Olga Frankfurt, MD Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL

1. Olga Frankfurt, MD Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL Acute Myeloid Leukemia - 2015

2. Acute Myeloid Leukemia (AML) • AML is a group of blood cancers in which the bone marrow makes abnormal immature blood cells • These cells also prevent the normal blood cells from maturation

4. Acute Myeloid Leukemia (AML) • New patients/deaths in 2014: 18,860/10,460 • Median age: 66 -72 years • Heterogeneity in genetics, clinical features and outcome • Outcome improved among age <60 with intensive post-remission strategies and transplantation • Prognostic factors exist; many new, molecular • Role of transplantation continues to be refined • Myriad of new agents available

5. AML Age-Specific Incidence Rates 24 Incidence/100,000 22 20 18 16 14 12 10 8 6 4 2 0 0-4 5-9 85+ 60-64 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 65-69 70-74 75-79 80-84 Age (y) NCI-SEER Program

6. Risk Factors for Developing AML • Previous exposure to radiation • Environmental factors : tobacco, benzene • Genetic factors • Down’s syndrome • Fanconi’s anemia, Bloom syndrome • Ataxia telangectasia

7. Risk Factors for Developing AML • Previous chemotherapy • Alkylating agents • del 5 and del 7 • 5 - 10 years latency • Epipodophyllotoxins (etoposide, anthracyclines) • Monocytic differentiation • 11q23 • 1-3 years after exposure • Evolving from the prior antecedent hematologic disorder

8. Clinical Features of AML • Constitutional symptoms • Infections • Abnormal blood counts • Complications related to the high WBC • Coagulation abnormalities • Metabolic abnormalities • Extramedullary tissue

9. Morphology peripheral blood smear bone marrow core biopsy

10. Evaluation of Patient with AML • History and Physical Examination • CBC with differential and platelet, peripheral smear, CMP, uric acid, DIC panel, pregnancy test • Bone marrow aspirate and biopsy/ Flow cytometry • Cytogenetics • Molecular studies: • FLT3, NPM1, c-kit, CEBPα, IDH1, IDH2, k-RAS, n- RAS • Next generation sequencing • HLA typing and eligibility for stem cell transplant • Serologies: hepatitis, HIV, CMV • Study specific correlative laboratory studies

11. Evolution of Prognostic Factors in AML

12. Cytogenetic Risk Groups Favorable inv(16); t(15;17) with any abn; t(8;21) lacking del(9q) or complex karyotype Intermediate Normal or +8 or +21 or others Unfavorable -5/del(5q), -7/del(7q), inv(3q), abn of 11q, 20q, 21q, 17p, del(9q), t(6;9), t(9;22), complex karyotypes with  3 abn Slovak ML, et al. Blood. 2000;96(13):4015-4083.

13. Overall Survival by Cytogenetic Group Estimate At Risk Deaths at 5 Years 100 Favorable 121 53 55% Intermediate 278 168 38% Unfavorable 184 162 11% 80 60 Favorable Cumulative Percentage 40 Intermediate 20 Unfavorable Heterogeneity of 3 Groups: P < 0.0001 0 0 2 4 6 8 Years After Entering Study Slovak ML, et al. Blood. 2000;96(13):4015-4083.

14. Therapy for AML- Principles • Without therapy AML is fatal – days-months • The therapy for AML: Induction and Consolidation • Chemotherapy may cure selected patients and prolong survival in responding patients • Chemotherapy is toxic and can cause substantial morbidity and mortality

15. Current AMLTherapy-2015 Younger Adults • Induction: dauno 60-90 mg/m2/d x 3d + ara-C 100/200 mg/m2/d x 7d CI. • Consolidation: high- or intermediate-dose ara-C (1-4 cycles) • Allogeneic HCT for intermediate- and high-risk • Consider in CBF with c-KIT, FLT3 • Not done in FLT3-/NPM1+ , CEBP+(double mutation) Paschka J ClinOncol, 2006; Schlenk N Engl J Med, 2008; Green J ClinOncol, 2010; Dohner Blood, 2010

16. Current AMLTherapy-2015 Older Adults • Decision: chemotherapy vs. hypomethylating agent • Intensive Chemotherapy • Induction: dauno 60-90 mg/m2/d x 3d + ara-C 100 mg/m2/d x 7d • Consolidation: intermediate-dose ara-C (1-4 cycles); no clear role in older adults • Low dose Chemotherapy • Hypomethylating agents: • Dacogen:5 days course or 10 days course • Vidaza : 7 days course • Reduced intensity HSCT

17. Investigational Approaches AMLTherapy-2015 • Autologous HSCT is not a standard of care; being studied • Maintenance is not a standard of care; being studied • Maintenance after allo HSCT is not a standard of care for AML; being studied; many use hypomethylating agents • Adding stem cells to expedite count recovery after the chemotherapy ; being studied • Adding agents that stimulate platelet recovery after chemotherapy is being studied • Altering the immune system to fight leukemia ( CAR-T cells)

18. Selected Agents in Clinical Trials • Chemotherapy - Clofarabine, CPX-351, Vosaroxin, Elacytarabine • Hypomethylating agents – Decitabine, Azacitidine • FLT3 inhibitors – Sorafenib, Quizartinib, Crenolanib, ASP2215 • MLL inhibitors – EPZ-5676 • IDH1 and IDH2 inhibitors, pan IDH inhibitor • Glutaminase inhibitor CB-839 • Exportin 1 inhibitor - Selinexor • Polo-like kinase inhibitor - Volasertib • C-kit inhibitors – Dasatinib • mTOR inhibitors – Temsirolimus • Histone deacetylase inhibitors – Vorinostat, Panobinostat • Antibody conjugates • Cycline-dependent kinase inhibitor – Flavoperidol • Hedgehog inhibitors • MEK1/2 inhibitors – Trametinib • Aminopeptidase inhibitors – Tosedostat

19. 312 695-6180 Academic Office • 312 695-0990 Cancer Center Olga Frankfurt, MD Co-director - Leukemia Program Director - Chronic Leukemia/MDS Associate Director for Umbilical Cord Blood Transplantation Robert H. Lurie Comprehensive Cancer Center, Northwestern Medicine