Outcome of Hematopoietic Stem Cell Transplantation in the Patients with Pediatric Acute Lymphoblastic Leukemia Enrolled in the Japan Association of Childhood Leukemia Study (JACLS) ALL-02

Background: Though the outcome of patients with acute lymphoblastic leukemia (ALL) has been greatly improved, some high-risk patients still need hematopoietic stem cell transplantation (HSCT). In this study, we evaluated clinical characteristics of children with ALL who were treated according to Japan Association of Childhood Leukemia Study (JACLS) ALL-02 trial and received HSCT to determine prognostic factors for the outcome of HSCT.

Methods: Between April 1, 2002 and March 31, 2008, 1,252 patients aged 1-18 years with newly diagnosed ALL were enrolled in JACLS ALL-02 trial. Ph+ALL, mature B-ALL, and NK-leukemia were excluded. Of all the 1,252 patients, 211 (16.8%) patients were reported to receive HSCT, of which 206 patients with adequate information of 1^st HSCT were subjected to further analysis. In this study, HSCT in 1^st complete remission (CR) in JACLS ALL-02 trial was indicated for the patients with extremely high risk (ER: BCP-ALL with PPR and/or evidence of t(4;11) (or KMT2A-AFF1 positive), hypodiploidy (≤ 44) and/or acute mixed lineage leukemia/ acute unclassified leukemia). As a precaution, in ER patients, the timing of HSCT differs depending on whether they have a matched related donor.

Results: Of all the 206 patients, 83 patients received HSCT in first CR (CR1), 68 patients in CR2, 54 patients in non-CR and 1 patient in induction failure (IF). 5-year overall survival (5y-OS) for 206 patients was 50% (95% CI 42.7-56.8). In detail, 73.8% (95% CI 62.6-82.1) for CR1 patients, 49.4% (95% CI 35.9-61.5) for CR2 patients, and 14.8% (95% CI 6.9-25.5) for non-CR patients, respectively. In univariate analysis, JACLS risk classification, disease status at HSCT (CR or non-CR or IF), stem cell source were significant prognostic factors. In multivariate analysis, only disease status retained as prognostic factor (p<0.01, HR=1.77). For CR1 patients, stem cell source was significant prognostic factor on multivariate analysis (5y-OS = 41.7%, 66.7%, and 79.3% for peripheral blood, cord blood, bone marrow; p = 0.023). When we focused on immunophenotype, stem cell source retained their effect only for patients with T-ALL. For CR2 patients, central nerves system involvement at diagnosis (p=0.02, HR=7.2), S classification (p=0.03, HR=1.2), and NCI risk (p=0.04, HR=2.5) were significant prognostic factors on multivariate analysis. S classification retained its prognostic impact only for patients with BCP-ALL (p=0.01, HR=1.5). For non-CR patients, NCI or JACLS risk classification at first diagnosis, S classification, frequency of relapse before HSCT, stem cell source, and conditioning for HSCT did not affect treatment outcome. Interestingly, non-CR patients with high-hyperdiploid (HHD) (n=5) had a significantly better 5y-OS (80%) than the other subtypes. In multivariate analysis, age at diagnosis (<10 years, p=0.04, HR=2.0)) and HHD (p=0.006, HR=1.74) contribute to the better outcome of HSCT in non-CR.

Conclusion: The current study showed that the prognostic factors for HSCT varied according to the disease status or disease immunophenotype. Also, it is noteworthy that HHD patients may be rescued even in non-CR status by HSCT.