TREATMENT Toxicity in Adolescents and Young ADULT (AYA) PATIENTS COMPARED with Younger PATIENTS TREATED for HIGH RISK B-Precursor ACUTE LYMPHOBLASTIC LEUKEMIA (HR-ALL): A REPORT From the CHILDREN'S Oncology GROUP STUDY AALL0232

Abstract 1510

Historically, AYA patients (>16yrs of age) with HR-ALL have lower event free survival and overall survival compared to younger patients (1–15 yrs of age) with HR-ALL. This inferior outcome is related to both a higher relapse rate and increased toxicity of therapy. Several underlying factors have been identified that may contribute to these differences including leukemia biology, host pharmacodynamics, relative intensity of treatment protocols, adherence to therapy, and supportive care measures, although their relative importance is largely unknown.

AALL0232 was a Phase 3 randomized trial for patients 1–30 years old with newly diagnosed B-precursor HR-ALL that utilized a 2 × 2 factorial design with an augmented intensity Berlin- Frankfurt-Münster (BFM) backbone. Patients were randomized to receive dexamethasone versus prednisone during Induction and high dose methotrexate versus escalating Capizzi methotrexate during Interim Maintenance I. The study accrued 3051 eligible, evaluable, non-Down Syndrome patients between January 2004 and January 2011. AYA patients comprised 20% of study enrollments (n=601) with 555 patients in the 16–21 year range and 46 patients in the 22–30 year range. Toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE version 4.0) and all grades 3 and 4 are reported. Bone toxicities including avascular necrosis are not included in this analysis.

During Induction, AYA patients when compared to younger patients had lower rates of febrile neutropenia (7.0% versus 13.4%, p<0.0001), higher rates of hyperglycemia (22.0% versus 15.4%, p=0.0002), hyperbilirubinemia (6.7% versus 3.7%, p=0.0022), but comparable rates for other measured toxicities including pancreatitis and thrombosis. There was no significant difference in Induction mortality between AYA patients and younger patients (2.2% versus 1.7%, p=0.39).

Post-induction, AYA patients experienced higher rates of oral mucositis secondary to methotrexate during Interim Maintenance I (18.5% versus 11.3%, p=0.0002), and higher rates of peripheral motor neuropathy during protocol therapy (11.5% versus 7.4%, p=0.0015). Despite lower rates of febrile neutropenia throughout protocol therapy (35.6% versus 48.6%, p<0.0001), AYA patients had a significantly greater likelihood of death during remission. The 5-year cumulative incidence of remission death for AYA patients was 4.4 + 1.1% compared to 1.8 + 0.4% for younger patients (p=0.0015). Of the 16 remission deaths in AYA patients, 11 occurred within one year post-induction and the remaining within 3 years post-induction. Of the 29 remission deaths in younger patients, 22 occurred within one year post-induction, 6 occurred between 1–3 years, and one between 4–5 years. Infectious complications were responsible for 11 of 16 (69%) of the remission deaths in AYA patients compared to 15 of 29 (52%) of the remission deaths in younger patients.

In conclusion, AYA patients experienced higher rates of hyperbilirubinemia and hyperglycemia during Induction, oral mucositis during Interim Maintenance I, and peripheral motor neuropathy throughout protocol therapy. Importantly, AYA patients experienced a higher rate of death during remission, predominantly due to infectious etiologies. Further analyses are needed to determine reasons for the increase in treatment related mortality, including, an evaluation of the responsible organisms, identification of periods of increased vulnerability because of concomitant mucositis, neutropenia, and/or delivery of specific chemotherapeutic agents.