Clofarabine and high-dose cytosine arabinoside in the treatment of refractory or relapsed acute myeloid leukaemia.

Clofarabine (40 mg/m(2)/day × 5) and high-dose cytosine arabinoside (Ara-C, 1-2 g/m(2)/day × 5) were used in 10 men and 11 women, at a median age of 45 (22-62) years, with refractory (N = 4) and relapsed (N = 17) acute myeloid leukaemia, after a median of 3 (2-5) prior regimens. Grade 4 myelosuppression was observed in all cases, with two patients dying of bacterial sepsis. Nine patients achieved a complete remission. Disease status, number of prior therapies, and cytogenetic aberrations were not associated with the outcome. However, remission was only achieved with Ara-C at 2 g/m(2)/day and not 1 g/m(2)/day (9/15 versus 0/4, P = 0.03).

BCR-ABL mutational studies for predicting the response of patients with chronic myeloid leukaemia to second-generation tyrosine kinase inhibitors after imatinib failure.

Imatinib is the standard treatment for chronic myeloid leukaemia. BCR-ABL kinase domain mutation is the commonest mechanism implicated in imatinib resistance. In in-vitro studies, kinase domain mutations are variably resistant to second-line agents. We performed BCR-ABL kinase domain mutational studies in 25 patients in five institutions who failed imatinib and were treated with either nilotinib or dasatinib, to see if their mutational status would predict their clinical responses. Kinase domain mutations involving 11 amino acid substitutions were found in 12 (48%) patients. Most patients showed single kinase domain mutations. There was some concordance between reported drug sensitivity patterns and patient responses. Discordant responses could be related to drug dosage variations and unknown BCR-ABL independent mechanisms. The response prediction for patients with multiple kinase domain mutations was challenging and their mutational patterns could change after tyrosine kinase inhibitor therapy. Although BCR-ABL kinase domain mutational analysis has limitations as a means of predicting the clinical response to second-line tyrosine kinase inhibitors, it helps inform therapy decisions in the management of chronic myeloid leukaemia after imatinib failure.

4q loss is potentially an important genetic event in MM tumorigenesis: identification of a tumor suppressor gene regulated by promoter methylation at 4q13.3, platelet factor 4.

In this study, we have elucidated the chromosomal imbalances in the multistep pathogenesis and delineated several critical tumor suppressor gene (TSG) loci in multiple myeloma (MM). By using comparative genomic hybridization, allelotyping, and multicolor interphase fluorescence in situ hybridization, 5 MM cell lines and bone marrow CD138+ plasma cells from 88 Chinese patients with monoclonal gammopathy of undetermined significance (MGUS) and early and advanced stages of MM were investigated. In all MGUS and MM samples, chromosome copy number abnormalities were detected. A higher number of chromosomal imbalances and specific genetic alterations are involved in MGUS to MM transition (-6q, +3p, and +1p) and MM progression (+2p and +9q). In addition to -13q, we first found high frequencies (42% to 46%) of -4q involving high percentages (70% to 74%) of clonal plasma cells in both MGUS and MM, suggesting that inactivation of TSG in this region is also a potentially critical genetic event in MM tumorigenesis. By high-resolution allelotyping, we defined a common deletion region on 4q13.3 and found that a candidate TSG, platelet factor 4, was frequently silenced by promoter hypermethylation in MM (15 of 28) and MM cell lines (5 of 5). These data have opened up a new approach in the molecular targeting therapy and provide novel insights into MM tumorigenesis.