Abstract
Our previous work showed that the major histocompatibility complex class II–related protein CD74 is overexpressed from the very early stages of chronic lymphocytic leukemia (CLL). Activation of CD74 with its ligand MIF leads to survival signals in all stages. Furthermore, it leads to increased VLA-4 expression, with resultant homing to the bone marrow in advanced stages of the disease. We also showed that blocking CD74 with the humanized monoclonal antibody milatuzumab leads to increased apoptosis and decreased migration to the bone marrow. We therefore decided to translate our results to a clinical trial using milatuzumab. So far, 6 patients with advanced refractory CLL have been recruited. Three of the 6 patients showed significant improvement in cytopenia, with no need for blood transfusions in 2 patients who were transfusion-dependent before enrolment. Five of 6 patients had significant improvement in B symptoms and functional level. No patient died or had significant treatment-related toxicity during the study period. Patient samples showed a decrease in bcl-2 , mcl-1 and VLA-4 mirroring those that we observed in the xenograft mouse model. Our results thus far, combinedwithdata fromother studiesofmilatuzumabintheUnitedStates, suggest that this agent is safe and improves quality of life and functional abilityofamongfrailelderlypatientswithadvanced-stageCLL.Thefindings also suggests that milatuzumab should be given continuously; in most patients, theeffectsdecreasedafter a shortperiodofdiscontinuationof therapy, in terms of both in clinical and laboratory variables. One patient received milatuzumab for more than 1 year with no significant adverse effects.
Published Version
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