Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.

Graphical abstract

Figure 1.

Kaplan-Meier plot of event-free survival in R/I patients. *The following were considered events during treatment: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR; MCyR includes both partial cytogenetic response [PCyR] and CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. †One patient had an event of progression to AP/BC.

Figure 2.

Kaplan-Meier plot of event-free survival in patients with newly diagnosed disease. *The following were considered events during treatment: loss of CHR, loss of MCyR (MCyR includes both PCyR and CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. †One month after the start of nilotinib treatment, 1 patient temporarily met the technical definition of progression to AP/BC because of increased basophil count. Treatment with nilotinib was temporarily interrupted for 13 days during the first 28-day cycle because of prolonged QT. The patient remained in the study, returned to CP 1 month after progression, and was in CHR after 5.8 months of treatment and in CCyR after 5.3 months of treatment. The patient discontinued from the study because of hyperbilirubinemia after 13.8 months on treatment without losing CHR and CCyR. Progression in this patient was not considered to be clinically notable based on clinical review; however, it was considered as progression to AP/BC in formal statistical analyses. The other patient with an event experienced confirmed loss of MCyR.