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Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined leukemia stem cells, while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anticancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived antiapoptotic proteins. Notably though, treatment with flavaglines, alone or in combination with other drugs, yields a much stronger cytotoxic activity toward leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Taken together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia. [ABSTRACT FROM AUTHOR]

RhoH is a hematopoietic-specific, GTPase-deficient member of the Rho GTPase family that functions as a regulator of thymocyte development and T-cell receptor signaling by facilitating localization of zeta-chain-associated protein kinase 70 (ZAP70) to the immunological synapse. Here we investigated the function of RhoH in the B-cell lineage. B-cell receptor (BCR) signaling was intact in Rhoh(-/-) mice. Because RhoH interacts with ZAP70, which is a prognostic factor in B-cell chronic lymphocytic leukemia (CLL), we analyzed the mRNA levels of RhoH in primary human CLL cells and showed a 2.3-fold higher RhoH expression compared with normal B cells. RhoH expression in CLL positively correlated with the protein levels of ZAP70. Deletion of Rhoh in a murine model of CLL (Emu-TCL1(Tg) mice) significantly delayed the accumulation of CD5(+)IgM(+) leukemic cells in peripheral blood and the leukemic burden in the peritoneal cavity, bone marrow and spleen of Rhoh(-/-) mice compared with their Rhoh(+/+) counterparts. Phosphorylation of AKT and ERK in response to BCR stimulation was notably decreased in Emu-TCL1(Tg);Rhoh(-/-) splenocytes. These data suggest that RhoH has a function in the progression of CLL in a murine model and show RhoH expression is altered in human primary CLL samples. [ABSTRACT FROM AUTHOR]

Rituximab has modest activity in relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma but is associated with tumor necrosis factor-alpha (TNF-alpha) release that can cause CLL proliferation and inhibit apoptosis. We examined whether disruption of TNF-alpha by etanercept improves response to rituximab in CLL. Eligible patients had previously treated CLL with performance status 0-3. Patients received etanercept 25 mg subcutaneously twice weekly (weeks 1-5) and rituximab 375 mg/m(2) intravenously thrice weekly (weeks 2-5) using a phase I/II design. Primary end points were response and toxicity. The 36 enrolled patients had a median of two prior treatments; 50% were fludarabine refractory and 22% had del(17p13.1). Of the 34 response-evaluable patients, 10 (29%) responded, including 9 partial responses and 1 complete remission. Response was not affected by prior rituximab or fludarabine-refractory status, but no patients with del(17p13.1) responded. Median progression-free survival for responders was 9.0 months (range 1-43). Ten patients have had treatment-free intervals exceeding 12 months, including four who have remained untreated for 32, 43, 46 and 56 months. Adverse events were mild, including mild infusion reactions, transient cytopenias and grade 3 infections in 14% of the patients. The combination of etanercept and thrice weekly rituximab produces durable remissions in non-del(17p13.1) CLL patients and is well tolerated. [ABSTRACT FROM AUTHOR]

Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1–12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 μg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3–6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2–5). Four patients developed delayed neutropenia (weeks 10–13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes >5 cm, lasting a median of 6.5 months (range 5–13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials.Leukemia (2005) 19, 1207–1210. doi:10.1038/sj.leu.2403782 Published online 28 April 2005 [ABSTRACT FROM AUTHOR]