Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) have worse prognosis than children. Differing biology of ALL may account for some of this disparity in outcome, with AYA patients having far lower incidence of good risk cytogenetic abnormalities, and higher proportion of patients with genetic lesions associated with inferior survival such as Ph-like ALL. Actual chemotherapy may also contribute to differences in outcome. Retrospective studies have shown that AYA patients treated on pediatric-based regimens had higher survival than those treated with adult regimens; the superiority of pediatric protocols has also been proven in several prospective comparative trials. Increase in rate of enrollment of AYA patients in clinical trials may further improve outcome. Cure based on chemotherapy may further limit the role of allogeneic hematopoietic cell transplantation (HCT) in AYA patients. The unique biology of AYA ALL may allow for novel methods of targeted therapy, while immunotherapy, the efficacy of which has been proven for both children and adults, may also play a major role in the treatment of relapsed/refractory ALL.
The biology of acute lymphoblastic leukemia (ALL) and response to therapy are different when comparing pediatric and adult patients. The adolescent and young adult patient population may represent a unique age-based subgroup that is distinct from both children and older adults. Appropriate treatment of this subgroup may allow for significant improvement in survival when compared with historical cohorts. This review summarizes recent studies on ALL in the AYA population to determine the current status of ALL therapy in this age cohort, and possibly to conclude upon means of further improving outcome.
The definition of the AYA patient group differs significantly according to clinical study. The broadest age group that may be termed AYA includes adolescents and adults up to the age of 40. Many studies in ALL, however, focus on patients who are 15–20 years old at the time of diagnosis [
Differences in the biology of the leukemic blast between children and AYA patients may partly explain disparities in patient survival. In terms of recurrent cytogenetic abnormalities, those associated with favorable prognosis such as high hyperdiploidy and
The proportion of patients with a non-recurrent cytogenetic abnormality, the prognostic implications of which are unclear, is highest in the AYA group [
Early T cell precursor (ETP)-ALL is a subtype of T-cell ALL with an immature phenotype defined as CD1a(–), CD8(–), CD5 weak, and expression of one or more myeloid or stem cell markers [
Overall, the lower incidence of cytogenetic abnormalities associated with favorable outcome, combined with the higher proportion of patients with poor risk genetic features such as Ph+ and Ph-like ALL in AYA patients contribute to their inferior survival compared with children. Recently reported recurrent genetic features such as
Many multi-institutional studies have compared the outcome of AYA ALL when treated with either a pediatric-based or adult-based chemotherapy regimen. In this context, a pediatric regimen refers to one incorporating multiple doses of asparaginase, with greater exposure to vincristine and steroids, intensive central nervous system (CNS) prophylaxis, and a prolonged maintenance phase based on anti-metabolite therapy. In contrast, an adult regimen such as hyper-fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone (hyper-CVAD) utilizes greater doses of cyclophosphamide and anthracycline and, as a result, is more myelotoxic.
One of the largest earlier studies retrospectively compared the outcome of 321 AYA patients aged 16–20 years old who were treated on either the Children’s Cancer Group (CCG) trials or the adult Cancer and Leukemia Group B (CALGB) protocols [
Overall, of 25 studies comparing pediatric and adult ALL treatment of AYA patients, all but two showed superior survival for patients treated with a pediatric regimen [
The efficacy of pediatric-based ALL therapy for AYA patients, evident in retrospective comparisons of pediatric and adult treatment groups, resulted in adoption and prospective evaluation of pediatric therapy in these patients by adult hematologists. The Japan Adult Leukemia Study Group reported the outcome of treating 139 Ph-ALL patients (age 15–24 yr) with a pediatric regimen; the 5-year disease-free survival (DFS) and OS rate was 67% and 73% respectively [
A recent study reported the outcome of the implementation of the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 in 1,509 patients aged 1–45. The study found a greater proportion of high risk ALL in older patients due to increased incidence of T-cell ALL,
Also, results from the recently reported prospective CALGB 10403 study, based on 295 patients diagnosed at age 17–39, showed estimated 3-year EFS and OS of 59% and 73% respectively. The median EFS duration of 78.1 months was significantly longer than that of a historical cohort [
In contrast to these studies which reported improved outcome of AYA patients treated with pediatric regimens, a study by the MD Anderson Cancer Center showed comparable outcomes for patients treated with pediatric and adult regimens. In this study, 208 AYA patients up to the age of 40 received either the pediatric augmented Berlin-Frankfurt-Münster (BFM) therapy or the adult hyper-CVAD therapy, resulting in CR rate of 93% and 98%, and 5-year complete remission duration rate of 53% and 55% respectively. The 5-year OS rates for the two treatment arms were both 60% [
Overall, several prospective studies indicate improved survival of AYA patients by adoption of pediatric regimens by adult hematologists. Still, the proportion of AYA patients treated with pediatric regimens remains unclear. One nationwide study of AYA patients in Australia found that 82% of ALL patients were treated with pediatric regimens regardless of treatment site, indicating that many adult hematologists had adopted pediatric therapy [
A key method of ensuring that pediatric regimens are implemented accurately is to increase the number of AYA patients who are enrolled in clinical trials of ALL. A population-based study from the United States showed a recent increase in clinical trial enrollment for AYA patients (age 15–39 years old) with various cancers including ALL [
The role of allogeneic HCT as a means of consolidation in first CR in pediatric ALL is diminishing, while it still remains a fundamental component of therapy for adult patients [
A recent population-based study of allogeneic HCT for AYA ALL patients in first CR reported that 28.5% of eligible patients underwent HCT in first CR resulting in 84% two-year OS [
Concurrent use of tyrosine kinase inhibitors (TKI) has markedly improved the outcome of Ph+ ALL. The Children’s Oncology Group (COG) trial AALL0622 incorporated dasatinib into chemotherapy for patients aged 1–30 years, using the TKI from day 15 of remission induction, while reserving allogeneic HCT for a minority of patients based on MRD and matched sibling donor availability [
As the incidence of Ph-like ALL is greater in the AYA population than among children, therapy targeting the kinase-activating lesion of this ALL subtype may be more relevant for the older patient population. In terms of the actual target,
Immunotherapy with chimeric antigen receptor (CAR) T-cells has significantly improved the outcome of patients who fail initial chemotherapy. The phase 2 trial of single infusion CAR T-cell therapy resulted in 50% EFS at 12 months for children and young adults with relapsed/refractory pre-B ALL, with the EFS maintained at this level beyond 12 months [
Lower rates of enrollment in clinical trials contributed to the inferior outcome of AYA patients with ALL compared with children. Increase in therapy of AYA patients within the auspices of clinical trials, and the wider use of pediatric-based regimens for the treatment of these patients may result in significant improvements in outcome. Utilization of more effective chemotherapy may limit and clearly define subsets of patients who may benefit from allogeneic HCT in first CR, a treatment modality reported to result in a higher rate of TRM for AYA patients than for children. The unique biology of ALL in AYA patients offers the chance for targeted therapy, as has been shown for patients with Ph-like ALL. Finally, although immunotherapy such as CAR T-cell therapy has proven to be extremely effective in leading to CR, its role within the long-term treatment strategy for relapsed/refractory AYA patients requires further study.
No potential conflicts of interest relevant to this article were reported.