Elsevier

Leukemia Research

Volume 36, Issue 10, October 2012, Pages 1278-1282
Leukemia Research

Rituximab in combination with high-dose dexamethasone for the treatment of relapsed/refractory chronic lymphocytic leukemia

https://doi.org/10.1016/j.leukres.2012.07.005Get rights and content

Abstract

Background

High-dose methylprednisolone is active in treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) but infectious toxicity is serious. The aim of this project was to retrospectively assess efficacy and safety of high-dose dexamethasone combined with rituximab (R–dex) in this setting.

Patients and methods

We treated 54 patients (pts) with relapsed/refractory CLL using R–dex regimen at two tertiary centers. Two schedules of rituximab were used (not randomized – based on the choice of the center): group 1, rituximab 500 mg/m2 day 1, 8, 15, 22 (375 mg/m2 in 1st dose) every 4 weeks (n = 29); group 2, 500 mg/m2 day 1 (375 mg/m2 in 1st cycle) repeated every 3 weeks (n = 25). The target dose of dexamethasone was 40 mg on days 1–4 and 10–13 or 15–18. Rai III/IV stages were present in 82%, unmutated IgVH genes in 82%, del 11q in 38% and del 17p in 19% pts; 46% had bulky lymph nodes; 82% were pretreated with fludarabine and 29% with alemtuzumab.

Results

Overall response rate/complete remissions were 62/21% (Group 1) and 72/4% (Group 2). In three patients, R–dex was successfully used for debulking before nonmyeloablative allogeneic stem cell transplantation. R–dex was particularly effective in improvement of anemia and thrombocytopenia (p = 0.0055 and p = 0.0036); B-symptoms resolved after treatment in 11/17 pts. Hematological toxicity was mild. Serious infections occurred in 32% pts. At the median follow-up of 9 and 10 months, median progression-free survival was 6 months in Group 1 and 6.9 months in Group 2 (p = ns); median overall survival was 14.1 months in Group 1 vs. not reached in Group 2 (p = ns).

Conclusions

R–dex appears to be an active and feasible treatment for relapsed/refractory CLL. Infectious toxicity remains an important issue. Further investigation of this regimen in larger studies appears fully warranted.

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.

Section snippets

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

References (18)

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