A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL)

Abstract

7040 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib. In a phase I trial, nilotinib demonstrated efficacy and favorable tolerability in these pts. These results expand upon the phase I experience Methods: This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in adult imatinib-resistant or - intolerant BC pts or pts with relapsed/refractory Ph+ALL. Primary endpoint was investigator assessment of best hematologic response for BC and complete response for Ph+ALL pts. Nilotinib was started at 400mg BID with escalation to 600mg BID if no adequate response. Results: Safety and efficacy data are reported for 120 BC (27 lymphoid, 87 myeloid, 6 unknown) and 41 Ph+ALL pts (37 active disease, 4 residual disease, 38 relapsed, 3 refractory). 60% of pts had >35% Ph+ metaphases for BC and 31% for Ph+ALL. Median ages was 54 yrs for BC and 46 yrs for Ph+ALL pts. Chromosomal abnormalities other than Ph+ were noted in 64 (53%) BC and 12 (29%) Ph+ALL pts. Extramedullary involvement was present in 44 (37%) BC and 3 (7%) Ph+ALL pts. Treatment is ongoing for 21 (18%) BC and 4 (10%) Ph+ALL pts. Majority of discontinuations were due to disease progression [61 (51%) in BC; 26 (63%) in Ph+ALL). Median treatment duration was 53 (1–441) and 72 (3–363) days for BC and Ph+ALL, respectively. Median dose intensity was 800mg/day for both pt groups. CHR was reported in 25 (21%) pts, marrow responses in 7 (6%) pts, and return to chronic phase in 10 (8%) pts. Complete response was reported in 10 (24%) Ph+ALL; of which, 1 patient had minimal residual disease. The most common Grade 3/4 AEs were thrombocytopenia (41%), neutropenia (28%), pneumonia (11%), and anemia (27%) in BC and thrombocytopenia (24%) in Ph+ALL pts. During study period death occurred in 9 (8%) BC and 3 (7%) Ph+ALL pts. No Ph+ALL pt developed CNS disease while on therapy. Conclusions: Nilotinib has significant clinical activity and is well tolerated in imatinib-resistant or -intolerant BC and relapsed/refractory Ph+ALL pts. Nilotinib represents an important new treatment option for these pts in which there remains a high unmet medical need. No significant financial relationships to disclose.

Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia

“…Notably, hematologic and CyRs were achieved with dasatinib in a substantial number of patients with advanced stage CML and Ph+ ALL [ 74 , 76 – 78 ]. This latter result is in marked contrast to the limited activity observed with imatinib and nilotinib in LBC CML and Ph+ ALL [ 66 , 82 ], further suggesting a potential role of SFKs in advanced disease. Collectively, the clinical data support the preclinical findings implicating SFKs in CML progression and imatinib resistance, and suggest that dual SFK/BCR-ABL inhibition may be more effective than inhibition of BCR-ABL alone.…”

Chronic Myeloid Leukemia Therapy: Focus on Second-Generation Tyrosine Kinase Inhibitors

“…49 A third phase II, open-label study evaluated the efficacy and tolerability of nilotinib in 120 patients with imatinib-resistant or intolerant CML in blast crisis (27 lymphoid, 87 myeloid, and 6 unknown) or relapsed/ refractory Ph+ ALL (38 relapsed, 3 refractory). 50 Best HR was evaluated for the BP-CML patients, while Ph+ ALL patients were evaluated for complete responses. Nilotinib was administered at 400 mg twice daily, with escalation to 600 mg twice daily for inadequate responses.…”

“…Of the 41 patients with Ph+ ALL, 10 patients (24%) achieved a complete response. 50 Twelve-month follow-up data are available evaluating efficacy of nilotinib in patients with BP-CML who are either resistant or intolerant to imatinib. 51 This phase II, open-label study evaluated 136 patients in BP-CML (105 myeloid blast crisis, 31 lymphoid blast crisis).…”

Treatment of Chronic Myeloid Leukemia Following Imatinib Resistance

“…Nilotinib (400 mg twice daily) was approved in 2007 based on results from a single phase II open-label trial in patients with Note. Based on information from Baccarani et al, 2006;Cortes et al, 2007;Larson et al, 2007;Martinelli et al, 2006;Rosti et al, 2007. CP or AP CML following imatinib failure. Marked activity was observed in patients with CP or AP CML resistant to or intolerant of imatinib (Kantarjian, Hochhaus, et al, 2007;le Coutre et al, 2007).…”