Oncology Conference Optimizing the Management of Acute Myeloid - PowerPoint PPT Presentation

2020 Spring Oncology Conference

Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

Learning Objectives • Describe diagnostic testing for risk stratification in AML and the role of cytogenetic and molecular factors in treatment selection • Identify individualized AML treatment approaches based on efficacy and safety data, as well as patient- and disease-related characteristics • Implement strategies to recognize, monitor, and manage toxicities associated with new agents used in the treatment of AML 3 AML = acute myeloid leukemia.

AML: Most Common Form of Acute Leukemia in Adults • Heterogeneous hematologic malignancy ‒ Accounts for largest number of annual deaths from leukemia in the United States ‒ Survival influenced by biological features of the disease and patient age Estimated New 5 19,940 100,000 Persons 5-Year Survival Cases in 2020 New cases Number per (2009-2015) % of All New 1.2% Cancer Cases 28.3% Deaths Estimated 11,180 Deaths in 2020 0 % of All 1.8% Cancer Deaths 1992 2003 2016 Year American Cancer Society. www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed Mar 20, 2020; National Cancer Institute. seer.cancer.gov/statfacts/html/amyl.html. Accessed Mar 20, 2020; NCCN Guidelines. Acute myeloid leukemia. 4 www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020.

AML Incidence Increases With Age • Most frequently diagnosed in people aged 65 to 74 New AML Cases by Age Group 30 years 25.1% ‒ Median age at diagnosis: 68 years 25 22.7% ‒ ~1/3 of patients with newly diagnosed AML are New Cases (%) ≥75 years of age 20 16.8% • Slightly more common in men than in women 15 • Lifetime risk: ~0.5% in both sexes 11.0% ‒ 9.1% De novo 10 ‒ 5.7% 5.3% Secondary 4.5% 5 • AML-MRC • Therapy-related 0 <20 20-34 35-44 45-54 55-64 65-74 75-84 >84 • Poor prognosis in people aged 75 to 84 years due Age, Years to adverse patient characteristics and comorbidities AML-MRC = AML with myelodysplasia-related changes. Granfeldt Østgård LS, et al. J Clin Oncol. 2015;31:3641-3649; Klepin HD, et al. Am Soc Clin Oncol Educ Book . 2019;39:421-432; National Cancer 5 Institute. seer.cancer.gov/statfacts/html/amyl.html. Accessed Mar 20, 2020; Vardiman JW, et al. Blood. 2009;114:937-951.

AML Treatment Paradigm and Goals Risk Stratify Induction Therapy Consolidation Allogeneic HSCT • Chemotherapy Performance Goal: Goal Relapse status, age, Goals: • • Achieve CR Cure comorbidities • Prevent recurrence • Preexisting • Bridge to transplant Risk Stratify myelodysplasia • Performance status, • Prior cytotoxic age, comorbidities therapy • Cytogenetics • Cytogenetics Relapse (6-9 months) • Genomic mutations • Genomic mutations or Refractory Low Intensity Therapy R/R Therapy/Clinical Trial Goal: Goal: Achieve CR • Achieve CR or Nonintensive Therapy stable disease Goals: • Stable disease • Slow disease progression CR = complete response; R/R = relapsed or refractory. 6 NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020.

Allogeneic HSCT • Allogeneic HSCT is a potentially curative therapy that may be used in patients with intermediate- or high-risk AML who have a suitable donor source and are considered to be good candidates • Historically, older patients with AML have not been considered for allogeneic HSCT due to the presence of comorbidities and the perceived risk of increased mortality • Reduced intensity and non-myeloablative conditioning regimens have enabled the use of allogeneic HSCT in a greater number of older patients with AML • Recent data support the use of allogeneic HSCT in selected, fit, older patients with AML after intensive chemotherapy; however, the number of older patients who receive allogeneic HSCT remains low 7 Lipof JJ, et al. Cancers . 2018;10:179.

Individualizing Treatment Goals in AML EXAMPLE: • Novel low- intensity induction regimens may provide patients ≥75 years old and those who have comorbidities with the goal of a complete response BUT: • Stable disease may be a reasonable therapeutic goal for some patients such as those who are elderly and/or frail BUT: • Patients may request high-intensity induction regimens and/or potentially curative, allogeneic HSCT regardless of age, performance status, and comorbidities 8 NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020.

Recently Approved Targeted Therapy for AML Drug Description Indication • Midostaurin Multikinase inhibitor with inhibitory Adults with newly diagnosed FLT3 -mutated AML activity against FLT3 -ITD and FLT3 - in combination with standard cytarabine and TKD mutations daunorubicin induction therapy and cytarabine consolidation therapy • Gilteritinib Inhibitor of multiple receptor tyrosine Adults with R/R FLT3 -mutated AML kinases, including FLT3 • Enasidenib Oral IDH2 inhibitor Adults with R/R IDH2 -mutated AML • Ivosidenib Oral IDH1 inhibitor AML with a susceptible IDH1 mutation in: ⎻ Adults with newly diagnosed AML who are aged ≥75 years or who have comorbidities that preclude the use of intensive induction chemotherapy ⎻ Adults with R/R AML TKD = tyrosine kinase domain. Idhifa [prescribing information]. Celgene Corporation; 2019; Rydapt [prescribing information]. Novartis Pharmaceuticals; 2019; 9 Tibsovo [prescribing information]. Agios Pharmaceuticals, Inc; 2019; Xospata [prescribing information]. Astellas Pharma US, Inc.;2019.

Recently Approved Novel Agents for AML Drug Description Indication • Gemtuzumab CD33-directed antibody- Adults with newly diagnosed CD33-positive AML (in combination with ozogamicin drug conjugate daunorubicin and cytarabine or as a single-agent regimen) • R/R CD33- positive AML in adults and in pediatric patients aged ≥2 years • Glasdegib Hedgehog pathway Newly diagnosed AML in combination with LDAC in adults who are aged ≥75 years or who have comorbidities that preclude the use of inhibitor intensive induction chemotherapy • Venetoclax BCL-2 inhibitor Newly diagnosed AML in combination with azacitidine, decitabine, or LDAC in adults who are aged ≥75 years or who have comorbidities that preclude intensive induction chemotherapy • CPX-351 Liposomal combination of Adults with newly diagnosed therapy-related AML or AML-MRC daunorubicin and cytarabine BCL-2 = B-cell lymphoma 2; LDAC = low-dose cytarabine. Daurismo [prescribing information]. Pfizer Inc; 2020; Mylotarg [prescribing information]. Pfizer Inc; 2018; Venclexta [prescribing information]. AbbVie Inc; 10 2019; Vyxeos [prescribing information]. Jazz Pharmaceuticals; 2019.

Case Study 1: Tom, 58 Years Old • • Presents to ED complaining of Laboratory results: extreme fatigue and abrupt onset of – WBCs: 120,000 cells/mm 3 shortness of breath – Hgb: 6.9 g/dL • 2-week history of worsening exercise – Platelets: 27,000/mm 3 tolerance – Blasts: 47% • No significant past medical history • Admitted to hospital for further • Enjoys bicycling, swimming, and testing painting 11 Hgb = hemoglobin.

Diagnostic Testing and Karyotyping for Risk Stratification • Bone marrow core biopsy and aspirate analysis, including immunophenotyping and cytochemistry • Molecular analyses: FLT3 (ITD and TKD), NPM1, CEBPA, IDH1, IDH2, TP53, c-KIT, RUNX1, ASXL1 • Karyotyping is an important prognostic factor for predicting remission rates, relapse risk, and OS ‒ Complex karyotype: independent unfavorable risk factor • With each additional karyotype abnormality, the risk of failing to achieve CR increases • SWOG analysis: • Complex cytogenetics without involvement of chromosome 5 or 7: CR 50%; OS 20% • Complex cytogenetics + involvement of chromosome 5 or 7: CR 37%; OS 3% ‒ Monosomal karyotype: very poor prognosis • 4-year OS 4% OS = overall survival; SWOG = Southwest Oncology Group. NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020; Orozco JJ, et al. 12 Oncology (Williston Park) . 2012;26:706-712; Slovak ML, et al. Blood . 2000;96:4075-4083; Xu J, et al. Turk J Haematol . 2017;34:126-130.

AML Disease Prognosis Influenced by Genetic Abnormalities Risk Category Genetic Abnormality 5-Year Survival • t(8;21)(q22;q22.1); RUNX1-RUNX1T1 • inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Favorable 34% to 65% • Mutated NPM1 without FLT3 -ITD or with FLT3 -ITD low • Biallelic mutated CEBPA • Mutated NPM1 and FLT3 -ITD high • Wild-type NPM1 without FLT3 -ITD or with FLT3 -ITD low (without adverse-risk genetic lesions) Intermediate 13% to 41% • t(9;11)(p21.3;q23.3); MLLT3-KMT2A • Cytogenetic abnormalities not classified as favorable or adverse • t(v;11q23.3); KMT2A rearranged • t(6;9)(p23;q34.1); DEK-NUP214 • Wild-type NPM1 and FLT3 -ITD high • t(9;22)(q34.1;q11.2); BCR-ABL1 • Mutated RUNX1 • inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); • Mutated ASXL1 Poor/Adverse 2% to 14% GATA2,MECOM(EVI1) Mutated TP53 • – 5 or del(5q); – 7; – 17/abn(17p) • Complex karyotype, monosomal karyotype 13 NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020.