Compassionate Use of Nilotinib (AMN107) in Mexican Patients with Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Imatinib.

Background: Nilotinib is a novel tyrosine kinase inhibitor(TKI) developed for the treatment of Ph+ CML patients(pts) with intolerance or resistance to imatinib. Phase I and II studies have shown efficacy and safety of nilotinib, however access to clinical development trials may be limited in some parts of the world. Alternatively, an investigational drug may be obtained as part of a Compassionate Use Program (CUP). We hereby describe the on-going results of the nilotinib compassionate use in Mexico prior to its approval by the Ministry of Health in March 2007.

Methods: The study population included adult pts with Ph+ CML, imatinib-resistant or-intolerant. Imatinib resistance was defined as:<15% blasts in peripheral blood or bone marrow; < 30% blasts plus promyelocytes in peripheral blood and bone marrow;<20% basophils in the peripheral blood;>/=100 × 10⁹/L (>/=100,000/mm³)platelets; no evidence of extramedullary leukemic involvement, with the exception of liver or spleen. Physical exam, EKG, bone marrow aspiration, karyotyping and screening for BCR-ABL mutations were performed in all pts before 1^st nilotinib dose. All pts gave their consent. Nilotinib was administered orally at a dose of 400 mg twice daily(BID) and was continued for as long as the Investigator felt there was clinical benefit and no safety concerns or until disease progression or development of drug intolerance. No dose escalation was allowed.

Results: Between October 2006 and June 2007, 53 pts were enrolled in the nilotinib CUP in Mexico. This analysis included data for the first 43 pts. The median age was 41.7(22–68) years;19(44%) were men and 24(56%) were women. Most pts (20, 47%) had accelerated phase (AP),15(35%) had chronic phase(CP), and 8 (19%) pts had blastic crisis(BC). The median duration since CML diagnosis was 73.8(14–183) months. The median duration of prior imatinib use was 27.6 months.37 pts(86%) were considered resistant. At the time of starting nilotinib, only 13(32%) pts presented BCR-ABL mutations (mutations reported were E355G, T315I, M351T, F359[V,F], F317L, F486[S,F], G250E, M315[T,M], E453K and F486[S,F]). The median duration of nilotinib exposure was 100 days. Most pts tolerated nilotinib well and 30(70%) remain on therapy at the time of data cut-off. The rate of overall hematological response (HR) was 79%. The most common hematological and non-hematological adverse events (AE) regardless of causality were:anemia(31%), neutropenia(21%), thrombocytopenia(34%) and pancytopenia(14%). Most common non-hematological AEs were rash(44%), fatigue (21%), bone pain(6%). All other non-hematologic AEs occurred at incidence of less than 5%. Biochemical abnormalities included elevation of indirect bilirubin(9%), alterations in AST/ALT(3%) and hyperglycemia(3%)

Conclusions: Nilotinib showed remarkable efficacy in imatinib-resistant or -intolerant CML pts in Mexico and was generally well tolerated.