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Treatment of Acute Lymphoblastic Leukemia in Adolescents and Young Adults
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Treatment of Acute Lymphoblastic Leukemia in Adolescents and Young Adults

Joseph Rosenthal, MD
Adolescent and young adults (AYA) constitute a distinct population amongst patients with cancer. Historically, AYA patients with ALL treated along pediatric-inspired protocols had better outcomes compared to those treated on standard "adult type" regimens.
Adolescents and Young Adults Constitutes a Distinct Group in Oncology

Adolescents and young adults (AYAs) with cancer have been recognized as a distinct subgroup of patients in the field of oncology since 2006. From the onset of symptoms until the completion of active therapy and beyond, the particular challenges this group faces have been overlooked and underestimated.
In 2006, it was noted that improvements in cancer outcomes observed for the US population as a whole had not been experienced by AYA patients.The reduction in the cancer mortality rate in this group has lagged behind the reduction noted in children and older adults. As a result, although AYAs with cancer had a relatively better prognosis a quarter of a century ago, compared with children with cancer, that advantage has now been lost.
AYA patients comprise a complex and diverse group with various levels of developmental maturity—and, consequently, unique and largely unmet clinical and psychosocial needs.2-4 Each year, nearly 70,000 individuals aged 15 to 40 years are diagnosed with cancer in the United States. Although overall cancer survival rates among pediatric and older adult patients have increased in recent decades, survival of AYA patients with cancer has seen little improvement since 1975 when collected data became adequate to evaluate this issue. In 2006, the National Cancer Institute and the Lance Armstrong Foundation (now the Livestrong Foundation) conducted a program review group of the AYA problem. Recommendations covered awareness, prevention/cancer control/epidemiology/risk, biology, access, health insurance, clinical care models, clinical trials/research, special populations, psychosocial and behavioral factors, health-related quality of life, and long-term effects.2-4
Acute Lymphoblastic Leukemia in AYA

Acute lymphoblastic leukemia (ALL) is one of the leading causes of cancer-related deaths among AYAs. Overall survival and disease-specific survival of ALL are clinically significantly poorer in AYA patients than in children aged 1 to 10 years. It is not known whether this difference in outcomes is due to distinct genetic and biological features, different therapeutic regimens and intensities, differences in compliance to therapy, or other social and behavioral issues. AYAs (16 to 21 years of age) with ALL have worse outcomes (7-year event-free survival [EFS] = 34%) than children between 1 and 10 years of age for whom the cure rate now approaches 80% to 85%.
Pediatric-Inspired Versus Standard “Adult” ALL Protocols

Several retrospective studies that focused on younger AYA patients (15 to 21 years old) reported that AYAs treated with standard adult protocols (SAPs) for ALL had unfavorable outcomes compared with similarly aged patients treated with pediatric-inspired protocols (PIPs). A large retrospective study reported on a comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome of 321 AYAs aged 16 to 20 years with newly diagnosed ALL who were treated in consecutive trials in either the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB). The CR rates were identical: 90% for CALGB and CCG AYAs. However, CCG AYAs had a 63% EFS and 67% overall survival (OS) at 7 years in contrast to the CALGB AYAs, among whom the 7-year EFS was 34% (P <.001; relative hazard rate [RHR] = 2.2) and OS was 46% (P <.001; RHR = 1.9). Comparison of the regimens showed that AYA patients treated on the CCG regimen received earlier and more intensive central nervous system prophylaxis and higher cumulative doses of non-myelosuppressive agents. There were no differences in outcomes of those who reached maintenance therapy on time compared with those who were delayed.Similar results have been observed in retrospective analyses of AYA patients in France,the United Kingdom,the Netherlands,and Japan(Table 1).
The most widely used regimen in adults with ALL is hyper-CVAD, consisting of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, developed at MD Anderson Cancer Center in Houston.10,11 A prospective cohort of AYA patients treated along the guidelines of a pediatric regimen, the augmented Berlin-Frankfurt-Munster (ABFM), was compared with a retrospective cohort of similar population treated with the hyper-CVAD regimen. The 3-year complete remission duration (CRD) and OS rates were similar between the groups (Table 1). Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients and pancreatitis in 11% of patients that were closely related to the use of asparaginase in the regimen. Other toxicities included osteonecrosis in 11% of patients and thrombosis in 22% of patients, which were similar to those reported with the hyper-CVAD regimen.12
Similar outcomes comparing SAP and PIP ALL regimens were reported in a prospective study from Finland. No significant differences were observed between AYAs treated on a PIP regimen and those treated on a SAP.13 Although reasons for the differences noted in a majority of the reports5-8,14are unclear, possible hypothetical explanations include potential clinical and biological differences among AYAs compared with adults, differences in protocol design and dose intensity, and potential variations in the degree of adherence to the treatment regimens administered by medical oncologists compared with pediatric oncologists.
To address many of these unanswered questions, the adult cooperative groups have performed a large prospective trial that focuses specifically on AYAs (Intergroup trial C10403).15 Newly diagnosed ALL patients aged 16 to 40 years were eligible for treatment that parallels the current Children Oncology Group (COG) study (AALL0232)10 consisting of 4 intensive courses: remission induction, remission consolidation, interim maintenance, and delayed intensification, followed by prolonged maintenance therapy (Table 2). The results show that of the 318 patients enrolled on the trial, 22 withdrew prior to therapy. The median age at diagnosis was 24 years (range: 17 to 39 years). Patients were stratified into 3 age groups: 25% were 17 to 20 years, 53% were 21 to 29 years, and 22% were 30 to 39 years. The majority had B-ALL (76%) and were male (61%).
Overall, treatment toxicities were similar to those reported in the standard arm of COG AALL0232, with an increased thrombosis and early hyperbilirubinemia observed in C10403 patients. The median EFS overall is 59.4 months (95% confidence interval (CI), 0.384 to not releasable) and the 2-year EFS rate overall was 66% (95% CI, 0.60-0.72), with similar 2-year EFS rates for B and T-ALL patients (65% and 68%, respectively). The 2-year OS rate was 78% (95% CI, 0.72-0.83), which is similar for B-ALL (78%; 95% CI, 0.72-0.84) and T-ALL (80%; 95% CI, 0.70-0.91). These results allow rejection of the null hypothesis of this phase 2 trial that the true median EFS is, at most, 32 months.
In multivariable analysis of presenting clinical features, being older than 20 years and having an initial white blood cell count 30,000/mcl were significantly associated with worse EFS and OS. Presence of minimal residual disease (MRD) at day 28 following initiation of induction therapy and presence of a Ph-like gene expression signature were significantly associated with both worse EFS and OS. Absence of detectable MRD noted in 22 of 58 (38%) evaluable patients at day 28 of induction was associated with 100% EFS (P = .0006). The Ph-like signature was detected in 28% of patients tested on C10403, and the 2-year EFS for these patients was 52% compared with 81% for those without Ph-like disease (P = .04). This large trial, employing an intensive pediatric regimen in AYA patients with ALL, demonstrates a significant improvement (compared with historical controls) in EFS and OS, and validates the approach of using pediatric regimens for treatment of AYAs with ALL by adult hematologists.
A majority of recent studies demonstrate a survival benefit using pediatric regimens for AYA; however, several recently published comparison studies of SAP versus PIP, such as the ABFM,16 found equivalent EFS (∼70%). Conceptually, the major difference between PIP and SAP regimens for ALL is in their toxicity profile: whereas PIPs are based on multiple phases and agents (including asparaginase) delivered over the long term, SAP regimens for ALL are focused on aggressive cytoreduction mimicking the approach to acute myelogenous leukemia, including reliance on allogeneic and autologous stem cell transplantation in first CR, fewer consolidations, shorter maintenance durations, and less intrathecal chemotherapy (Table 2).

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