A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403

Abstract

Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

Conflict of interest statement

Conflict-of-interest disclosure: W.S. served on advisory boards for Pfizer, Amgen, and Jazz Pharmaceuticals; S.M.L. received clinical trial support from Onconova, Celgene, Cyclacel, Hoffman-La Roche, Onconova, Incyte, Biosight, and Kura and served on an advisory board for Pfizer; A.S.A. received honoraria from Pfizer, Sigma Tau, and Jazz Pharmaceuticals; C.G.M. received honoraria from Amgen and Pfizer; E. Parker owns stock in Teva Pharmaceuticals and Johnson & Johnson; M.S.T. received research funding from AbbVie, AROG, Cellerant, Orsenix, ADC Therapeutics, and Biosight and served on advisory boards for Daiicho-Sankyo, Orsenix, KAHR, Rigel, Abbvie, and Nohla. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Treatment schema for CALGB 10403. *Maintenance therapy consisted of 12-week courses continuing until 3 years from initiation of interim maintenance for male and 2 years for female patients. Patients with precursor T-cell ALL received 24 Gy of prophylactic cranial irradiation during first cycle of maintenance therapy; those with CNS involvement at presentation received 18 Gy. 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine; Ara-C, cytarabine; CTX, cyclophosphamide; DEX, dexamethasone; DNR, daunorubicin; IT, intrathecally; MTX, methotrexate; PEG, pegylated asparaginase; PO, orally; pred, prednisone; VCR, vincristine.

Figure 2.

This figure is a graphical representation of enrollment, treatment, and follow-up of the 318 patients registered to CALGB 10403.

Figure 3.

Survival data. After median follow-up of 64 months for surviving patients, 190 (64%) were alive and 105 (36%) had died. (A) Median OS was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). (B) Median EFS was 78.1 months (95% CI, 41.8 months to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-66%). (C) Median DFS was 81.7 months (95% CI, 58.4 months to not reached); 3-year DFS was 66% (95% CI, 60%-72%). (D) In comparison with patients with BMI <30 kg/m2, those with BMI between 30 and 40 kg/m2 and those with BMI >40 kg/m2 had significantly higher risk of death (HR, 1.72 and 3.29, respectively). Estimated 3-year survival for patients with BMI <30 kg/m2 was 79% (95% CI, 73%-85%); for those with BMI from 30 to 40 kg/m2, 3-year survival was 64% (95% CI, 54%-77%); and for those with BMI >40 kg/m2, 3-year survival was 46% (95% CI, 29%-72%; P = .0003). (E) Ph-like signature was associated with worse survival; 3-year OS rate was 63% (95% CI, 50%-81%) for patients with Ph-like signature, in contrast to 81% (95% CI, 73%-89%) for those without Ph-like signature. (F) Detection of MRD using quantitative polymerase chain reaction after induction therapy was strongly associated with worse DFS; 3-year DFS rate for those with undetectable MRD was 85% (95% CI, 74%-98%); in contrast, for those with detectable MRD, DFS was only 54% (95% CI, 41%-71%; P = .001). KM est, Kaplan-Meier estimate.

Figure 4.

Forest plot for univariable model of DFS. Impact of pretreatment characteristics on DFS is shown. HR is depicted on the x-axis, and each prognostic variable is listed on the y-axis. Estimates to the right of 1.0 indicate worse DFS. Measurement for initial WBC was found to be prognostic for DFS only in B-cell ALL patients. For multivariable models, variables with P < .2 from the univariable models were included; only obesity (BMI >30 kg/m2; HR, 1.82; P = .04) and aberrant CRLF2 expression (HR, 2.84; P < .001) were associated with significantly worse DFS. CG, cytogenetics.