Early reduction of BCR-ABL at 3 months predicts deeper molecular remission in pediatric CML

Abstract

Abstract Background: Chronic myeloid leukemia (CML) is extremely rare in pediatric populations, and clinical features and therapeutic responses in children differ significantly from those observed in adults. This study aimed to analyze the characteristics of molecular response and associated influencing factors in pediatric patients with chronic-phase CML treated with tyrosine kinase inhibitors (TKIs). Methods: This retrospective study enrolled pediatric patients newly diagnosed with chronic-phase CML who received TKI treatment. Inclusion criteria were as follows: age at diagnosis less than 18 years, and diagnosis consistent with European LeukemiaNet (ELN) criteria. Patients with an interval greater than 6 months between diagnosis and initiation of TKI therapy or those lacking critical clinical data were excluded. Results: From July 2007 to February 2025, a total of 88 pediatric patients younger than 18 years with chronic-phase CML were included. Among them, 73% were male, and the median age at diagnosis was 9.2 years (range: 1.0–17.0 years). The most common clinical presentations at diagnosis were fever (32%), asymptomatic disease (28%), and fatigue (27%). The median white blood cell (WBC) count at diagnosis was 156.8×109/L (range: 23.9–709.6×109/L). Splenomegaly was observed in 69% of the patients, with a median spleen size of 9.0 cm below the costal margin (range: 1.0–25.3 cm). According to the Eutos Long Term Survival (ELTS) score, 63% of patients were classified as low risk, 17% as intermediate risk, and three patients as high risk. Additional chromosomal abnormalities (ACAs) were detected in five patients. With a median follow-up duration of 56.5 months (range: 4–215 months), 95% of patients achieved complete hematologic remission (CHR) within 3 months of treatment initiation. By the last follow-up, 20 patients experienced treatment failure, including loss of major molecular response (MMR) in 8 patients, disease progression to blast crisis in 3 patients, and 7 patients were lost to follow-up. Imatinib was administered as first-line therapy in 86 patients (97.7%), and 25 patients required second-line or subsequent TKI therapy. The 5-year overall survival (OS), event-free survival (EFS), failure-free survival (FFS), and progression-free survival (PFS) rates were 100.0%, 63.1%, 71.0%, and 95.9%, respectively. The cumulative incidence rates at 5 years for achieving complete cytogenetic response (CCyR), MMR, MR4, and MR5 were 88.9%, 87.3%, 74.8%, and 71.0%, respectively. Median time to achieve CCyR, MMR, MR4, and MR5 were 6, 12, 20, and 22 months, respectively. Among 61 patients who achieved MMR, 44 subsequently reached deep molecular response (DMR). Median interval from MMR to DMR was 5 months (95% CI: 3–9). Patients stratified by BCR-ABL reduction at 3 months (cutoff at 10-1.6 baseline) showed significantly shorter median times to MMR (6 vs. 14 months, p=0.0002) and DMR (11 vs. 20 months, p=0.016) in rapid-decline versus slow-decline groups, respectively. The 5-year FFS rate was higher in ELTS low-risk patients (78.1%, 95% CI: 66.4–91.9%) compared to intermediate/high-risk patients (53.6%, 95% CI: 31.9–90.1%; p=0.095), and the 5-year EFS showed a similar trend (low risk: 71.3%, 95% CI: 57.8–88.0%; intermediate/high risk: 53.6%, 95% CI: 31.9–90.1%; p=0.23). Of the 61 patients undergoing bone marrow biopsy, 30 had varying degrees of marrow fibrosis (grade 1: n=23, grade 2: n=6, grade 3: n=1). Patients with marrow fibrosis had significantly lower cumulative rates of MMR at 12 months compared to those without fibrosis (48.0% vs. 55.9%, p=0.026). Conclusions This study demonstrates favorable long-term outcomes in pediatric chronic-phase CML patients receiving TKIs. A rapid reduction of BCR-ABL transcript levels (below 10-1.6 of baseline) at 3 months significantly predicts earlier achievement of both MMR and DMR. Additionally, marrow fibrosis identified at diagnosis emerges as a potential negative predictor for molecular response. These findings underscore the necessity of early molecular monitoring and individualized risk assessment to optimize therapeutic strategies in pediatric CML populations.