Fax: (011) 34-93-2483343
Version of Record online: 11 AUG 2009
Copyright © 2009 American Cancer Society
Volume 115, Issue 22, pages 5210–5217, 15 November 2009
How to Cite
Salar, A., Domingo-Domenech, E., Estany, C., Canales, M. A., Gallardo, F., Servitje, O., Fraile, G. and Montalbán, C. (2009), Combination therapy with rituximab and intravenous or oral fludarabine in the first-line, systemic treatment of patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type. Cancer, 115: 5210–5217. doi: 10.1002/cncr.24605
Presented at the 44th Annual Meeting of the American Society for Clinical Oncology, Chicago, Illinois, May 30-June 3, 2008.
We thank Marta Pulido, MD, for editing the article and for editorial assistance.
- Issue online: 3 NOV 2009
- Version of Record online: 11 AUG 2009
- Manuscript Accepted: 22 JAN 2009
- Manuscript Revised: 18 JAN 2009
- Manuscript Received: 4 NOV 2008
- Instituto de Salud Carlos III
- Spanish Ministry of Science and Technology. Grant Number: PI07/0586
- Institut Municipal de Investigació Médica
- Hospital del Mar. Grant Number: ASS/2008
- B cells;
- non-Hodgkin lymphoma;
- mucosa-associated lymphoid tissue;
Currently, there are no consensus guidelines regarding the best therapeutic option for patients with extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
Patients with systemically untreated or de novo extranodal MALT lymphoma received rituximab 375 mg/m2 intravenously on Day 1 and fludarabine 25 mg/m2 intravenously on Days 1 through 5 (Days 1-3 in patients aged >70 years) every 4 weeks, for 4 to 6 cycles. After the first cycle, oral fludarabine could be given orally at 40 mg/m2 on the same schedule. After 3 cycles, a workup was done. Patients who achieved a complete remission (CR) received an additional cycle, and patients who achieved a partial remission (PR) received a total of 6 cycles.
Twenty-two patients were studied, including 12 patients with gastric lymphoma and 10 patients with extragastric MALT lymphoma. Six patients (27%) had stage IV disease. In total, 101 cycles were administered (median, 4 cycles per patients). After the third cycle, 13 patients (62%) achieved a CR, and 8 patients (38%) achieved a PR. Primary extragastric disease was an adverse factor to achieve CR after 3 cycles of chemotherapy (hazard ratio, 23.3; 95% confidence interval, 2.0-273.3). At the end of treatment, the overall response rate was 100%, and 90% of patients achieved a CR. The progression-free survival rate at 2 years in patients with gastric and extragastric MALT lymphoma was 100% and 89%, respectively. Toxicities were mild and mainly were hematologic.
Combination therapy with rituximab and fludarabine is a very active treatment with favorable safety profile as first-line systemic treatment for patients with extranodal MALT lymphoma. Cancer 2009. © 2009 American Cancer Society.
Mucosa-associated lymphoid tissue (MALT) lymphoma1 represents 8% to 10% of all non-Hodgkin lymphomas.2, 3 This type of lymphoma usually affects elderly patients, and the clinical course is indolent, mainly involving the stomach, parotid or salivary glands, skin, lung, and many other extranodal sites.4-6 Although the majority of patients are diagnosed with localized disease, sometimes, advanced stages with multifocal involvement can be observed.7
Early stage gastric MALT-type lymphomas associated with Helicobacter pylori (HP) infection are treated first with specific antibiotic therapy against the bacilli, and complete regression of the lymphoma is achieved in up to 75% of patients.8-11 However, currently, there are no widely accepted therapeutic guidelines for the treatment of patients with primary gastric MALT lymphomas who have failed after antibiotics, patients with HP-negative lymphomas, patients with multifocal or disseminated disease, and patients with primary extragastric MALT lymphoma. Several therapeutic options are available for treating these patients. Surgery has been abandoned in recent years.12, 13 Radiation therapy has been used either as sole treatment or as an adjunct to surgery and had produced good control of the disease in patients who have localized lymphoma.14, 15
Several prospective studies have produced encouraging results with chemotherapy, such as cyclophosphamide, chlorambucil, 2-chorodeoxyadenosine (2CdA), and combinations with fludarabine or other drugs.16-22 Rituximab, an anti-CD20 monoclonal antibody, has demonstrated activity in patients with recurrent/refractory gastric MALT lymphoma who underwent anti-HP therapy or who were not eligible for anti-HP therapy.23-25 The combination of rituximab with chemotherapy achieved better results that either option separately, similar to the results observed in follicular or diffuse large B-cell lymphoma and without a significant addition of toxicity.26, 27 Recently, it was demonstrated that oral fludarabine phosphate is safe and effective for patients with recurrent, indolent B-cell non-Hodgkin lymphoma.28-30 In addition, oral formulation is more convenient, because it can be administered in an outpatient setting.31, 32 Therefore, in the current article, we present our experience with rituximab plus fludarabine as first-line treatment in patients with chemotherapy-naive, extranodal MALT lymphoma.
MATERIALS AND METHODS
This multicenter, open-label, single-arm, nonrandomized phase 2 trial was approved by the local investigational review board. Written informed consent was obtained from all patients before enrolment. The study was carried out in 5 University Medical Centers in Spain.
Eligible patients had to have histologically confirmed, extranodal, marginal zone, B-cell, MALT-type lymphoma with positive CD20 immunohistochemistry; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; age ≥18 years; adequate bone marrow, hepatic, and renal function; and a life expectancy >3 months. Patients were ineligible if they had uncontrolled infections, human immunodeficiency virus infection, viral hepatitis, or immunosuppression; if they had received previous chemotherapy for other tumors, if they were pregnant or were breast feeding, if they had a history of another malignancy within the past 5 years, if they had psychiatric disorders, or if they had transformation to diffuse large B-cell lymphoma. Patients with gastric MALT lymphoma could enter into the study if they had recurrent/refractory lymphoma after anti-HP therapy or of they were not eligible for anti-HP because they had HP-negative lymphoma. Patients also were required to have symptomatic or progressive disease.
Eleven of 12 patients (92%) with MALT gastric lymphoma had documented HP infection at diagnosis and received eradication antibiotic therapy as their sole initial treatment. All 3 patients with cutaneous MALT lymphoma had received several types of local therapy, including surgical removal, radiotherapy, topical corticosteroids, psoralene plus ultraviolet A light treatment, or other treatments.
Patients received rituximab 375 mg/m2 intravenously on Day 1 and fludarabine 25 mg/m2 intravenously or 40 mg/m2 orally daily on Days 1 through 5. In patients with gastric lymphoma, the first cycle of fludarabine was given intravenously to guarantee drug absorption. In patients aged >70 years, fludarabine could be reduced to a total of 3 days (Days 1-3). All treatments were given in an outpatient setting. The regimen was administered in 28-day cycles up to a maximum of 6 cycles. After the third cycle, restaging was performed. The patients who were in complete remission (CR) received a fourth cycle of combined rituximab and fludarabine, and the patients who had a partial response received a total of 6 cycles. Patients who had less than a partial response after the third cycle were excluded.
A subsequent cycle was administered if the absolute neutrophil count (ANC) was >1 × 109/L and if the platelet count was >100 × 109/L. For patients who had an ANC <1 × 109/L and/or platelets <50 × 109/L, the next treatment cycle was delayed by 1 week until normal values were achieved. A 20% reduction in the fludarabine dose was recommended for the subsequent cycles. Treatment was stopped if the delay in administering the subsequent cycle exceeded 2 weeks. Prophylaxis with cotrimoxazole was received according to the physician's preference. Granulocyte-colony–stimulating factor and antiviral prophylaxis were not considered routinely. Safety evaluation, which consisted of a physical examination, full blood cell counts, and routine chemical values, were measured before each cycle.
Baseline and Outcome Assessments
All patients underwent a disease extension study that included medical history, physical examination, and laboratory and x-ray studies before entry onto the study. These tests included a complete blood count with differential; tests for electrolytes, renal and liver parameters, lactate dehydrogenase, uric acid, β2 microglobulin, and immunoglobulins; a direct antiglobulin test; computed tomography scans of the chest, abdomen and pelvis; and a bone marrow biopsy. In patients who had lymphoma restricted to the stomach, upper endoscopy and upper ultrasound endoscopy were performed.33 Additional radiologic studies were performed according to the primary anatomic site of disease, such as magnetic resonance imaging of the salivary glands or orbit. Stage was determined according to the Lugano system.34 All patients were re-evaluated after the third cycle post-therapy, every 6 months during the first 2 years, and annually thereafter. Procedures included computed tomography scans and upper endoscopy with multiple biopsies in patients with gastric lymphoma.
All patients who received at least 1 cycle of therapy were considered assessable for response and for toxicity. Response was classified according to the definitions recommended by the International Workshop to Standardize Response Criteria for non-Hodgkin lymphomas.35 In gastric lymphomas, histologic responses were defined according to the criteria of Copie-Berman et al for the posttreatment evaluation of MALT lymphoma.36 Toxic effects were evaluated throughout treatment using the National Cancer Institute's Common Toxicity Criteria version 3.0.37
The t(11;18)(q21;q21) translocation was analyzed on diagnostic pretreatment specimens using fluorescent in situ hybridization with the commercially available break-apart locus-specific identifier/MALT1 (LSI-MALT1) probe (Vysis, Downers Grove, Ill) or by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for the apoptosis-inhibitor 2/MALT1 (API2/MALT1) fusion product, as described previously.38
Univariate analysis for response after 3 cycles of combined rituximab and fludarabine was performed through logistic regression analysis. The actuarial probability of survival was calculated with survival tables using SPSS software (SPSS, Inc., Chicago, Ill).
Twenty-two patients were enrolled on the trial. The median patient age was 60 years (range, 32-83 years), and 45% of patients were men. The baseline characteristics of all 22 eligible patients are summarized in Table 1. It is noteworthy that 12 patients (55%) had primary gastric involvement, including 8 with stage I1 disease and 4 patients with stage II1 disease according to the Lugano classification system. Three of 12 patients who had gastric involvement had t(11;18)(q21;q21).
|Characteristic||No. of Patients|
|Total no. of patients||22|
|Median age (range), y||60 (32-83)|
|Parotid gland (unilateral)||1|
|Parotid gland (bilateral)||1|
|Submaxilar gland (unilateral)||1|
|ECOG PS 0 or 1||22|
Response and Survival Data
The number of cycles of chemotherapy was <4 cycles in 2 patients (10%), 4 cycles in 12 patients (54%), and 6 cycles in 8 patients (36%).
Response evaluation was feasible in 21 patients, because 1 patient with gastric lymphoma refused her consent after 3 cycles. After the third cycle, 13 patients (62%) achieved a CR, and 8 patients (38%) achieved a partial remission; thus, an objective response was obtained in all patients. At the end of therapy, 19 patients (90%) had achieved a CR, and 2 patients (10%) had achieved a partial remission; thus, an objective response was obtained in 100% of patients. Univariate analysis identified primary nongastric disease as an adverse factor to reach CR after 3 cycles of combined rituximab and fludarabine (hazard ratio, 23.3; 95% confidence interval [CI], 2.0-273.3). No other variables were associated with response after 3 cycles of combined chemotherapy. All 7 patients who had gastric stage I1 tumors achieved a CR after 3 cycles compared with 3 of 4 patients (75%) who had stage II1 disease, although the differences were not significant (P = .165). In patients who had extragastric disease, no differences in the CR rates after 3 cycles of chemotherapy was observed: 1 of 4 patients (25%) and in 2 of 6 patients (33%) who had stage I and II cancer and stage III and IV cancer, respectively (P = .778). It is interesting to note that 2 of 3 patients (67%) who had primary cutaneous involvement achieved a CR with 3 cycles of rituximab and fludarabine. Complete and overall response rates did not differ significantly between patients with gastric lymphoma and patients with nongastric lymphoma at the end of treatment (Table 2). In addition, the 3 patients who had a t(11;18)(q21;q21) translocation achieved CR after 3 cycles (2 patients) and 6 cycles (1 patient).
|Response||After 3 Cycles||After 6 Cycles|
|Overall response rate||21||100||21||100|
|Primary gastric (n=11)|
|Primary extragastric (n=10)|
The median follow-up was 23 months (95% CI, 18-27 months). Two patients with parotid gland and submaxillary gland involvement at diagnosis developed recurrent disease relapsed at 6 months and 18 months. One patient received further treatment with immunochemotherapy and was free of disease at the last follow-up. The second patients did not receive treatment, and she had stable disease at the last follow-up. The progression-free survival (PFS) rate for the entire series at 24 months was 88% (95% CI, 80%-100%). PFS at 24 months in patients with gastric and nongastric MALT lymphoma were 100% and 79%, respectively. All patients were alive at the last follow-up. Therefore, the actuarial overall survival (OS) rate at 24 months was 100%.
In total, 101 cycles of combined rituximab and fludarabine were given to the 22 patients (median, 4 cycles per patient; range, 2-6 cycles per patient). Oral fludarabine was administered in 65 cycles. Toxicities generally were mild and mainly were hematologic. Overall, 9 patients (41%) had any grade 3 or 4 hematologic toxicity (Table 3), and 3 patients (14%) patients had any nonhematologic toxicity (Table 4). Grade 1 nausea was reported in 2 patients, both of whom were receiving intravenous fludarabine. Standard infusion-related reactions during the first infusion of rituximab occurred. Prophylaxis with cotrimoxazole was received by 16 of 22 patients (73%). No episodes of febrile neutropenia leading to hospitalization occurred. Only 1 patient had to be admitted because of grade 3 diarrhea without neutropenia or fever, and a lower intestinal endoscopy in that patient revealed diverticulitis. One patient had an episode of herpes zoster 2 months after concluding therapy. No cases of autoimmune hemolytic anemia developed. Treatment was discontinued in only 1 patient who had an episode of grade 4 neutropenia; she recovered despite the neutropenia and was in good health, and she received no further treatment because of her advanced age and her status of CR after 2 cycles of chemotherapy. Two patients had prolonged, mild thrombocytopenia after finishing the treatment, and 1 patient had prolonged, mild neutropenia. Bone marrow aspirates revealed no signs of myelodysplasia, and cytogenetic studies were normal. Compared with mean pretreatment lymphocyte levels (1.97 × 109/L; 95% CI, 1.51-2.45 × 109/L), marked decreases in total lymphocyte counts were observed at the end of rituximab and fludarabine therapy (0.76 × 109/L; 95% CI, 0.56-0.96 × 109/L), at 6 months (1.07 × 109/L; 95% CI, 0.92-1.22 × 109/L), at 12 months (1.33 × 109/L; 95% CI, 1.11-1.54 × 109/L), and at 18 months (1.4 × 109/L; 95% CI, 1.16-1.69 × 109/L). Quantitative serum immunoglobulin levels were stable in 12 of 14 patients who had sequential samples taken over time. In 3 patients, therapy was given from Day 1 to Day 3 in the first cycle because of advanced age. Two other patients had reductions in the planned dose because of hematologic toxicity after the second and third cycles of treatment.
|Toxicity||Grade 3||Grade 4|
|Toxicity||Grade 2||Grade 3|
|Upper airway infection||1||5||0||0|
Our results indicate that the anti-CD20 monoclonal antibody rituximab in combination with fludarabine can be administered safely in chemotherapy-naive patients who have extranodal MALT lymphoma. This regimen yields an overall response rate of 100% and a CR rate of 90%. To our knowledge, the current study represents the first evidence of clinical activity of immunochemotherapy with rituximab in combination with fludarabine in this type of lymphomas. Although a profound change in therapeutic approaches to MALT lymphoma has occurred in recent years, data on chemotherapy are still scarce in the literature, and only 3 prospective series have been published. Hammel et al reported a 75% CR rate in 24 patients who had MALT lymphoma.18 Those patients, who had predominantly gastric involvement, were received treatment with either oral chlorambucil or cyclophosphamide administered on a daily basis for 12 months to 24 months. The event-free survival rate at 5 years was 50% in that study. Jager et al reported an 84% CR rate in 26 patients who received systemic treatment with the nucleoside analogue 2-chlorodeoxyadenosine (2CdA) administered for 4 to 6 cycles.19 However, striking differences were observed in the CR rate between patients with gastric and extragastric disease (100% vs 43%, respectively). More recently, rituximab was reported as a promising agent against MALT lymphoma.23 In that study, which included 27 patients with gastric MALT, 12 patients achieved a CR, and 8 patients had a partial response (overall objective response rate, 77%). It is noteworthy that none of the 4 patients in that study who had stage IV disease achieved CR. In our experience, rituximab and fludarabine produce a higher CR rate, and patients reach this status in less than 3 months, a time frame similar to that observed with 2CdA19 or rituximab23 (2 months and 2.3 months, respectively) and faster than that observed with chlorambucil or cyclophosphamide18 (9 months in patients with localized disease and 15 months in patients with advanced disease). In addition, our results produced a longer PFS compared with these schemas. However, longer follow-up will be necessary to determine whether this benefit will translate into a longer OS, as in the case of other lymphoid entities such follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia (CLL).
Two situations merit special consideration. First, all of our patients who had skin involvement maintained their CR status although they all had numerous recurrences after they received several lines of local therapies. Second, our 3 patients who had gastric lymphoma and t(11;18)(q21;q21) translocation achieved CR, and neither developed recurrent disease. Therefore, contrary to the negative impact of this translocation for lymphoma regression after eradication therapy or alkylating agents, t(11;18)(q21;q21) does not appear to affect outcomes when immunochemotherapy with rituximab and fludarabine is administered to patients with gastric MALT lymphoma. These results are in concordance with those reported by Streubel et al.39 with 2CdA and by Conconi et al.25 with rituximab and with our previous observations.38 Monitoring of minimal residual disease is ongoing.
Combined rituximab and fludarabine generally was well tolerated, and many patients favored the oral formulation. Infusion-related toxicity associated with rituximab was in line with expectations. Toxicities were mainly hematologic. Rituximab causes profound and prolonged depletion of B lymphocytes,40, 41 and fludarabine causes profound and prolonged depletion of T cells.28 Combining fludarabine and rituximab in CLL was associated with excess neutropenia when administered in either a concurrent or sequential regimen. In contrast, grade 4 neutropenia in our study was lower than that reported in CLL40 and did not predispose patients to an excess number of neutropenic fever episodes or life-threatening infections. Infectious toxicity generally was mild, and only 1 patient had to be admitted to hospital. Only a few patients required treatment delays or dose modifications. It is noteworthy that >66% of our patients received only 4 cycles of rituximab and fludarabine. The lowering of the cumulative dose of fludarabine potentially may reduce the hematopoietic stem cell damage or the risk of myelodysplasia.
Some previous studies reported an increased risk of opportunistic infections observed with fludarabine-based therapies.42 Prophylaxis against Pneumocystis jiroveci was given to 73% of our patients, and we did not observe any episodes of pneumocystis infection. Considering the profound lymphocytopenia observed with rituximab and fludarabine, routine prophylaxis against P. jiroveci seems to be a safe and reasonable preventive measure in this setting, at least during treatment and up to 6 months later. We noted only 1 case of herpetic infection in our study. This is in contrast to a higher number of herpes virus infections in previously untreated patients with CLL who received rituximab and fludarabine, suggesting that the regimen produces a more profound, innate immunosuppression in CLL.40 Two episodes of prolonged, mild thrombocytopenia and 1 episode of prolonged, mild neutropenia were observed at the end of treatment. However, no evidence of myelodysplasia has been observed in these patients to date. In addition, the low rate of side effects also was observed in elderly patients, and no apparent difference in toxicities were reported between the 5 patients aged >70 years and the young patients in our study.
In conclusion, the current results indicate that immunochemotherapy with combined rituximab and fludarabine achieves a high CR rate in both gastric and extragastric MALT lymphoma. Patients with gastric MALT respond faster, and approximately 66% require only 4 cycles. This regimen is well tolerated, and granulocytopenia is the main adverse event. However, establishing the long-term benefit of this therapy will require continued follow-up examining both PFS and OS.
Conflict of Interest Disclosures
Supported by grants from Instituto de Salud Carlos III, Spanish Ministry of Science and Technology (grant PI07/0586) and Institut Municipal de Investigació Médica, Hospital del Mar (grant ASS/2008).
- 4Extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001: 157-160., , , et al.
- 28Fludarabine. An update of its pharmacology and use in the treatment of haematological malignancies. Drugs. 1997; 43: 1005-1037., , .
- 37Cancer Therapy Evaluation Program, National Cancer Institute. Common Toxicity Criteria. NCI-CTC version 3.0. Bethesda, Md: National Cancer Institute, 1998. Available at: http://ctep.cancer.gov/reporting/CTC-3.html. Accessed August 9, 2006.
- 40Randomised phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003; 101: 6-14., , , et al.