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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 1st 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.

No abstract

Background: Nilotinib, a potent and highly selective BCR-ABL inhibitor, has been approved in more than 50 countries including Mexico. Nilotinib is indicated for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) patients (pts) in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib (IM). Before the approval of nilotinib by FDA or EMEA a Compassionate Use Program (CUP) of nilotinib was initiated in Mexico. Methods: The pts included in this program were adults pts with Ph+ CML, IM-resistant or –intolerant in all phases of the disease. IM resistance and intolerance were defined according to current guidelines (NCCN and ELN). Physical examination, EKG, bone marrow aspiration, karyotyping and BCR-ABL mutation screening were performed in all pts before starting nilotinib. All pts signed an informed consent. Nilotinib was administered orally at a dose of 400 mg twice daily (BID). No dose escalation was allowed. All pts were monitored with karyotyping. Patients that achieved CCyR were evaluated with quantitative RT-PCR for molecular evaluation. The results of CUP of nilotinib in Mexico are reported in this abstract including the cytogenetic, qRT-PCR and mutational analysis in a highly-resistant CML patient population. Results: Between October 2006 and June 2007, 47 pts were included in the nilotinib CUP in Mexico. The median age was 41.7 years (range 22–68) and 20 (44%) were men. Of the 47 pts, 28 (59.6%) had advanced phase CML which includes 7 (14.9%) blastic phase (BP) and 21 (44.7%) accelerated phase (AP) pts. 19/47 pts (40%) were in chronic phase (CP) of CML. Most patients were resistant to IM (86%) and 14% were IM-intolerant/resistant. The median duration since CML diagnosis was 73.8 months (range 14–183). The median duration of prior IM use was 27.6 months. All pts had been treated with hydroxiurea, interferon, and/or cytarabine prior to IM. At the time of starting nilotinib 17/47 pts (36.12%) had BCR-ABL mutations (P-loop mutations in 3 pts, IM binding mutations in 5 pts, catalytic domain mutations in 5 pts, and A-loop mutations in 4 pts). Only 3/47 pts (6.38%) had T315I mutation. The median duration of exposure to nilotinib was 304 days (range 19–632). Most pts tolerated nilotinib well and only one severe adverse event (AE) was reported (long-term myelosupression). At the time of data cut-off (July 31, 2008), 25 pts (53.2%) remain on therapy. Reasons for discontinuation of therapy were: lack of efficacy in 7/47 pts (14.9%) including 3 pts with T315I mutation; disease progression in 13/47 (27.5%); adverse events in 1/47 (2.1%); lost of follow-up in 1/47 (2.1%). The cytogenetic and molecular evaluation was performed after 12 and 18 months of treatment with nilotinib, respectively. The rate of overall hematological response (HR) was 79%. The major cytogenetic response (MCyR) according the phase of the disease were as follows: 57% in CP, 40% in AP and no MCyR was observed in BP. Of the 47 pts, 11 (23.4%) achieved CCyR, 5 (10.63%) achieved molecular responses including 2 (4%) with complete molecular response (CMR) and 3 (6%) with major molecular response (MMR). The current status of pts according baseline mutational analysis was: mutation detected/alive (8/47, 17%); no mutation detectable/alive (22/47, 46.8%); mutation detected/deceased (9/47, 19.2%); no mutation detectable/deceased (8/47, 17%). Conclusions: Nilotinib showed efficacy in IM-resistant or -intolerant CML pts in Mexico regardless of the presence or absence of BCR-ABL mutations. Nilotinib induced complete cytogenetic and molecular responses in some of the advanced and resistant CML patient population.