A previous study in relapsed/refractory AML, combining re-induction chemotherapy with imatinib as a c-kit inhibitor, demonstrated that effective inhibition of downstream pAkt was associated with a higher CR rate (Brandwein et al, 2011). Nilotinib is also a c-kit inhibitor which diffuses into cells and is therefore not affected by potential defects in active cellular influx mechanisms.
Patients age 18-65 with acute myeloid leukemia (AML) who had persistent leukemia after 3+7 induction with cytarabine and daunorubicin, or relapsed within 24 months of achieving CR, and whose blasts were c-kit (CD117) positive, were enrolled in a phase I clinical trial with nilotinib on Days 1-12 combined with mitoxantrone 10 mg/m2/day IV Days 6-10, etoposide 100 mg/m2/day IV Days 6-10 and cytarabine 1.5 g/m2 IV q12h x 4 doses on Days 11-12. None of the cases harbored c-kit mutations. Nilotinib was escalated through 2 dose levels (400 mg daily and 400 mg BID) in successive 6 patient cohorts; up to 2/6 dose-limiting toxicities (DLTs) were permitted.
At the 400 mg once daily nilotinib dose there were 2 DLTs, both hematologic and consisting of prolonged platelet and neutrophil recovery. At the 400 mg BID dose there was one DLT, consisting of grade 3 transient liver enzyme elevation; 5/6 patients experienced transient grade I-II bilirubin elevations at this dose. The median time to ANC > 0.5 x109/L was 38 days (range 28-54) and to platelets > 20 x109/L was 30 days (range 28-54). Complete responses were seen in 10 patients, 5/6 at each dose level.
AML blasts from peripheral blood were assayed for pAKT, pERK and pS6 by flow cytometry, after stimulation with stem cell factor (SCF), on Days 1 and 6, pre- and 1.5 and 3 hours post-nilotinib dosing on each day. A decrease in the level of SCF-stimulated pAkt of at least 50% on Day 6 post-nilotinib, as compared to baseline, was seen in 1/6 patients at the 400 mg BID dose; the remaining 11 cases did not demonstrate an appreciable decrease in pAkt and other intermediates as compared to pre-nilotinib levels. Ex vivo dose titration curves showed that nilotinib inhibited c-kit mediated ERK and Akt activation in the blast cells of all cases, but concentrations >10 micromolar were needed to produce 50% inhibition in most cases.
The results indicate that nilotinib can be safely combined with this re-induction chemotherapy regimen, at doses up to 400 mg BID. Although the CR rate was high, in most cases nilotinib did not demonstrate significant inhibition of the c-kit pathway in leukemia cells in vivo. Dose titration curves showed that concentrations needed to produce 50% inhibition were generally above those achievable in vivo.
Brandwein:Novartis: Honoraria, Research Funding. Off Label Use: nilotinib for acute myeloid leukemia.
Asterisk with author names denotes non-ASH members.