Interim Analysis of a Multicenter, Prospective Study for Pediatric Chronic Myeloid Leukemia in Chronic Phase: The JPLSG CML-08 Study

Background: The Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) CML-08 prospective study was designed to determine the efficacy and tolerability of tyrosine kinase inhibitor (TKI) in children and adolescents with newly diagnosed CML in chronic phase (CP).

Methods: Monitoring of response to TKI and the treatment were conducted according to the modified ELN-2009 guidelines.

Results: From October 2009 until September 2014, 78 patients (49 males and 29 females) from age 1 to 17 years (median: 11 years) were enrolled in 45 hospitals in Japan. As of May 2015, the median observation period was 31 months (662 months). Median WBC, Hb and platelet counts were 275x10⁹/L (8 to 765), 9.6g/dL (5.8 to 14.6) and 560x10⁹/L (110 to 2875), respectively. Splenomegaly was found in 76%. High scores of Sokal, Hasford and EUTOS were observed in 21, 13 and 27%, respectively. Clonal chromosome abnormalities in Ph-positive cells occurred in 3 patients 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. Of 69 patients with a first-line imatinib, 30 (43%) have been continued imatinib treatment, and the others were switched to second TKI (dasatinib or nilotinib) or hematopoietic stem cell transplantation (HSCT) due to poor response or intolerance to imatinib. The most common cause of intolerance to imatinib was musculoskeletal events. At the last observation, HSCT had been conducted in 8 patients (10%). 4y-PFS and 4y-OS was 97.1% (95%CI, 88.7 to 99.3%) and 97.8% (95%CI, 85.3 to 99.7%), respectively. One patient was dead because of blast crisis followed by transplant-related complications. CHR was achieved in 96.2% at 3 months, CCyR in 76.8% at 12 months, MMR in 40.8% at 18 months, and CMR^4.0 in 22.4% at 24 months. Cumulative incidence of CMR^4.0 by 24 months was 27.8% and 7.5% in patients with BCR-ABL (IS) of ≤ 10% and > 10% at 3 months with a first-line imatinib, respectively (P=0.0435). In patients with a first-line imatinib, age and WBC count at diagnosis were found to be potential prognostic factors for cumulative incidence of molecular response. Patients with a first-line second TKI had a higher 12-months cumulative incidence of MMR (60.0% vs 21.7%, P = 0.0460) and CMR^4.0 (35.1% vs 6.3%, P = 0.0061) than patients with a first-line imatinib. There were no significant differences between their clinical characteristics including sex, WBC count, Hb, platelet count, Sokal score, Hasford score, and EUTOS score, except for age. Second TKI was used as a first-line treatment only for patients ≥ 9 years of age. In this study, the follow-up is planned to continue until 2019.

Conclusion: A first-line second TKI was more effective than imatinib for inducing molecular responses also in pediatric CML-CP, as reported in adult CML-CP. Discontinuation of TKI after achieving CMR is a desirable strategy especially for children and adolescents. Thus, considering prognosis factors including age and WBC count, pediatric CML patients with unfavorable prognosis should be treated by second TKI rather than imatinib as a first-line treatment.