Long-term outcome of 6-month maintenance chemotherapy for acute lymphoblastic leukemia in children

Abstract

In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1 (n=11) and ETV6-RUNX1 (n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.

Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia

“…Unexpectedly, TCF3-PBX1 patients, an intermediate-risk abnormality, demonstrated an even faster MRD clearance, with 43% achieving MRD negativity ( Fig 2 ) compared with 36% of ETV6-RUNX1 patients. These observations correlate with the recent report from the TCCSG L92-13 trial 28 that showed that ETV6-RUNX1 and TCF3-PBX1 patients had an excellent outcome despite receiving less maintenance therapy. Thus, a greater understanding of disease kinetics could help tailor treatments to different subtypes.…”

Quantitative monitoring of minimal residual disease in childhood acute lymphoblastic leukemia using TEL‐AML1 fusion transcript as a marker

“…In childhood ALL, TEL‐AML1 fusion gene is related to favorable outcome. Studies on TEL‐AML1 positive groups in different treatment protocols have shown EFS around 90%, at 5 to 10 years during follow‐up . In the present study ( n = 62), EFS at 7 years from diagnosis was 87.0% ± 4.3%, which was close to the results of Enshaei et al (81%) …”

Treatment and biology of pediatric acute lymphoblastic leukemia

“…A UK group showed that 20% of deaths resulting from infection occurred during maintenance therapy, and a Scandinavian group demonstrated that a longer duration of maintenance therapy and a higher dose of 6‐MP increased the risk of secondary malignancy . In view of these adverse events, the TCCSG re‐analyzed their anecdotal evidence from the L92‐13 study with additional genomic analysis and found that female patients with TCF3‐PBX1 or ETV6‐RUNX1 had favorable outcomes even when maintenance therapy was terminated early, while full duration of maintenance therapy was required for male patients, and patients with HHD …”

“…51 In view of these adverse events, the TCCSG re-analyzed their anecdotal evidence from the L92-13 study with additional genomic analysis and found that female patients with TCF3-PBX1 or ETV6-RUNX1 had favorable outcomes even when maintenance therapy was terminated early, while full duration of maintenance therapy was required for male patients, and patients with HHD. 52 In previous trials, treatment stratification generally consisted of intensification or reduction according to the relapse risk. For further improvement, however, the duration of therapy may also be optimized based on the patient characteristics ( Fig.…”