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Evolving Treatment Options in Acute Myeloid Leukemia

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Evolving Treatment Options in Acute Myeloid Leukemia Evolving Treatment Options in Acute Myeloid Leukemia Lydia Benitez, PharmD, BCOP Adult Outpatient Leukemia Specialist, Michigan Medicine Adjunct Faculty, University of Michigan College of Pharmacy Disclosures I have no conflicts of interest with relation to the content of this presentation 2 Learning Objectives • Describe the mechanism of action of novel agents in treatment of AML • Examine the efficacy and safety data for newly approved agents • Evaluate the place in therapy for discussed therapeutic agents, including the role of stewardship • Develop a treatment plan for a patient with AML based on disease features 3 Abbreviations Disease Related Efficacy Endpoints • AML: acute myeloid leukemia • CR: complete remission — NOS: not otherwise specified • CRh: complete response with partial hematologic recovery — AML-MRC: AML with myelodysplastic related changes — platelets > 50,000/µL and absolute neutrophil count > 1000/µL — sAML: secondary AML — CBF: core binding factor • CRi: complete remission with incomplete count recovery — platelets < 100,000/µL and/or absolute neutrophil count < 1000/µL • AlloHCT: allogeneic hematopoietic cell transplant • CRp: complete response with incomplete platelet hematologic recovery • ECOG PS: Eastern Cooperative Oncology Group performance status — platelets < 100,000/µL • IDH: isocitrate dehydrogenase • DFS: disease free survival • MDS: myelodysplastic syndrome • DoR: Duration of response • WBC: white blood cell • MLFS: morphologic leukemia free-state Safety • MRS: measurable residual disease • AE: adverse event • NR: not reached • ALT: alanine aminotransferase • NS: no statistically significant difference • AST: aspartate aminotransferase • ORR: overall response rate • EKG: electrocardiogram • PR: partial response • DDI: Drug-drug interactions • R/R: relapsed/refractory • T. bili: total bilirubin • RFS: relapse-free survival 4 Audience Participation How many new agents have been approved in the last 2 years for the treatment of AML? A. Five B. Six C. Seven D. Eight 5 Timeline of Drug Approvals for AML Daunorubicin Idarubicin Midostaurin Venetoclax Enasidenib Ivosidenib 1969 1979 1987 1990 2000 2017 2018 GO Gilteritinib Cytarabine Mitoxantrone Gemtuzumab CPX-351 Glasdegib Ozogamicin (GO) (2000-2010) 5 Setting Up the Stewardship Mindset Pay for Service Price Therapeutic Inelasticity Monopolies Drug High Cost of Market Discovery Therapeutics Exclusivity Ramsey SD, et al. J Clin Oncol. 2016;34(9):980-6 Siddiqui M, et al. Mayo Clin Proc. 2012;87:935-43. Targeted Therapies IDH Inhibitors FLT3 Inhibitors CD33 drug-antibody complex 8 IDH Mutations in AML citrate isocitrate isocitrate IDH2 mIDH2 Enasidenib Ivosidenib mIDH1 IDH1 α-ketoglutarate α-ketoglutarate 2-hydroxyglutarate TET2 DNA JmjC histone hydroxylases demethylases Block in cellular differentiation and progression to leukemia IDH1 (R132) IDH2 (R140,R172) De Novo AML 6-16% 8-19% Cantor JR, et al. Cancer Discovery. 2012;(10):881-98 Nassereddine S, et al. Ann Hematol. 2017;96(12)1983-1991. MDS 2-3% 2-7% Mondesir J, et al. J Blood Med. 2016;7:171. 9 Enasidenib in IDH2 Mutant Relapsed AML Patients with relapse/refractory mutant- IDH2 AML/MDS Enasidenib once daily Aged ≥18 yrs and ECOG 0-2 Expansion cohort – 100 mg daily (N = 176) Phase I/II open label dose escalation study Disease Expansion cohort All doses Characteristics (n = 109) (n = 176) Expansion cohort All doses Demographics (n = 109) (n = 176) Prior outcome1 1° refractory 35 (32) 57 (32) Age1, yrs 67 (19-100) 67 (19-100) Relapsed < 1 yr 278 (25) 41 (23) Prior alloHCT 12 (11) 24 (14) AML 2nd or later relapsed 13 (12) 22 (13) Classification1 1 AML-MRC 27 (25) Cytogenetics NOS 64 (57) Intermediate 51 (64) 85 (66) Poor 29 (36) 43 (34) ECOG PS1 0 25 (23) 39 (22) Co-occurring mutations1 1 68 (62) 106 (60) NPM1 8 (17) 16 (16) 2 16 (15) 31 (18) CEBPA 1 (2) 6 (6) 1n (%), 2median (range) FLT3-ITD 1 (2) 4 (4) 1 2 Stein E, et al. Blood. 2017;130(6):722-731. n (%), median (range) Enasidenib Phase I/II Trial Results Expansion cohort All doses (n = 109) (n = 176) ORR1 42 (38.5) 71 (40.3) 1 CR 0.9 Non-CR Responder CR1 22 (20.2) 34 (19.3) 0.8 No Response CRi1 7 (6.4) 12 (6.8) 0.7 0.6 PR1 3 (2.8) 11 (6.3) 0.5 0.4 Time to CR2 3.7 (0.7-11.2) 1.9 (0.5-9.4) Survival Probability Survival 0.3 DoR in patients 8.8 (5.3 – NR) 8.8 (6.4-NR) 0.2 attaining CR2 0.1 1n (%), 2median mo. (range) • Effect of co-mutational burden 3 6 9 12 15 18 21 24 27 — Low mutational burden (< 3): ORR 70.4% and CR: 41% — High mutational burden (> 6): ORR 21.9 % and CR: 0% Months • RAS pathway mutations associated with lower response —Mutational burden in patients with nRAS mutations was higher —86% of patients with mutant NRAS did not respond to enasidenib (p<0.001) Stein E, et al. Blood. 2017;130(6):722-731. Amantangelo M, et al. Blood. 2017;130:732. 11 Ivosidenib in IDH1 Mutant Relapsed AML Patients with IDH1 mutation: R/R AML or MDS with excess blasts Ivosidenib once daily Untreated AML > 60 yrs not candidates for standard chemo Expansion cohort – 500 mg daily (N = 258) Phase I open-label dose escalation study 1° Efficacy group R/R AML 1° Efficacy group R/R AML Demographics Disease characteristics (n = 125) (n = 179) (n = 125) (n = 179) 1 Age2, yrs 67 (18-87) 67 (18-87) Prior outcome 10 refractory 86 (69) 106 (59) AML type1 Relapsed < 1 yr 13 (10) 17 (9) De novo 83 (66) 120 (67) Prior alloHCT 36 (29) 43 (24) sAML 42 (34) 59 (33) 2nd or later relapse 20 (16) 26 (15) tAML 14 (11) 16 (9) Cytogenetics1 Prior therapy1 Intermediate 66(53) 105 (59) Intensive 92 (74) 127 (71) Poor 38 (30) 50 (28) Non-intensive 82 (66) 115 (64) Co-occurring mutations1 Investigational 37 (30) 55 (31) NPM1 24 (20) 44 (26) 1n (%), 2median (range) CEBPA 3 (3) 4 (2) FLT3 9 (8) 11 (6) 1n (%), 2median (range) DiNardo C, et al. N Engl J Med. 2018;378:2386-98. 12 Ivosidenib Phase I/II Trial Results 1° Efficacy Group R/R AML (n = 125) (n = 179) 1 1 ORR 52 (41.6) 70 (39.1) 0.9 CR 0.8 Non-CR Responder CR1 27 (21.6) 39 (21.8) No Response 0.7 0.6 CRi + CRp1 16 (12.8) 21 (11.7) 0.5 0.4 MLFS1 9 (7.2) 10 (5.6) Survival Probability Survival 0.3 Median OS 8.8 mo (95% CI 6.7-10.2) Time to first 0.2 1.9 (0.8-4.7) 1.9 (0.8-4.7) response, mo2 0.1 DoR in patients 9.3 (4.6-9.3) 9.3 (4.6-9.3) 2 6 10 14 18 22 26 30 attaining CR, mo3 Months 1n (%), 2median (range) 3median (95%CI) • Significant association between low co-mutational burden and CR/CRh attainment (p=0.02) • No association seen with NRAS mutational status individually and response • RTK pathway mutations (NRAS, FLT3, PTPN11, KRAS) more frequent in non-responders (p=0.003) DiNardo C, et al. N Engl J Med. 2018;378:2386-98. 13 Safety with IDH Inhibitors Enasidenib (Idhifa) Quick Facts Ivosidenib Grade > III AEs Enasidenib (Idhifa) Approval R/R AML with IDH2 mutation (Tibsovo) Administration 100 mg daily Hyperbilirubinemia 15% 1% Metabolism UGT1A1 DDI Inhibits various CYP enzymes Diarrhea 8% 2% Contraception Hepatic impairment 50 mg daily if T.bili > 3xULN for 2 wks w/o AST/ALT elevation Nausea 5% 1% WAC Price $1029/day $28,812/28-day cycle ↓Ca2+, K+, Phos 15% 6% (K+) Ivosidenib (Tibsovo) Quick Facts QT prolongation --- 10% Approval R/R AML with IDH1 mutation Administration 500 mg (2 tablets) daily Leukocytosis 6% 8% (no high fat meal) Metabolism CYP3A4 substrate Differentiation Syndrome 7% 13% DDI CYP3A4 inducer QT prolongation EKG weekly x 3 then monthly ↓dose to 250 mg if QTc > 500 msec w/o other causes DiNardo C, et al. N Engl J Med. 2018;378:2386-98. Tibsovo [package insert]. Cambridge, MA: Agios Pharmaceuticals, Inc. 2018. WAC Price $1,044/day Idhifa [package insert]. Summit, NJ: Celgene Corp. 2017. $29,232/28-days Thomson Reuters Micromedex: RED BOOK Drug References. IBM Corporation 2019. IDH Inhibitor Differentiation Syndrome Time to Onset Days to months (median 1 month) Signs/Symptoms • Fever • Leukocytosis • New/worsening progressive dyspnea • Increasing O2 demands • New or worsened pulmonary infiltrates • Peripheral edema • Rapid weight gain • ↑Serum creatinine • Rash Management 1. Start corticosteroids and slowly taper Michigan Medicine Patient Education Materials 2. Hydroxyurea recommended if WBC> 30K Created by UMHS Oral Chemotherapy Team 3. Interrupt IDH inhibitor if severe pulmonary symptoms and/or renal dysfunction for > 48 hours of treatment with steroids Patient Case-ARS #1 SZ is a 68yoM with relapsed AML and an IDH2 R140 mutation From an oncology stewardship perspective, which factor would suggest increased financial toxicity with low probability of response attainment? A. Intermediate risk cytogenetics B. Concomitant NPM1 mutation C. An NRAS mutation D. Concomitant SRSF2 and RUNX1 mutations 16 Patient Case-ARS #2 • SV is initiated on enasidenib 100 mg daily. On Day 15 after starting therapy he presents overnight to the ED with new shortness of breath and fevers over last 48 hrs. Temperature (oC) Weight (Kg) 40 82 39 80 38 78 37 76 36 74 35 72 15 15.5 16 Days 16.5 17 17.5 15 15.5 16 Days 16.5 17 17.5 O2 Requirement (L NC) WBC 4 50 40 3 30 2 20 1 10 0 0 15 15.5 16 16.5 17 17.5 15 15.5 16 16.5 17 17.5 Days Days Which intervention(s) would you recommend on Day 16? A.
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