Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph ؉ ) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph ؉ leukemia. Clinical dasatinib treatment in patients with CNS Ph ؉ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph ؉ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinibresistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials. gov as CA180006 (#NCT00108719) and

The FIP1L1-PDGFRA fusion gene is a recurrent molecular lesion in eosinophiliaassociated myeloproliferative disorders, predicting a favorable response to imatinib mesylate. To investigate its prevalence, 376 patients with persistent unexplained hypereosinophilia were screened by the United Kingdom reference laboratory, revealing 40 positive cases (11%).

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Primary myelodysplastic syndromes progress to acute myeloid leukaemia (AML) in about 30% of cases. We have sought evidence of pre-existing trilineage myelodysplasia (TMDS) using the FAB criteria (1982) in 160 consecutive cases of primary de novo AML. TMDS was found in 24 cases (15%) including two of 33 cases of M1 (6%), four of 40 cases of M2 (10%), none of 18 cases of M3, five of 31 cases of M4 (15%), six of 30 cases of M5 (20%), all of six cases of M6 and one of two cases of M7. The median presentation bone-marrow blast-cell count in the 24 AML/TMDS cases was 53% (30-90%) and 82% (45-100%) in the 136 cases of AML without TMDS. 60% of the AML/TMDS bone-marrow aspirates contained fewer than 60% of blasts compared with only 11% of those from AML without TMDS (P less than 0.001). In AML the occurrence of symptomatic cytopenias when the marrow blast-cell count is below 60% and the peripheral blood blast-cell count is below 20% is highly correlated with dysplastic haemopoiesis (P less than 0.001).

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We treated 14 patients with Ph-chromosome-positive chronic myeloid leukaemia still in chronic phase by autografting with blood-derived haemopoietic stem cells. Eleven patients were autografted electively after cytoreductive treatment with busulphan (16 mg/kg) and melphalan (60 mg/m2) and three were autografted after marrow cells from HLA-identical sibling donors had failed to engraft. In 13 patients haemopoiesis recovered; one failed to engraft and died 114 d after autografting. Two other patients became pancytopenic and received further stem cell transfusions at 3 and 40 months respectively after first autografting. One patient entered lymphoid transformation and died 14 months after autografting. Twelve patients survive at a median of 41 months (range 24-53) after autografting. Nine of the survivors have required further chemotherapy after autografting and four of the nine were electively autografted on a second occasion. Three patients surviving after autografting for 28, 43 and 53 months respectively have not required further chemotherapy. In two of these patients haemopoiesis is now predominantly Ph-negative. We conclude that autografting in chronic phase might prolong survival in some cases by reducing the size of the leukaemic stem cell population. The fact that initially successful grafts failed in two patients suggests that blood-derived stem cells may have a finite potential for self-replication.

Capillary leak syndrome (CLS) commonly occurs in the intensive care setting. CLS is seen in conditions such as septic shock or may result from conditions such as multitrauma and pancreatitis, which result in the systemic inflammatory response syndrome (SIRS). We present two cases in which both patients suffered with CLS, which we believe was caused following administration of granulocyte colony-stimulating factor, to our knowledge not described in the intensive care patient previously. We discuss how these patients management differs from other intensive care unit patients with CLS and how it is important to diagnose this condition early in haematological oncology cases.

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