ALBERT

Description: INTRODUCTION: Several studies have reported the presence of expanded T-cell clones in patients with multiple myeloma (MM), which could be involved in an anti-tumour response and extended survival. The Human Leukocyte Antigen (HLA) system seems to play an essential role in MM control and could influence disease control. This feature has been poorly studied and there are only few data favouring higher incidence of some HLA specifities such as B18 and B5 in myeloma patients. AIM: To compare HLA-DRB1 phenotypic frequencies in smoldering MM versus symptomatic MM patients and control individuals. PATIENTS: A total of 181 patients with a diagnosis of MM were analysed. According to their behaviour patients were classified into two subsets: 128 symptomatic MM who were homogeneously treated according to the GEM-2000 protocol (Spanish Myeloma Group/PETHEMA protocol) and 53 patients with the diagnosis of smoldering MM according to the criteria of the International Myeloma Working Group and who were free of therapy for at least 1 year following diagnosis. Additionally, 1818 healthy donor individuals from the Castilla y Leon registry for hematopoietic stem cell-transplantation were included as control population. All three populations involved Caucasian individuals. METHODS: After genomic DNA extraction, HLA-DRB1 typing at low-resolution level (two digits) was carried out using the PCR-rSSO methodology according to the standards of the European Federation of Immunogenetics. Allele frequencies were estimated by direct counting. Comparisons of allele and phenotype frequencies between populations were performed with the two-sided Fisher’s exact test using GraphPad Prism 4.0 Software. The strength of associations was estimated by the odds ratio (OR), and their 95% confidence intervals (CI) were calculated by Cornfield methods (values of p 〈 0.05 were considered statistically significant). P-value was corrected (Pc) for the number of valid comparisons made (Bonferroni correction). RESULTS: DRB1 phenotypic frequencies were not significantly different among MM patients and healthy control individual. In contrast, when the two MM cohorts were analyzed, DRB1*01 phenotypic frequencies were significantly higher in the smoldering patients as compared to symptomatic MM patients (37.7% vs. 14.1, p=0.0011, Pc=0.0143, OR: 3.7, 95% CI: 1.76–7.81). Furthermore, DRB1*01 phenotypic frequencies were significantly higher in the smoldering patients as compared to the healthy control individuals (37.7% vs. 21.7%, p=0.0106, Pc〉0.05, OR: 2.19, 95% CI: 1.24–3.86). In addition, symptomatic MM patients showed a higher incidence in DRB1*07 phenotypic frequencies as compared to control population (38.3% vs. 27.6%, p=0.0111, Pc〉0.05, OR: 1.63, 95% CI: 1.12–2.36). CONCLUSIONS: The present data suggest that HLA-DRB1*01 phenotype is associated with indolent MM and this may reflect a better ability to efficiently present myeloma-related antigens to immunocompetent cells.

Description: 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:/=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.