A canadian perspective on the first-line treatment of chronic lymphocytic leukemia.

Despite important advances in the treatment of first-line chronic lymphocytic leukemia (CLL) over the past decade, CLL remains an incurable disease with significant unmet needs. The combination of rituximab with fludarabine and cyclophosphamide (FCR) significantly improved overall survival and progression-free survival compared with fludarabine and cyclophosphamide alone in first-line treatment of CLL. However, because of its high toxicity, FCR is only recommended for younger, fit patients who can tolerate the treatment. This excludes a large fraction of CLL patients who are elderly and/or who have comorbidities. Thus, determining the appropriate treatment choices for this group of patients who are unfit for FCR treatment is a significant challenge in CLL. Current treatment choices in Canadian practice include bendamustine with rituximab, fludarabine with rituximab, and chlorambucil with rituximab. Two novel monoclonal antibodies, ofatumumab and obinutuzumab, have also recently received Health Canada approval for the first-line treatment of CLL patients in combination with chlorambucil. In addition, the Bruton tyrosine kinase inhibitor, ibrutinib, has recently been approved by Health Canada for the first-line treatment of CLL patients with deletion 17p. In the coming years, several other novel agents that are being developed are likely to change the CLL treatment landscape dramatically, however, because these novel agents are currently unavailable, the purpose of this review is to recommend the best treatment approaches in Canada using currently available therapies.

Evidence that donor intrinsic response to G-CSF is the best predictor of acute graft-vs-host disease following allogeneic peripheral blood stem cell transplantation.

OBJECTIVE: Risk factors of acute graft-vs-host disease (GVHD) following allogeneic bone marrow transplantation have been well described before. In this study, we tested the hypothesis that acute GVHD after allogeneic peripheral blood stem cell (PBSC) transplant might be associated with donors' responsiveness to granulocyte colony-stimulating factor (G-CSF), rather than the dose of CD34(+) cells infused. PATIENTS AND METHODS: We retrospectively analyzed mobilization and transplant data (demographic characteristics, donor blood cell subsets after G-CSF, graft composition) in 149 consecutive HLA-identical donor/recipient pairs in order to identify acute GVHD risk factors. RESULTS: In 25% of donors, G-CSF mobilization led to an outstanding response, defined as greater than 117 x 10(6) CD34(+) cells/L. Overall, incidence of grades II-IV acute GVHD was 20.1% (95% CI: 16.6-23.6). Following univariate analysis, the incidence increased significantly in recipients receiving greater than 10 x 10(6) CD34(+) cells/kg (35% vs 15%; p = 0.007), and those transplanted from outstanding mobilizers (41% vs 12%, p < 0.0001). In multivariate analysis, only transplantation from outstanding mobilizers remained significant (p = 0.02). Donor or recipient demographic characteristics and lymphocyte subsets reinfused in the graft had no impact. CONCLUSIONS: We demonstrate for the first time that donor responsiveness to G-CSF is associated with acute GVHD following PBSC transplantation. If confirmed, this correlation will help to identify recipients who could potentially benefit from improved prophylaxis. As further corollary, decreasing the dose of CD34(+) cells infused is unlikely to prevent acute GVHD. Future studies should focus on the molecular bases of interindividual discrepancies in response to G-CSF.