Nilotinib Is Associated with Minimal Cross Intolerance to Imatinib in Patients with Imatinib-Intolerant Philadelphia-Positive (Ph+) Chronic Myelogenous Leukemia (CML) in Either Chronic Phase (CP) or Accelerated Phase (AP).

Nilotinib, a highly selective BCR-ABL tyrosine kinase inhibitor that is 30-fold more potent than imatinib, represents an important treatment option for pts with imatinib-resistant or -intolerant Ph+CML. Reported are results from a phase II, open-label study evaluating the safety and efficacy of nilotinib in imatinib-resistant or -intolerant Ph+CML. Imatinib resistance was defined as treatment with imatinib ≥600 mg/d with disease progression (≥50% increase in WBCs, blasts, basophils, or platelets) or no hematologic response after 4 wks. Imatinib intolerance was defined as no prior MCyR and discontinuation of imatinib due to Grade 3/4 AE or persistent (>1 mo) or recurrent Grade 2 AE (recurred >3x) despite optimal supportive care. Nilotinib-imatinib cross-intolerance was defined as treatment with nilotinib and occurrence (regardless of causality) of Grade 3/4 of the same AE that led to discontinuation of imatinib therapy. Planned starting dose was nilotinib 400 mg BID but could be escalated to 600 mg BID for lack of response. Of 320 pts with CML-CP, 94 (29.4%) were enrolled for imatinib-intolerance for either nonhematologic and/or hematologic AEs, of these, 71 (76%) had Grade 3/4 AEs at study entry. Of 127 pts with CML-AP, 24 (18.9%) were enrolled for nonhematologic and/or hematologic imatinib-intolerance; of these, 16 (67%) had Grade 3/4 AEs at study entry. Some pts had >1 AE satisfying criteria for intolerance. Only 2/71 (3%) pts with nonhematologic imatinib-intolerance experienced a recurrence of similar Grade 3/4 AEs during nilotinib therapy. Of 37 pts with hematologic intolerance to imatinib, 19/37 (51%) did not develop Grade 3/4 or similar events during nilotinib therapy. Median duration of nilotinib exposure was 350.5 days in CML-CP and 141.5 days in CML-AP with median dose intensities of 725.8 mg/d and 768.8 mg/d, respectively. Only 1 pt (CML-AP) required a dose escalation to 600 mg BID. Although nilotinib and imatinib have some molecular similarities, these results support previous findings of minimal occurrence of cross-intolerance. These results also suggest important differences in safety profiles between imatinib and nilotinib. Thrombocytopenia appears to be the only intolerant AE that may recur with nilotinib. These results support nilotinib’s excellent tolerability and indicate that it can be used effectively in both CML-CP and -AP pts with imatinib-intolerance.