Nilotinib in Patients (pts) with Relapsed/Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Who Are Resistant or Intolerant to Imatinib.

Background: Ph+ ALL occurs in about 15% of adults with ALL and is characterized by a poor prognosis. Imatinib in combination with systemic chemotherapy has become the standard therapy for adults with Ph+ ALL. Nilotinib is a highly specific BCR-ABL inhibitor, which is 30-fold more potent than imatinib and active in vitro against 32 of a panel of 33 BCR-ABL mutations. Nilotinib was demonstrated in a phase I study to be active against a small subset of imatinib-resistant Ph+ ALL adult pts. Based on this preliminary data, a phase II, open-label study was designed to further evaluate the safety and efficacy of nilotinib in pts with relapsed/refractory Ph+ ALL.

Methods: The initial dose of nilotinib was 400 mg twice daily (BID) with escalation to 600 mg BID, when there was an inadequate response and no safety concerns.

Results: The safety and efficacy data were reported for 41 Ph+ ALL pts in which 38 had relapsed and 3 were refractory [(37 had active disease; 4 had minimal residual disease (MRD)]. The median age at study entry was 46 (18–75) years and 54% were men. At study entry 31% of pts had >35% Ph+ metaphases; chromosomal abnormalities other than Ph+ were noted in 32% (13/41) pts, and extramedullary involvement was present in 3 pts. The median time since initial diagnosis of Ph+ ALL was 15 months. Treatment with nilotinib is ongoing for 2 pts (5%). Most discontinuations were due to disease progression (68%). The median treatment duration was 53 (1–563) days and the median dose intensity was 800 mg/day. Thirty-one percent of pts had >35% of Ph+ metaphases, chromosomal abnormalities other than Ph+ were noted in 32% of the pts, and extramedullary involvement was present in 7% of pts. Complete response (CR) was reported in 10 (24%) pts including 1 patient with MRD. Hematological improvement was observed in 1 (3%) pt, stable disease was observed in 9 pts, 14 pts had progressive disease. The most common Grade 3/4 laboratory abnormalities were thrombocytopenia (60%), neutropenia (43%), anemia (21%), and hypophosphatemia (22%).

Conclusions: Nilotinib as a monotherapy appears to have promising activity and a favorable safety profile in relapsed/refractory Ph+ ALL pts. The use of nilotinib in combination with chemotherapy for Ph+ ALL merits further investigation.