Acute lymphoblastic leukemia is one of the leading causes of cancer-related deaths among adolescents and young adults. Overall survival and disease-specific survival of ALL are clinically significantly poorer in AYA patients than in children between 1 and 10 years of age. It is not known whether these outcome differences are due to distinct genetic and biological features, different therapeutic regimens and intensities, differences in compliance to therapy, or other social and behavioral issues ().
Special features of cancers in adolescent and young adult (AYA) patients
Dr Cheryl Willman (University of New Mexico Cancer Research and Treatment Center) discussed evidence that outcomes among pediatric ALL patients vary depending on the presence of various recurring cytogenetic abnormalities. ALL patients with “good” prognosis cytogenetics (such as trisomies of chromosomes 4, 10, or 17, or t(12;21)/TEL-AML1
) had relatively high survival rates, whereas those with other recurring abnormalities had intermediate or poorer outcomes (1
). Substantial differences existed in the frequencies of various cytogenetic abnormalities among AYA patients compared with younger ALL patients, including a precipitous decline in the frequency of the “good prognosis” abnormalities by approximately 20 years of age. The “poor prognosis” abnormalities, such as t(9;22)/BCR-ABL
, were more common in AYA ALL (2
). Under the auspices of the National Cancer Institute’s (NCI’s) Strategic Partnering to Evaluate Cancer Signatures (SPECS) program and its Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project, Willman and colleagues recently completed gene expression profiling studies to identify and characterize novel genetic abnormalities and therapeutic targets in a cohort of 207 older children with “high-risk” ALL (mean age = 13.5 years, with white blood cell counts higher than 50 000/mm3
at presentation) who had been treated on the Children’s Oncology Group (COG) 9906 protocol. Gene expression clustering algorithms revealed eight gene expression cluster groups, two of which were associated with distinct cytogenetic abnormalities [11q23 rearrangements MLL
or t(1;19) E2a-PBX1
] and six of which were entirely novel, in which the underlying genetic abnormalities were unknown. One of the novel clusters, which represented 12%–15% of all high-risk ALL cancers studied in this series, was characterized by high expression of CRLF2
, and other genes associated with activated tyrosine kinases, and frequent deletions of IKZF1
, and EBF1
. It was also associated with Hispanic or Latino race (P
= .001) and with very poor 4-year relapse-free survival (21%, P
< .001) (3
). Because these gene expression profiles were characteristic of activated tyrosine kinase pathways, some kinases were resequenced, leading to the discovery of novel Janus kinase 2 (JAK2
) and other kinase mutations in this high-risk form of the disease. These studies suggest that perturbation of these signaling pathways, along with IKZF1
deletion, cooperate to promote leukemogenesis. Early phase clinical trials to test JAK inhibitors in patients with high-risk ALL are ongoing (3
). Dr Willman noted that in preliminary studies, AYA ALL cancers appeared to be genetically similar to high-risk pediatric ALL. Working with the NCI adult cooperative groups, the TARGET cohort is being expanded to include 400 AYA ALL patients (NCI 1RC1 CA145707; Willman and Mullighan, principal investigators).
Treatment failure remains a major problem in the management of pediatric, adolescent, and young adult ALL. The genetic basis of treatment failure is particularly poorly understood in the AYA population because it often occurs in patients lacking known high-risk alterations such as MLL-rearrangement or BCR-ABL1. Dr Charles Mullighan (St Jude Children’s Research Hospital) presented the results of an integrated genomic analysis of B-cell precursor (BCP) samples that lacked known high-risk genetic alterations from a cohort of high-risk pediatric and adolescent ALL patients (COG P9906 cohort). They identified deletions and point mutations of the lymphoid transcription factor IKZF1 that were associated with a nearly threefold increased risk of relapse (hazard ratio = 2.40; 95% confidence interval = 1.38 to 4.2). The gene expression signatures of these patients were very similar to those of BCR-ABL1 ALL patients, and by resequencing, activating mutations of Janus kinases (JAK1, JAK2, and JAK3) were identified in 11% of the cohort. The mutated JAK kinases could transform cells in vitro, were responsive to JAK inhibitors, and were associated with very poor outcome when combined with IKZF1 deletions. When analysis was restricted to the adolescent ALL cases (N = 58; 16–21 years of age), similar results were found: 50 of these patients lacked a sentinel chromosomal alteration; however, they had a high frequency of JAK mutations and IKZF1 deletions, and in 5 years, there was a 71% incidence of a recurrence in patients harboring both lesions as compared with 18% incidence in patients with neither lesion.
Although much is known about the genetics of childhood ALL, data are limited for AYA ALL. Dr Christine Harrison (Northern Institute for Cancer Research at Newcastle University) described the UK’s Leukaemia Research Cytogenetics Group database, which includes cytogenetic information and records of treatments on 1205 AYA patients, aged 13–24 years (8
). Nearly 500 of these patients were treated on adult ALL clinical trials. Analyses of overall survival and event-free survival (EFS) revealed that AYA patients of the same age had worse outcomes when treated on an adult ALL protocol vs a pediatric ALL protocol. Of this group of patients, 432 were aged 13–14 years, 544 were aged 15–19 years, and 229 were aged 20–24 years; 63% were young men. Most patients had BCP-ALL (79%) and 21% had T-lineage ALL. The incidence of T-lineage, ALL-specific cytogenetic abnormalities varied among children, AYAs, and adults. For example, the CALM-AF10
translocation occurred more frequently in AYAs than in children or adults. Of the 837 AYA patients in this group who had BCP-ALL there were more 13–24 year olds with t(4;11)(q21;q23) translocations (4%) than children aged 1–12 years with the same translocation (2%). Greater than 50% of AYA BCP-ALL patients had a visible abnormality of chromosome arm 9p, whereas other AYA BCP-ALL patients exhibited trisomies of chromosomes 21, 8, or 5. Trisomy 5 as a sole cytogenetic change has previously been associated with a poor outcome (9
). Intrachromosomal amplification of chromosome 21 (iAMP21) has an incidence of about 3% in older children with ALL (median age 9 years) and accounts for 5% of AYA (10
); it is associated with BCP immunophenotype and low white blood cell count. Data from the Medical Research Council ALL97 trial revealed that patients with iAMP21 had very poor EFS and experienced both early and late relapses. However, the overall patient survival was relatively good (5-year EFS was 29%, whereas overall survival was 71%) following treatment for their relapsed disease (11
). Currently, these patients are being treated as at high risk in the Medical Research Council ALL2003 childhood ALL trial. Other translocations observed in BCP-ALL involve the immunoglobulin heavy chain locus (IGH@
) and are seen more frequently in older children and adolescents as compared with younger children (12
Dr Wendy Stock (University of Chicago) described the challenges of treating ALL in the AYA population. Older adolescents and young adults with ALL (16–21 years of age) have worse outcomes (7-year EFS = 34%) than children at 1–10 years of age for whom the cure rate now approaches 80%–85%. A retrospective comparison of 16–20 year olds with ALL who were treated on the Children’s Cancer Group (CCG) or Cancer and Leukemia Group B (CALGB) ALL protocols revealed that despite similar remission rates between the two treatment groups, there was a statistically significantly lower 7-year EFS among those participants treated on the CALGB protocol as well as a higher rate of central nervous system relapse (16
) (7-year EFS = 63% [CCG AYAs] vs 35% [CALGB] AYAs; relative incidence ratio = 9.2, 95% confidence interval = 2.0 to 42.7; P
< .001). Compared with adult protocols, the pediatric protocols featured substantially more nonmyelosuppressive therapy (vincristine, corticosteroids, and L
-asparaginase) elements and more intensive early CNS-directed therapy. Similar results have been observed in retrospective analyses of AYA patients in France, the United Kingdom, and the Netherlands; nearly identical remission rates were observed, but EFS and survival were substantially better for AYA patients enrolled on the pediatric trials (67% vs 41% 5-year EFS in France; 71% vs 56% 5-year overall survival in the United Kingdom, and 71% vs 38% 5-year EFS in the Netherlands) (17
Explanations for these striking differences include potential, clinical, and biological differences among adolescents who received treatment at pediatric centers compared with adult centers, differences in protocol design and dose intensity, and potential variations in the degree of adherence to the protocol drug administration by medical oncologists and their patients compared with pediatric oncologists and by their patients. To address many of these unanswered questions, the adult cooperative groups are performing a prospective trial that focuses specifically on AYAs (Intergroup trial C10403). Newly diagnosed ALL patients between ages 16 and 40 years are eligible for treatment that parallels the current COG study for adolescents and high-risk children (AALL0232).
Asparginase, which deprives the leukemic cells of asparagine that is essential for growth, is considered to be part of the standard treatment in pediatric ALL protocols. However, because of toxicity and limited tolerability in older adults, medical oncologists do not routinely use it. Since 1973, the Dana-Farber Cancer Institute ALL Consortium has conducted randomized multi-institutional clinical trials for children up to 18 years of age with newly diagnosed ALL. Older adolescents (15–18 years old) have been treated as high-risk, and postinduction consolidation (follow-up therapy after the induction of remission in the patient) has focused on continuous asparagine depletion by administration of asparginase for 20–30 weeks. Fifty-one patients aged 15–18 years were treated in two consecutive Dana-Farber Cancer Institute ALL Consortium trials. Compared with patients aged 1–10 years, older adolescents experienced more thromboembolic complications (2% in 1–10 year olds vs 14% in 10–15 year olds vs 10% in 15–18 year olds, P
< .01) but had similar rates of pancreatitis and asparginase allergy. The 5-year EFS for these older adolescents was 78%. Based on this favorable outcome, Dr Lewis Silverman (Dana-Farber Cancer Institute) described a pilot study that was initiated to determine the feasibility of administering the Dana-Farber Cancer Institute pediatric regimen to young and middle-aged adults between 18 and 50 years of age (20
). Preliminary results suggest that an asparginase-intensive pediatric regimen is feasible in older adolescents (aged 15–18 years) and young adults (aged 18–50 years) with ALL.