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1 ALL in AYAs: Health Outcomes as a Criterion for Selecting Optimal Therapy David R. Freyer, DO, MS Director, Survivorship and Supportive Care Program, Children s Center for Cancer and Blood Diseases, Children s Hospital Los Angeles Co-Director, Adolescent & Young Adult Cancer Program, USC Norris Comprehensive Cancer Center Professor of Clinical Pediatrics and Medicine Keck School of Medicine, University of Southern California Chair, Adolescent and Young Adult Oncology Discipline Committee, Children s Oncology Group 7 th Annual Texas AYA Oncology Conference March 4, 2017 San Antonio, TX 1 Potential Explanations for Poorer AYA Outcomes Cancer Same names but different biology? Host Developmental differences? Different drug disposition (PK)? Different tolerance of therapy (PD)? Different level of treatment adherence? Treatment Optimized? Health Services Adequate? Low awareness and delayed diagnosis Limited access to appropriate care Low accrual to clinical trials 3 Disclosures No financial conflicts of interest No off-label use of medications discussed The Importance of Toxicity May decrease survival Treatment-related mortality Compromised therapy Dose reduction Treatment delay Deletion of agents Premature discontinuation of therapy May decrease quality of life Importance self-evident Could lead to reduced treatment adherence 2 4

2 Outline 1. Treatment-related Toxicity: Vulnerability of the AYA Cancer Patient 2. C10403 vs Hyper-CVAD Backbones: Comparison of Treatment Exposures 3. Evaluation of Comparative Risk 4. Conclusions Simplified Classification of AYA Toxicity * Acute Develops During AYA Window May Resolve Vincristine-induced peripheral neuropathy Pancreatitis Treatment-related mortality (Acute Ovarian Failure) (Azospermia) Chronic Develops During AYA Window Usually Persist Osteonecrosis Persistent Ovarian Failure (Azospermia) Late Onset Prior Exposure First Manifests During AYA Window Second Cancers Ovarian Failure (premature menopause) Organ Dysfunction (e.g., cardiotoxicity) * Published data suggest excess risk for AYAs relative to younger children 5 7 Osteonecrosis Treatment-related Toxicity: Vulnerability of the AYA Cancer Patient CCG-1961 Randomized trial for NCI highrisk ALL (B and T cell) Enrolled Sept 1996-May 2002 Overall design: 2x2 comparison of intensified vs. standard intensity and extended vs. standard duration therapy Comparison of continuous 21 day DXM (one IM) vs. discontinuous (two 7 day blocks DXM (two IM) Outcome: Cumulative incidence of ON yrs Girls yrs 6 Mattano L et al. Lancet Oncol 2012; 13:

3 Secondary Breast Cancer Observational cohort study HL treated on serial trials Prior chemotherapy and irradiation (decreasing doses by era) Data by patient report and medical sources N=1407 (590 females) Med age at dx: 13.8 y ( ) Alive at f/u: 534 Med age at f/u: 31.1 y ( ) Med f/u: 17.8 y ( ) No. with breast cancer: 26 Med interval: 20.7 y ( ) Med age: 35.3 y ( ) Advanced stage: 13 Bilateral: 6 16% at 30 yrs of f/u 30% if RT at > 9 yrs old 10% at 40 yrs old C10403 vs Hyper-CVAD Backbones: Comparison of Treatment Exposures Schellong G et al. Dtsch Arztbl Int 2014; 11: Cardiovascular Disease Among Survivors of AYA Cancer Chao C et al. J Clin Oncol 2016; 34: Retrospective cohort analysis Kaiser Permanente Southern California (KPSC) Cancer: years old, diagnosed , survived 2 years from diagnosis (index date) Non-cancer: matched 10:1 on age, sex, index date n = 5,673 cancer; n = 57,617 non-cancer Data from KPSC electronic health records and clinical databases using ICD-9/10 and CPT-4 codes Treatment Exposures: R-HCVAD vs. ABFM R-HCVAD 1 ABFM 2 Per dose Cumulative Per dose Cumulative VCR 2 mg x mg 2 mg/m 2 x mg PDN mg/m 2 x 28 1,680 mg/m 2 DOX/DNR 50 mg/m 2 x mg/m 2 25 mg/m 2 x mg/m 2 Asparaginase L-asp 20,000 U x 8 Lasp 160,000 U PEG 2,500 U/m2 x 7 PEG 17,500 U/m 2 CPM 1.8 gm/m 2 x gm/m 2 1 gm/m 2 x 3 3 gm/m 2 Cytarabine 3 gm/m 2 x gm/m 2 75 mg/m 2 x gm/m 2 MTX 1 gm/m 2 x 4 4 gm/m mg/m2 + esc late 1 gm/m 2 DXM 160 mg x mg 10 mg/m 2 x mg/m 2 IT-MTX 12 mg x 8 96 mg 15 mg x mg IT-Cytarabine 100 mg x mg 70 mg x 1 70 mg Rituximab 375 mg/m 2 x 10 3,750 mg/m R-HCVAD (J Clin Oncol 2010; 28:3880-9): Induction, Consolidation x 8, Intensification x 4 (excludes POMP Maintenance x 25 months) 2 ABFM (ALL0232, Regimen PC - J Clin Oncol 2016; 34:2380-8): Induction through DI-1 (excludes POMP Maintenance)

4 HCVAD vs. ABFM: Acute Toxicity Retrospective cohort analysis MD Anderson Cancer Center Ph-negative ALL ABFM: Frontline 40 yrs old HCVAD: Previously published; here only 40 yrs old n = 106 ABFM; n = 102 HCVAD C10403 vs Hyper-CVAD Backbones: Evaluation of Comparative Risk Am J Hematol 2016; 91: What About Bone Marrow Transplant? Blood 2013; 121: Conditioning Regimens Classical 1 Cyclophosphamide 120 mg/kg Total Body Irradiation 12 Gy in 6 fractions Newer 2 Etoposide 60 mg/mg Total Body Irradiation 13.2 Gy in 9 fractions Other Issues Transplant-related Mortality Graft vs. Host Disease Agent-specific Comparisons Alkylators (Cyclophosphamide) Gonadal dysfunction Second malignant neoplasm Anthracyclines (Doxorubicin/Daunorubicin) Left ventricular dysfunction (cardiomyopathy) Second malignant neoplasm (AML) BMT (high-dose alkylators/tbi): multiple potential complications Other potential agents Vincristine: peripheral neuropathy Methotrexate/IT therapy: neurotoxicity Asparaginase: pancreatic dysfunction Steroids: bone demineralization, osteonecrosis 1 Dhawan R, Marks DI. Curr Hematol Malig Rep 2017; Epub 18 Feb 2017 doi: /s Marks DI. Bio Blood Marrow Transplant 2006; 12:438-53

5 Male Infertility Cardiotoxicity Most common: cardiomyopathy and subclinical LV dysfunction Major risk factor: higher cumulative anthracycline dose mg/m 2 in patients age 18+ years at treatment 300 mg/m 2 in patients age < 18 years at treatment Incidence increases with time van Dalen EC et al. Eur J Cancer 2006; 42: Cumulative cyclophosphamide dose > 7.5 gm/m 2 Alkylating chemotherapy for BMT conditioning (cyclophosphamide, busulfan, melphalan) Total body irradiation for BMT Testicular irradiation dose > 2.5 Gy in men CCSS (n=14,383) Congestive Heart Failure Dutch Registry (n=830) Levine J et al. J Clin Oncol 2010; 28: Mulroony DA et al. BMJ 2009; 339:b Female Infertility Cardiotoxicity Risk for cardiomyopathy is dose-dependent Elevated risk observed even at lower cumulative anthracycline doses Van der Pal HJ, et al. J Clin Oncol 2012; 30: Cumulative cyclophosphamide dose > 7.5 gm/m 2 age < 20 years Cumulative cyclophosphamide dose > 5 gm/m 2 age 40+ years Alkylating chemotherapy for BMT conditioning (cyclophosphamide, busulfan, melphalan) Total body irradiation for BMT Levine J et al. J Clin Oncol 2010; 28: Blanco JG, et al. J Clin Oncol 2012; 30(13):

6 Secondary Cancers (SC) After ALL Most late effects data derived from adult survivors of childhood/adolescent cancer Risk factors pertinent to ALL: alkylating agents (CPM), topoisomerase inhibitors (anthracyclines) and RT Cumulative incidence at 25 years = 5.2% CCSS survivor and sibling cohorts 5,760 ALL survivors 730 deaths SC was 2 nd most common cause (12.2%) 199 SC in 185 survivors 81% had RT (most CNS) 19% no RT AML, CNS, breast, lymphoma, invasive skin, sarcoma SIR for neoplasms 5.0 (95%CI, ) R-HCVAD vs. ABFM: Conclusions Acute Toxicity: apparent differences in types, but not clearly mortality Late Toxicity Potential Most agents: exposures not substantially different Cyclophosphamide and Anthracyclines: higher cumulative exposures in R-HCVAD With BMT, treatment exposures much higher No data: # hospital days required to deliver Age- and regimen-specific prospective and longitudinal data needed for better comparisons Mody R et al. Blood 2008; 111: Complications of BMT Exposure Selected Late Effects Alkylating Agent Gonadal dysfunction Hemorrhagic cystitis saml/mds Bladder cancer TBI Cataracts Endocrinopathies Pulmonary fibrosis Cardiac toxicity Diabetes Gonadal dysfunction Pre-transplant exposures Combined risks Chronic GVHD Xeropthalmia Xerostomia GI strictures Skin and joint changes Immunodeficiency Secondary cancers BMT Experience Diminished QoL Psychosocial disability Financial toxicity Chow EJ et al. Biol Blood Marrow Transplant 2016; 22:782-95