Pediatric-Inspired Treatment Regimens for Adolescents and Young Adults With Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Review

Abstract

Importance: The incidence of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adolescent and young adult (AYA) patients (age range, 15-39 years) in the United States is increasing at a greater rate than in younger or older persons. Their optimal treatment has been increasingly debated as pediatric regimens have become more widely used in the age group. This review compares the basic features of pediatric and adult chemotherapy regimens for ALL and LBL, recognizes and describes the challenges of the pediatric regimen, and suggests strategies to facilitate its adoption for AYAs with ALL and LBL.

Observations: All but 2 of 25 published comparisons of outcomes with pediatric and adult regimens for ALL and LBL in AYAs and 1 meta-analysis favor the pediatric regimen. After more than a half-century of clinical trials of the pediatric regimens, including at least 160 phase 3 trials in the United States, the pediatric regimens have become far more complex than most adult regimens. Asparaginase, a critical component of the pediatric regimens, is more difficult to administer to AYAs (and older patients) but nonetheless has a favorable benefit to toxicity ratio for AYAs. A dramatic reduction in outcome of ALL and LBL during the AYA years (the "survival cliff") is coincident with similar reductions in proportions of AYAs referred to academic centers and enrolled on clinical trials (the "accrual cliff" and "referral cliff").

Conclusions and relevance: The accumulating data increasingly support treating AYAs with ALL and LBL with a pediatric-inspired regimen or an approved institutional or national clinical trial tailored for this patient group. A need to develop clinical trials specifically for AYAs and to encourage their participation is paramount, with a goal to improve both the quantity and quality of survival.

Figure 1.. Annual Incidence and New Cases in the United States of Adolescents and Young Adults (AYAs) With Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma (ALL/LBL), 2000 to 2014

A and B, Shown in A are incidence data from the Surveillance, Epidemiology, and End Results (SEER) 18 data on which the estimated numbers of new cases in B are based. The age range of the AYAs was 15 to 39 years. Average percentage change (APC) represents the mean percentage change of logarithmic values, with APC values and P values for incidence provided by SEER and calculated by us for new case numbers. The International Classification of Diseases–Oncology, Third Edition codes used for ALL and LBL are available in the eTable in the Supplement.

Figure 2.. Five-Year Relative Survival Rate of Patients With Acute Lymphoblastic Leukemia by Single Year of Age at Diagnosis, 2000 to 2007, From the Surveillance, Epidemiology, and End Results 18 Data

A, Included is joinpoint analysis that created linear regressions for ages 1 to 17 years and 20 to 68 years and associated statistical variables. B, The pediatric age-dependent survival trend in A is extrapolated into the adult age range. The solid lines are the regressions created by joinpoint analysis, and the vertical solid lines indicate the ages at which the joinpoints were identified. The diagonal dashed line in B is an extension of the survival regression of children.

Figure 3.. Children’s Cancer Group and Pediatric Oncology Group Phase 3 Randomized Trials in Adolescents and Young Adults With Acute Lymphoblastic Leukemia

Each horizontal bar represents the patient accrual interval.

Figure 4.. Estimated Accrual Proportion From 2000 to 2009 and 2010 to 2015 Onto National Cancer Institute–Sponsored National Treatment Acute Lymphoblastic Leukemia Trials

AYAs indicates adolescents and young adults. Data by single year of patient age are from the National Cancer Institute Cancer Therapy Evaluation Program. The accrual proportion curves are 2-year running age means. The arrows signify trend changes from 2000–2009 to 2010–2015.