Switch to Subsequent Line of Treatment in Children and Adolescents with Chronic Myeloid Leukemia (CML) Treated with Imatinib: Experience of the International Registry for Chronic Myeloid Leukemia in Children and Adolescents (I-CML-Ped Study)

Aims: To determine in children and adolescents with chronic myeloid leukemia (CML) in chronic phase (CP) treated with imatinib front line, (i) the probability of switch to a second line therapy, (ii) to characterize the reasons and the type of switch and (iii) to determine the impact of the switch on outcome.

Methods: Children and adolescents (<18 years) with CML diagnosed later than the year 2000 and enrolled in the international registry for childhood CML (I-CML-Ped Study) were the subjects of the study.

Results: The I-CML-Ped study enrolled 301 children and adolescents with CML in CP treated with imatinib front line. Among them 112 patients subsequently switched to a second line therapy (median duration of imatinib treatment before the switch: 16 months [range: 1-111]).The probability of switch at 38 months was 50% (95% CI: 29-60). Primary resistance was the cause of switch in 47% of the patients: failure to achieve complete hematologic response (CHR, 1%), complete cytogenetic response (CCR, 20%) or major molecular response (MMR, 24%); not detailed (2%). A loss of response (CHR loss [2%] or CCR loss [4%] or MMR loss [13%]) or progression were the cause of switch in 19% and 4% of the patients, respectively. Occurrence of non hematologic toxicity (mainly muscle-skeleton pain) was the cause of switch in 10% of the patients. The reason of switch was the physician's choice in 20% of the patients (switch to hematopoietic stem cell transplantation [HSCT] while the patients were in MMR or deeper molecular response). The second line therapy consisted of second generation tyrosine kinase inhibitors (63%), chemotherapy (4%) or HSCT (33%). With a median follow up of 38 months (range: 2-150), overall, 8 deaths were recorded among switching patients: all were patients transplanted for acute phase (4 patients), hematologic resistance (1 patient), loss of hematologic response (1 patient) or physician's choice (2 patients). The causes of death were treatment related mortality (7 patients) and relapse (1 patient). One death only was recorded among the non switching patients. The probability of overall survival at 48 months was 90% (95% CI: 81% - 95%) for switching patients and 98% (95% CI: 89% - 100%) (p=0.005) for the non switching patients.

Conclusion: Treatment failure is the main reason for a switch to a second line therapy in children and adolescents treated with imatinib front line. Efficacy of second line therapy still needs improvement.