The pediatric approach to ALL treatment relies on high cumulative doses of nonmyelosuppressive drugs, such as vincristine, glucocorticoids, and asparaginase, to be given during periods of neutropenia induced by anthracyclines, alkylators, and antimetabolite chemotherapy [15, 17, 18, 33, 34]. Most cooperative groups use an approach pioneered by the Berlin-Frankfurt-Münster (BFM) study group, with each group having made modifications based on the nuances of their own approach to risk stratification and their approach to treating particular subsets of patients. Remission induction (referred to as “protocol IA” in Europe) includes vincristine, prednisone or dexamethasone, asparaginase, and daunorubicin and is followed by consolidation therapy/protocol IB consisting of cyclophosphamide, cytarabine, and 6-mercaptopurine (6MP). Following these initial intense months, there is a phase termed “interim maintenance” (IM) in the USA, or “protocol M” in Europe, which consists largely of intravenous methotrexate (MTX) given in intermediate or high doses with leucovorin rescue, in conjunction with oral 6MP, and in the USA intravenous vincristine is administered as well. Subsequently, there is a return to intense therapy (“delayed intensification” in the United States, “protocol II” or “protocol III” in Europe) which is essentially re-induction and reconsolidation phases. Typically at this time, prednisone is replaced by dexamethasone, daunorubicin by doxorubicin, and 6-mercaptopurine by 6-thioguanine. On some US protocols, a second IM phase may be administered, but this time using vincristine, escalating doses of intravenous MTX without rescue, and asparaginase (“Capizzi methotrexate”). Debate continues regarding the benefits of this second IM phase. All protocols call for a prolonged maintenance phase that relies mainly on antimetabolite therapy. Dedicated treatment of the central nervous system (CNS) with intensive intrathecal chemotherapy begins during induction and continues throughout therapy. On many protocols, patients with overt CNS disease at diagnosis or with certain very high-risk features are also treated with cranial irradiation.

While there is a discrepancy between improvements in outcomes between younger children compared to the AYA age group, adolescents on cooperative group studies fare better now than in previous eras. On Children’s Oncology Group (COG) ALL studies from 1990 to 2005, the 5-year OS for patients 15–22 years of age improved from 66.1 ± 2.3 % in the early 1990s to 75.9 ± 2.6 % in the early 2000s. Also improved was the percentage of adolescents diagnosed with ALL who enrolled onto clinical trials. From 1990 to 2005, 33.5 % of adolescents aged 15–19.99 years predicted to develop ALL were enrolled onto COG trials. Heightened awareness of the issues surrounding AYA oncology and the importance of enrollment on clinical trials led to that number increasing to 51 % by 2009 [12]. Similarly, good results have been reported by other groups. For adolescents treated on Dana-Farber Cancer Institute (DFCI) protocols 91-01 and 95-01, 5-year EFS was 77 % (SE, 4 %) and 78 % (SE, 6 %), and 5-year OS was 78 % (SE, 4 %) and 81 % (SE, 6 %) for 10–15- and 15–18-year-olds, respectively [35]. DFCI protocols include frequent doses of vincristine, asparaginase, and corticosteroids, as well as high cumulative doses of anthracyclines. Untoward toxicities were not observed in the adolescent patients, although there were higher rates of pancreatitis and thrombosis compared to patients <10 years old [35].

The importance of enrollment onto clinical trials cannot be stressed enough. Treatment regimens for ALL are prolonged and complex, and adherence to therapy is crucial. Providers must be familiar with the entirety of the treatment, and must be vigilant in administration of chemotherapy according to the prescribed schedule. Medical professionals who care for AYAs with ALL must also recognize the challenges faced by AYAs as they attend frequent clinic visits while maintaining educational and employment responsibilities, and who struggle to comply with oral chemotherapy schedules while simultaneously exerting independence and autonomy from parents or other guardians. Uniform treatment of large numbers of patients on clinical trials will continue to raise awareness of appropriate treatment regimens as well as the unique needs of the AYA population.

There have been essentially two approaches by medical oncologists to the treatment of ALL in adults. One approach is administration of BFM-like chemotherapy, as outlined above. The other is the “hyper-CVAD” regimen, which consists of cycles composed of two alternating courses of chemotherapy (course A and course B) [36]. Course A consists of cyclophosphamide and mesna given every 12 h on days 1–3, followed by doxorubicin on day 4. Vincristine is given on day 1, and there are 2, 4-day pulses of dexamethasone on days 1–4 and 11–14. Course B consists of intermediate-dose methotrexate on day 1 with leucovorin rescue followed by high-dose cytarabine given every 12 h on days 2–3. Methylprednisolone is administered on days 1–3. Intrathecal MTX and cytarabine and cranial radiation are used for CNS prophylaxis and incorporated into both course A and course B, the amount of which depends on a risk categorization for CNS relapse. Rituximab is added to each A and B course for patients with CD20+ ALL. After eight cycles of therapy, patients receive POMP maintenance therapy, consisting of 6MP, vincristine, MTX, and prednisone, with two courses of intensification with hyper-CVAD and MTX/asparaginase at months 6–7 and 18–19 of maintenance therapy. When treated with hyper-CVAD, patients receive each course of myelosuppressive drugs followed by several weeks of rest while awaiting count recovery. With either the BFM or the hyper-CVAD approach, the maintenance phase of therapy tends not be as prolonged as that of pediatric protocols [36–40].

A number of studies have compared outcomes for similarly aged AYA patients treated with either pediatric or adult regimens or have reported outcomes specifically of AYA patients treated on pediatric-inspired regimens (Table 7.1). In many of these, survival was significantly better for those patients treated with a pediatric regimen [6, 39, 41–45]. Encouraged by these results, several adult groups have prospectively applied a pediatric-inspired treatment regimen to a young adult population, managed by medical, rather than pediatric, oncologists.

From 2002 to 2008, DFCI investigators administered a DFCI Pediatric ALL Consortium regimen to 92 patients 18–50 years of age, reaching an 85 % complete remission (CR) rate (90 % CI, 77–91 %) and 4-year disease-free survival (DFS) rate of 69 % (95 % CI, 56–78 %) for those patients achieving CR, which was much better than historical survival rates of <50 % [46]. The regimen, which relied heavily on intensive asparaginase administration, was well tolerated in the young adult population, and in fact the primary endpoint of the study was the feasibility of weekly asparaginase administration for the 30-week intensification phase of therapy. Fifty-seven patients were evaluable for the endpoint, and 36 of them (63 %) completed all 30 doses. Forty-one (72 %) completed at least 26 doses, an important benchmark, as the pediatric DFCI data suggests that administration of at least 26 doses of asparaginase is as efficacious as administration of all 30 [47]. In a larger cooperative group trial (C10403) that was conducted from 2007 to 2012, 296 evaluable patients between the ages of 16 and 39 were treated by medical oncologists, using one arm of the most recent COG study (AALL0232) for patients with B-ALL [48]. The 2-year EFS was 66 % (95 % CI, 60–72 %) with a median EFS of 59.4 months, significantly longer than the null hypothesis, which was that the median EFS for this patient population would be ≤32 months. The observed toxicities were similar to that reported on the pediatric trial with the exception of higher rates of thrombosis, neuropathy, osteonecrosis (ON), and mucositis in patients ≥20 years of age on C10403, but higher rates of hypersensitivity and motor neuropathy on AALL0232 [49]. Taken together, these studies demonstrate that not only is pediatric therapy feasible in a young adult population but it also appears to improve outcomes.

Other retrospective studies have reported similar outcomes for patients treated on either adult or pediatric regimens. In a population-based study, Usvasalo et al. reported that consecutive patients aged 10–25 years treated in Finland for ALL from 1990 to 2004 had comparable outcomes when treated on either pediatric or adult regimens. The 5-year EFS/OS for pediatric versus adult patients were 67 % versus 60 % (EFS) and 77 % versus 70 % (OS) (p = ns for both) [50]. In a study from MD Anderson Cancer Center, 85 AYA patients (12–40 years) were treated with a BFM-based chemotherapy regimen, and outcomes were compared to a historical control group (71 patients aged 16–40 years) treated with hyper-CVAD [36]. Similar to the study out of Finland, outcomes on each regimen were comparable. Overall survival at 3 years was 74 % for patients treated with BFM-based therapy and 71 % for those treated with hyper-CVAD (p = ns).

It is worth noting that the adult regimens used in Finland tended to incorporate higher doses of MTX, epipodophyllotoxins, and anthracyclines than the pediatric protocols, but they also included high cumulative doses of vincristine, asparaginase, and corticosteroids – tenets of BFM-based therapy. Furthermore, the authors point out that all patients in Finland, regardless of age, are treated at one of five centralized academic centers, and the culture and healthcare system is such that adherence to therapy is universally very good. Likewise, the study from MD Anderson Cancer Center is a single-institution study, and the treating physicians were very familiar with the complexity and nuances of the treatment regimens.

The potential and accrued toxicity of therapy and the late adverse effects are also increasingly major considerations, especially as the long-term survival and cure rates have improved in AYAs with ALL. As a result of decades of attempts by pediatric oncologists to reduce the adverse late effects of their regimens, the pediatric regimens have low gonadotoxic, cardiotoxic, infertility, and carcinogenic potential, achieved in part by successful limitation of their total alkylating, anthracycline, and radiation exposure, manifesting as favorable long-term follow-up results [51]. In contrast, the hyper-CVAD regimen has substantially greater exposure to alkylators, anthracyclines, and radiation, and for patients with CD20+ ALL, rituximab [52]. Hyper-CVAD requires hospitalization for the A and B courses, and there is a high rate of admission for fever and neutropenia and for other signs of infection or cytopenia [52]. Secondary acute myelogenous leukemia and myelodysplasia may also occur more frequently after hyper-CVAD than with a pediatric type of regimen, which has led to discontinuation of the regimen at some centers [52]. Hyper-CVAD is also regarded to have high potential for rendering males and females infertile, with more than 80 % of women predicted to develop amenorrhea posttreatment and a majority of men predicted to have prolonged azoospermia [52].

Some studies have supported a role for hematopoietic stem cell transplant (HSCT) in first remission (CR1). In a joint trial between the MRC and the Eastern Cooperative Oncology Group (ECOG), patients aged 15–59 years were treated with two identical cycles of induction chemotherapy, followed by allogeneic HSCT if a matched sibling donor (MSD) was available, or if there was no MSD, randomized to chemotherapy alone versus autologous HSCT [53]. A donor versus no-donor analysis of Philadelphia chromosome-negative (Ph-) patients revealed a 5-year OS of 54 % compared to 44 % (p = 0.007) for patients with and without a MSD, respectively. This survival benefit was observed in patients considered to have standard-risk disease (5-year OS 63 % versus 52 %, p = 0.02), but not necessarily in high-risk patients (5-year OS 42 % versus 35 %, p = 0.2). In a meta-analysis of 20 studies in which adult patients with ALL who had a MSD underwent allogeneic HSCT, and those who did not underwent either autologous HSCT or were treated with chemotherapy alone, there was no benefit found for autologous HSCT [54]. Overall survival was longer for those patients with a donor (OR = 0.87, 95 % CI 0.79–0.96, p = 0.006), despite higher treatment-related mortality (TRM) (OR = 2.36, 95 % CI 1.94–2.86, p < 0.00001). TRM was particularly high in patients ≥35 years of age, with 32 % of those with a donor and 14 % of those without a donor dying in remission. In patients <35 years of age, 19 % of those with and 8 % of those without a donor died without relapse. This led to higher 5-year survival rates for patients <35 years of age with a donor (55 % versus 45.1 %), but not for those ≥35 years of age (39.2 % versus 37.2 %).

Results such as these have led many oncologists to consider HSCT in CR1 for young adult patients with ALL, who are able to tolerate the toxicity of HSCT better than their older adult counterparts [55]. However, a benefit for HSCT in CR1 is not necessarily evident. A study from the International Bone Marrow Transplant Registry (IBMTR) compared outcomes between 422 patients aged 18–50 years who underwent related or unrelated HSCT and 108 patients aged 18–50 years who were treated with chemotherapy alone, according to a pediatric regimen [56]. Cumulative incidence of relapse was similar between the groups, but TRM was significantly lower in patients treated with chemotherapy alone. Disease-free survival at 4 years was significantly higher in the cohort treated with chemotherapy (71 % [60–79 %] versus 40 % [35–45 %], p < 0.0001), as was 4-year OS (73 % [63–81 %] versus 45 % [40–50 %], p < 0.0001). In a large study conducted by the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), investigators evaluated the role of HSCT in adults (15–55 years) with Ph- ALL who were treated with a pediatric-inspired regimen [57]. Only patients who were considered to have high-risk disease based on a combination of cytogenetics/disease biology, CNS status, and disease response were eligible for HSCT; out of 522 study patients, 282 were in the HSCT cohort. For patients who underwent HSCT, there was no benefit regarding relapse-free survival (RFS) (hazard ratio [HR], 0.80; 95 % CI, 0.6–1.06; p = 0.12) or OS (HR, 0.76; 95 % CI, 0.57–1.02; p = 0.069). There was a lower cumulative incidence of relapse in the HSCT group (HR, 0.5; 95 % CI, 0.35–0.7; p < 0.001), but this was countered by higher rates of non-relapse mortality (HR 1.46; 95 % CI, 1.09–1.95; p = 0.011), leading to the similar survival outcomes. Note, however, that on subgroup analysis, there appeared to be a benefit with HSCT for patients with poor disease response, defined as residual disease ≥10⁻³ after induction chemotherapy; HR was 0.37 for RFS (95 % CI, 0.2–0.69; p = 0.001) and 0.41 for OS (95 % CI, 0.22–0.76; p = 0.005). Patients with IKZF1 gene deletions also appeared to benefit from HSCT, but this may have been related to poor disease response, as often occurs in these patients. No randomized comparisons currently exist between continuation of intensive pediatric-inspired chemotherapy regimens and allogeneic HSCT in CR1 for AYAs with Ph- ALL, and these data suggest that there may not be a general survival benefit for HSCT in CR1 for this population. However, there may be identifiable subgroups of patients for whom HSCT in CR1 is beneficial.

Asparaginase has long been established as an integral drug in pediatric ALL regimens [47, 58–62] and is effective for adults with ALL as well [6, 46, 63–65]. With its efficacy, however, comes not insignificant toxicity [66–69], and asparaginase toxicity is of concern as pediatric ALL protocols are being increasingly applied to the AYA population [70].