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. Hydroxyurea 1g Q12H B. Dexamethasone 10 mg BID C. Discontinuation of enasidenib D. All of the above IDH Inhibitor and Chemotherapy Combination
Induction Consolidation Maintenance mIDH1 HIDAC† or ME‡ + Adults with newly 7+3* + Ivosidenib Ivosidenib daily for 2 yrs OR alloHCT diagnosed AML with Ivosidenib IDH mutations HIDAC† or ME‡ + (N = 153) 7+3* + Enasidenib Enasidenib daily for 2 yrs OR alloHCT mIDH2 Enasidenib *7+3: daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 and cytarabine 200 mg/m2 †HIDAC: high-dose cytarabine ‡ME: mitoxantrone and etoposide Phase I multicenter open-label dose escalation study (NCT 0263270)
Ivosidenib combo Enasidenib combo AML Characteristics Ivosidenib combo Enasidenib combo (n = 60) (n = 93) Demographics (n = 60) (n = 93) Risk stratification1 Favorable 12 (20) 11 (12) Age1, yrs 62.5 (24-76) 63 (27-77) Intermediate 26 (43) 46 (49) Poor 20 (33) 29 (31) AML type1 1 De novo 42 (70) 59 (63) IDH1 mutation type sAML 18 (30) 34 (37) R132 57 (95) 2 (2) Prior HMA* 4(22) 17 (50) Other/unknown 3 (5) 2 (2) 1 1n (%) *HMA: hypomethylating agent IDH2 mutation type R140 1 (2) 65 (70) R172 2(3) 23 (25) Other/unknown 5 (5) Stein E. Blood. 2018;132 (Suppl1): Abstr 560. http://www.bloodjournal.org/content/132/Suppl_1/560 . Accessed Jan 26, 2019. Frontline IDH Inhibitor Combinations Results
90 80 All 70 de novo 60
50 Secondary
40
30
CR after Induction Induction (%) CR after 20
10
0 Ivosidenib combo Enasidenib combo Ivosidenib combo Enasidenib combo Results (n = 60) (n = 93) CR+CRi+CRp, n (%) 48 (80) 67 (72) MRD negativity among patients responding, n (%) 53 (88) 42 (45) Median time to hematologic recovery, days (95%CI) 28 (27-32) 34 (29-35)
Stein E. Blood. 2018;132 (Suppl1): Abstr 560. http://www.bloodjournal.org/content/132/Suppl_1/560 . Accessed Jan 26, 2019. Safety with IDH Combinations
Ivosidenib combo Enasidenib combo Discontinuation, n (%) (n = 60) (n = 93) Ivosidenib Enasidenib Grade III-V AEs, n combo combo Total 33 (55) 78 (84) (%) (n = 60) (n = 93) AlloHCT 17 (52) 41 (53) Differentiation 2 (3) 1 (1) AE 8 (24) 11 (14) syndrome Progressive disease 4 (12) 7 (9) QT prolongation 1 (2) 0
Patient/Physician Decision 2 (6) 9 (12) Total bilirubin increase 4 (7) 13 (14) Mortality Death 1 (3) 4 (5) 30-day 3 (5) 5 (5) 60-day 5 (8) 8 (9) Other 1 (3) 6 (8)
• Overall high remissions with combination, 1 yr OS > 75% for overall sample • High rate of discontinuation of IDH inhibitors after induction • Upcoming randomized Phase III trial to follow Targeted Therapies IDH Inhibitors FLT3 Inhibitors CD33 drug-antibody complex
21 FLT-3 Mutation in AML
Transmembrane domain
FLT3 • Present in ~20-30% of all AML • FLT3-ITD historically associated with high-risk disease JAK2 JAK2 RAS RAS GDP GTP GDP GTP • FLT3-TKD has unclear prognostic significance
STAT RAF
Survival and uncontrolled proliferation
Hassanein M, et al. Clinical Lymphoma, Myeloma & Leukemia. 2016;16(10):543-9. FLT3 Kinase Domain Inhibitors
Class I Class II
Midostaurin (Rydapt) Sorafenib (Nexavar) First Generation Class I • Approved for treatment • Studied prospectively in in • Promiscuous • Bind to ATP site when naïve AML in combination combination with cytotoxic • Off-target toxicities receptor is active with cytotoxic chemo chemo for treatment naïve • ITD and TKD activity • Targets ITD and TKD AML (SORAML) mutations • Targets ITD mutations only
Second Generation Class II First Generation • ↑Specificity & potency • Bind adjacent ATP • No efficacy against site when receptor Gilteritinib (Xospata) Quizartinib parallel or inactive • Approved as single agent • FDA Breakthrough for R/R downstream • mD835 = ↑active therapy in relapsed/refractory AML based on prospective pathways • Low or no TKD AML trial (QUANTUM-R) activity • In-vitro efficacy in ITD and • Targets ITD mutations only TKD mutations
Crenolanib (Phase III ongoing)
Second Generation
Larrosa-Garcia M. Mol Cancer Ther 2017.16(6):991-1001 23 Gilteritinib for Relapsed AML – ADMIRAL trial
Gilteritinib 120 mg PO daily Adult patients with R/R AML At least one prior cycle of therapy • Prior exposure to midostaurin or sorafenib allowed Physician’s Choice therapy: (N = 369 (planned enrolment)) LoDAC, MEC, Aza, or FLAG-IDA
LoDAC: low-dose cytarabine MEC: mitoxantrone, etoposide, high-dose cytarabine Aza: Azacitidine FLAG-IDA: fludarabine, high-dose cytarabine, G-CSF, idarubicin Phase III randomized open-label trial Primary Endpoint: OS Secondary Endpoints: EFS, CR
Disease Gilteritinib Physician’s choice Gilteritinib Characteristics (n = 138) Demographics Physician’s choice (n = 138) Disease Status1 First Relapse 82 (59) Age2, years 60 (20-84) 1⁰ Refractory 56 (41) No information presented or No information 1 ECOG1 published at the time of slide Prior AlloHCT 27 (20) presented or preparation published at the time 0-1 113 (82) FLT3 Mutation1 of slide preparation > 2 25 (18) ITD 121 (88) 1n (%), 2median (range) TKD 12 (9) ITD + TKD 5 (4) 1n(%) Xospata [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2018. Perl A, et al. J Clin Oncol. 2017;35(15)Suppl.Abstr 7067. http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.TPS7067 . Accessed Jan 25, 2019. 24 Efficacy and Safety
Gilteritinib (n = 292) Gilteritinib Frequent AEs Responses (n = 138) Any Grade Grade > 3 CR or CRh1 29 (21) Myalgias/Arthalgia1 123 (42) 13 (5) CR 16 (11.6) CRh 13 (9.4) AST, ALT elevations1 121 (41) 47 (16) CR in FLT-TKD 0 (0) Dyspnea1 98 (34) 36 (12) Time to CR2, mo 3.6 (0.9 – 9.6)
1 DoR in CRc2, mo 4.6 (0.1 – 15.8) Pneumonia 89 (30) 66 (23)
1 Transfusion Independence1 33/106 (31.1) Rash 87 (30) 8 (3)
1n (%), 2median mo. (range) Sepsis1 43 (15) 41 (14)
QTc prolongation1 (7) (1.4)
1n (%)
Xospata [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2018. 25 Gilteritinib Summary and On-Going Trials
Gilteritinib (Xospata) Quick Facts • No current information on comparison to chemotherapy Approval R/R AML with FLT3 mutation • Small TKD sample to inform use in this population Administration 120 mg (3 tablets) daily • Additional ongoing studies with data Metabolism CYP3A4 substrate —NCT02997202: Post-alloHCT maintenance in FLT3-ITD DDI CYP3A4, P-gp inhibitors/inducers AUC ↑ 120% with itraconazole —NCT02927262: Post CR1 maintenance in FLT3-ITD AUC ↑ 40% with fluconazole —NCT02236013: Frontline in combo with chemotherapy Dosing Decreases recommended for Modifications QTc↑ and pancreatitis WAC Price $900/ day $25,2000/28-days
Xospata [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2018. Thomson Reuters Micromedex: RED BOOK Drug References. IBM Corporation 2019. 26 Quizartinib for R/R AML (QUANTUM-R)
Quizartinib 60 mg daily Quizartinib maintenance Patients with R/R FLT3-ITD+ AML AlloHCT Physician’s Choice chemotherapy: (N = 367) LoDAC, MEC, or FLAG-IDA No maintenance
Phase III randomized open-label trial Primary Endpoint: OS Secondary Endpoint: EFS
Quizartinib Physician choice Responses P Quizartinib Physician choice (n = 245) (n = 122) Baseline Characteristics (n = 245) (n = 122) ORR1 170 (69) 37 (30) NS 2 Median Age 55 (19-81) 58 (18-78) CRcomposite1 118 (48) 33 (27) 1 <0.0001 Median duration of CR1, CRi 99 (40) 1 (1) 2 15 (2.1-57.0) 16.0 (2.3-165.0) wks Median OS2, mo 6.2 (5.3-7.2) 4.7 (4.0-5.5) 0.0177 Prior therapy response1 Refractory 80 (33) 41 (34) Median EFS2, mo 6.0 (0.1-8.3) 3.7 (0.4-5.9) 0.107 Relapsed post AlloHCT 56 (23) 27 (22) Relapsed w/o AlloHCT 109 (45) 54 (44) Time to CR2, wks 4.9 (3.7-19.7) 4.0 (2.0-14.9) NS 1n (%), 2median (range) DoR in CRc2, wks 12.1 (10.4-27.1) 5.0 (3.3-12.6) NS
1n (%), 2median mo. (96% CI)
Cortes JE, et al. Blood. 2018;132 (Suppl1): Abstr 563. http://www.bloodjournal.org/content/132/Suppl_1/563. Accessed Jan 25, 2019. Patient Case-ARS #3
KT is a 64 yoF T+100 post-AlloHCT with relapsed AML —Karyotype: 46,XX —Molecular Abnormalities: NPM1+, FLT3-ITD+ • Prior Treatment History: —CR1 post induction with 7+3 —Patient underwent match-related AlloHCT with myeloablative Busulfan/Fludarabine conditioning
• Which of the following treatments has demonstrated OS benefit over standard therapy? A. Re-induction with conventional chemotherapy + midostaurin B. Gilteritinib monotherapy C. Quizartinib monotherapy D. B and C
28 Treatment Decisions for FLT3 mutated AML Maintenance post TKI FLT3 Targets Treatment Naive Relapsed/Refractory Disease Allo-HCT
Midostaurin FLT3-ITD N/A (Rydapt) FLT3-TKD (combined with 7+3)
Sorafenib FLT3-ITD (combined with 7+3) (Nexavar) (combined with HMA)
Gilteritinib FLT3-ITD NCT02236013* NCT02997202 (Xospata) FLT3-TKD NCT02752035 (with HMA)
Quizartinib FLT3-ITD NCT02668653 (with 7+3)
FLT3-ITD NCT03258931 (with 7+3) NCT02626338 (with chemo) Crenolanib NCT02400255* FLT3-TKD NCT01522469 (monotherapy)*
Prospective trials have been completed and have published results Drug has FDA approval in this setting *On-going trials with results published in abstract form 29 Post AlloHCT Maintenance
Maintenace post AlloHCT TKI FLT3 Targets Reference for Results Available Studies Active or Completed
Midostaurin FLT3-ITD Thomas R, et al. Blood. 2018;132 (Suppl1): Abstr 662. NCT01883362 (RADIUS) http://www.bloodjournal.org/content/132/Suppl_1/6 (Rydapt) FLT3-TKD 62. Accessed Jan 25, 2019.
Sorafenib Burchet A, et al. Blood. 2018;132 (Suppl1): Abstr 661. FLT3-ITD NCT01398501 (SORMAIN) http://www.bloodjournal.org/content/132/Suppl_1/5 (Nexavar) 63. Accessed Jan 25, 2019.
Gilteritinib FLT3-ITD NCT02997202 Recruiting; no results available (Xospata) FLT3-TKD
Cortes JE, et al. Blood. 2018;132 (Suppl1): Abstr 563. Quizartinib FLT3-ITD NCT02039726 (QUANTUM-R) http://www.bloodjournal.org/content/132/Suppl_1/5 63. Accessed Jan 25, 2019.
Safety results: FLT3-ITD Oran B, et al. Blood. 2018;132 (Suppl1): Abstr 3426. Crenolanib NCT02400255* FLT3-TKD http://www.bloodjournal.org/content/132/Suppl_1/3 426. Accessed Jan 25, 2019.
30 Targeted Therapies IDH Inhibitors FLT3 Inhibitors CD33 drug-antibody complex
31 Gemtuzumab Ozogamicin (Mylotarg, GO)
Blast Cell • Drug-Antibody Complex —Near universal CD33 expression in AML —Ozogamicin causes double-stranded DNA breaks • FDA Approvals for AML —In combination with daunorubicin and cytarabine in newly diagnosed AML —Monotherapy in newly diagnosed —Monotherapy in R/R AML CD33 • Dosing improvements —Lower dose = ↓Adverse events gemtuzumab —↑Frequency = Higher efficacy ozogamicin • WAC Price of Induction: $30,405
Mylotarg [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc. Pfizer, Inc. 2018. Thomson Reuters Micromedex: RED BOOK Drug References. IBM Corporation 2019. 32 GO in Combination with Chemo - ALFA-0701 Induction Re-induction Consolidation (if needed) 7+3* & Daunorubicin + GO GO Days** 1, 4, 7 High-Dose AraC† Adult patients with treatment Daunorubicin + naïve AML † (N = 278) High-Dose AraC Daunorubicin + High- 7+3* Dose AraC†
*daunorubicin 60 mg/m2 and cytarabine 200 mg/m2 **GO dose: 3 mg/m2 (max = 4.5 mg) † High-Dose AraC: Cytarabine 1000 mg/m2 Days 1-4 Phase III randomized open-label trial Primary Outcome: EFS Secondary: CR, RFS, OS
GO+7+3 Control Disease Characteristics (n = 139) (n = 139) GO+7+3 Control Demographics (n = 139) (n = 139) Cytogenetic Risk Favorable 3 (4) 6 (4) Intermediate 91 (65) 91 (65) Median Age2, yrs 62.8 (59.3-66.8) 61.7 (57.4-65.6) Unfavorable 28 (20) 30 (22) ECOG PS1 Genotype 0-1 119 (85.6) 119 (86) Favorable 24 (17) 24 (17) 2 75 (9) 17 (2) Unfavorable 95 (68) 101 (73) 1n (%), 2median (range) Unknown 20 (14) 14 (10) 1n (%), 2median (range)
Castaigne S, et al. Lancet. 2012;329:1508-16. 33 ALFA-0701 Trial Results 1 GO 0.8 Control GO+7+3 7+3 Response 3-yr EFS: 31% GO vs. 19% control (n = 139) (n = 139) P 0.6 (HR: 0.66, 95% CI:0.5-0.87)
1
CR+CRi 113 (81) 104 (75) 0.25 0.4
Free Survival (%) Survival Free - Median EFS2 15.6 (NR) 9.7 (NR) 0.0026 Event 0.2 3yr OS3 44% 36% 0.18
Median OS2 25.4 (NR) 20.8 (NR) NS 10 20 30 40 50 60 1n (%), 2median (range) 3% (%) Months Safety GO+7+3 (n = 139) Control (n = 139) P VOD/SOS1 2 (1.4) 0 NR Treatment Related Death in CR1 8/104 (8) 2/113 (2) 0.051 Grade > III Hepatotoxicity1 18 (13) 9 (6) 0.100 Thrombocytopenia2, days induction 25 (20-30) 25 (20-30) 0.0006 consolidation 17 (11-27) 17 (11-27) < 0.0001 Second consolidation 24 (15-35) 24 (15-35) < 0.0001 Hemorrhage1 12 (9) 4 (3) 0.068 1n (%), 2median (range) 3% (%) Castaigne S, et al. Lancet. 2012;329:1508-16. Castaigne S, et al. Blood. 2014;124(21):376. http://www.bloodjournal.org/content/124/21/376?sso-checked=true. Accessed Jan 26, 2019 34 Clear Benefit in CBF-AML?
Additional Patient Population Comparator Arm Trial Results Trials SWOG De-novo Treatment Naïve AML 7+3(45 mg/m2) +GO (6mg/m2) D4 No improvement in CR S0106 Ages: 18-60 yrs Control: 7+3 (60 mg/m2) Higher mortality in GO arm (6% vs. 1%) (N = 595) (17% favorable cytogenetics) De-novo Treatment Naïve AML GOELAMS No improvement in CR Ages: 18-60 yrs 7+3(60 mg/m2) +GO (6mg/m2) D4 AML 2006 Treatment mortality 10.5% vs. 4.5% (100% intermediate risk Control: 7+3 (60 mg/m2) (N = 238) No difference in 3yr EFS or OS cytogenetics) Any of 3 inductions +/- GO (3mg/m2) No improvement in CR Treatment naïve AML 3+10 followed by 3+8* ↑hepatotoxicity, transfusions, antibiotic use w GO NCRI AML16 Median Age 49 yrs (0-71) ADE** No difference in EFS, OS (N = 1113) (4% favorable risk cytogenetics) FLAG-Ida Benefit seen in favorable risk subgroup with Consolidation: limited use of HIDAC addition of GO (HR = 0.32; 95% CI: 0.18-0.59) *daunorubicin 50 mg/m2 , cytarabine 100 mg/m2 **ADE: daunorubicin 50 mg/m, cytarabine 100 mg/m2, etoposide 100 mg/m2
Meta-Analysis results: GO improved OS in favorable risk cytogenetics (OR:0.47; 95% CI: 0.73-0.90; p=0.0006) Potential Reasons for Observed Benefits in Favorable Risk cytogenetic subgroups • Lower P-gp expression associated with higher CD33 expression and better response to GO • Suboptimal anthracycline dosing in younger favorable risk patients • Suboptimal exposure to high-dose cytarabine in GO studies Hills R, et al. Lancet. 2014;15:986-96. Burnett A, et al. J Clin Oncol. 2011;29:369-77. Petersdorf S, et al. Blood. 2013;4854-60. Delaunay J, et al. Blood. 2011;118(21):79. http://www.bloodjournal.org/content/118/21/79?sso-checked=true. Accessed Jan 26, 2019 35 sAML and Options for Elderly Patients
36 CPX-351 (Vyxeos) Approval INDUCTION (1-2 cycles) Consolidation (1-2 cycles) CPX-351* CPX-351* Patient with treatment naïve (n = 153) (n = 49) tAML or AML-MRC AlloHCT if Age 60-75 yo 7+3† eligible ‡ (N = 309) Re-induction: 5+2 5+2 (n = 156) (n = 33) *CPX351: (liposomal daunorubicin-cytarabine in a 5:1 molar ratio) 44mg/m2 – 100mg/m2 Days 1, 2, 3 induction and 29mg/m2-65mg/m2 Days 1 and 3 consolidation †7+3: daunorubicin 60 mg/m2 and cytarabine 100 mg/m2 ‡5+2: daunorubicin 60 mg/m2 and cytarabine 100 mg/m2 Phase III multicenter randomized controlled trial Primary Outcome: OS Secondary: CR+CRi, EFS, duration of response
60 CR 1 Things to consider: CRi 50 0.9 Median OS 9.56 vs. 5.95 mo P=0.016 0.8 (HR 0.69, 95% CI 0.52-0.90) 40 P = 0.003 • alloHCT in CR1 was higher in CPX-351 0.7 arm (57.7% vs. 19.2%) 30 0.6 0.5 CPX-351 7+3 followed by 5+2 20 0.4 • Non-traditional consolidation strategy
10 Probability Survival 0.3 Complete Remission (%) Remission Complete 0.2 • No benefit of CPX-351 in pts with prior 0 0.1 HMA exposure CPX-351 7+3 3 6 9 12 15 18 21 24 27 30 Lancet J, et al. J Clin Oncol. 2018;36(26):2684-2692. Months sAML with Prior HMA Exposure?
CPX-351* Patients with sAML and prior † HMA exposure 7+3 AlloHCT if eligible (N = 309) CLA +/- G +/- M‡
*CPX351: 44mg/m2 – 100mg/m2 Days 1, 2, 3 †7+3: daunorubicin 60 mg/m2 and cytarabine 100 mg/m2 ‡CLA+/-G+/-M: cladribine and high-dose cytarabine +/- G-CSF +/- mitoxantrone Multicenter Retrospective Review
CLA based 7+3 CPX-351 Characteristics CLA based 7+3 CPX-351 (n = 114) (n = 94) (n = 34) Disease Related (n = 114) (n = 94) (n = 34) Median Age, yrs2 65 (33-82) 66 (26-82) 69 (36-82) Karyotype1 Prior HMA1 Intermediate 62/107 (57.9) 51/78 (65.4) 22/21 (71) Azacitidine 110 (88.7) 79 (84.9) 28 (82.4) Poor 45/107 (42.1) 27/78 (34.6) 9/31 (29) Decitabine 14 (11.3) 14 (15.1) 6 (17.6) Blast %1 33.3 (20-96) 36.9 (20-93) 34.7 (9-76) Prior HMA cycles2 6 (1-47) 4 (1-72) 5 (1-36) 1n (%), 2median (range) 1n (%), 2median (range)
Talati C, et al. Blood. 2018;132 (Suppl1): Abstr 665. http://www.bloodjournal.org/content/132/Suppl_1/665. Accessed Jan 25, 2019. Treatment after HMA Exposure- Results
70
60 P=0.0068 CLA based 7+3 CPX-351 Results P 50 (n = 114) (n = 94) (n = 34)
Treatment related 14 (12) 7 (8) 1 (2.9) 0.200 40 mortality1
Proceed to AlloHCT1 24/60 (40) 11/29 (36.7) 7/14 (50) 0.192 30 CR/CRi (%) CR/CRi 1n (%), 2median (range)
20 Cost per Induction CLA+/-G+/-M 7+3 CPX-351
10 WAC Price (based on BSA = $2,284 - $5,891 $2,147 - $3,350 $57,474 2m2) 0 All < 4 cycles > 4 cycles CLA based 7+3 CPX-351
Talati C, et al. Blood. 2018;132 (Suppl1): Abstr 665. http://www.bloodjournal.org/content/132/Suppl_1/665. Accessed Jan 25, 2019. Thomson Reuters Micromedex: RED BOOK Drug References. IBM Corporation 2019. Venetoclax
BAX BAK Cellular stress BAK BAX BAX BAX BAX BAX
BCL2 mediated survival and BH3 mimetic facilitated leukemic proliferation caspase mediated cell death
KEY
V Venetoclax
BCL-2 protein
Anderson et al. Semin Hematol. 2014;51:219-227. Cytochrome C Venetoclax + HMA in Untreated AML
Physician’s Choice Chemo
Patients > 65yo with untreated Venetoclax and 7-day Azacitidine AML and ineligible for standard chemotherapy (N = 145) Venetoclax and 5-day Decitabine
Phase Ib dose-escalation and expansion study VEN dosing expansion phase: 400 mg and 800 mg
VEN All cohorts AML Characteristics VEN All cohorts (n = 145) Baseline Characteristics (n = 145) Cytogenetic Risk1 Intermediate 74 (51) Age2, years 74 (65-86) Poor 71 (49)
ECOG1 Secondary AML1 36 (25) 0 32 (22) 1 1 90 (62) Antecedent Heme disorder 26 (18) 2 23 (16) Mutations1 1n (%), 2median (range) FLT3 18 (12) IDH1 or 2 25 (24) NPM1 23 (15) TP53 36 (25) DiNardo C, et al. Blood.2019;133(1):7-15. 1n (%) Venetoclax + HMA in untreated AML: Results
Frequent AEs All Grades Grade > III ALL DAC+ AZA+ DAC+ Aza+ Response Cohorts 400 mg 400 mg 800 mg 800 mg VEN Febrile 63 (43) 63 (43) (N = 145) (n = 31) (n = 29) (n = 37) (n = 37) Neutropenia1
Nausea1 88 (61) 2 (1) CR+CRi1 54+43 (67) 22 (71) 22 (76) 27 (73) 21 (57) Diarrhea1 75 (52) 7 (5)
Duration of 11.3 12.5 NR 9.2 11.7 Fatigue1 57 (37) 8 (6) Response2, mo (8.9-NR) (5.1-NR) (5.6-NR) (5.9-NR) (4.6-12.9) Leukopenia1 45 (31) 45 (31) 17.5 14.2 NR 17.5 15.2 Median OS2, mo Hypokalemia1 49 (34) 15 (10) (12.3-NR) (7.7-NR) (9.0-NR) (10.3-NR) (9.1-NR)
1 1n (%), 2median (95% CI) ↓Appetite 48 (33) 2 (2)
1n (%) • Median time to first response 1.2 mo (0.8-13.5 mo) • Median time to CR 2.1 mo (0.9-13.5 mo)
DiNardo C, et al. Blood.2019;133(1):7-15. Venetoclax + HMA Results by Subgroup
CR+CRi 100 90 80 Response Subgroup Median OS 70 Duration (%of N) median mo (95%CI) median mo (95%CI)
60 (%) 50 sAML (25) NR (12.5-NR) NR (14.6-NR)
CR+CRi 40 30 Poor Risk (49) 6.7 (4.1-9.4) 9.6 (7.2-12.4) 20 10 > 75 yo (57) 12.8 (9.2-NR) 17.7 (14.2-NR) 0 Mutations FLT3 (12) 11 (6.5-NR) NR (8-NR) IDH1/2 (24) NR (6.8-NR) 24.4 (12.3-NR) NPM1 (16) NR (6.8-NR) NR (11-NR) TP53 (25) 5.6 (1.2-9.4) 7.2 (3.7-NR)
• Median follow-up was 15.1 mo • Median OS across all groups: 17.5 mo (95% CI: 12.5 – NR) DiNardo C, et al. Blood.2019;133(1):7-15. Venetoclax Dosing & Schedule
Frontline Dosing VEN Schedule Studies Cycle #1 Days 1 through 28 If morphologic CR at completion of C1: DiNardo. Blood, 400 mg Cycle #2 VEN can be interrupted for up to 14 days 2019. 800 mg Cycle #3 and Recurrent neutropenia addressed with reduction to 21 days of VEN beyond Days 1 through 28 Maiti A. ASH 400 mg Cycle #1 (could stop earlier if D21 marrow showed CRi) 2018. Abstract (200 mg if on 286. 3A4 inhibitor) Cycle #2 and Days 1 through 21 beyond
Venclexta Package Insert Dosing Recommendations Evidence Based Simplified Dosing Algorithm Combined with HMA 400 mg Combined with HMA Day 1 through 28 on Cycle #1 Once in CR decrease to days 1 through 21 Combined with LDAC 600 mg Combined with LDAC 600 mg day 1 through 28 DDI Adjustments moderate CYP3A4 inhibitor: 200 mg strong CYP3A4 inhibitor: 100 mg Antifungal adjustments Fluconazole > 400 mg : Reduce by 50% strong CYP3A4 & Pgp inhibitor: 70 mg Isavuconazole: Reduce by 50% How Supplied 20 mg tablets Posaconazole/Voriconazole: Reduce by 75% 50 mg tablets WAC Price $111.50 – 446.00/day (based on dose) 100 mg tablets $3,345-13,380/28-days DiNardo C, et al. Blood.2019;133(1):7-15. Venclexta [package insert]. North Chicago, IL. AbbVie, Inc.2018. Maiti A, et al. Blood. 2018;132 (Suppl1): Abstr 286. http://www.bloodjournal.org/content/132/Suppl_1/286. Accessed Jan 25, 2019. Thomson Reuters Micromedex: RED BOOK Drug References. IBM Corporation 2019 Glasdegib – BRIGHT 1003 Trial
HH
Transmembrane domain PTCH SMO GTP Survival and GLI GLI GDP GTP uncontrolled
STAT proliferation
Glasdegib 100 mg daily + LDAC* Patients with de novo AML or (n = 88) high-risk MDS unfit for intensive chemotherapy* LDAC** (N = 126) (n = 44)
* One or more of the following: > 75yo, severe cardiac disease, ECOG 2, serum creatinine > 1.3mg/dL **LDAC: low-dose cytarabine 20 mg subcutaneously BID for 10 days
Multicenter Phase II randomized open-label trial Primary Outcome: OS
Aberger F, et al. Cell Commun SignaI. 2017;15(1):8. Cortes JE, et al. Leukemia. 2018; [E pub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30555165. Accessed Jan 25, 2019. Glasdegib Phase II Results
Glasdegib + Baseline Glasdegib + LDAC LDAC LDAC Responses LDAC P Characteristics (n = 88) (n = 44) (n = 44) (n = 88)
Age >75 yrs1 53 (60.2) 24 (54.5) ORR in AML1 21/78 (26.9) 2/38 (5.3) NR
ECOG1 0 11 (12.5) 3 (6.8) CR1 15 (17) 1 (2.3) < 0.05 1 29 (33) 18 (40.9) 2 47 (53.4) 23 (52.3) Response Duration2 CR 9.9 (0.03-28.8) NR NR sAML1 39 (51) 20 (53) CRi + MLFS 6.5 (0.03-28.8)
Cytogenetic Risk1 Favorable / Intermediate 52 (59.1) 25 (56.8) Median OS2 8.8 (6.9-9.9) 4.9 (3.5-6.0) 0.00004 Poor 36 (40.9) 19 (43.2)
Prior therapy for MDS1 1n(%), 2median (range), NR: not reported Azacitidine 13 (14.8) 8 (18.2) Decitabine 2 (2.3) 1 (2.3)
n (%)
Cortes JE, et al. Leukemia. 2018; [E pub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30555165. Accessed Jan 25, 2019. Glasdegib Safety and Summary
Glasdegib + LDAC Frequent AEs LDAC Glasdegib (Daurismo) Quick Facts (n = 41) (n = 84) Approval Newly diagnosed AML in pts > 75 yrs unfit for Febrile1 intensive chemotherapy 30 (35.7) 10 (24.4) Neutropenia Administration Take 100 mg (1 tablet) daily Available in 100 mg and 25 mg tabs Nausea1 28 (33.3) 4 (9.8) Grade III-IV 2 (2.4) 1 (2.4) Metabolism CYP3A4 substrate ↓Appetite 25 (29.8) 3 (7.3) Grade III-IV 3 (3.6) 2 (4.9) DDI CYP3A4 inhibitors and inducers Dysgeusia1 21 (25) 1 (2.4) QTc↑ drugs Grade III-IV 0 0 Hepatic/Renal impairment Has not been studied in moderate-to-severe Muscle Spasms 5 (17.9) 2 (4.9) organ impairment Grade III-IV 4 (4.8) 0
Dizziness1 17 (20.2) 4 (9.8) WAC Price $677/day Grade III-IV 1 (1.2) 0 $18,956/28-days 1n (%) • Additional option for unfit elderly AML (p-values for tolerability differences not reported) • May present option for patients who have failed HMA therapy Cortes JE, et al. Leukemia 2018. Daurismo [package insert]. NY, NY: Pfizer, 2018. Patient Case-ARS #4
• 75 yo M recently diagnosed with AML —Disease Characteristics: • sAML (AML-MRC) • ECOG PS 1
• Which of the following is most likely to result in a response? A. Glasdegib + LDAC B. Venetoclax + Decitabine C. LDAC alone D. A and C are expected to produce similar responses
48 Some Agents In the Pipeline…
Agent MOA Development Stage
Crenolanib FLT3 inhibitor Phase III ongoing
Quizartinib FLT3 inhibitor Phase III completed
Guadecitabine Next-generation HMA Phase III ongoing
AMV564 CD33 BiTE Phase I ongoing AMG330 CD33 BiTE Phase I ongoing CD123CAR-CD28-CD3zeta-EGFRt CAR-T cells Phase I ongoing
49 Suggested Readings
• Review of new approvals – —Wei A, et al. Blood. 2017;130(23):2469-2474. • FLT3 mutation targeting – —Daver N, et al. Leukemia. 2019 [Epub ahead of print]. https://www.nature.com/articles/s41375- 018-0357-9. Accessed Jan 25, 2019. • Economic burden of AML treatment – —Zaidab A, et al. Expert Rev Hematol. 2016;9(1):79-89. • sAML treatment review – —Cheung E, et al. Annals of Hematology. 2019. [Epub ahead of print]. https://rdcu.be/bhWt7. Accessed Jan 25, 2019.
50 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