Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.

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SummaryAlemtuzumab has shown considerable activity in untreated and relapsed chronic lymphocytic leukaemia. We report our long-term experience in 21 patients within a randomized phase III trial investigating the role of alemtuzumab for consolidation therapy after first-line fludarabine ± cyclophosphamide, which was stopped prematurely due to severe infections. However, after a median follow-up of 48 months, progressionfree survival was significantly prolonged for patients receiving alemtuzumab consolidation compared to those with no further treatment (P = 0AE004). Minimal residual disease (MRD) levels were persistently reduced after consolidation. Therefore, despite toxicity, MRD reduction by alemtuzumab consolidation translates into a significantly improved long-term clinical outcome.

While numerous mouse models of B cell malignancy have been developed via the enforced expression of defined oncogenic lesions, the feasibility of generating lineage-defined human B cell malignancies using mice reconstituted with modified human hematopoietic stem cells remains unclear. In fact, whether human cells can be transformed as readily as murine cells by simple oncogene combinations is a subject of considerable debate. Here, we describe the development of humanized mouse model of MYC/BCL2-driven “double-hit” lymphoma. By engrafting human hematopoietic stem cells transduced with the oncogene combination into immunodeficient mice, we generate a fatal B malignancy with complete penetrance. This humanized-MYC/BCL2-model (hMB) accurately recapitulates the histopathological and clinical aspects of steroid-, chemotherapy- and rituximab-resistant human “double-hit” lymphomas that involve the MYC and BCL2 loci. Notably, this model can serve as a platform for the evaluation of antibody-based therapeutics. As a proof of principle, we used this model to show that the anti-CD52 antibody alemtuzumab effectively eliminates lymphoma cells from the spleen, liver, and peripheral blood, but not from the brain. The hMB humanized mouse model underscores the synergy of MYC and BCL2 in “double-hit” lymphomas in human patients. Additionally, our findings highlight the utility of humanized mouse models in interrogating therapeutic approaches, particularly human-specific monoclonal antibodies.