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 [3]. The study found a significantly higher 7-year event-free survival (EFS) rate for patients treated with CCG regimens than for patients treated with CALGB regimens (63% vs. 34%, P<0.001). Of note, 18–20 year old patients treated with the adult regimen had much lower survival than those treated with a pediatric regimen, although 16–17 year old patients had comparable outcome regardless of treatment type.

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 [13]. The advantage of pediatric-based therapy for AYA patients was also proven in a meta-analysis of 11 comparative studies, with patients treated with pediatric regimens having a lower rate of relapse, similar non-relapse mortality, and higher EFS than patients treated with adult regimens [14]. Also, a recent Korean study based on 1,168 AYA patients showed that OS of pediatric treatment recipients was significantly higher than those who received adult treatment [15]. Importantly, the study also showed that the majority of AYA patients (65%) received pediatric-based therapy for ALL.

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 [16]. The DFS was higher for recipients of pediatric therapy compared with a cohort of patients given adult-based therapy, irrespective of risk group.

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, KMT2A rearrangements, and post-induction minimal residual disease (MRD) [17]. The 5-year EFS of patients aged 18–45 was 74%. Treatment of young adult patients with a pediatric-based regimen was safe, with no significant difference between pediatric and adult patients with regards to rates of induction death. In terms of the specific adverse events, adult patients experienced a significantly higher incidence of thrombosis compared with children [18]. The rate of avascular necrosis was highest among 10–14 year old patients, but was also increased in older adults compared with younger children.

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 [19]. As was found for the NOPHO ALL2008 study, implementation of a pediatric protocol in adults was safe, with a 3% rate of treatment-related mortality.

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% [20]. The study found that although outcomes for the different treatment strategies were similar, the resulting toxicities were different, with the augmented BFM notable for asparaginase-related complications such as hyperbilirubinemia, hypofibrinogenemia, pancreatitis and thrombosis, while hyper-CVAD caused more myelosuppression and subsequent episodes of infection and bleeding.

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 [21]. A recent study, however, pointed to the potential for persistent disparity in outcome of AYA patients between pediatric and adult medical centers. The study found that AYA patients (age 15–21 years old) who received pediatric therapy at an adult center had significantly higher survival than those who received adult therapy, but still lower than patients who were treated at a pediatric center [22].

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 [23]. Further efforts to fully utilize pediatric regimens in the context of a clinical trial may contribute to improved outcome of AYA patients.

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 [24]. Indications for HCT in AYA patients remain unclear, although adverse cytogenetic features such as BCR-ABL1, KMT2A rearrangement and hypodiploidy, and post-induction MRD may be widely accepted criteria for HCT. Whether broader application of HCT in first CR results in superior outcome compared to pediatric-based chemotherapy remains unclear, although one retrospective study showed a similar relapse rate for the two treatment strategies, with lower treatment-related mortality (TRM) and increased OS for patients treated with pediatric chemotherapy [25].

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 [26]. Although rate of relapse-free survival (RFS) was higher in patients who received allogeneic HCT compared with those treated with chemotherapy only, the OS between the two groups was similar possibly due to increased TRM associated with HCT. Similarly, a nationwide study on allogeneic HCT for AYA ALL patients in first CR or beyond reported lower OS compared with children due to a higher rate of TRM, although rates of relapse were similar [27]. Overall, several studies consistently underscore the potential for greater TRM in AYA HCT recipients; more extensive use of pediatric chemotherapy for AYA may limit and clearly define the indications for allogeneic HCT in first CR.

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 [28]. Cranial irradiation was limited to patients with CNS leukemia. The study reported EFS and OS rates of 60% and 86% overall, results comparable to patients treated with imatinib in the previous COG AALL0031 trial, all of whom received cranial irradiation [29].

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, CRLF2 rearrangements with or without JAK mutations, JAK2 rearrangements and other mutations activating the JAK-STAT pathway have a greater incidence in AYA patients, whereas ABL1 class rearrangements are more important in children [8]. Case reports have shown that treating adolescent patients with ABL1 class rearrangement or activating JAK2 mutation, who previously showed poor response to conventional chemotherapy, with imatinib or ruxolitinib respectively resulted in MRD(–) remission as a bridge to successful allogeneic HCT [30, 31].

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 [32]. However, the median age at treatment for the 75 patients was 11 years, with the oldest patient reported to be 23 years old. Hence, the patients treated in this cohort did not encompass the broader definition of young adults up to the age of 30, or even 40. In contrast, the study of CAR T-cell therapy in adults, with a median age at infusion of 44 years, showed a much lower EFS at 12 months, with the survival rate continuing to fall beyond one year post-infusion [33]. Whether CAR T-cell therapy alone without further treatment may be curative, or whether this mode of immunotherapy may act as bridge to curative consolidation with allogeneic HCT in AYA patients, and whether expected therapeutic benefit may differ according to age sub-brackets within the broad definition of AYA require further investigation.