Spitzer Paul O Donnell Areej l-jawahri Bimal Dey Zack DeFilipp Thanks! tgraubert@mgh.harvard.edu 6