decreased activity against HMC-1.2 cells (IC 50 ¼ 15 mM). Dasatinib inhibited proliferation of both cell lines, albeit with 2-3 log less potency against HMC-1.2 as compared to HMC-1.1 (IC 50 ¼ 308 and 1 nM, respectively).We found KIT and JAK2 to be constitutively phosphorylated in HMC-1.1 and HMC-1.2 cells, in the absence of exogenous cytokines (Figure 1). Consistent with observations from aforementioned in vitro enzyme assays, TG101348 did not inhibit phosphorylation of KITV560G or KITD816V within the context of the two HMC-1 clones at concentrations up to 25 mM (Figure 1, top panel). In contrast, imatinib mesylate potently inhibited the kinase activity of KITV560G, but not KITD816V, with IC 50 for receptor phosphorylation of o150 and 425 mM, respectively ( In summary, we have shown the viability of targeting JAK-STAT signaling downstream of KITD816V in human mast cell leukemia cells as a potentially novel therapeutic approach in SM. Our experience to date with currently available JAK2-selective drugs, such as TG101348, which are orally bioavailable and have a favorable safety profile, leads us to believe that clinical trials with such agents for SM therapy are warranted. Recent clinical experience with TG101348 has shown that it is feasible to achieve serum drug concentrations that are predicted, based on our data, to be therapeutically relevant in SM. The concurrent use TG101348 and dasatinib targets known signaling pathways of major pathogenetic relevance in SM, namely KIT, JAK-STAT and SRC; this approach is clinically feasible given the synergy between the two drugs that should permit therapeutic activity to be manifest at doses that are lower than those used as monotherapy, thereby preserving an overall favorable therapeutic safety profile.
for the SFGM-TC Previous data suggested that allo-SCT might be an effective therapy in the setting of chemo-refractory/relapsed diseases because of the potent long-term immune-mediated tumor control. This retrospective study aimed to analyze the outcome of adult patients who received allo-SCT in a chemo-refractory/relapsed status. The series included 840 patients with active or progressive disease at the time of transplant. Median age was 50 years. With a median follow-up of 40 months, 3-year OS, disease-free survival (DFS), and non-relapse mortality rates were 29 ± 2, 23 ± 2, and 30 ± 2%, respectively. At the last follow-up, 252 patients (30%) were still alive (of whom 201 were in CR (24%). In a Cox multivariate analysis, the use of a reduced-intensity conditioning (RIC) before allo-SCT and use of an HLA-identical sibling donor remained independently associated with a better OS (hazard ratio (HR) ¼ 0.82; 95% confidence interval (CI), 0.69-0.98, P ¼ 0.03; and HR ¼ 0.79; 95% CI, 0.66-0.93, P ¼ 0.006, respectively). Also, a diagnosis of myelodysplastic syndrome/myeloproliferative disorder, Hodgkin lymphoma and non-Hodgkin lymphoma compared with acute leukemia had a favorable impact on OS (HR ¼ 0.55; 95% CI, 0.45-0.68, Po0.0001; HR ¼ 0.49; 95% CI, 0.31-0.75, P ¼ 0.001; and HR ¼ 0.47; 95% CI, 0.35-0.63, Po0.0001, respectively). In conclusion, this study suggests that allo-SCT may be of benefit in some subgroups of patients with active or progressive hematological malignancies at the time of allo-SCT.
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