Rituximab in combination with high-dose dexamethasone for the treatment of relapsed/refractory chronic lymphocytic leukemia
Introduction
Chronic lymphocytic leukemia (CLL), the most common leukemic disorder in the Western hemisphere [1], remains a difficult-to-treat disease despite remarkable improvements in diagnosis, prognostication, and therapy, with allogeneic transplantation being the only potentially curable option [2]. While combination of fludarabine, cyclophosphamide, and rituximab (FCR) is currently accepted as the gold standard in treatment of younger and physically fit CLL patients [3], [4], treatment of relapsed/refractory CLL remains highly challenging [5]. One of emerging treatment options for relapsed/refractory CLL is the use of high-dose corticosteroids [6]. High-dose methylprednisolone (HDMP, 1 g/m2 for 5 days repeated every 4 weeks) has been used in monotherapy [7], [8], in combination with rituximab [9], [10], [11], [14] or alemtuzumab [12]. Life-threatening infections are the most serious side effects. Use of high-dose dexamethasone (40 mg on days 1–4 repeated every 28 days) with rituximab in six CLL patients (pts) has been recently reported in a small study with similar activity to R–HDMP [13]. Therefore, the aim of the present project was to retrospectively assess the efficacy and toxicity of rituximab–dexamethasone (R–dex) combination in pts with relapsed/refractory CLL.
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Patients and methods
Between September 2008 and August 2010, we treated 54 patients (pts) with relapsed/refractory CLL requiring therapy by R–dex regimen at two tertiary centers. Inclusion criteria were: patients with flow-cytometry confirmed CLL and relapsed or refractory disease. Patients with Richter's transformation were not eligible. Patients with concurrent CLL progression and active autoimmune hemolytic anemia, immune thrombocytopenia or pure red cell aplasia were also eligible. Staging investigations
Results
Both patient groups displayed highly unfavorable prognostic factors (high proportion of advanced Rai stages, unmutated IgVH, del 11q, bulky disease – see Table 1). Median cycles of R–dex was 1 (range, 1–3) in Group 1 and 5 (range, 1–8) in Group 2. The only pretreatment parameter with significant difference between the two groups was incidence of bulky disease (higher in Group 2, p = 0.0012); however, it is important to emphasize that this was not a randomized study and was not powered to detect
Discussion
Use of high-dose corticosteroids in relapsed/refractory CLL was first reported by Thornton in 1999 with promising activity [7]. Logical combinations of rituximab and HDMP (and a pilot study of alemtuzumab plus HDMP) were later published by several groups [9], [10], [11], [12], [13], [14]. The overall response rate ranged from 62% [14] to 93% [10], [11]. It is important to point out that most of the published results are pilot studies with only two having more than 20 pts [9], [14]. We herein
Conclusions
We conclude that R–dex appears to be an active and feasible treatment option for relapsed/refractory patients with CLL with no unexpected toxicities. Efficacy is remarkable in patients with autoimmune cytopenias, these patients could be treated safely with FCR after resolution of AIHA/ATP with R–dex. Furthermore, R–dex was very effective in improving anemia, thrombocytopenia and B-symptoms caused by CLL. Finally, the regimen appears to be a reasonable option for debulking before allogeneic stem
Conflict of interest
L.S., M.D., A.P., M.S., Y.B., D.B., M.M., and J.M. have received honoraria and/or travel grants from Roche.
Acknowledgements
Supported by grants IGA NS9858-4/2009, IGA NS10439-3/2009, IGA MZ ČR NT11218-6/2010, GAČR P301/10/0590, MPO FR-TI2/254, IGA NT/13412, by the Research Project MZO00179906 and MSM0021622430. The work was also supported by Czech CLL Study Group (CSGCLL) and Czech Leukemia Study Group for Life (CELL).
Contributions. L.S. and M.D. contributed equally to this work. L.S. and M.D. provided the conception and design of the study, acquisition of data, analysis and interpretation of data, drafted the
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