Stock W, Luger SM, Advani AS, et al.
A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403.
2019; doi: 10.1182/blood-2018-10-881961. [Epub ahead of print].

Acute lymphoblastic leukemia (ALL) occurring in the adolescent and young adult (AYA) patient population (defined as 15-39 years of age) has a disease biology and clinical course that is distinct from childhood and adult ALL. Thus, research efforts during the past decade have focused on discovery of the ALL “genomic landscape” in AYA patients, as well as on optimizing the therapeutic regimen for these patients.1,2  Intensive multiagent chemotherapy remains the standard of care in newly diagnosed patients with this disease, but pediatric and adult ALL therapeutic regimens differ in important ways. Pediatric protocols for ALL include higher cumulative doses of nonmyelosuppressive chemotherapy (glucocorticoids, vincristine, and l-asparaginase), early and more intensive central nervous system therapy, a longer period of maintenance therapy, and restricted indications for hematopoietic stem cell transplantation (HSCT) in first remission (CR1). Adult chemotherapy protocols include higher doses of myelosuppressive chemotherapy (daunorubicin, cytarabine, and cyclophosphamide) and broader indications for HSCT in CR1. Importantly, retrospective analyses and a meta-analysis demonstrate that AYA patients with ALL have superior outcomes when treated with pediatric protocols and by pediatric treatment teams.3-6  Whether the adult treatment teams could implement a pediatric-like protocol with the same rigor as pediatric teams and achieve comparable outcomes for young adult patients has not been studied.

Dr. Wendy Stock and colleagues conducted a prospective, multicenter, phase II, single-arm trial (Cancer Leukemia Group B [CALGB] 10403) to test the efficacy and feasibility of a pediatric regimen for AYA patients with newly diagnosed B- or T-lineage Philadelphia chromosome–negative ALL. The three U.S. adult cooperative groups, CALGB, Eastern Cooperative Oncology Group, and Southwest Oncology Group, enrolled 318 young adult patients with a median age of 24 years (range, 17-39 years) in the study between November 2007 and September 2012. The treatment regimen of CALGB 10403 was a replica of the high-risk arm of the Children’s Oncology Group trial, AALL0232, which comprised a four-drug induction followed by consolidation, interim maintenance, delayed intensification, and long-term maintenance therapy.

Two hundred ninety-five patients were eligible for treatment and evaluation. The complete marrow response rate was 89 percent (n=263), with most responses (90%) occurring at the end of induction (n=237), though additional responses occurred after the extended induction therapy (n=26). Minimal residual disease (MRD) assessment using quantitative polymerase chain reaction was performed on a subset of patients (n=80) following induction therapy. The MRD-negative remission rate was 44 percent (n=35). Detection of MRD following induction therapy was associated with an inferior three-year disease-free survival (DFS; 54% for patients with detectable MRD [>10–4] vs. 85% for undetectable MRD; p=0.001). The median follow-up for the cohort was 64 months; 190 patients (64%) are alive and 105 (36%) have died. The median event-free survival (EFS) was 78.1 months (95% CI, 41.8–not reached), three-year EFS was 59 percent (95% CI, 54-65%), and the estimated three-year overall survival (OS) was 73 percent (95% CI, 68-78%). Twenty patients (4%) underwent allogeneic HSCT in CR1, and the DFS for the transplant cohort was 36 months. These data indicate a significant improvement in outcomes compared with historical controls , among whom the three-year OS was 58 percent (95% CI, 52-64%) and median EFS was 30 months (95% CI, 22-38).

Treatment-related mortality was 3 percent (n=8), and most treatment related deaths occurred during induction therapy (n=6). More than 10 percent of patients experienced grade 3 to 4 nonhematologic toxicities. These adverse effects included hypofibrinogenemia (42%), hyperglycemia (30%), elevated transaminases (28%), hyperbilirubinemia (18%), febrile neutropenia (22%), and infection (18%).

In univariate models, the initial white blood count was greater than 30 × 109/L in B-lineage patients; obesity, the Ph-like signature, and aberrant CRLF2 expression were associated with inferior EFS, DFS, and OS. There was no significant difference in outcomes between patients with a B-cell versus T-cell phenotype, or in CD20 expression. Historically, both T-cell phenotype and CD20 expression have been associated with a poor outcome. Multivariate analysis of pretreatment characteristics on treatment outcomes revealed that obesity (hazard ratio [HR], 1.82; p=0.04) and aberrant CRLF2 expression (HR, 2.84; p<0.001) were associated with inferior DFS.

The study results are important for several reasons. Outcomes were improved significantly in both B- and T-cell lineage ALL subtypes by using a pediatric therapeutic regimen. The regimen was safe in the AYA population, though adverse effects occurred, specifically related to hepatic and thrombotic complications in obese patients. This trial has established a specific chemotherapeutic approach that provides a basis for future clinical trials that examine the efficacy of novel and/or targeted therapies for AYA patients. To this end, a successor trial for B-lineage ALL (A041501; Identifier: NCT03150693) is studying the addition of the antibody drug conjugate, inotuzumab ozogamicin, to examine whether it will increase the MRD-negative remission rate and further improve survival . Finally, despite the recognition of the superiority of a pediatric regimen, many AYA patients are treated in adult community cancer facilities and are more likely to receive an adult ALL regimen.2  Adult oncologists should consider applying the CALGB 10403 therapeutic approach or refer newly diagnosed AYA patients with ALL to centers with experience treating these patients.

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What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies.
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Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis.
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Competing Interests

Dr. Boulware and Dr. O'Dwyer indicated no relevant conflicts of interest.