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Keywords:

  • immunochemotherapy;
  • fludarabine;
  • cyclophosphamide;
  • and rituximab;
  • Waldenstrom macroglobulinemia;
  • purine analogs

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

BACKGROUND:

The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced promising results in chronic lymphocytic leukemia and other lymphoproliferative disorders. The authors report the final results from a multicenter, prospective study examining FCR in Waldenstrom macroglobulinemia (WM).

METHODS:

Forty-three patients with symptomatic WM that was untreated or pretreated with 1 line of chemotherapy received rituximab 375 mg/m2 intravenously on day 1 and fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 intravenously on days 2 through 4. FCR was repeated every 28 days for up to 6 courses.

RESULTS:

The overall response rate was 79%, and the major response rate of 74.4%, including 11.6% complete remissions (CRs) and 20.9% very good partial remissions. An amelioration of the quality of responses was observed during follow-up, leading to 18.6% of CRs. No differences in terms of responses were observed among previously treated or untreated patients. Among the clinical and laboratory features that were considered, only the β2-microglobulin level had a significant impact in terms of achieving a major response. The major toxicity reported was grade 3/4 neutropenia, which occurred in 45% of courses and was the main reason for treatment discontinuation. After the end of treatment, 19 patients (44%) had long-lasting episodes of neutropenia. Three patients developed myelodysplastic syndrome during follow-up.

CONCLUSIONS:

The FCR regimen was capable of neutralizing adverse prognostic factors and proved to be active in patients with WM, leading to rapid disease control and good-quality responses. Because myelosuppression was the main concern, further studies are warranted to optimize dosages and treatment duration. Cancer 2011;. © 2011 American Cancer Society.

Waldenstrom macroglobulinemia (WM) is a low-grade lymphoproliferative disorder characterized by bone marrow (BM) infiltration with lymphoplasmacytic cells along with the presence of a monoclonal immunoglobulin M (IgM) in serum.1 Over the last 20 years, purine nucleoside analogues have been used in monotherapy for the treatment of WM and have proven to be effective as both front-line and salvage therapy. In the largest studies, response rates of 30% to 40% and duration of response of 20 to 24 months have been reported with the use of fludarabine.2-6

Subsequent attempts to augment response rates have been made combining purine analogues with alkylating agents.7-10 Although the combination of fludarabine and cyclophosphamide has led to high overall response (OR) rates (range, 55%-85%), in all series, the responses have been categorized only as partial responses (PRs).

Rituximab, a chimeric monoclonal antibody that targets the B-lymphocyte antigen CD20, has been used successfully in the treatment of WM, because most tumor cells widely express CD20.11-14 Response rates to rituximab monotherapy reportedly vary between 20% and 50% irrespective of whether patients have been exposed previously to chemotherapy. An increase in the clinical activity of rituximab, mostly in terms of the time to progression, reportedly was observed using an extended schedule in which 8 infusions of 375 mg/m2 per week were administered in weeks 1 through 4 and weeks 12 through 16.15, 16

Preclinical data based on lymphoma cell lines indicated that rituximab sensitized cells to both fludarabine and cyclophosphamide, enhancing their cytotoxic activity.17, 18 Furthermore, in some cell lines, fludarabine exposure resulted in the down-regulation of complement-defense proteins CD55 and CD59.19, 20

Clinical trials in patients with WM produced a high response rate and long-lasting responses when rituximab was added to nucleoside analogues.10, 21, 22-26 Treon et al administered rituximab together with fludarabine to 43 patients with WM and obtained an objective response in 95.3% of patients with a median time to progression of 51.2 months.21 Similar response rates have been observed in smaller series of patients after the introduction of cyclophosphamide in regimens that contained either cladribine or pentostatine in association with rituximab (94% and 90%, respectively).10, 22

Experience with the combination of fludarabine, cyclophosphamide, and rituximab (FCR) in WM is limited.24-26 The only experience published in the literature is a report by Tam et al, who obtained a 56% PR rate with this regimen in 9 patients with WM.24 A better OR rate (79%) was achieved in our pilot study, which included heavily pretreated and untreated patients.26 Although no patients achieved complete remission (CR) after the first response evaluation, an improvement in the quality of response was observed in 66% of patients later during follow-up. To confirm the efficacy of the FCR regimen, we designed a multicenter, prospective clinical trial that included 43 patients with WM who were previously untreated or pretreated with 1 line of chemotherapy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Patients with a diagnosis of WM who were symptomatic and required therapy based on the consensus recommendation of the Second International Workshop on Waldenstrom Macroglobulinemia27 and who had received ≤1 previous therapies were eligible for the study. Patients were excluded if they had received prior rituximab or concurrent fludarabine and cyclophosphamide. All patients provided informed written consent in accordance with the declaration of Helsinki and the institutional guidelines.

To be enrolled in the study, patients had to meet the following pretreatment laboratory criteria: alanine transaminase and aspartate transaminase levels ≤3 times the upper limit of normal; total bilirubin ≤2 times the upper limit of normal, unless clearly related to the disease; and a calculated or measured creatinine clearance ≥60 mL per minute. Baseline evaluation consisted of physical examination, blood counts, hepatic and renal function tests, serum and urine electrophoreses, quantification of serum immunoglobulins, β2-microglobulin level, BM aspiration and biopsy, and computed tomography scans of the chest, abdomen, and pelvis.

The FCR regimen consisted of rituximab 375 mg/m2 intravenously on day 1 and fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 intravenously on days 2 through 4. Rituximab premedication included intravenous diphenhydramine and oral acetaminophen. During treatment and for 6 months after the end of treatment, patients received prophylaxis for Pneumocystis carinii with oral trimethoprim-sulfamethoxazole thrice weekly and for herpes simplex and zoster infection with acyclovir 800 mg daily.

Courses were repeated every 28 days, depending on recovery of blood counts, for a maximum of 6 cycles. For episodes of grade 3/4 hematologic toxicity, treatment was withheld until the patient recovered to pretreatment baseline values. A 25% dose reduction of fludarabine and cyclophosphamide was allowed for grade 3/4 cytopenia, and a subsequent 25% further reduction was allowed for other episodes of grade 3/4 cytopenias. Erythropoietin administration was permitted during therapy. Granulocyte colony-stimulating factor administration was allowed at the physician's discretion either as prophylaxis or at the onset of neutropenia.

Before each course of treatment, 1 month after the completion of FCR, and every 3 months during follow-up, patients underwent physical examination, blood counts, hepatic and renal function tests, serum protein electrophoresis, and serum IgM quantification. The first disease reassessment, with BM evaluation and CT scans (for patients who had extramedullary disease at baseline), was performed after the third course of treatment; patients who had progressive disease at that assessment were removed from the study. BM evaluations and CT scans were performed to confirm response or progression after the end of treatment. During follow-up, restaging also consisted of BM biopsy and aspiration (to confirm CR or to evaluate a change in response), CT scans, or abdominal ultrasound studies at the physician's discretion.

Patients who received at least 1 day of FCR were eligible for the toxicity and response assessment, and the results were evaluated on an intent-to-treat basis. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria. All adverse events and serious adverse events were recorded, and serious adverse events that were collected during treatment and 6 months post-treatment were reported to the local authorities.

Responses were assessed using modified consensus panel criteria from the Third International Workshop on Waldenstrom Macroglobulinemia.28 A CR was defined as the resolution of all symptoms, normalization of serum IgM levels with the complete disappearance of IgM paraprotein by immunofixation, no evidence of disease on BM examination, and the resolution of any adenopathy or splenomegaly. A very good PR (VGPR), a PR, and a minor response were defined as achieving a reductions in serum IgM levels >90%, 50% to 90%, and 25% to 50%, respectively. Stable disease was defined as a change in serum IgM level <25% in the absence of new or increasing adenopathy or splenomegaly and/or other progressive signs or symptoms of WM. Progressive disease was defined as an increase in serum IgM level >25% from the lowest attained response value or progression of clinically significant disease-related symptoms. A major response was defined as the sum of all CRs, VGPRs, and PRs. Variables that were considered for a possible association with achieving an OR, major response, CR plus VGPR, developing major infections, and premature treatment discontinuation were age; sex; time from diagnosis to FCR treatment; pretreatment IgM value >7000 mg/dL; presence of light chain; percentage of BM involvement; extramedullary involvement; a platelet count <100 × 109/L; hemoglobin, albumin, and β2-microglobulin levels; the presence of Bence-Jones; and International Prognostic Scoring System for Waldenstrom Macroglobulinemia (IPSSWM) score.

Statistical Analysis

Differences in response rates were analyzed for statistical significance using the Fisher exact test, and associations of continuous or discrete variables were measured with the Wald test after logistic regression. Repeated-measures analyses of variance were used to evaluate variations in IgM levels within patients. Overall survival (OS) was measured from the start of FCR treatment to death because of any cause, progression-free survival (PFS) was measured from the end of FCR treatment to disease progression, and event-free survival (EFS) was measured in responding patients from the end of treatment to progression or death from any cause. OS, PFS, and EFS were analyzed with the Kaplan-Meier method, and differences were tested for statistical significance using the long-rank test. P values < .05 were considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Clinical Characteristics

From February 2005 to April 2008, 43 patients were enrolled in this study. Baseline clinical and laboratory features are listed in Table 1. The median patient age was 65 years (range, 36-77 years).

Table 1. Baseline Characteristics of 43 Patients Enrolled in the Current Study
CharacteristicNo. of Patients (%)Median [Range]
  1. Abbreviations: FCR, combined fludarabine, cyclophosphamide, and rituximab; IgM, immunoglobulin M; PMN, polymorphonuclear leukocytes; IPSSWM, International Prognostic Scoring System for Waldenstrom Macroglobulinemia.

Age, y 65 [36-77]
Sex  
 Men25 (58) 
 Women18 (42) 
Time from diagnosis to FCR, mo 25.5 [0.3-180.3]
Disease status at treatment  
 First-line treatment28 (65) 
 Relapsed12 (28) 
 Refractory3 (7) 
IgM >7000 mg/dL5 (12)4380 [926-8500]
Light chain  
 κ34 (79) 
 λ9 (21) 
Bone marrow involvement, % 70 [10-95]
Adenopathy, and/or splenomegaly, and/or extranodal involvement25 (58) 
β2-microglobulin, mg/dL 2.97 [1.6-5.5]
Hemoglobin <10 g/dL16 (37) 
Platelets <100×109/L1 (2) 
PMN <1.5×109/L6 (15) 
Albumin, g/dL 3.8 [2.73-5.5]
IPSSWM score  
 Low risk14 (33) 
 Intermediate risk16 (38) 
 High risk12 (29) 

Most of patients (65%) received FCR as first line-treatment. Twenty-eight percent of patients were in relapse, and 7% had disease that was refractory to a previous line of treatment. Previous treatments included chlorambucil alone or with steroids in 8 patients and cyclophosphamide alone or with steroids in 7 patients. At the time of treatment, the median percentage of BM involvement with lymphoplasmacytic cells was 70% (range, 10%-95%), and the median serum IgM level was 4380 mg/dL (range, 926-8500 mg/dL). According to the IPSSWM score, the majority of patients presented with intermediate-risk or high-risk disease (67%). The primary reasons for initiating treatment, some of which overlapped, were: worsening cytopenia (n = 32); splenomegaly, lymphadenopathy, or organ involvement (n = 25) assessed by CT scan; symptoms and signs of hyperviscosity (n = 6); and peripheral neuropathy (n = 4).

Response

All 43 enrolled patients received the first cycle of treatment and received a median of FCR 6 courses (range, 2-6 courses). Disease reassessment was performed in 39 patients, and the remaining 4 patients were not evaluated (all received <4 courses) were considered failures. On an intent-to treat basis, the OR rate evaluated at the end of therapy was 79% (95% confidence interval, 64%-90%), including 11.6% CRs, 20.9% VGPRs, 41.8% PRs, and 4.6% minor responses, for a major response rate of 74.4% (Table 2). Among responders, the median time to 25% and 50% reductions in serum monoclonal protein was 2 months and 3 months, respectively.

Table 2. Response Rates After Combined Fludarabine, Cyclophosphamide, and Rituximab in 43 Patients With Waldenstrom Macroglobulinemia Enrolled in the Current Study
 No. of Patients (%)
ResponseEnd of TreatmentBest Response During Follow-Up
Overall response rate34 (79)34 (79)
Major response32 (74.4)33 (76.7)
Complete remission5 (11.6)8 (18.6)
Very good partial remission9 (20.9)6 (13.9)
Partial remission18 (41.8)19 (44.1)
Minor response2 (4.6)1 (2.3)
Stable disease4 (9.3)4 (9.3)
Progressive disease/failure1/4 (11.6)1/4 (11.6)

In 5 patients, an improved response was achieved during follow-up after a median of 6 months (range, 3-12 months). In 1 patient, a minor response converted to a PR, and 3 patients who were categorized with VGPRs achieved CR. Considering the best response, we observed a 76.7% major response rate (33 patients), including 18.6% CRs (8 patients), 13.9% VGPRs (6 patients), and 44.1% PRs. No statistical difference in terms of response was observed between pretreated and untreated patients, although, in naive patients, a trend was detected toward achieving a better quality of response (43% vs 14%; P = .086) (Table 3) 4.

Table 3. Impact of Clinical and Biologic Parameters on Response Achievement
 Response Category: P
ParameterOverall Response (CR+VGPR+PR +Minor Response)Major Response (CR+VGPR+PR)CR+VGPR
  • Abbreviations: CR, complete remission; FCR, combined fludarabine, cyclophosphamide, and rituximab; IgM, immunoglobulin M; IPSSWM, International Prognostic Scoring System for Waldenstrom Macroglobulinemia; PR, partial remission; VGPR, very good partial remission.

  • a

    Wald test after logistic regression.

  • b

    Fisher exact test.

Agea.649.723.840
Men vs womenb>.999>.999.325
Time from diagnosis to FCR treatmenta.362.508.174
Pretreated vs untreatedb.696>.999.086
IgMa.530.935.071
IgM >7000 mg/dLb>.999>.999.156
Light chain κ vs λb>.999>.999.694
Bone marrow involvement, %a.113.373.931
Adenopathy, and/or splenomegaly, and/or extranodal involvementb.122.080.111
Hemoglobin <10 g/dLb.706>.999>.999
Platelets <100×109/Lb>.999>.999>.999
Albumina.051.338.715
β2-microglobulina.115.039.070
Bence-Jones presenceb.564.318.571
IPSSWM scorea.525.818.606
Table 4. Hematologic and Extrahematologic Toxicity During Combined Fludarabine, Cyclophosphamide, and Rituximab Treatment
 Grade 1-2Grade 3-4
ToxicityPercentage of 43 PatientsPercentage of 226 CyclesPercentage of 43 PatientsPercentage of 226 Cycles
Hematologic toxicity    
 Neutropenia11.619.488.344.6
 Anemia30.28.42.30.4
 Thrombocytopenia2.6114.60.8
Extrahematologic toxicity    
Rituximab infusional reaction/hypersensitivity48.812.84.61.3
Nausea/vomiting20.94.400
Arrhythmia4.60.800
Dyspnea2.30.400
Biliary colic2.30.400
Cutaneous pemphigus vulgaris002.30.4
Liver2.30.400
Lipothymia002.30.4
Polyuria2.30.400

Figure 1 illustrates the progressive, significant decrease in serum IgM levels observed from baseline and during treatment; a loss of significance was observed between IgM values detected between the sixth course and the final evaluation. A progressive, significant decrease in IgM levels was observed among responders between the end of therapy and up to 18 months of follow-up (P < .001) (Fig. 2). Furthermore, in patients who had the longest follow-up, reduced IgM levels still were detected after 48 months and 56 months.

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Figure 1. These charts illustrate changes in serum immunoglobulin M (IgM) levels (A) during combined fludarabine, cyclophosphamide, and rituximab treatment and (B) during follow-up. ANOVA indicates analysis of variance.

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Figure 2. Progression-free survival (PFS) is illustrated for responding patients according to the quality of response (complete responses [CR] plus very good partial responses [VGPR] vs partial responses [PR] plus minor responses [MR]).

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Statistical analyses of clinical and laboratory features revealed that only the β2-microglobulin level (cutoff, ≤2.5 mg/dL) had a significant impact on the achievement of major response (Table 3). None of the other prognostic features that we considered in the study were predictive of achieving a response.

Follow-up

After a median follow-up of 37.2 months (range, 1.0-60.5 months), in total, 5 patients, including 2 treatment-naive patients and 3 previously treated patients, met the criteria for disease progression, and 1 patient required retreatment. No difference was observed in terms of PFS when we compared the patients who achieved CRs plus VGPRs versus patients who achieved PRs plus minor responses (Fig. 3). The median EFS was reached after 50.1 months (Fig. 4); however, even in this analysis, no difference was observed when patients were stratified according to the quality of response (CR plus VGPR vs PR plus minor response; log-rank test, P = .99).

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Figure 3. Event-free survival (EFS) is illustrated for responding patients.

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Figure 4. Overall survival (OS) is illustrated for all 43 patients who were enrolled in the current study.

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After a median follow-up of 38.8 months (range, 6.6-58.2 months) 11 of 43 enrolled patients died, for an OS rate of 69.1%. The OS was 88.4% at 2 years and 69.1% at 4 years (Fig. 5). In 5 patients, including 4 nonresponders to FCR, death was related to disease progression. One patient died from conditions not related to disease or treatment complications. In 1 patient, death was secondary to the development of acute myeloid leukemia. One patient who had hypoplastic BM was lost to follow-up and died from an unknown cause. Deaths were related to pneumonia in 3 patients, including 1 patient who died 2 years after the end of treatment while in continuous CR.

Toxicity

Overall, 226 courses of FCR treatment were administered. The toxicities observed during treatment are listed in Table 3. In 15 patients (35%), <6 courses were administered for the following reasons: disease progression (1 patient), pneumonia (2 patients), fever of unknown origin associated with neutropenia (1 patient), development of hemolytic anemia (1 patient), rituximab hypersensitivity (1 patient), and medical decision based on persisting cytopenia that required continuous supportive treatment with granulocyte colony-stimulating factor (9 patients).

The first rituximab administration was associated with grade 1/2 infusional symptoms in 18 patients, and 2 patients developed grade 3 hypotension. In the subsequent FCR courses, only 9 episodes of grade 1/2 infusional symptoms were observed. One patient discontinued treatment after the fourth cycle because of a grade 3 cutaneous rash, which was categorized as rituximab hypersensitivity.

No patients experienced an increase in serum monoclonal protein levels after the first course of treatment. Grade 3/4 neutropenia occurred in 44.6% courses, at least 1 episode developing in 38 patients. Granulocyte colony-stimulating factor was administered in 68.5% of courses. In 19 patients (44%), long-lasting episodes of neutropenia, alternating in grade, that persisted after the last course of treatment for a median of 7 months (range, 3-24 months) were recorded. Two patients developed grade 4 thrombocytopenia, which resolved in both patients after the administration of steroids because of a suspicion of autoimmune phenomena. Hemolysis leading to severe grade 4 anemia was observed in 1 patient.

Three patients who were heavily pretreated with alkylating agents developed myelodysplastic syndrome with a complex karyotype after 5 months, 24 months, and 60 months, respectively. One of those patients died from acute myeloid leukemia evolution. None of the patients developed high-grade non-Hodgkin lymphoma.

Severe extrahematologic toxicity (grade 3/4) occurred in 2 patients, both of whom required hospitalization because of cutaneous pemphigus vulgaris in 1 patient and hypotension with lipothymia in the other. Fever of unknown origin was recorded in 7 patients (9 episodes) during treatment and in 3 patients (6 episodes) during follow-up.

Nine infectious episodes, including 3 minor episodes and 6 major episodes, that occurred along with neutropenia were documented during treatment and during the first 6 months of follow-up. The 6 major infections, which developed in 5 patients (12%), were characterized by 5 pneumonias (only radiologically documented) and 1 sepsis sustained by Enterococcus faecalis. In 2 of these patients, pneumonia was the cause of treatment discontinuation. Minor infections consisted of 2 urinary tract infections and 1 herpes zoster.

Three major infections (only radiologically documented pneumonias) were observed after 6 months of follow-up in 3 patients. In 2 of these patients, infection developed during tardive neutropenia. None of the clinical or disease variables that were analyzed and no previous treatments had any prognostic significance for the development of delayed neutropenia, major infections, or premature treatment discontinuation.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Because of its activity, tolerance, and synergy with other agents, rituximab is now a component of most frontline and salvage regimens in WM. The combinations of rituximab with cyclophosphamide and dexamethasone29; or rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)30, 31; and, more recently, with bendamustine32 have produced promising results. Furthermore, Buske et al reported a significantly superior response rate (94%) and time to treatment failure in patients with WM and lymphoplasmocytoid lymphoma who received R-CHOP compared with patients who did not receive the monoclonal antibody (69%).33

Several studies have assessed the activity of the combination of purine analogues and rituximab in WM. The addition of rituximab to fludarabine determined a high rate of response with a long time to progression, especially in patients who achieved at least a VGPR.21 A high remission rate with good-quality responses and mild toxicities also were achieved with the administration of 4 courses of rituximab and subcutaneous 2-chloro-2′-deoxyadenosine.23 Similarly, in smaller series of patients, cladribine and pentostatine in combination with cyclophosphamide and rituximab produced OR rates of 94% and 76.9%, respectively, including 18% and 15.3% CR rates, respectively.10, 22 In the literature, many trials have reported high efficacy and an increase in the quality of responses after FCR in patients with indolent B-cell malignancies and chronic lymphocytic leukemia.24, 34-36 To our knowledge, ours is the first study directed specifically at a large population of patients with WM to assess the efficacy of the FCR regimen.

On an intent-to-treat basis, we observed an OR rate of 79%, which is in line with other results reported in literature from larger series of patients with WM who received rituximab-containing combination chemotherapy regimens. Treon et al,21 in their series of 43 patients, obtained a major response rate of 86% with combined fludarabine and rituximab, which is slightly superior to the rate we achieved with the same drugs plus cyclophosphamide. However, in contrast to Treon et al, we observed a progressive improvement in responses during follow-up, leading to a higher CR rate (19% vs 5%). Furthermore, it is noteworthy that the inclusion of cyclophosphamide allowed us to achieve similar response rates while administering a lower cumulative dose of fludarabine (450 mg vs 750 mg) without increasing infective toxicity. This is an important issue when considering recently reported concerns regarding the use of purine analogues in WM.37

Even if the OR rate obtained in this study may be considered similar to the rate reported by Tamburini et al with the same chemotherapeutic regimen without the addition of the rituximab monoclonal antibody (77.6%; all PRs),9 it is important to note that, in our patients, the addition of rituximab improved of the quality of response, and 33% achieved at least a VGPR. The importance of achieving a good-quality response has been reported recently by Treon et al21 in a series of 43 patients who received fludarabine and rituximab; because, in that study, after a long follow-up of 40.3 months, the time to progression was significantly shorter in patients who attained less than a VGPR. In our current study, the follow-up was too short to determine whether the good quality of response may translate into longer PFS or OS.

The FCR regimen was effective in obtaining rapid responses, because the median time to achieving 25% and 50% reductions in monoclonal protein was shorter than what has been reported with other regimens or immunomodulatory agents in combination with rituximab.21, 29, 38, 39 Furthermore, none of our patients had a paradoxical increase in serum IgM levels after the initiation treatment. These data suggest that the concomitant administration of both fludarabine and cyclophosphamide may prevent the flare phenomena and that the FCR regimen should be considered for patients who require rapid disease control.

Hematologic toxicity was considerable, and we observed a high percentage of grade 3/4 neutropenia. A high incidence of neutropenia, leading to treatment delays or dose reductions, also has been reported using other immunochemotherapeutic regimens with or without purine analogs. Grade 3/4 granulocytopenia occurred in 72% of patients who received R-CHOP patients,33 and numerous episodes of grade 4 neutropenia were observed after patients received combined fludarabine and rituximab.21 It should be stressed that myelosuppression after FCR contributed to a high rate of premature discontinuation of intended therapy and led to prolonged episodes of neutropenia in 44% of patients.

In our study, the infectious episodes observed during treatment and during the first 6 months of follow-up were in line with those observed using other schedules that included rituximab.29 The long-lasting tardive neutropenia and the well known immunosuppression related to purine analogs led to a high incidence of major infections, which were fatal in 2 patients. Therefore, accurate follow-up of patients and prolonged prophylaxis are warranted in patients who receive combined FCR.

The phenomenon of late-onset neutropenia, which usually occurs several months after the administration of rituximab or rituximab-based therapies, is well known.40 The high incidence of delayed neutropenia observed may raise the question whether the intended therapy should be limited to 4 courses of therapy or whether the doses of fludarabine and cyclophosphamide should be reduced, as reported recently in patients with chronic lymphocytic leukemia (FCR lite).41 Although the patient numbers were small, in our series, we observed similar response rates between patients who completed 6 courses and patients who completed only 4 or 5 courses. This observation and the progressive amelioration of responses during follow-up are in favor of reducing the cumulative doses of fludarabine, cyclophosphamide, and rituximab administered to patients with WM.

Because an objective of our study was the evaluation of PFS, further chemotherapy to attempt stem cell harvesting was not allowed by study design. Although the role of autologous stem cell transplantation in WM has not yet been established, treatment strategies that include high-dose chemotherapy in young patients with poor prognostic features may be considered.42, 43 From the pronounced and prolonged myelosuppression associated with BM hypocellularity observed after treatment, we speculate that stem cell mobilization may be impaired after FCR.

An increased incidence of Richter transformation and the development of myelodysplastic syndrome/acute myeloid leukemia in patients with WM who received nucleoside analog-containing regimens, independent from previous alkylator therapy, have been recently reported.37 Although the median follow-up of our study was shorter than the follow-up in studies that revealed the long-term consequences of these agents,21, 37 3 of our patients developed myelodysplastic syndrome. These patients had been heavily pretreated with chlorambucil; thus, it is plausible that the alkylator played a role in the occurrence of myelodysplastic syndrome.

In conclusion, the current results demonstrate that FCR produces rapid responses with high rates of CR and VGPR in patients with WM. Because myelosuppression was the most common cause of early discontinuation an d led to a high incidence of prolonged episodes of neutropenia, further studies are needed to optimize the doses and duration of this combined treatment regimen.

By modulating doses and therapy duration, FCR may be considered an effective salvage regimen capable of neutralizing adverse prognostic factors in patients with WM. On the basis of the potential risk of secondary malignancies and the myelosuppressive effects of this regimen, FCR should be avoided as first-line treatment in younger patients.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

This study was supported by “Associazione Malattie del Sangue,” Milano, Italy.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES
  • 1
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  • 4
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    Dimopoulos MA, Hamilos G, Efstathiou E, et al. Treatment of Waldenstrom's macroglobulinemia with the combination of fludarabine and cyclophosphamide. Leuk Lymphoma. 2003; 44: 993-996.
  • 8
    Tam CS, Wolf MM, Westerman D, Januszewicz EH, Prince HM, Seymour JF. Fludarabine combination therapy is highly effective in first-line and salvage treatment of patients with Waldenstrom's macroglobulinemia. Clin Lymphoma Myeloma. 2005; 6: 136-139.
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