Nilotinib Treatment in Pediatric Patients (pts) with Philadelphia Chromosome- Positive (Ph+) Leukemia Refractory to Prior Tyrosine Kinase Inhibitor (TKI) Therapy: Results from Nilotinib Compassionate Use Program
Authors: Wayne Alan S. , Macedo Carla Renata , Szczudlo Tomasz , Woodman Richard C. 
Published: April 2020

Abstract
Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of adults with Ph+ chronic myelogenous leukemia (CML) in chronic (CP) or accelerated phase (AP) resistant to prior therapy including imatinib. Pts &lt;18 years were not included in the pivotal nilotinib phase I/II registration study. The mechanisms of BCR-ABL resistance to imatinib are reported to be similar in pediatric and adult pts. We describe the use of nilotinib in pediatric pts (≤18 years) with advanced refractory Ph+ leukemia through a global compassionate use program. These represent the first reported results of nilotinib in pediatric pts.
Methods : Between June 2006 and April 2008, pts were evaluated for compassionate use of nilotinib for the treatment of Ph+ CML or Ph+ acute lymphoblastic leukemia (ALL) resistant or intolerant to other therapies including imatinib alone or sequential imatinib and dasatinib. Resistance and intolerance were defined using the same criteria as those previously reported in the nilotinib phase II study. Pediatric pts with body weight ≥40 kg received nilotinib at a starting dose of 400 mg twice daily (BID) while pediatric pts &lt; 40 kg started at 300 mg BID. Dose modifications were performed based on tolerance and response.
Results : A total of 36 pts were evaluated for compassionate use of nilotinib, of which 16 received treatment with nilotinib. Mean age was 15 yrs (range 10–18). There were 9 males. 8 pts had Ph+ CML: 3 CP; 3 AP; 2 blast crisis (BC) and 8 pts had Ph+ ALL. 15/16 pts were resistant to imatinib, 1 pt was intolerant to imatinib, 7 pts (6 Ph+ ALL; 1 BC) had also received dasatinib and 6 pts had undergone SCT prior to receiving nilotinib. Starting dose was 400 mg BID in 12 pts and 300 mg BID in 4 pts. Two pts had dose reductions (1, 200 mg BID; 1, 400 mg with 200 mg QD) while 3 pts had dose escalation (2, 400 mg BID; 1, 600 mg BID). At the time of data analysis 9/16 pts remained on nilotinib therapy with clinical benefit. Mean duration of nilotinib treatment was 3.3 mos (range 1–9). Seven pts had disease progression while on nilotinib and discontinued therapy at a mean of 2.1 mos (1–5) duration of therapy. Six of these pts had received 2 prior TKIs, 1 of whom (18 yrs, Ph+ ALL) had a T315I mutation at the time of progression. Nilotinib serum levels were obtained from 1 pt (10 yrs, 29 kg female with Ph+ ALL) who received a dose of 300 mg BID. The trough (prior to morning dose) concentrations were determined to be 2,430 ng/mL on Day 10 and 1,890 ng/mL on Day 24, similar to that observed for adults in the phase I study with nilotinib dosing of 400 mg BID. AEs reported during treatment include thrombocytopenia (unknown grade), grade 1 skin toxicity, and grade 1 chest and bone pain. 3 SAEs were reported: grade 4 neutropenia (Ph+ ALL); relapsed disease with hepatomegaly and grade 3 increased liver transaminases (Ph+ ALL); 1 death due to disease progression (11 yrs, Ph+ ALL).
Conclusions : Nilotinib safety profile in this group of pediatric pts appears to be similar to that reported in adult pts. Similar to adults, these results suggest that nilotinib has activity in pediatric pts with Ph+ leukemias and that heavily treated pts with advanced Ph+ leukemia resistant to 2 TKIs have a poor prognosis. A phase I/II study with nilotinib in pediatric pts with imatinibresistant or intolerant Ph+ leukemia is planned.