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The most important thing is to keep your routine the same, because the biggest enemy that I've found is distraction. So if you can develop a routine at home and […]

Sometimes you just lighten things up. One time. I brought out a pirate sword during a speech and compared players' being ready to how a sword is ready. They kind […]

Alemtuzumab is a humanized anti-CD52 antibody licensed for refractory B-cell chronic lymphocytic leukemia (B-CLL), when given intravenously at 30 mg thrice weekly. However, the intravenous route is associated with infusion-related reactions and is inconvenient. We measured blood concentrations in 30 relapsed patients treated with intravenous alemtuzumab and in 20 patients from a previously untreated group who received similar doses subcutaneously. Highest trough samples in the intravenous group were less than 0.5 μg/mL to 18.3 μg/mL (mean 5.4 μg/mL). The cumulative dose required to reach 1.0 μg/mL was 13 mg to 316 mg (mean 90 mg). Higher blood concentrations correlated with the achievement of better clinical responses and minimal residual disease. The highest measured concentrations in the subcutaneous group were similar (0.6 μg/mL to 24.8 μg/mL, mean 5.4 μg/mL). However, the cumulative dose to reach 1.0 μg/mL was higher: 146 mg to 1106 mg (mean 551 mg). No antiglobulin responses were detected in 30 patients given intravenous alemtuzumab whereas 2 of 32 patients given subcutaneous alemtuzumab made substantial anti-idiotype responses. Thus, subcutaneous alemtuzumab achieved concentrations similar to those for intravenous alemtuzumab, although with slightly higher cumulative doses. Subcutaneous alemtuzumab is more convenient and better tolerated but may be associated with some patients forming anti–alemtuzumab antibodies, particularly those patients who were previously untreated.

Travers: Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. McKay:Janssen: Honoraria, Speakers Bureau; Epizyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leach:Abbvie: Honoraria; Janssen: Consultancy, Honoraria; Roche: Honoraria.

Middleton: GlaxoSmithKline UK Ltd: Research Funding. Leach:GlaxoSmithKline UK Ltd: Research Funding. Michie:GlaxoSmithKline UK Ltd: Research Funding. Wheadon:GlaxoSmithKline UK Ltd: Research Funding.

Recent advances in chronic lymphocytic leukaemia (CLL) biology indicate that a plethora of micro-environmental factors are important in promoting the pathogenesis of the disease. As B cell antigen receptor (BCR) signalling plays a critical role in CLL progression, we chose to study the effect of dasatinib, a dual src/abl tyrosine kinase inhibitor, on CLL cells, thus targeting the key, BCR-proximal tyrosine kinases Lyn and c-Abl that are over-expressed in CLL. We were interested to determine the impact of BCR-signalling directed therapy on CLL cell viability in the context of the leukaemic micro-environment.Clinically relevant concentrations of dasatinib (100 nM) both inhibited ERK-MAPK and Akt phosphorylation, and prevented calcium mobilisation following BCR crosslinking. Furthermore, dasatinib prevented up-regulation of Mcl-1 observed on prolonged BCR stimulation, abrogating the BCR-driven increase in CLL cell survival. Dasatinib induced apoptosis of CLL cells, with a mean reduction in viability of 35.2% ± 3.8% following 48 hr exposure (n=26). Neither ZAP-70 expression nor cytogenetic abnormalities were predictive of response. In addition, dasatinib exhibited synergy with both fludarabine and chlorambucil, with mean ED50 combination indices of 0.29 and 0.62 respectively. Additional micro-environmental elements responsible for the maintenance and progression of CLL include stromal or ‘nurse-like’ cells and activated T lymphocytes, the latter of which express CD40 ligand and secrete IL-4. CLL cell co-culture with the murine bone marrow stromal cell line NT-L significantly inhibited both spontaneous and dasatinib induced apoptosis. As we observed that stromal co-culture significantly increased phosphorylation of both ERK-MAPK and the Akt/mTOR target p70 S6 kinase in CLL cells, we investigated whether pharmacological inhibition these signalling pathways may re-sensitise CLL cells to dasatinib in co-culture. Both the MEK inhibitor PD98059 and PI3K inhibitor LY294002 significantly increased the level of apoptosis observed on dasatinib treatment of CLL cells in stromal co-culture. Dasatinib also retained the ability to potentiate the effects of fludarabine and chlorambucil in stromal co-culture, however, CLL cells co-cultured with NT-L cells stably transfected with CD40 ligand (CD154L cells) were resistant to all drug combinations. Furthermore, on CD154L/IL-4 co-culture, dasatinib failed to prevent up-regulation of Bcl-xL and Mcl-1, or inhibit CLL cell proliferation.While dasatinib was capable of reversing BCR-mediated survival signals, it was unable to overcome stromal-derived survival signals, indicating that combination of dasatinib with agents targeting antigen-independent micro-environmental pathways are required to effectively target CLL cells in tissue niches.No relevant conflicts of interest to declare.

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