• fludarabine;
  • rituximab;
  • marginal zone lymphoma;
  • bone marrow aplasia;
  • myelodysplasia


  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The marginal zone lymphomas (MZLs) are a recently defined group of related diseases that probably arise from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric mucosa-associated lymphoid tissue (MALT) lymphoma has been largely limited to retrospective case series. This prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas enrolled 26 patients, 14 with nodal MZL, eight with MALT lymphomas and four with splenic MZL; 81% were receiving initial systemic therapy. Only 58% [95% confidence interval (CI) 37–77%] of patients completed the planned six cycles, due to significant haematological, infectious and allergic toxicity. Four late toxic deaths occurred due to infections [15% (95% CI 4·3–35%)], two related to delayed bone marrow aplasia and two related to myelodysplastic syndrome. Nonetheless, the overall response rate was 85% (95% CI 65–96%), with 54% complete responses. The progression-free survival at 3·1 years of follow-up is 79·5% (95% CI 63–96%). We conclude that, although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of MZLs, the significant haematological and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study MZLs as a separate entity.

The marginal zone lymphomas (MZLs) have been recently defined as a group of related diseases that probably arise from a common cell of origin, the marginal zone B cell (Harris et al, 1994; Berger et al, 2000). Although extranodal or mucosa-associated lymphoid tissue (MALT) lymphomas have been recognized for some time, splenic and nodal MZLs have been identified more recently as sharing the same monocytoid features and immunophenotype (Sheibani et al, 1986; Melo et al, 1987; Nathwani et al, 1999; Matutes et al, 2008).

The clinical presentation and disease course of each subtype varies. The non-MALT MZLs have been subcategorized in a large natural history study as nodal only, splenic only, disseminated (nodal and splenic) and leukaemic only (Berger et al, 2000). Although the median time to progression of the splenic and leukaemic subtypes was >5 years, the median time to progression was only about 1 year for the nodal and disseminated subtypes, despite combination chemotherapy (Berger et al, 2000). Although median survival was >5 years for all subtypes, the rapidity of progression of the nodal and disseminated subtypes suggested the potential for a more aggressive clinical course. Furthermore, a recent prognostic model identified a subgroup of splenic MZLs with a 5-year cause-specific survival of only 50% (Arcaini et al, 2006).

Given the recently developed classification of MZLs, data on therapy has necessarily been limited and almost entirely retrospective. These retrospective studies have found complete response (CR) rates with alkylating agent-based therapies, either single agent or CHOP (cyclophosphamide, doxorubicin, prednisone, vincristine)-like regimens, to vary between 30% and 60% (Thieblemont et al, 1997, 2000; Parry-Jones et al, 2003). Purine analogues have appeared more promising, with initial reports of not infrequent complete remissions in patients refractory to alkylators (Mulligan et al, 1991; Troussard et al, 1996; Bolam et al, 1997; Yasukawa et al, 2002; Matutes et al, 2008). More recent series have suggested that single agent rituximab is also highly active, particularly in splenic MZLs (Tsimberidou et al, 2006; Kalpadakis et al, 2007).

To date, only three disease-specific prospective studies have been reported and these enrolled only MALT lymphoma patients. The first looked at daily oral cyclophosphamide or chlorambucil in mostly stage I (with about a third stage IV) MALT lymphoma patients and found a 75% CR rate after 1 year (Hammel et al, 1995). The second reported a 84% CR rate with cladribine in chemotherapy-naïve MALT lymphoma patients, with median progression-free survival (PFS) not yet reached at 27 months (Jaeger et al, 2002). The most recent reported that rituximab alone had an overall response rate (ORR) of 87% with a PFS of 22 months in chemotherapy-naïve MALT patients, and ORR 45% with a PFS of 12 months in previously-treated MALT patients (Conconi et al, 2003). These studies suggest significant activity of a variety of chemotherapy agents in mostly early stage MALT lymphoma patients, but the efficacy of these regimens in advanced disease and the expected duration of response remain unclear. Furthermore, no prospective chemotherapy studies have been reported in other subtypes of MZLs. We therefore decided to undertake this disease-specific prospective study, combining the purine analogue fludarabine with rituximab (FR), in an effort to prolong PFS compared to rituximab in this patient population.


  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References


This prospective study was performed at the Dana-Farber Cancer Institute, University of Rochester James P Wilmot Cancer Center, Massachusetts General Hospital and Beth Israel Deaconess Medical Center between January 2004 and June 2007. Patients were enrolled who had newly diagnosed or relapsed, histologically confirmed MALT lymphoma, nodal or splenic MZL, or a CD5/CD10 negative low-grade B cell lymphoproliferative disorder that the haematopathologists were unwilling to definitively subclassify. However, the latter patients were assigned a subtype of MZL on clinical grounds, and patients with pathologically or clinically identifiable lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia were excluded. Enrolled patients could not be candidates for potentially curative local radiation or antibiotic therapy. Prior therapy with rituximab or radiation was permitted, but patients who had received prior fludarabine-based therapy were excluded. All patients were required to have normal renal function prior to enrollment.

Treatment programme

The planned therapy included six cycles of fludarabine at the standard dose of 25 mg/m2 on days 1–5 with rituximab 375 mg/m2 on day 1 of a 28 day cycle (Czuczman et al, 2005). The rituximab dose in the first cycle was split between days 1 and 3 for patients with absolute lymphocyte counts >10 × 109/l. During the first cycle all patients also received allopurinol and intravenous hydration. All patients received infection prophylaxis with trimethoprim-sulfamethoxazole (or equivalent) for Pneumocystis jiroveci (PCP) pneumonia and acyclovir (or equivalent) for varicella zoster virus reactivation. These drugs were continued for a minimum of 1 month after therapy. After significant allergic hypersensitivity and/or rash were seen in the first several patients, the protocol was modified to require daily administration of a prophylactic antihistamine, preferably diphenhydramine but non-sedating antihistamines were also permitted.

In order to receive the next cycle of therapy, haematological recovery with absolute neutrophil count (ANC) >1·5 × 109/l and platelet count >75 × 109/l was required. Subjects who experienced grade 3 or 4 neutropenia received myeloid growth factors in subsequent cycles. Those subjects whose haematological recovery did not meet the above criteria had delay of their therapy, and in subsequent cycles received myeloid growth factors. If treatment delay continued despite myeloid growth factors, or for those patients experiencing grade 3 or 4 thrombocytopenia, dose reductions of fludarabine to 80% dose and then to 60% dose were required. A delay >6 weeks in initiating the next cycle resulted in mandatory removal from the study.

Study evaluations

Screening evaluation included computed tomography (CT) scans of the chest/abdomen/pelvis, bone marrow biopsy and histology review for confirmation of diagnosis. Fluorescence in situ hybridization (FISH) for BCL6, trisomy 3, MALT1 and chromosome 1 rearrangements (using probes for 1p36 and 1q25) was performed on paraffin-embedded diagnostic tissue biopsies or bone marrow biopsies when possible (n = 19 available tissue biopsies). Karyotypes from tissue biopsies were not routinely available but deletion of 7q was identified in one case. CT scans were repeated after three cycles of therapy and again after six cycles of therapy or at the time of removal from study. Response evaluation was based on the Cheson criteria for all patients (Cheson et al, 1999a). A bone marrow biopsy was repeated at the conclusion of therapy only if the initial biopsy was involved with lymphoma. Patients were followed with clinic visits, laboratory evaluation and CT scanning every 6 months for 4 years following therapy.

Statistical methods

Overall survival (OS) was defined as the time from initiation of study therapy to death from any cause. PFS was defined as the time from initiation of study therapy to the first reported outcome event. Outcome events include progression of disease or death from any cause. PFS and OS curves were obtained using the Kaplan–Meier method, with 95% confidence intervals (95% CI) calculated using Greenwood’s formula (Kaplan & Meier, 1958; Mantel, 1966). The effects of potential prognostic factors for PFS and OS were assessed using Cox multivariate regression models. P values ≤0·05 were considered significant.


  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patient characteristics

Twenty-six patients were enrolled on this prospective phase 2 study between January 2004 and June 2007. The characteristics of the patients are detailed in Table I. All patients had MZL, with nodal predominating (N = 14) followed by MALT (N = 8). The sites of extranodal involvement of MALT lymphomas included lung (4), gastric (2), orbital adnexae (1) and skin (1). The predominant cytogenetic abnormalities involved chromosome 3, seen in 37% of evaluable patients, including five nodal and one splenic MZL. Four patients (21%) had co-existent lesions of chromosomes 3 and 1. Two patients, one with MALT and one with nodal MZL, had rearrangements of MALT1.

Table I.   Patient characteristics.
  1. MZL, marginal zone lymphoma; MALT, mucosa-associated lymphoid tissue; BM, bone marrow.

N 26
Median age (range), years63·7 (31·4–84·0)
Median time from diagnosis to treatment (range), months1·6 (0·5, 75·2)
Previously untreated21 (81%)
 Nodal MZL14 (54%)
 MALT8 (31%)
 Splenic MZL4 (15%)
 IE1 (4%)
 II2 (8%)
 III5 (19%)
 IV18 (69%)
BM involvement
 Yes8 (31%)
 No13 (50%)
 Unknown5 (19%)

The great majority of the patients were previously untreated, with stage IV disease. Six of the eight patients with MALT lymphoma had stage IV disease, and none were candidates for local therapy. Three of the four splenic MZL patients had recurrent disease after prior splenectomy. Five of the 26 patients had received prior systemic therapy, although prior fludarabine-based therapy was an exclusion criterion. The study therapy was the second regimen for two patients [R-CVP (cyclophosphamide, vincristine, prednisone + rituximab) or rituximab previously], the third regimen for two patients (rituximab × 2 for one, chlorambucil then cyclophosphamide-rituximab for the other) and the final patient had been treated with CVP, rituximab twice and R-CHOP and ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) followed by BEAM (carmustine, etoposide, cytarabine, melphalan)-autologous stem cell transplantation.

Planned therapy

Although the planned therapy included six cycles of FR, only 58% (95% CI 37–77%) of patients were able to complete the planned therapy. The majority discontinued therapy due to unacceptable toxicity (N = 9, 35%), with one additional patient removed at the site investigator’s discretion (for confusion probably unrelated to therapy) and a second additional patient removed to receive therapy for a newly diagnosed but pre-existing second malignancy. Of those who discontinued therapy for toxicity, the majority did so for haematological toxicity (6), two for unacceptable or recurrent rash (2) and one for a delayed hypersensitivity reaction to rituximab (1). After the addition of daily prophylactic antihistamine therapy to the protocol requirements, the frequency of rash and hypersensitivity reactions declined significantly.


The overall rate of grade 3–4 toxicities was significant and is detailed in Table II. Seventy-seven percent of patients experienced at least one grade 3 or higher toxicity, and 42% of patients experienced at least one grade 4 or higher toxicity. All grade 4 toxicities were haematological, including 38% of patients who experienced grade 4 neutropenia at some point in their course and 12% of patients who experienced grade 4 thrombocytopenia. The use of myeloid growth factors after the first cycle of therapy was at the discretion of the treating physician. Eighteen of 26 patients received myeloid growth factors at some point during the study (69%). Despite this, over half of the patients had at least one treatment delay (14 of 26; 54%), and 31 out of a total of 126 cycles of therapy were delayed (25% of cycles), most frequently due to neutropenia. Seven patients were treated with fludarabine at a reduced dose, with three receiving 80% dose, and one of those and four others receiving 60% dose; in all, 14 of 126 cycles (11%) were given with reduced doses of fludarabine.

Table II.   Treatment-related toxicities.
ToxicityPatients (%)
  1. MDS, myelodysplatic syndrome.

Any grade 39 (35)
Any grade 411 (42)
Neutropenia15 (57)
 Grade 35 (19)
 Grade 410 (38)
 Febrile neutropenia2 (8)
Thrombocytopenia7 (27)
 Grade 34 (15)
 Grade 43 (12)
Rash2 (8)
Grade 3 toxicities seen once7 (26)
 Allergic reaction
 Upper resp/pulm infection
Delayed toxicities
  Nocardia1 (4)
  Pneumocystis jiroveci Confirmed + presumed1 + 1 (4–8)
  Aplastic anaemia2 (8)
  MDS (refractory cytopenia with multilineage dysplasia)2 (8)

Significant delayed infectious toxicity was also observed. The protocol required that all patients receive prophylaxis against PCP during therapy and for at least 1 month afterward; nonetheless, one patient who continued prophylaxis for 6 months after therapy developed confirmed PCP 9 months after therapy. A second patient was treated for presumed PCP (without confirmation of diagnosis) at 4 months after therapy, and recovered. An additional patient developed Nocardia pneumonia at 4·5 months after completion of protocol therapy.

Delayed haematological toxicity was also evident. Two patients developed bone marrow aplasia in the first months after completing therapy. The first patient, whose sixth and final cycle of therapy started on 5 November 2007, was admitted with fever and neutropenia on 11 March 2008 and died the following day of gramme negative sepsis. Bone marrow biopsy was severely hypocellular, without evidence of lymphoma, and cytogenetics showed a normal karyotype. The second patient, whose last cycle of therapy was on 7 March 2005, went on to develop a cold agglutinin haemolytic anaemia concomitant with bone marrow aplasia, and ultimately died of sepsis in the setting of neutropenia in January 2006. Her bone marrow biopsy performed on 2 December 2005 showed a markedly hypocellular marrow (<5% cellular) consistent with aplastic anaemia, with insufficient cells for cytogenetic analysis but FISH analysis did not reveal deletion or monosomy of chromosomes 5 or 7.

Two other patients have subsequently developed biopsy-proven myelodysplasia, specifically refractory cytopenia with multilineage dysplasia (RCMD). The first had developed progressive lymphoma for which a course of single-agent rituximab was given, which was complicated by multiple infections and worsening pancytopenia. Bone marrow biopsy performed 38 months after conclusion of study therapy was consistent with RCMD, with complex cytogenetics including monosomy 5 and monosomy 7. The second patient, who had been previously treated with R-CVP but who had no additional therapy after completing study therapy in February 2005, presented with rapid onset pancytopenia in July 2008 and bone marrow biopsy revealed RCMD, with complex cytogenetics including 5q deletion. Both of these patients succumbed to infection shortly after their diagnoses of myelodysplasia.

Thus, four of 26 patients (15%; 95% CI 4–35%) developed significant delayed bone marrow toxicity, which led to their deaths in all four cases. These patients had received nearly full-dose therapy with minimal to no growth factor exposure (three received six full-dose cycles and the fourth five cycles; two did not receive any myeloid growth factors while the other two each received a single dose of pegfilgrastim). Two had received no prior therapy, one had been previously treated with two courses of single-agent rituximab and the fourth had received prior R-CVP. Development of grade 5 delayed bone marrow toxicity was not significantly associated with a history of therapy prior to this study, with the number of cycles of FR received, or with grade 4 haematological toxicity during the study therapy.

Treatment outcomes

Despite the shortened course of therapy for many patients, FR was highly effective, with 14 patients achieving CR/unconfirmed CR and eight patients achieving partial response (Table III). The objective response rate was 85% (95% CI 65–96%), with 54% CRs. Only one patient progressed on therapy. With a median follow-up of 3·1 years (range 1·0–4·7), three additional patients have relapsed, at 13, 33 and 38 months after therapy. The PFS at 3·1 years of follow-up was therefore 79·5% (95% CI 63·4–95·6%; Fig 1).

Table III.   Patient outcomes.
  1. CR/CRu, complete response/unconfirmed complete response; MDS, myelodysplastic syndrome.

Overall response rate (N = 26)22 (85%; 95% CI 65–96%)
 CR/CRu14 (54%)
Relapses1 PD and 3 relapses
Deaths6 (two lung cancers; four infections, two with MDS and two with delayed bone marrow aplasia)

Figure 1.  Progression-free and overall survival. At a median follow-up of 3·1 years, 79·5% (95% CI 63·4–95·6%) of patients remain in ongoing remission. 87·4% (95% CI 74·0–99%) of patients are alive. No deaths have occurred due to lymphoma.

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Six deaths have occurred, none due to lymphoma. As detailed above, four patients have died of infections in the setting of bone marrow disorders, two with aplasia and two with myelodysplasia. Two additional deaths were due to lung cancers, neither of which appeared to be related to study therapy. One lung cancer was present prior to the start of study therapy, while the other was diagnosed 29 months after completion of study therapy, in a patient with a history of asbestos exposure. The OS at 3·1 years of follow-up was therefore 87·4% (95% CI 74·0–99%; Fig 1). No significant difference in PFS or OS was observed based on the time from diagnosis to treatment, subtype of MZL, or number of treatment cycles received.


  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The provisional description of MZLs as a group of indolent lymphomas separable from follicular lymphomas and chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) has been recent, and data on natural history and treatment response have therefore been very limited. The Southwest Oncology Group (SWOG) found through pathological review that MZL patients actually represented about 10% of advanced stage indolent lymphoma patients enrolled on their older upfront CHOP studies (Fisher et al, 1995). The MZLs had similar outcomes to the other indolent lymphomas on those studies, albeit with some heterogeneity (Fisher et al, 1995). Since then, the advent of rituximab has significantly impacted the natural history of follicular lymphoma (Fisher et al, 2005; Marcus et al, 2005; van Oers et al, 2006), yet little to no data are available to address whether the natural history of MZLs has changed, given improved supportive care and the significant activity of rituximab in MZL (Conconi et al, 2003; Tsimberidou et al, 2006; Kalpadakis et al, 2007).

Our goal in this study was to improve upon the PFS of single-agent rituximab in MALT lymphomas, by investigating the safety and efficacy of combining rituximab with fludarabine in patients with more aggressive MZLs. In this paper we report the first prospective treatment study enrolling exclusively MZLs and including subtypes other than extranodal MALT lymphomas. We found that, although the FR regimen is highly effective, its short and long-term haematological and infectious toxicity is prohibitive in this patient population. Although cytopenias have been significant in all studies, the observed toxic death rate of 15% was meaningfully greater than the 0% toxic death rate reported for FR in both follicular lymphoma (Czuczman et al, 2005) and CLL/SLL (Byrd et al, 2003).

The patient population targeted by this study was the subset with advanced stage aggressive MZL, and that subgroup was well-represented among the patients treated. Most of the patients had nodal MZL or stage IV MALT lymphomas, and 75% of the splenic MZLs had recurred with disseminated disease after splenectomy. Despite this patient population, we found that the FR combination was a highly effective therapy in this disease subgroup, resulting in an 85% response rate and a 79·5% 3-year PFS, with only three relapses. This high efficacy is similar to that reported in previous studies of FR in other low-grade lymphomas (Savage et al, 2003; Czuczman et al, 2005), CLL (Schulz et al, 2002; Byrd et al, 2003) and Waldenstrom macroglobulinemia (Treon et al, 2008), and does represent an improvement over prior studies in MZLs (Hammel et al, 1995; Jaeger et al, 2002; Conconi et al, 2003).

However, these results came at a significant cost: haematological and allergic toxicity, as well as a high rate of infections during and shortly after therapy. Although the rate of grade 3 or 4 neutropenia during therapy in this study was approximately comparable to other studies (58% vs. 70–80%) (Byrd et al, 2003; Czuczman et al, 2005; Treon et al, 2008), the occurrence of treatment-related rash requiring discontinuation of therapy has not been reported in other series and may therefore be more common in patients with MZL. Furthermore, although the overall rate of grade 3 or 4 fever or infection in this study (27% including three fevers, one pulmonary infection during therapy and three shortly after) was similar to two prior studies (Byrd et al, 2003; Czuczman et al, 2005), both of these prior studies included in their total infection rate a significant number of dermatomal varicella zoster infections and localized herpes simplex infections, which did not occur in this study due to the incorporation of antiviral prophylaxis. The rate of other serious fever or pulmonary infection in those studies was 6–10%, significantly lower than observed in this patient population.

Of particular concern, however, was the occurrence in this study of delayed neutropenia several months after completion of therapy, which led directly to two infectious deaths. Although grade 3–4 neutropenia is commonly seen during therapy, neutropenia occurring outside the usual post-therapy window but earlier than expected for secondary myelodysplasia has not been reported in prior studies of FR (Schulz et al, 2002; Byrd et al, 2003; Savage et al, 2003; Czuczman et al, 2005) or in long-term follow-up studies of the rate of secondary myelodysplasia and acute myeloid leukaemia (AML) (Cheson et al, 1999b; Morrison et al, 2002; McLaughlin et al, 2005). Both of these patients had aplastic bone marrow affecting all lineages but without evidence of cytogenetic abnormalities associated with myelodysplastic syndrome (MDS). The natural history of this apparent aplastic anaemia is unknown because both patients died of infectious complications; their bone marrow might have recovered spontaneously with time, remained unchanged, or progressed to MDS.

Two other patients of the 26 treated were subsequently diagnosed with MDS. Although multiple cases of MDS/AML occurring after fludarabine have been reported, systematic studies have suggested that the risk is low. A recent retrospective study in Waldenstrom macroglobulinemia patients treated with nucleoside analogues reported a 1·6% rate of MDS/AML (Leleu et al, 2009). However, long-term follow-up of 724 CLL patients treated with fludarabine on National Cancer Institute protocols identified one case of AML (Cheson et al, 1999b). In the Cancer and Leukemia Group B (CALGB) 9011 study, only one of 188 patients (0·5%) receiving fludarabine alone developed MDS/AML, as compared to five of 142 (3·5%) patients treated with fludarabine and chlorambucil (Morrison et al, 2002). Similarly, the MD Anderson Cancer Center has reported that eight of 202 low-grade lymphoma patients (4%) treated with fludarabine, mitoxantrone and dexamethasone developed MDS between 1 and 5 years later (McLaughlin et al, 2005). Another recent report on 137 patients treated with fludarabine and cyclophosphamide-containing therapies in Australia found that previously untreated patients had MDS rates of 2·5%, compared to 9·3% for previously treated patients (Tam et al, 2006). These reports strongly suggest that fludarabine may induce MDS at higher rates when combined with cytotoxic chemotherapy, but rituximab would not be expected to produce this effect. In fact, the only other report of MDS/AML occurring after FR has just been published, with three cases occurring in 43 patients enrolled on a prospective study of FR in Waldenstrom macroglobulinemia (Treon et al, 2008). This variability in rates of MDS/AML may suggest that certain lymphoma patient populations have unique susceptibility.

We conclude that, although FR has been reasonably well-tolerated in CLL and other low-grade lymphomas, this study, which was restricted to patients with MZLs, found that the regimen results in significant allergic, infectious and, in particular, haematological toxicity, leading to a toxic death rate of approximately 15%. These findings underscore the importance of performing disease-specific prospective trials whenever possible, and suggest that future studies in MZL patients could focus on alkylating agents in combination with rituximab, which have not been formally studied in this disease, or alterations in dose and schedule to reduce the toxicity of FR, which remains a highly effective regimen in this patient population.


  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We are indebted to the nurses of all the participating institutions for their excellent care of these patients. This work was supported in part by NIH grant K23 CA115682 to JRB. JWF is a Scholar in Clinical Research of the Leukemia and Lymphoma Society. JWF and RIF are supported in part by NIH SPORE grant P50CA130805. ASF is supported in part by NIH grants 2P01CA092625 and CA-103244.


  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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