Systemic mastocytosis is a myeloproliferative neoplasm with varying presentation that is caused by infiltration of neoplastic mast cells into extracutaneous tissues. Cytoreductive therapy is used to control organ dysfunction in aggressive systemic mastocytosis and is sometimes needed for control of severe refractory symptoms in patients with indolent disease. However, current standard cytoreductive agents are limited by their suboptimal degree and duration of response and associated significant toxicities, highlighting the need for novel treatments for systemic mastocytosis. Recent studies have identified CD30 as a therapeutic target in systemic mastocytosis, as CD30 is expressed on a majority of neoplastic mast cells. In this case series, the clinical outcomes of 4 patients with aggressive or indolent systemic mastocytosis treated with the anti-CD30 antibody-drug conjugate brentuximab vedotin are reported. Two patients showed evidence of a response to treatment with a reduction in disease burden, 1 of which has demonstrated a durable response with ongoing benefit for more than 3 years. Treatment with brentuximab vedotin was well-tolerated with side effects that were effectively managed by dose modifications. The results presented suggest that brentuximab vedotin is active in systemic mastocytosis and can induce durable responses with a manageable toxicity profile.

thrombocytopenia was 13 months (range 0-147), median platelet count at nadir was 12 Â 10 3 /ml (range 1-70), with all patients except one requiring specific therapy for thrombocytopenia. An exceedingly high prevalence of un-mutated IgVH was found in patients with IT (16 out of 20, 80%). For comparison only six out of 20 (30%) of controls showed un-mutated IgVH, a figure consistent with their early RAI stage. 3 The odds ratio of developing IT in un-mutated CLL could be estimated as 9.33 (95% CI 1.82-52.6, P ¼ 0.001). In addition, in patients who developed IT we found an excess of VH1 and VH3 families without any case of VH4, usually reported as one of the most frequent gene assortment in CLL 4,5 (P ¼ 0.0004, by w 2 test, see Table 1).Although the results of this study warrant further confirmation from multicenter investigations because of the low incidence of IT in CLL, for the first time they strongly correlate the development of IT to IgVH un-mutated status in CLL patients. One could speculate that in the un-mutated CLL group, which is characterized by a peculiar antibody reactivity and by a more aggressive clinical course, 6 there would be a major failure in controlling the emergence of auto-antibodies from normal B cells.

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Resistance to Ara-C, a deoxynucleoside analogue used to treat acute myeloid leukemia (AML) plays an important role in AML treatment failure and disease recurrence. Two different murine AML cell lines (B117P and B140P) derived from BXH2 mice were used to create highly Ara-C resistant cell lines (B117H and B140H) with consecutive in vitro selection. We performed oligonucleotide microarray analysis (430A GeneChip, Affymetrix) on triplicate samples of each of the four lines. Significance analysis of microarray, principal components analysis, hierarchical clustering, t-test and fold change analysis were performed (SAM and GeneData Expressionist Analyst) to identify an evaluable list of 555 genes that differed by 2-fold or greater with a p-value of 0.001 or less. Quantitative RT-PCR to confirm expression levels for the most relevant genes is in progress. Genes from several potentially interesting and relevant pathways (Ara-C metabolism, asparagine biosynthesis, cholesterol metabolism, DNA damage repair, and apoptosis) were identified. Nt5e and Nt5c2, involved in nucleotide catabolism and transport, were up-regulated in Ara-C resistant cells. Gstm1 and Gstt2, suspected to be involved in chemotherapy resistance, were also up-regulated in resistant cells. Interestingly, the gene asparagine synthetase (Asns) and several others involved in asparagine and glutamine metabolism (Nars, Asph, Got1, Glrp1) were altered in Ara-C resistant cells. L-Asparaginase, a drug commonly used to treat ALL, has previously been reported to be effective in treatment of relapsed or refractory AML. A number of genes involved in cholesterol and fatty acid metabolism were altered in resistant cells (Fdps, Acadl, Elovla6, Hdlbp, Hsd17b1). Recently farnesyl transferase and cholesterol biosynthesis inhibitors have shown activity in myeloid malignancies. The known inhibitors of apoptosis, Bcl2 and Bclxl, were up-regulated in Ara-C resistant cells. Additionally, a number of genes involved in the regulation of stress reponse were altered (Dnajc3, Dnajb10). Many genes involved in repair of DNA damage were down-regulated in resistant cells (Ddb1, Msh2, Msh6, Xpc, Xrcc5). Other genes known to be invovled in the pathogenesis of human AML and other malignancies (Kit, Kit/Scf, Cmet) were over-expressed, suggesting an additional role in chemoresistance. One of the most dramatically and significantly up-regulated genes was the amyloid beta (A4) precursor protein gene (App), which has previously been described in relation to its role in Alzheimer’s disease, although there has been another recent study describing its over-expression in AML with complex karyotype. In conclusion, we were able to clearly differentiate Ara-C sensitive from resistant murine AML cells with microarray analysis. Our data corroborate a number of genes well described in AML and chemotherapy resistance. We have also identified a number of novel genetic targets for future study in the therapeutic intervention of chemotherapy-resistant AML.