Rituximab combined with cladribine or with cladribine and cyclophosphamide in heavily pretreated patients with indolent lymphoproliferative disorders and mantle cell lymphoma

Authors


  • Presented in preliminary form at the 11th Congress of the European Hematology Association, Amsterdam, the Netherlands, June 15–18, 2006.

Abstract

BACKGROUND

In vitro studies have shown synergistic or additive interactions between rituximab and purine nucleoside analogues. The results of recent clinical trials seem to confirm these preclinical observations.

METHODS

For the current study, the authors evaluated the feasibility, efficacy, and toxicity of combined regimens that consisted of either rituximab plus cladribine (2-CdA) (the RC regimen) or RC plus cyclophosphamide (the RCC regimen) in the treatment of patients with heavily pretreated, indolent lymphoid malignancies. Fifty-four adult patients with recurrent or refractory, low-grade non-Hodgkin lymphoma (LG-NHL) and B-cell chronic lymphocytic leukemia (B-CLL) were treated according to the RC/RCC regimens. The RC protocol consisted of intravenous rituximab at a dose of 375 mg/m2 on Day 1 and 2-CdA at a dose of .12 mg/kg per day on Days 2 through 6. The RCC protocol consisted of rituximab at a dose of 375 mg/m2 on Day 1, 2-CdA at a dose of 0.12 mg/m2 on Days 2 through 4, and intravenous cyclophosphamide at a dose of 250 mg/m2 per day on Days 2 to 4. The RC/RCC courses were repeated at 4-week intervals.

RESULTS

Thirty-three patients with B-CLL, 12 patients with LG-NHL and 9 patients with mantle cell lymphoma (MCL) entered the study. Thirty-three patients (61%) had recurrent disease after prior therapy, and 21 patients (39%) had refractory disease. Thirty-one patients were treated on the RC regimen, and 23 patients were treated on the RCC regimen. Six patients (11%) achieved a complete response, and 33 patients (60%) achieved a partial response. The median failure-free survival of responders was 10.5 months. The treatment revealed tolerability, with episodes of severe neutropenia (Grade 3 and 4 [according to World Health Organization criteria]) observed in 6 patients (11%), episodes of Grade 3 and 4 infections observed in 11 patients (20%), and episodes of Grade 3-4 thrombocytopenia observed in 4 patients (7%).

CONCLUSIONS

The RC and RCC regimens were highly effective and well tolerated modalities of treatment in heavily pretreated patients with indolent lymphoproliferative disorders. Cancer 2006. © 2006 American Cancer Society.

The purine nucleoside analogs (PNAs) fludarabine (FA), cladribine (2-CdA), and pentostatin (deoxycoformycin [DCF]) represent a group of cytotoxic agents with high activity in indolent lymphoid malignancies (ILM).1, 2 More recently, the chimeric anti-CD20 monoclonal antibody rituximab has emerged as an effective single agent for patients with CD20-positive B-cell lymphoma.3, 4 Rituximab and PNAs have nonoverlapping mechanisms of action and, consequently, lack cross-resistance.5, 6 Several recent in vitro studies have shown synergistic or additive effects of rituximab combined with FA or 2-CdA.6, 7 The results of recent clinical studies confirm these preclinical observations and suggest that, in patients with ILM, rituximab in combination with FA can increase the response rate, including the complete response (CR) rate, compared with FA or rituximab alone and has acceptable toxicity.8–12 In our preliminary study, we demonstrated that the combination of rituximab and 2-CdA is an effective and well tolerated treatment even for heavily pretreated patients with ILM, and the results appeared to be better than the results produced in patients who were treated previously in our institution with 2-CdA alone.13

Taking into account the observation that the combination of PNA with cyclophosphamide may be more effective than PNA alone, the combined use of rituximab with FA or 2-CdA and cyclophosphamide is an attractive option.14 Investigators at The University of Texas M. D. Anderson Cancer Center have observed high activity of the rituximab, FA, and cyclophosphamide (RFC) regimen in previously treated and untreated patients with B-cell chronic lymphocytic leukemia (B-CLL).8, 9 The protocol that combines DCF, cyclophosphamide, and rituximab also showed high activity in pretreated patients with B-CLL.15, 16 In this report, we present the results of our study evaluating the feasibility, efficacy, and toxicity of the combined regimens consisting of rituximab plus 2-CdA (the RC regimen) or RC plus cyclophosphamide (RCC) in the treatment of patients with heavily pretreated ILM, B-CLL, and low-grade non-Hodgkin lymphoma (LG-NHL), and we also included patients with mantle cell lymphoma (MCL).

MATERIALS AND METHODS

Between March 2001 and November 2005, 54 adult patients with recurrent or refractory B-CLL or LG-NHL entered the study after giving their informed consent. The diagnosis was based on the World Health Organization (WHO) classification for LG-NHL17 and the National Cancer Institute-sponsored Working Group guidelines for B-CLL.18 Pretreatment evaluation included physical examination; complete blood count; reticulocyte count; Coombs test; serum chemistry profile, including lactate dehydrogenase (LDH) level; renal and liver function tests; serum immunoglobulin levels; urinalysis; bone marrow biopsy; chest X-ray; electrocardiogram; and imaging studies of the abdomen with computed tomography. Immunophenotyping was performed on leukemic peripheral blood and bone marrow by flow cytometry using a simultaneous dual color-staining technique before treatment. Immunophenotype was determined by using the monoclonal antibodies against the following antigens: CD19/CD5, CD19/CD23, CD20/CD5, CD19/CD22, CD3/CD4, and κ and λ light chains. The clinical stage of B-CLL was determined at the time of initiation of RC or RCC treatment according to the classification of Rai et al.,19 and LG-NHL stage was determined as outlined by the Ann Arbor Conference. All patients had undergone treatment of at least 2 lines of chemotherapy, including 1 alkylating agent and prednisone, and had either failed to respond (refractory disease) or developed progressive disease after the discontinuation of previous treatment (recurrent disease). Further inclusion criteria were a WHO performance status of 0, 1, or 2; age at least 18 years; a life expectancy of 3 months; and, in patients with LG-NHL and MCL, at least 1 area of measurable disease. The patients had to be free of active infections and must not have received radiation or chemotherapy at least 3 weeks prior to the initiation of RC or RCC treatment. Only patients with CD20-positive malignant cells were included into the studies. Exclusion criteria were human immunodeficiency virus infection; any significant organ dysfunction (i.e., elevated creatinine [>2 mg/dL], elevated total bilirubin [>2 mg/dL], elevated transaminases or alkaline phosphatase [>2 × normal values]); and symptoms of heart failure (New York Heart Association Grade III or IV). Pregnant or lactating women also were excluded. The protocol was approved by our local ethical committee (no. RNN/84/06/KE), and all patients were required to provide written informed consent prior to treatment.

Treatment Protocols

The RC protocol consisted of the anti-CD20 monoclonal antibody rituximab at a dose of 375 mg/m2 as a 6-hour intravenous infusion on Day 1 and 2-CdA (Biodribin; Bioton, Warsaw Poland) given at a dose of 0.12 mg/kg per day on Days 2 through 6 according to the previously described method.13 The antibody was diluted in normal saline up to a maximum concentration of 1 mg/mL. Premedication with acetaminophen 250 mg and diphenhydramine 50 mg was administered. In the RCC protocol, rituximab was administered at a dose of 375 mg/m2 as a 6-hour intravenous infusion on Day 1. 2-CdA was administered at a dose of .12 mg/kg as a 2-hour intravenous infusion on Days 2 through 4. Cyclophosphamide was administered at a dose of 250 mg/m2 intravenously on Days 2 through 4. If a response was documented, then patients were treated until maximal response or prohibitive toxicity was achieved. If no response or progression of the disease was observed after 2 courses, then the treatment was interrupted. The cycles were repeated every 28 days. In patients who had a platelet count <50 × 109/L, and/or a neutrophil count <1.0 × 109/L, or who developed an infection, drug administration was resumed at time intervals >4 weeks until recovery of hematologic parameters or recovery from infection was noted. No patients received antibiotics, antiviral agents, or hematopoietic growth factors prophylactically. However, granulocyte-colony stimulating factor (G-CSF) was given if patients had an absolute granulocyte count <1 × 109/L and active infection was present.

Response and Toxicity Criteria

Guidelines for response were those developed by the National Cancer Institute-sponsored Working Group for patients with B-CLL18 and for patients with LG-NHL.20 Toxicity was monitored and assessed according to WHO criteria.

Statistical Analysis

Ninety-five percent confidence intervals (95% CIs) for response probability were calculated by using the method described by Duffy and Santner.21 Failure-free survival was calculated from the time patients achieved a complete response (CR) or a partial response (PR) after RC or RCC to the time of recurrence or death. Overall survival was measured from the first date of treatment to the date of death from any cause or to the date of last observation. The duration of response was calculated from the time of onset of PR or CR to the time of recurrence, last follow-up, or death. In addition, significant differences in response to treatment or in the frequency of side effects were calculated by using the chi-square test.

RESULTS

Fifty-four patients (33 patients with B-CLL, 12 patients with LG-NHL, and 9 patients with MCL) were enrolled onto the study, and all of them were available for evaluation of response. Their characteristics are presented in Table 1. All patients received ≥5 cycles of chemotherapy before RC or RCC treatment. The median number of different regimens of first-line and second-line therapy administered in particular patients was 2 regimens per patient (range, 1–5 regimens per patient). Thirty-three patients (61%) had disease recurrence after prior therapy, and 21 patients (39%) had refractory disease. In total, 154 courses of RC/RCC were given to the entire group. All patients received ≥2 courses of RC/RCC. The median number of RC/RCC courses was 3 (range, 2–6 courses). Thirty-nine patients responded (72%; 95%CI, 21–40%), including 79% of patients with B-CLL (95% CI, 65–93%), 62% of patients with LG-NHL (95% CI, 34–89%), and 67% of patients with MCL (95% CI, 36–98%). Six patients (11%; 95% CI, 1–36%) achieved a CR, and 33 patients (60%; 95% CI, 43–77%) achieved a PR. The remaining 15 patients (28%; 95% CI, 5–51%) had either stable disease or developed disease progression.

Table 1. Patient Characteristics
CharacteristicNo. of patients
TotalRCRCC
  1. RC indicates rituximab and cladribine; RCC, RC and cyclophosphamide; B-CLL, B-cell chronic lymphocytic lymphoma; LG-NHL, low-grade non-Hodgkin lymphoma; MCL, mantle cell lymphoma.

Total no. of patients543123
Gender: no. of patients (%)
 Male27 (50)18 (58)9
 Female27 (50)13 (42)14
Median age (range), y55 (33–80)55.5 (33–80)54 (35–73)
Diagnosis
 B-CLL331716
 Rai stage at diagnosis (before RC/RCC treatment)
   Stage II844
   Stage III1064
   Stage IV1578
 LG-NHL1275
  Histology
   Follicular lymphoma844
   Small lymphocytic lymphoma220
   Marginal zone lymphoma211
  Ann Arbor stage (before RC/RCC treatment)
   Stage II211
   Stage III1082
   Stage IV954
 MCL972
  Ann Arbor stage (before RC/RCC treatment)
   Stage III543
   Stage IV431
Median no. of previous regimens (range)2 (1–5)2 (1–5)2 (1–4)
No. of patients pretreated with 2-CdA422418
Pretreatment
 No. of prior chemotherapy courses641338303
 Median no. of prior pretreatment (range)8 (5–22)8.5 (5–22)8 (5–18)

According to the particular regimen, the overall response (OR) was obtained in 22 patients (71%) for RC and in 17 patients (74%) for RCC (Table 2). A CR was observed in 4 patients (13%) who received RC and in 2 patients (9%) who received RCC, and a PR was observed in 18 patients (58%) who received RC and in 15 patients (65%) who received RCC. No statistically significant differences in response to RC versus RCC were noted.

Table 2. Comparison of Activity and Toxicity of the Rituximab and Cladribine Schedule and the Rituximab, Cladribine, and Cyclophosphamide Schedule
CharacteristicNo. of patients (%)P
RC (n = 31)RCC (n = 23)
  1. RC indicates rituximab and cladribine; RCC, RC and cyclophosphamide; OR, overall response; CR, complete response; PR, partial response.

OR22 (71)17 (74).924
CR4 (13)2 (9).693
PR18 (58)15 (65).794
Median OR duration (range), mo13 (3–37)8 (4–15).722
Grade 3/4 neutropenia2 (6)4 (17).261
Grade 3/4 thrombocytopenia04 (17).026
Grade 3/4 anemia2 (6)2 (9).772
Grade 3/4 infections7 (22)4 (17).702
Treatment-related deaths01 (4).251

The responses to RC/RCC according to diagnosis are summarized in Table 3. OR was obtained in 26 patients (79%) with B-CLL, in 7 patients (58%) with LG-NHL, and in 6 patients (67%) with MCL and no statistically significant differences were observed in response to RC versus RCC within the particular groups. Detailed characteristics of the patients who responded to RC/RCC are shown in Tables 4 and 5 .

Table 3. Response to the Rituximab and Cladribine Schedule and the Rituximab, Cladribine, and Cyclophosphamide Schedule According to Diagnosis
DiagnosisNo. of patientsNo. of patients (%)
ORCR
TotalRC*RCC*TotalRC*RCC*
  • OR indicates overall response; CR, complete response; RC, rituximab and cladribine, RCC, RC and cyclophosphamide; B-CLL, B-cell chronic lymphocytic leukemia; LG-NHL, low-grade non-Hodgkin's lymphoma FCL, follicular cell lymphoma; SLL, small cell lymphoma; MZL, marginal zone lymphoma; MCL, mantle cell lymphoma.

  • *

    RC vs. RCC: The differences were not statistically significant.

B-CLL3326 (79)13 (39)13 (39)2 (7)1 (3)1 (3)
LG-NHL127 (58)5 (42)2 (17)2 (17)2 (17)0
 FCL84 (50)3 (37)1 (12)1 (12)1 (12)0
 SLL22 (100)2 (100)01 (50)1 (50)0
 MZL21 (50)01 (50)000
MCL96 (67)4 (44)2 (22)2 (22)1 (11)1 (11)
Total5439 (72)22 (41)17 (31)6 (11)4 (8)2 (4)
Table 4. Characteristics of Patients with B-Cell Chronic Lymphocytic Leukemia who Responded to Rituximab and Cladribine/Rituximab, Cladribine, and Cyclophosphamide Therapy
Patient no.ProtocolRai stagePrior treatment (No. of courses)No. of RC coursesMean weeks between coursesResponse to treatment
  1. RC indicates rituximab and cladribine (2-CdA); VP, etoposide; PR, partial response; Chl, chlorambucil; COP, cyclophosphamide, vincristine, and prednisone; CHOP, COP plus doxorubicin; CR, complete response; CHOP-Bleo, CHOP and bleomycin; Ida, idarubicin; CVP, cyclophosphamide, vinblastine, and prednisone; CC, cyclophosphamide and 2-CdA; RCC, RC and cyclophosphamide; CMC, CC and mitoxantrone; FC, fludarabine and cyclophosphamide.

1RCIV2-CdA + VP (6)24PR
2RCIV2-CdA (6), Chl (2)45.5PR
3RCIIICC (2), CHOP (3)35PR
4RCIIChl (12)54PR
5RCIVChl (9)55CR
6RCIVChl (6), COP (3)24PR
7RCIIIChl (5)64PR
8RCIIIChl (6)310PR
9RCIICC (3), CHOP (2)44PR
10RCIVChl (5), CC (3)35PR
11RCIIIChl (3), 2-CdA (11), CHOP (6)35PR
12RCIIICC (3), CHOP (7)44.5PR
13RCIVChl (9), CHOP (2)64PR
14RCCIIChl (6)44PR
15RCCIICMC (×5)44PR
16RCCIIICMC (3), C + VP (2)44.5PR
17RCCIVCMC (6), 2-Cda + VP (5)36PR
18RCCIVCMC (7), COP (1), CC (1)54PR
19RCCIVCMC (5), CHOP (3)44PR
20RCCIVChl (×3), FC (×6)44PR
21RCCII2-CdA (5), COP (6)36PR
22RCCIVCC (7)48PR
23RCCIVCampath (6 months)44PR
23RCCIVChl (6), 2-Cda (3), CC (3)64PR
25RCCIVCC (6), CHOP (6)34PR
26RCCIVCC (12), C + VP (2)64CR
Table 5. Characteristics of Patients with Low-Grade Non-Hodgkin Lymphoma and Mantle Cell Lymphoma who Responded to Rituximab and Cladribine/Rituximab, Cladribine, and Cyclophosphamide Therapy
Patient no.DiagnosisProtocolAnn Arbor stagePrior treatment (No. of courses)No. of RC coursesMean weeks between coursesResponse to treatment
  1. RC indicates rituximab and cladribine (2-CdA); LG-NHL, low-grade non-Hodgkin lymphoma; FCL, follicular cell lymphoma; CHOP, cyclophosphamide, vincristine, prednisone, and doxorubicin; PR, partial response Bleo, bleomycin; CMC, cyclophosphamide and mitoxantrone; CR, complete response; CC; cyclophosphamide and 2-CdA; RCC, RC and cyclophosphamide; COP, cyclophosphamide, vincristine, and prednisone; SLL, small lymphocytic lymphoma; CVP, cyclophosphamide, vinblastine, and prednisone; Ida, idarubicin; MZL, marginal zone lymphoma; MCL, mantle cell lymphoma; VP, etoposide; Ch1, chlorambucil.

LG-NHL
 1FCLRCIIICHOP (5)35PR
 2FCLRCIIICHOP (7), CHOP-Bleo (4), CMC (4)54CR
 3FCLRCIIICHOP (4), CC (2)34.5PR
 4FCLRCCIVCOP (10), CHOP (10)34PR
 5SLLRCIICOP (12); CVP (4), Ida + 2CdA (2); CMC (4)55.5PR
 6SLLRCIVCHOP (8)34CR
 7MZLRCCIICHOP (7), 2-Cda + VP (3)34PR
MCL
 1MCLRCIIICHOP (5)44CR
 2MCLRCIVCHOP (8), 2-CdA (1), Chl (1)35PR
 3MCLRCIIICOP (5)36PR
 4MCLRCIIICHOP (4), CMC (2)54.5PR
 5MCLRCCIVCOP (5)36CR
 6MCLRCCIIICHOP (4), CMC (2)44.5PR

The median follow-up for the entire group was 17.5 months (range, 3–46 months). There was no statistical difference in failure-free survival between patients with B-CLL, LG-NHL and MCL (log-rank test; P < .5). Fifteen patients (28%) who achieved a CR or a PR were still in remission at the time of this report with a median follow-up of 10.5 months (range, 3–37 months). During the whole period of follow-up, 16 patients died, including 15 deaths died from disease progression and 1 treatment-related death. There were significant differences in overall survival between responders and nonresponders after either the RC regimen or the RCC regimen (log-rank test; P = .003 and P = .005, respectively) (Fig. 1A,B). There were no statistically significant differences between responders to RC and RCC either in overall survival (log-rank test; P = .128) or failure-free survival (log-rank test; P = .724) (Fig. 2A,B).

Figure 1.

Kaplan–Meier overall survival (OS) curves for response to the (A) rituximab plus cladribine (RC) regimen and (B) RC plus cyclophosphamide regimen. A significant difference was observed between responders and nonresponders, as assessed by the log-rank test, for both treatment regimens.

Figure 2.

Kaplan–Meier survival curves for responders to the rituximab plus cladribine (RC) regimen and the RC plus cyclophosphamide (RCC) regimen. (A) Overall survival (OS) and (B) failure-free survival (FFS) are illustrated for patients who responded to either RC or RCC. There was no statistical difference noted in FFS or OS between those patients who received RC and those who received RCC.

Hypersensitivity to rituximab (fever, chills, rush, hypotonia) was the major toxicity of the RC/RCC regimens and occurred in 19 patients (35%), including 13 patients (42%) who received RC and 6 patients (26%) who received RCC (Table 6). These symptoms were observed mostly during the first infusion of rituximab. The treatment was stopped only in 1 patient after the first cycle because of a severe allergic reaction during the second administration of rituximab. Severe neutropenia (Grade 3-4) was observed in 6 patients (11%), including 2 patients (6%) who received RC and 4 patients (17%) who received RCC. Eleven episodes (20%) of Grade 3 or 4 infections were observed, including 7 episodes (22%) after RC and 4 episodes (17%) after RCC. They were 5 episodes (9%) of severe pneumonia (3 episodes after RC and 1 episode after RCC), 1 (4%) herpes zoster infections (both after RC), and 3 episodes (6%) of influenza-like syndrome (2 episodes after RC and 1 episode after RCC). Overall, 6 patients (11%) received G-CSF support, including 2 patients on the RC regimen and 4 patients on the RCC regimen. One patient died from severe pneumonia complicated by septic shock after the second cycle of RCC. A Grade 3 anemia associated with RC/RCC treatment was observed only in 4 patients (7%), including 2 patients (6%) who received RC and 2 patients (9%) who received RCC. Grade 3 or 4 thrombocytopenia occurred in 4 patients (7%), and all 4 patients received RCC (vs. RC; P = .026).

Table 6. Toxicity of the Rituximab and Cladribine Schedule and the Rituximab, Cladribine, and Cyclophosphamide Schedule
ToxicityB-CLLLG-NHL and MCLTotal
No. of patients (%)No. of courses (%)No. of patients (%)No. of courses (%)No. of patients (%)No. of courses (%)
  1. B-CLL indicates B-cell chronic lymphocytic leukemia; LG-NHL, low-grade non-Hodgkin lymphoma; MCL, mantle cell lymphoma; PRCA, pure red-cell aplasia.

Total33 (100)43 (100)21 (100)39 (100)54 (100)71 (100)
Neutropenia
 Grade 1-26 (18)10 (23)3 (14) (Grade II only)6 (15)9 (17)15 (21)
 Grade 3-44 (12)7 (17)2 (9)7 (18)6 (11)12 (17)
Thrombocytopenia
 Grade 1-22 (6)2 (5)1 (5)6 (15)3 (5.55)8 (11)
 Grade 3-42 (6)6 (14)2 (9)8 (20)4 (7)12 (17)
Anemia
 Grade 1-24 (12)3 (7)2 (9)8 (20)6 (11)5 (7)
 Grade 34 (12)4 (9)04 (7)5 (7)
PRCA
 Grade 1-21 (3)2 (5)01 (1.9)32 (45)
Grade 3-4 infections7 (21)3 (7)4 (19)5 (13)11 (20)4 (6)
 Herpes zoster02 (9)6 (15)2 (4)6 (8)
 Pneumonia4 (12)1 (2.3)1 (5)3 (8)5 (9)3 (4)
 Influenza3 (9)3 (7)03 (5)3 (5)5 (7)
Hypersensitivity  (fever, chills, hypotension)12 (36)5 (12)7 (33)4 (10)19 (35)10 (14)

DISCUSSION

In the current report, we have presented up-dated results on the effectiveness and toxicity of rituximab combined either with 2-CdA or with 2-CdA plus cyclophosphamide in patients with resistant or recurrent ILM and MCL. The results indicate high activity and good tolerability of both combinations. Among 54 evaluated patients, the response to treatment was observed in 38 patients (72%), including 6 patients (11%) who achieved a CR. These results seem to be superior to those achieved earlier with 2-CdA alone, as reported by us and by other authors.22–24 The RC/RCC regimens also seem at least to be equally as efficient as 2-CdA in combination with cyclophosphamide and prednizone25 and cyclophosphamide combined with either mitoxantrone26 or etoposide.27 Laurencet et al.25 reported a response in 88% patients, including 4 CRs among 19 patients who received 2-CdA combined with cyclophosphamide and prednisone. However, 11 of those patients were not treated previously, and no patients in the examined group received PNAs. In contrast, 42 patients (78%) in our current study were treated previously with 2-CdA, including 12 patients who received 2-CdA plus cyclophosphamide (CC) and 9 patients who received 2-CdA combined with mitoxantrone, and cyclophosphamide (CMC), and showed resistance to this therapy.

The high effectiveness of rituximab in patients with ILM also was observed when the drug was given in combination with 2 other PNAs: FA and DCF.5, 8–12, 28–32 Those studies showed that the combined use of rituximab and FA or DCF, with or without cyclophosphamide, resulted in higher OR and CR rates compared with rituximab or PNA alone. It is noteworthy that rituximab increases the effectiveness of standard chemotherapy regimens used in ILM. Marcus et al.33 showed in a randomized clinical trial that the addition of this antibody to a regimen of cyclophosphamide, vincristine, and prednisone significantly prolonged the time to disease progression and had no influence on treatment toxicity.

The randomized studies in NHL and B-CLL have shown that 2-CdA and FA have equivalent action in those disorders.34, 35 Moreover, preliminary results from a randomized study comparing the CC protocol with the FA plus cyclophosphamide (FC) protocol showed similar response and cytotoxicity for both regimens in patients with B-CLL.36 Based on those results, we expected that RCC and CC would have action similar to that of combined FA, cyclophosphamide, and rituximab (FCR) and FC, respectively, in patients with indolent malignancies.

Both the RC regimen and the RCC regimen were tolerated well in our heavily pretreated patients. Hypersensitivity to rituximab was the most common side effect and was observed in 19 patients (35%). Severe Grade 3 or 4 neutropenia developed in only 6 patients (11%), and Grade 3 or 4 infections developed in 9 patients (17%). Grade 3 or 4 thrombocytopenia was observed in 4 patients (7%), and it is noteworthy that it occurred in all 4 of those patients after they received RCC. In general, according to our experience, RC/RCC treatment is distinctly less toxic and is at least as effective as the CMC regimen used by us in similar groups of heavily pretreated patients ILM.26 Equally good tolerability was observed in patients who received combinations of rituximab with FA or DCF.30–32

We did not observe any statistically significant differences in response to RC and RCC in the examined groups of patients. However, our study was not randomized; therefore, it did not allow us to determine definitively whether the RCC regimen was more effective than the RC regimen. Other previously performed, randomized studies in patients with untreated B-CLL showed that the addition of cyclophosphamide to PNAs increased their activity with only a slight enhancement of toxicity.37, 38 However, our current data do not indicate an advantage of RC or RCC. A prospective, randomized study comparing the efficacy of both protocols in patients with B-CLL is necessary and already has been planned.

In conclusion, both the RC regimen and the RCC regimen were found to have high therapeutic activity and relatively low cytotoxicity in heavily pretreated patients with ILM and MC. Based on these results, further prospective, randomized studies evaluating the efficacy of those protocols appear to be warranted.

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