Frontline-Treatment Of Acute Lymphoblastic Leukemia (ALL) In Older Adolescents and Young Adults (AYA) Using a Pediatric Regimen Is Feasible: Toxicity Results of the Prospective US Intergroup Trial C10403 (Alliance)
Authors: Advani Anjali S. , Sanford Ben , Luger Selina , Devidas Meenakshi , Larsen Eric C. , Liedtke Michaela , Voorhees Peter M , Foster Matthew C. , Claxton David F. , Geyer Susan , Parker Edy , Coffan Kristin , Carroll William L. , Winick Naomi J. , Coutre Steven E. , Tallman Martin S , Appelbaum Frederick R. , Erba Harry Paul , Stone Richard M. , Hunger Stephen P. , Larson Richard A. , Stock Wendy 
Published: October 2019

Abstract

Background
Several retrospective trials suggest a superior outcome for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) when they are treated with pediatric-inspired therapeutic regimens. C10403 is the largest prospective study to evaluate the feasibility of a pediatric regimen (Children’s Oncology Group (COG) AALL0232: COG0232) (Larsen et al. JCO 2011; 29(18) suppl: 3) in AYA ALL patients (pts) (16-39 yrs of age) treated by adult hematologist/ oncologists (HO). One objective was to identify age-related increases in specific treatment-related toxicities that may limit the applicability of these regimens. We describe here the adverse event (AE) profiles by age cohorts for pts enrolled on C10403 and compare them with data reported from the pediatric COG0232 trial in pts ≥ 16 yrs of age using the same regimen. In the COG study, AYA comprised 20% of enrolled pts, 66% were ages 16-21.

Methods
C10403 was a single arm study. All pts received treatment with the “PC” (prednisone/ ‘Capizzi’ methotrexate) Interim Maintenance (IM) arm from the AALL0232 regimen and were treated by adult HO. Descriptive statistics were used to summarize toxicities. For this report, we focused on Grade 3-5 events with at least a possible relationship to treatment. The comparison group from COG0232 included 159 pts randomized to the PC arm; however, in COG0232 slow responders received additional treatment compared to C10403 pts.

Results
Between Nov 2007 and Dec 2012, 318 pts in the United States 16-39 yrs of age were enrolled by 3 cooperative groups (CALGB, SWOG, ECOG). 61% were male; 74% white, 10% African American, and 16% Hispanic. The median age was 25 yrs, older than the COG0232 AYA pts. 14% were < 20, 58% 20-29, and 28% 30-39 yrs of age. Induction (indn) toxicities are summarized in Table 1. The rates of Grade 3-4 hyperglycemia, hyperbilirubinemia, pancreatitis, thrombosis, and febrile neutropenia during indn in the C10403 trial were higher than in AYAs treated on COG0232. However, indn mortality rates for C10403 and COG0232 were both low, 2%. Grade 3-5 AEs at any point during treatment are listed in Table 2. During IM, 5.6% of pts on C10403 developed Grade 3-4 mucositis. Grade 3-4 hypersensitivity reactions to peg-asparaginase declined from 12.9% to 7.9% after a C10403 protocol amendment to require premedication. There were no significant differences in the incidence of Grade 3-5 AEs by age cohort among C10403 pts except for increased incidences of neuropathy, osteonecrosis, and mucositis in pts ≥ 20 yrs old. In comparison, AYAs on COG0232 had higher rates of hypersensitivity (no premedication) and motor neuropathy and lower rates of thrombosis than the C10403 pts. Hepatic toxicities, incidence of pancreatitis and osteonecrosis were similar between the two studies. Toxicities were manageable by adult HO on C10403, and the overall treatment-related mortality rate on C10403 was low (3%). Attribution of toxicities to specific components of therapy, particularly peg-asparaginase, is being evaluated. Clinical outcomes of pts enrolled on C10403 are still being evaluated.

Conclusions
These data indicate that treatment with a pediatric regimen (C10403) is feasible when administered by adult HOs to an AYA population up to 40 years of age. C10403 can be used as a foundation for the design of successor trials in this pt population.
(1) Larsen E, Salzer W, Nachman J, et al. Blood, Nov 2011; 118: 1510.

Disclosures:
Stone: Amgen: Consultancy.