Improved Prognosis for Older Adolescents with Acute Lymphoblastic Leukemia
Authors: Jeha Sima , Pei Deqing , Campana Dario , Bowman W. Paul , Sandlund John , Kaste Sue , Ribeiro Raul C. , Rubnitz Jeffrey E. , Coustan-Smith Elaine , Cheng Cheng , Metzger Monika L. , Bhojwani Deepa , Inaba Hiroto , Raimondi Susana C. , Onciu Mihaela , Howard Scott C. , Leung Wing H. , Downing James R. , Evans William E. , Relling Mary . , Pui Ching-Hon 
Published: October 2019

Abstract
Abstract 498
Older adolescents and young adults with acute lymphoblastic leukemia (ALL) have historically had a worse prognosis than younger patients. We reviewed the outcome of older adolescents (15 to 18 years old) treated in four consecutive Total Therapy studies to determine if recent improvement in outcome for childhood ALL, achieved with more effective risk-adapted chemotherapy, extend to this high-risk group.
Between 1991 and 2007, 963 pediatric patients including 89 older adolescents with newly diagnosed ALL were enrolled in Total Therapy studies XIIIA, XIIIB, XIV and XV. We compared the presenting features and clinical outcomes of the older adolescent group to those of younger patients 1 to 14 years old. In the first three studies, treatment assignment was based on presenting clinical features and genetic abnormalities of the leukemia cells. In Study XV, the level of minimal residual disease (MRD) was used to guide treatment, which featured intensive methotrexate, glucocorticoids, vincristine and asparaginase, 4 courses of high-dose methotrexate (5 g/m2 over 24 hours) as consolidation therapy, and early and extended triple intrathecal therapy for patients with higher-risk ALL. None of the patients received prophylactic cranial irradiation.
The 89 older adolescents were significantly more likely to have T-cell ALL, the t(4;11)/MLL-AF4 and detectable MRD during or at the end of remission induction, and less likely to have t(12;21)/ETV6-RUNX1 compared with younger patients. In the first three studies, the 44 older adolescents had a significantly poorer event-free (P=0.0002) and overall (P<0.0001) survival than the 403 younger patients. This gap in prognosis was abolished in Study XV in which 6 of the 45 older adolescents and 28 of 453 younger patients underwent allogeneic transplantation for high-risk presenting features or high level of MRD (≥1%) at the end of 6-week remission induction treatment. Complete remission was achieved in 44 (97.8%) of the older adolescents and 448 (98.9%) of the younger patients (p=0.44). There were 6 treatment failures among adolescents: 1 induction failure, 2 hematological relapses, and 3 toxic deaths during remission. There was no difference in event-free survival between the two age groups (p=0.61): the 5-year rate was 86.4% (95% confidence interval [CI], 72.1 to 93.6) for the 45 older adolescents and 87.4% (95% CI, 83.7 to 90) for the 453 younger patients. The overall survival was also comparable (p=0.13): the 5-year rate was 87.9% (95% CI, 73. 1 to 94.9) vs. 94.1 % (95% CI, 91.4 to 96). The results for older adolescents in Study XV were markedly superior to those attained in the earlier studies (5-year event-free and overall survival rates, both 59.1% [95% CI, 43 to 72], P=0.006 and P=0.007, respectively).
These results demonstrate that it is possible to achieve high cure rate in older adolescents with ALL, at levels similar to the highest ever reported in younger children. The strategy used in this study, based on careful risk assignment, intensive chemotherapy including glucocorticoids, high-dose methotrexate, vincristine, asparaginase and triple intrathecal therapy, but without prophylactic cranial irradiation or routine hematopoietic stem cell transplantation should be tested in young adults with ALL.

Disclosures:
Jeha: Genzyme: Honoraria, Research Funding. Sandlund: Seattle Genetics: Research Funding. Bhojwani: MedImmune: Research Funding. Relling: St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding. Pui: EUSA Pharma: Honoraria; Enzon: Honoraria; Sanofi-Aventis: Honoraria.