A Multicenter, Prospective Study for Pediatric Chronic Myeloid Leukemia in Chronic Phase: The JPLSG CML-08 Study

Background: Tyrosine kinase inhibitor (TKI) has been used in pediatric chronic myeloid leukemia (CML) for more than 10 years, but only a few prospective clinical studies have been conducted in pediatric patients with CML due to their rarity. We conducted the JPLSG CML-08 study to determine the efficacy and tolerability of TKIs in children and adolescents with newly diagnosed CML in chronic phase (CML-CP).

Methods: The JPLSG CML-08 study was a prospective multicenter observational study (UMIN000002581). Patients under 18 years of age with untreated BCR-ABL1-positive CML-CP were eligible and treated according to the modified ELN-2009 recommendation, and the efficacy and safety of TKIs were evaluated.

Results: From October 2009 until September 2014, 79 patients were enrolled in 46 hospitals in Japan. A total of 78 patients (49 males and 29 females) were eligible for inclusion. Median age at diagnosis was 11 years (range, 1-17). Median observational period for survivors was 82 months (range, 48-118). Median WBC, Hb and platelet counts were 275x10 ⁹/L (range, 8-765), 9.6g/dL (range, 5.8-14.6) and 560x10 ⁹/L (range, 110-2875), respectively. Splenomegaly was found in 76%. High risk of Sokal, Hasford, EUTOS, and ELTS scores were observed in 21, 13, 27, and 9%, respectively. Clonal chromosome abnormalities in Ph-positive cells occurred in 1 patient at diagnosis. Imatinib, dasatinib, and, nilotinib were used as a first-line treatment in 69 (88%), 7 (9%), and 2 (3%) patients, respectively. The median initial dose of imatinib, dasatinib, and nilotinib was 276, 63, and 262mg/m2, respectively. 5y-PFS and OS was 96.2% (95%CI, 88.6 to 98.7%) and 97.4% (95%CI, 90.1 to 99.4%), respectively. Deaths were observed in 2 patients due to transplant complications. Hematopoietic cell transplantation was conducted in 14 patients (18%). Nine patients (12%) discontinued TKI with the aim of treatment-free remission (TFR), and five of them achieved TFR. In 69 patients with first-line imatinib, complete hematologic response was achieved in 95.7% at 3 months, complete cytogenetic response in 75.4% at 12 months, major molecular response (MMR) in 40.1% at 18 months, and MR4.0 in 52.8% at 60 months; If a transplant was performed, the follow-up period was censored at the date of transplant. Of the 69 patients, 52% changed treatment from imatinib to another TKI or transplant due to poor response, and 20% did due to intolerance. The most common cause of intolerance to imatinib was musculoskeletal events. BCR-ABL1 (IS) <10% at 3 months strongly correlated with higher achievement of MMR, MR4.0, and MR4.5. The EUTOS score was significantly associated with achievement of IS <10% at 3 months. Patients with a first-line second-generation TKI had a higher cumulative incidence of MR4.5 (P = 0.0191) than patients with a first-line imatinib. Second-generation TKI was used as first-line therapy only in patients older than 9 years, but other clinical characteristics, including risk scores, did not differ significantly between the two groups. The incidence of grade 3/4 adverse events (≥ 10%) included neutropenia (47%), anemia (39%), leukopenia (13%), arthralgia (13%), and myalgia (11%) for imatinib, neutropenia (21%), anemia (13%), and thrombocytopenia (11%) for dasatinib, and neutropenia (14%), elevated ALT (14%), hyperbilirubinemia (14%), skin rash (14%), and high CPK (14%) for nilotinib. Gastrointestinal bleeding was an adverse event specific to dasatinib (11% in all grades).

Conclusion: This clinical study extends and confirms previous data showing that first-line treatment with imatinib is effective in children and adolescents, with response rates similar to those seen in adults. Although longer follow-up is needed to fully assess the long-term toxic effects, adverse events with imatinib, dasatinib, and nilotinib have been acceptable. As reported in adults, there was an advantage in selecting second-generation TKI over imatinib as first-line therapy to achieve deep molecular remission (DMR). Since discontinuation of TKI after achieving DMR is the preferred strategy, second-generation TKI is expected to become the standard therapy for children and adolescents.