Abstract
The optimal treatment strategy and outcome of non-gastric marginal zone lymphoma (MZL) remains undefined. The role of rituximab and fludarabine in MZL has not been critically appraised and compared with conventional chemotherapy. We retrospectively analyzed 81 consecutive patients with non-gastric MZL (mucosa-associated lymphoid tissue lymphoma, n = 66; splenic MZL, n = 11; nodal MZL, n = 4). As a group, the treatment results were favorable, with an overall response rate of 87% and a complete response (CR) rate of 73%. The CR rate was similar for conventional chemotherapy, and rituximab- and fludarabine-containing regimens. However, the relapse rate was significantly decreased in rituximab- and fludarabine-containing regimens. The use of rituximab and fludarabine was associated with acceptable side effects. For splenic MZL, splenectomy was significantly associated with a superior CR rate. Early stage, good performance status, and low international prognostic index risk scores significantly impacted on CR rate and survivals. Rituximab and fludarabine were safe for non-gastric MZL and resulted in more durable remissions.
Keywords: Non-gastric marginal zone lymphoma, Mucosa-associated lymphoid tissue, Splenic marginal zone lymphoma, Rituximab, Fludarabine
Introduction
The World Health Organization (WHO) classification of lymphoid malignancies distinguishes between three different subtypes of marginal zone B cell lymphomas: splenic B cell marginal zone lymphoma (splenic MZL) [1], extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) [2], and nodal marginal zone lymphoma (nodal MZL) [3]. MZLs are derived putatively from memory B cells that have passed through the germinal center (post-germinal center memory B cells) [4]. The lymphoma cells, similar to their putative normal counterparts, possess a remarkable capability to home to sites where they have undergone antigenic stimulation, including MALT, the spleen, and lymph nodes [5], accounting for the formation of lymphomas in these sites. However, despite a common cell origin, MZL originating at different anatomical sites have distinct clinicopathologic features and treatment outcome [1–3].
Infections or chronic inflammation may provide the antigenic stimulation in the initial stages of lymphomagenesis. Relevant infections include Helicobacter pylori in gastric MALT lymphoma, Campylobacter jejuni, Borrelia burgdorferi, and Chlamydia psittaci in extranodal MZL, and hepatitis C virus in splenic MZL [6]. Chronic inflammation due to autoimmune diseases, commonly involving Sjögren syndrome and Hashimoto thyroiditis, also predisposes to extranodal MZL [6].
MZLs are considered low-grade lymphomas. Gastric MALT lymphoma is the most common MZL. The efficacy of H. pylori eradication and the subsequent therapeutic strategies for gastric MZL have been well defined [7]. For non-gastric MZL, however, the optimum treatment is less well established because most large series contained a mixture of gastric and non-gastric MZL and rarely analyzed these disease entities separately.
Two classes of drugs, rituximab and purine analogues (including fludarabine and 2-chlorodeoxyadenosine), have made a major positive impact on the treatment outcome of low-grade lymphomas, particularly follicular lymphoma. However, their efficacy in the management of MZL has only recently been examined [8–11], although their role in comparison with other conventional regimens is still undefined.
In this study, we retrospectively analyzed a consecutive cohort of patients with non-gastric MZL in order to define the clinicopathologic features and the role of rituximab and the purine analogue fludarabine in comparison with alkylating agents in the treatment of these lymphomas. Although there is as yet no definitive evidence that non-gastric MZL, splenic MZL, and nodal MZL are distinctive diseases, increasing evidence suggests that they have different clinicopathologic features and treatment outcome. Therefore, they were also both analyzed individually and together as a group in this study.
Materials and methods
Patients
Consecutive patients with non-gastric MZL diagnosed between January 1998 and January 2010 were analyzed. There were no exclusion criteria. The diagnoses were based on the WHO classification criteria of MZL [1–3].
Investigations and treatment
Standard staging procedures including bilateral bone marrow trephine biopsies were adopted. Computerized tomography, magnetic resonance imaging, or positron emission tomography/computerized tomography was used for the detection of organ or tissue involvement at the primary site, thorax and abdomen. Treatment regimens were determined at the discretion of the attending physicians.
Statistical analysis
Response to treatment was determined by standard criteria [12]. Overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up. Disease-free survival (DFS) was calculated from the date of achievement of complete response to date of death, disease relapse/progression, or date of last follow-up. Difference between treatment groups was calculated by chi-square test. Prognostic factors for complete response (CR) and mortality were identified with logistic regression analysis. Five-year OS and DFS were estimated through the Kaplan–Meier method, and comparisons between treatment regimens were performed using Cox regression analysis.
Results
Patients
Eighty-one patients were identified (Table 1). There was no gender preference, with a median age of presentation at 57 (15–86) years. MALT lymphomas were most prevalent, followed by splenic and nodal MZL. Patients predominantly presented with early-stage disease, with good performance status and no B symptoms. Therefore, the majority of patients had favorable International Prognostic Index (IPI) scores. Paraproteins were present in 15 of 81 (18%) patients. About 20% of patients had a known underlying autoimmune disease. Chronic hepatitis B virus infection was found in 17% of patients, which was comparable with the general population. Hepatitis C infection was only found in one patient. Notably, two of the patients were siblings, having splenic and nodal MZL, respectively.
Table 1.
Clinicopathological features of 81 patients with marginal zone lymphoma
| Clinicopathological features | Number (%) |
|---|---|
| Gender | |
| Male | 38 (47) |
| Female | 43 (53) |
| Median age (range), years | 57 (15–86) |
| Diagnosis | |
| Non-gastric MALT lymphoma | 66 (81) |
| Splenic marginal zone B cell lymphoma | 11 (14) |
| Nodal marginal zone lymphoma | 4 (5) |
| Ann Arbor stage | |
| I | 41 (51) |
| II | 13 (16) |
| III | 5 (6) |
| IV | 22 (27) |
| Presence of B symptoms | 6 (7) |
| Performance status | |
| 0 | 46 (57) |
| 1 | 21 (26) |
| 2 | 11 (13) |
| 3 | 3 (4) |
| 4 | 0 (0) |
| International prognostic index | |
| Low (0 or 1) | 35 (43) |
| Low/intermediate (2) | 23 (28) |
| Intermediate/high (3) | 16 (20) |
| High (4 or 5) | 7 (9) |
| Lactate dehydrogenase | |
| Increased | 65 (80) |
| Normal | 14 (17) |
| Not available | 2 (3) |
| Paraprotein | |
| Immunoglobulin G | 4 (5) |
| Immunoglobulin M | 6 (7) |
| Immunoglobulin A | 2 (2) |
| Two monoclonal antibodies | 3 (4) |
| Not present | 60 (74) |
| Not available | 6 (7) |
| Hepatitis B virus infection | |
| Positive | 14 (17) |
| Negative | 64 (79) |
| Not available | 3 (4) |
| Concomitant autoimmune disorders | |
| Present | 18 (22) |
| Absent | 63 (79) |
Non-gastric MALT lymphoma
Sixty-six patients had MALT lymphomas (Table 2). Early-stage (stage I/II) disease was found in 80% of patients. The most common sites of presentation were ocular and ocular adnexal structures (29%), followed by the salivary glands (20%). Multiple sites of involvement were found in eight patients (12%). None of the patients with ocular MALT lymphoma had autoimmune disorders. However, seven patients with salivary gland (11%) and two patients with thymic involvement (4%) had underlying Sjögren syndrome. All four patients with thyroid MALT lymphoma had autoimmune thyroiditis with hypothyroidism. Autoimmune thyroid disease was also found in a patient with skin MALT lymphoma. Other associations were mixed connective tissue disease in a patient with submandibular involvement and Graves’ disease in a patient with conjunctival involvement. Therefore, the frequency of autoimmune diseases in this group of patient was 24% (16/66). A monoclonal paraprotein was detected in 12 patients (18%). Whereas immunoglobulin (Ig) M and G were found in MALT lymphoma in various sites, IgA was detected only in two patients with thymic involvement.
Table 2.
Clinicopathological features of 66 patients with non-gastric MALT lymphoma
| Clinicopathological features | Number (%) |
|---|---|
| Gender | |
| Male | 27 (41) |
| Female | 39 (59) |
| Median age (range), years | 57 (15–86) |
| Primary site(s) of presentation | |
| Ocular and ocular adnexae | 19 (29) |
| Salivary gland | 13 (20) |
| Buccal mucosa | 2 (3) |
| Nasopharynx | 1 (2) |
| Cricoid | 1 (2) |
| Tonsils | 1 (2) |
| Thyroid gland | 4 (6) |
| Thymus | 1 (2) |
| Lungs | 6 (9) |
| Intestine | 5 (8) |
| Omentum | 1 (2) |
| Testes | 1 (2) |
| Cutaneous | 3 (5) |
| Two or more anatomical sites | 8 (12) |
| Ann Arbor stage | |
| I | 41 (62) |
| II | 12 (18) |
| III | 4 (6) |
| IV | 9 (14) |
| International Prognostic Index | |
| Low (0 or 1) | 55 (83) |
| Low/intermediate (2) | 9 (14) |
| Intermediate/high (3) | 2 (3) |
| High (4 or 5) | 0 (0) |
| Paraprotein | |
| Immunoglobulin G | 3 (5) |
| Immunoglobulin M | 4 (6) |
| Immunoglobulin A | 2 (3) |
| Two monoclonal antibodies | 3 (5) |
| Not present | 49 (74) |
| Not available | 5 (8) |
| Associated autoimmune diseases | |
| Sjögren syndrome | 9 (14) |
| Parotid MALT lymphoma | 4 (6) |
| Submandibular MALT lymphoma | 1 (2) |
| Minor salivary gland MALT lymphoma | 2 (3) |
| Thymic MALT lymphoma | 1 (2) |
| Multifocal MALT lymphoma involving also the thymus | 1 (2) |
| Autoimmune thyroiditis with hypothyroidism | 5 (8) |
| Thyroid MALT lymphoma | 4 (6) |
| Cutaneous MALT lymphoma | 1 (2) |
| Mixed connective tissue disease | 1 (2) |
| Submandibular MALT lymphoma | 1 (2) |
| Graves’ disease | 1 (2) |
| Conjunctival MALT lymphoma | 1 (2) |
Splenic MZL
Eleven patients (nine men, two women) had splenic MZL (Table 3). Moderate splenomegaly (median size 10 cm below costal margin) was found in all the cases. There were varying degrees of peripheral blood cytopenias. Although neoplastic infiltration of the marrow was observed in all patients, circulating lymphoma cells were detectable in only six patients (55%). Monoclonal immunoglobulin was detected in two patients (18%). One patient was positive for lupus anticoagulant. In one patient, the lymphoma cells were positive for CD5 with an absolute lymphocytosis of 10.8 × 109/L at presentation.
Table 3.
Clinicopathologic features and treatment results of 11 patients with splenic marginal zone lymphoma
| Parameters | Number (%) |
|---|---|
| Gender | |
| Male | 9 (82) |
| Female | 2 (18) |
| Median age (range), years | 50 (35–80) |
| B symptoms | 3 (27) |
| Splenomegaly | 11 (100) |
| Median size (range), cm below left costal margin | 10 (5 25) |
| Hepatomegaly | 2 (18) |
| Hematological parameters | |
| Anemia (Hb <11 g/dL) | 7 (64) |
| Lymphocytosis (>4 × 109/L) | 5 (45) |
| Neutropenia (<2 × 109/L) | 2 (18) |
| Thrombocytopenia (<100 × 109/L) | 5 (45) |
| Leukemic phase | 5 (55) |
| Marrow infiltration | 11 (100) |
| Paraproteinemia | |
| IgG | 1 (9) |
| IgM | 1 (9) |
| International prognostic index | |
| Low (0 or 1) | 1 (9) |
| Low/intermediate (2) | 3 (27) |
| Intermediate/high (3) | 5 (45) |
| High (4 or 5) | 2 (18) |
| Treatment and outcome | |
| Splenectomy + chemotherapya | 3 (27) |
| CR | 2/3 (67) |
| PR | 1/3 (33) |
| Splenectomy + rituximab + chemotherapya | 2 (18) |
| CR | 2/2 (100) |
| Chemotherapya | 5 (45) |
| CR | 1/5 (20) |
| NR | 4/5 (80) |
| Chemotherapya + rituximab | 1 (9) |
| PR | 1/1 (100) |
Ig immunoglobulin, CR complete response, PR partial response, NR no response
aChemotherapy included chlorambucil, FND (fludarabine, mitoxantrone, dexamethasone), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), CEOP (cyclophosphamide, epirubicin, vincristine, prednisolone), and M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone)
Nodal MZL
There were four patients (two men, two women) with NMZL. IgM monoclonal protein was detected in one patient. In one patient, there was coexisting autoimmune hemolytic anemia, vitiligo, and common variable immunodeficiency diagnosed prior to the occurrence of NMZL.
Treatment outcome of non-gastric MZL
Local therapy (excision with or without involved field radiotherapy) was administered in 17 patients (26%). Twenty-seven patients (41%) received systemic chemotherapy. Twelve patients (18%) received rituximab-containing chemotherapeutic regimens. Eight patients (12%) received rituximab alone. The response rates for this group of patients were presented in Table 4.
Table 4.
Treatment and outcome of 66 patients with non-gastric MALT lymphoma
| Treatment and outcome | Number (%) |
|---|---|
| Refused treatment or defaulted | 2 (3) |
| Local resection only | 11 (17) |
| CR | 8/11 (73) |
| PR | 0/11 (0) |
| NR | 3/11 (27) |
| Radiotherapy alone | 3 (5) |
| CR | 3/3 (100) |
| PR | 0/3 (0) |
| NR | 0/3 (0) |
| Local resection + radiotherapy | 3 (5) |
| CR | 3/3 (100) |
| PR | 0/3 (0) |
| NR | 0/3 (0) |
| Rituximab ± local treatment | 8 (12) |
| CR | 7/8 (88) |
| PR | 1/8 (12) |
| NR | 0/8 (0) |
| Chemotherapy ± local treatment | 27 (41) |
| CR | 20/27 (74) |
| PR | 5/27 (19) |
| NR | 2/27 (7) |
| Rituximab + chemotherapy ± local treatment | 12 (18) |
| CR | 10/12 (83) |
| PR | 2/12 (17) |
| NR | 0/12 (0) |
CR complete response, PR partial response, NR no response
Splenic MZL
The treatment regimens and responses for this group of patients were presented in Table 3. Splenectomy was performed in five patients, which was followed by chemotherapy in three patients and rituximab and chemotherapy in two patients. Six patients received chemotherapy without splenectomy, one of whom received rituximab as well. The CR rate was significantly better in patients who were splenectomized as compared with those who were not (CR: 4/5 splenectomized versus 1/6 non-splenectomized, P = 0.035).
Nodal MZL
Two patients were treated with the regimen fludarabine, mitoxantrone, dexamethasone (FND): one patient with R-FND (rituximab 375 mg/m2 before each course of FND) and one patient with chlorambucil followed by rituximab (375 mg/m2 given weekly for four doses). CR was achieved in two patients and partial response (PR) in one patient.
Relapse characteristics and transformation
The features and outcome of relapsed cases of the non-gastric, splenic, and nodal MZL were presented individually in Table 5. Fifteen patients with non-gastric MALT lymphoma relapsed, three with high-grade histological transformation. Ten patients underwent further treatment, with nine (90%) achieving a second CR. The only patient who did not respond to treatment had small bowel and pleural involvement, which at relapse showed transformation into diffuse large B cell lymphoma. Of the nine cases achieving CR2, two patients had subsequent relapses, presenting as transformation into high-grade follicular lymphoma and diffuse large B cell lymphomas. Both patients died ultimately of refractory lymphoma despite intensive chemotherapy and hematopoietic stem cell transplantation. Three patients with splenic MZL relapsed, two of whom showed high-grade histological transformation. Only one patient achieved a CR2 after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation. One patient with nodal MZL relapsed as a high-grade lymphoma and achieved CR after chemotherapy and ibritumomab tiuxetan therapy.
Table 5.
Clinicopathological features and outcome of 19 patients with relapsed non-gastric marginal zone lymphoma
| Clinicopathological features and outcome | Number (%) |
|---|---|
| Non-gastric MALT lymphoma | 15/66 (23) |
| Site of relapse | |
| Same | 8 (53) |
| Different | 7 (47) |
| Pattern of relapse | |
| Locoregional | 8 (53) |
| Advanced/disseminated | 7 (47) |
| Transformation | |
| None | 63/66 (95) |
| Diffuse large B cell lymphoma | 2/66 (3) |
| High-grade follicular lymphoma | 1/66 (2) |
| Treatment and outcome | |
| Radiotherapy alone | 1 |
| CR | 1/1 (100) |
| Radiotherapy + FND | 1 |
| CR | 1/1 (100) |
| Excision + radiotherapy + rituximab | 1 |
| CR | 1/1 (100) |
| Excision + R-COPP | 1 |
| CR | 1/1 (100) |
| FND | 2 |
| CR | 2/2 (100) |
| CEOP | 1 |
| CR | 1/1 (100) |
| NOPP | 1 |
| NR | 1/1 (100) |
| CEOP followed by autologous PBSCT consolidation | 1 |
| CR | 1/1 (100) |
| DHAP followed by autologous PBSCT consolidation | 1 |
| CR | 1/1 (100) |
| Splenic marginal zone lymphoma | 3/11 (27) |
| Site of relapse | |
| Same | 3 (100) |
| Pattern of relapse | |
| Advanced/disseminated | 3 (100) |
| Transformation | |
| Diffuse large B cell lymphoma | 1/11 (9) |
| T cell-rich B cell lymphoma | 1/11 (9) |
| Treatment and outcome | |
| FND | 1 |
| PR | 1/1 (100) |
| CEOP | 1 |
| NR | 1/1 (100) |
| DHAP followed by matched sibling allogeneic BMT | 1 |
| CR | 1/1 (100) |
| Nodal marginal zone lymphoma | 1/4 (25) |
| Site of relapse | |
| Same | 1 (100) |
| Pattern of relapse | |
| Advanced/disseminated | 1 (100) |
| Transformation | 1/4 (25) |
| Diffuse large B cell lymphoma | 1/4 (25) |
| Treatment and outcome | |
| R-CEOP followed by 90Y-irbitumomab tiuxetan consolidation | 1 |
| CR | 1/1 (100) |
CR complete response, PR partial response, NR no response, FND fludarabine–mitoxantrone–dexamethasone, CEOP cyclophosphamide–epirubicin–vincristine–prednisolone, NOPP mitoxantrone–vincristine–procarbazine–prednisolone, DHAP dexamethasone–cytarabine–cisplatin, COPP cyclophosphamide–vincristine–procarbazine–prednisolone, PBSCT peripheral blood stem cell transplantation, BMT bone marrow transplantation, R rituximab at 375 mg/m2 before each course of chemotherapy
Toxicity of treatment
Grade 4 neutropenia and febrile neutropenia was encountered in 14 (17.3%) and 13 (16%) patients, respectively (Table 6). Treatment-related mortality due to sepsis occurred in two cases (2.5%). Therapy-related acute myeloid leukemia developed in one patient with parotid MALT lymphoma 6 years after diagnosis.
Table 6.
Therapy-related toxicities in 81 patients with non-gastric marginal zone lymphomas
| Toxicity | Number (%) |
|---|---|
| Anemia | |
| Grade 1 | 10 (12) |
| 2 | 6 (7) |
| 3 | 3 (4) |
| 4 | 2 (3) |
| Neutropenia | |
| Grade 1 | 5 (6) |
| 2 | 4 (5) |
| 3 | 10 (12) |
| 4 | 14 (17) |
| Thrombocytopenia | |
| Grade 1 | 1 (1) |
| 2 | 3 (4) |
| 3 | 4 (5) |
| 4 | 8 (10) |
| Intracranial hemorrhage | 1 (1) |
| Febrile neutropenia | 13 (16) |
| Bacteraemia | 9 (11) |
| Invasive fungal infections | 1 (1) |
| Reactivation of tuberculosis | 1 (1) |
| Localized herpes zoster | 1 (1) |
| Disseminated herpes zoster | 1 (1) |
| Reactivation of hepatitis B virus infection | 1 (1) |
| Therapy-related acute myeloid leukemia | 1 (1) |
| Miscellaneousa | 4 (5) |
| Therapy-related mortality | 2 (3) |
aIncluding two cases of vincristine-related neuropathy, one case of chlorambucil-related liver function derangement, and one case of acute graft-versus-host disease of the skin after matched sibling bone marrow transplantation
Prognostic factors
Treatment results of the entire group were shown in Table 7. The overall response rate was 87% (69/79 patients) with a CR of 73% (58/79 patients). Various regimens designed for indolent lymphomas were used (Table 8). Fludarabine regimens and non-fludarabine regimens did not impact on CR rates. However, relapses were significantly reduced in patients receiving fludarabine regimens as compared with those receiving non-fludarabine regimens (3/23, 13% versus 9/22, 41%, P = 0.03). Interestingly, rituximab-containing regimens and non-rituximab regimens also did not impact on CR rates. However, relapses were significantly decreased in patients receiving rituximab-containing regimens as compared with those receiving non-rituximab regimens (2/21, 10% versus 10/24, 42%, P = 0.015). Similarly, when these regimens were analyzed according to whether fludarabine and/or rituximab were used, the CR rates were comparable. However, relapse rates were significantly lower in patients receiving both rituximab and fludarabine as compared with patients receiving none (P = 0.008), while patients receiving either rituximab or fludarabine showed intermediate results (Table 8). The impact of stage, performance status, and IPI risk score on response rates was evaluated using logistic regression. Favorable prognostic factors for CR were early-stage (stage I/II) disease (OR = 3.11, P = 0.039), good performance status (≤1, OR = 9.36, P < 0.001), and low IPI risk score (<3, OR = 4.17, P = 0.011). These factors, nevertheless, did not impact on the relapse rates.
Table 7.
Treatment results of 79 patients with non-gastric marginal zone lymphomas
| Treatment | Number | OR | CR | PR | SD | PD | Relapse |
|---|---|---|---|---|---|---|---|
| Local treatment alone | 17 | 14/17 (82%) | 14/17 (82%) | 0/17 (0%) | 2/17 (12%) | 1/17 (6%) | 5/14 (36%) |
| Systemic chemotherapy | |||||||
| Fludarabine containing | 28 | 25/28 (89%) | 23/28 (82%) | 2/28 (7%) | 1/28 (4%) | 2/28 (7%) | 3/23 (13%) |
| Non-fludarabine containing | 34 | 28/34 (82%) | 22/34 (65%) | 6/34 (18%) | 3/34 (9%) | 3/34 (9%) | 9/22 (41%) |
| Rituximab | |||||||
| Rituximab ± chemotherapy | 25 | 23/25 (92%) | 21/25 (84%) | 2/25 (8%) | 1/25 (4%) | 1/25 (4%) | 2/21 (10%) |
| Non-rituximab-containing chemotherapy | 37 | 30/37 (81%) | 24/37 (65%) | 6/37 (16%) | 3/37 (8%) | 4/37 (11%) | 10/24 (42%) |
| Fludarabine and rituximab | |||||||
| Fludarabine + rituximab containing | 11 | 10/11 (91%) | 10/11 (91%) | 0/11 (0%) | 0/11 (0%) | 1/11 (9%) | 0/10 (0%) |
| Fludarabine, non-rituximab containing | 17 | 15/17 (88%) | 13/17 (76%) | 2/17 (12%) | 1/17 (6%) | 1/17 (6%) | 3/13 (23%) |
| Rituximab, non-fludarabine containing | 14 | 13/14 (93%) | 11/14 (79%) | 2/14 (14%) | 1/14 (7%) | 0/14 (0%) | 2/11 (18%) |
| Non-fludarabine, non-rituximab | 20 | 15/20 (75%) | 11/20 (55%) | 4/20 (20%) | 2/20 (10%) | 3/20 (15%) | 7/11 (64%) |
OR overall response, CR complete response, PR partial response, SD stable disease, PD progressive disease
Table 8.
Impact of pretreatment characteristics on outcome in non-gastric marginal zone lymphomas
| Pretreatment characteristics | Number | OR | CR | PR | SD | PD | Relapse |
|---|---|---|---|---|---|---|---|
| Disease stage | |||||||
| Stage I/II disease | 52 | 50/52 (96%) | 44/52 (85%) | 6/52 (12%) | 1/52 (2%) | 1/52 (2%) | 13/44 (30%) |
| Stage III/IV disease | 27 | 19/27 (70%) | 14/27 (52%) | 5/27 (19%) | 4/27 (15%) | 4/27 (15%) | 6/14 (43%) |
| Performance status | |||||||
| ≤1 | 65 | 60/65 (92%) | 53/65 (82%) | 7/65 (11%) | 2/65 (3%) | 3/65 (5%) | 13/53 (25%) |
| >1 | 14 | 9/14 (64%) | 5/14 (36%) | 4/14 (29%) | 3/14 (21%) | 0/14 (0%) | 1/5 (20%) |
| IPI score | |||||||
| <3 | 56 | 53/56 (95%) | 46/56 (82%) | 7/56 (13%) | 2/56 (4%) | 1/56 (2%) | 15/46 (33%) |
| ≥3 | 23 | 16/23 (70%) | 12/23 (52%) | 4/23 (17%) | 3/23 (13%) | 4/23 (2%) | 4/12 (33%) |
OR overall response, CR complete response, PR partial response, SD stable disease, PD progressive disease
Survivals
The 5-year OS for the whole cohort was 84.6% (95% confidence interval, CI = 0.73–0.92; Fig. 1a) and the 5-year DFS was 82.2% (95% CI = 0.70–0.90; Fig. 1b). During the follow-up period, 14 patients (non-gastric MZL, n = 9; splenic MZL, n = 5) died: ten from refractory diseases, two from treatment-related causes, one from therapy-related leukemia, and one from unrelated causes. Prognostic factors associated with a lower mortality included stage I/II disease (odds ratio = 0.08, P < 0.001) and IPI risk score <3 (odds ratio = 0.09, P < 0.001). No differences in survival or mortality were observed between different treatment regimens.
Fig. 1.
Survival of patients with marginal zone lymphoma. a Overall survival. b Disease-free survival
Discussion
In this study, we have analyzed a cohort of MZL patients separately according to whether they had non-gastric, splenic, and nodal disease and also as a group for their responses to treatment. The reason for analyzing three MZL as a group with respect to treatment outcome is because similar drugs and strategies are often employed in their treatment. This series showed features characteristic of MZL. There was a slight female predominance (women/men = 1.4:1), probably related to a higher frequency of autoimmune diseases in women, which predisposes to MZL. In fact, the association of non-gastric MALT lymphomas with autoimmune diseases was clearly observed [13, 14], including salivary gland and thymic MALT lymphomas with Sjögren’s syndrome and thyroid MALT lymphomas with autoimmune thyroiditis. The most common primary site was ocular and ocular adnexal structures, followed by salivary glands and lungs, similar to previously reported findings [15, 16]. About 30% of patients had stage IV disease at presentation, often with multiple sites of involvement, which is in contrast to gastric MALT lymphomas that are usually localized [17].
For the whole cohort, treatment results were favorable, with CR achieved in 73% of patients. The impact of surgical removal of the lymphoma, particularly in localized non-gastric MALT lymphomas in the salivary and thyroid glands, has not been fully evaluated. We showed that splenectomy, even in our small series of splenic MZL, had a significantly favorable impact on CR. Splenectomy has traditionally been considered to be an important first-line treatment for splenic MZL [18]. However, with the advent of effective drugs including rituximab and fludarabine, the role of splenectomy has been questioned [19]. In a recent series of splenic MZL, the purine analogue 2-chlorodeoxyadenosine with or without rituximab has been reported to result in a CR rate of only 52%, very few of the patients having undergone a splenectomy [11]. The role of splenectomy might be clarified by a trial comparing splenectomy + immunochemotherapy versus immunochemotherapy alone. However, such a study is unlikely to be performed because of the rarity of splenic MZL and the general reluctance of using surgery to treat lymphoma patients. Hence, it may not be unreasonable to start treatment with a combination of rituximab and a purine analogue and reserve the more invasive splenectomy for patients with unsatisfactory responses or relapses after immunochemotherapy.
Similarly, although rituximab has significantly improved the outcome of aggressive [20] and indolent [21] B cell lymphomas, its role in MZL has not been critically appraised. If fact, data of the impact of rituximab on the outcome of MZL have not been well documented. Likewise, whereas purine analogues have improved the treatment outcome of low-grade lymphomas [22], their therapeutic efficacy has only recently been examined in MZL. Combination treatment with rituximab and fludarabine had been reported in two series [9, 23] comprising only 36 patients with non-gastric MZL. The CR rate varied from 54% to 80%. In another series of 82 patients with non-gastric MZL, the purine analogue 2-chlorodeoxyadenosine ± rituximab resulted in a CR rate ranging from 60% to 73% [24]. However, none of these studies compared their results with conventional regimens containing alkylating agents. Therefore, whether rituximab and purine analogues actually resulted in better outcome than alkylating agents could not be determined. In fact, the European Society for Medical Oncology guideline has stated that for gastric MALT lymphoma at least, no clear evidence in the literature exists to indicate the superiority of any of these drugs [7].
Our study was retrospective so that treatment regimens were very heterogeneous. Therefore, firm conclusions are not possible. However, we had the opportunity of comparing rituximab, fludarabine, and alkylating agent-containing regimens in the treatment of MZL. We also showed that CR rates were not different between regimens containing alkylating agents, rituximab, fludarabine, and rituximab + fludarabine. The CR rates in our study varied from 65% to 91%, comparable with data reported previously from regimens containing rituximab and purine analogues [9, 10, 24]. However, we showed that relapse rates were significantly different, with regimens containing rituximab and fludarabine giving significantly fewer relapses. The results suggested that the depth of remission, reflecting the extent of clearance of lymphoma cells, might be better with rituximab- and fludarabine-containing regimens.
Concerns have been expressed over the use of rituximab and purine analogues in MZL. In one study, the combined use of rituximab and fludarabine resulted in significant hematologic toxicities (grade III, 77%; grade IV, 42%), with 15% of patients developing delayed marrow toxicity that resulted in death [9]. In this study, however, grade IV toxicity appeared to be acceptable at about 15%, with treatment-related-mortality at only 2%. Therefore, rituximab + fludarabine appeared to be safe in our patient population, in accordance with experience of the use of this combination in chronic lymphocytic leukemia. Another issue is the possibility of myelodysplastic syndrome related to the use of purine analogues [7], particularly fludarabine [25]. One patient in our series developed acute myeloid leukemia 6 years after receiving FND. Hence, it is important that patients who have received fludarabine should have life-long follow-up.
In conclusion, we showed that non-gastric MZL as a group showed favorable response to treatment. The use of rituximab and fludarabine reduced the relapse rate as compared with conventional chemotherapy. Therapy with rituximab and fludarabine was associated with acceptable side effects. These data obviously have to be interpreted in light of the heterogeneity of patients and treatment in this series. Therefore, the combination of rituximab and fludarabine should be fully evaluated systemically in prospective trials.
Acknowledgments
Conflict of interests
The authors have no conflict of interests to declare.
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References
- 1.Isaacson PG, Piris MA, Berger F, Swerdow SH, Thieblemont C, Pitaluga S, Harris NL. Splenic B-cell marginal zone lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. pp. 185–187. [Google Scholar]
- 2.Issacson PG, Chott A, Nakamura S, Muller-Hermelink HK, Harris NL. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. pp. 214–217. [Google Scholar]
- 3.Campo E, Pileri SA, Jaffe ES, Muller-Hermelink HK, Nathwani BN. Nodal marginal zone lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. pp. 218–219. [Google Scholar]
- 4.Kwong YL. Predicting the outcome in non-Hodgkin lymphoma with molecular markers. Br J Haematol. 2007;137:273–87. doi: 10.1111/j.1365-2141.2007.06571.x. [DOI] [PubMed] [Google Scholar]
- 5.Jaffe ES, Harris NL, Stein H, Campo E, Pileri SA, Swerdlow SH. Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. pp. 157–166. [Google Scholar]
- 6.Jaffe ES, Harris NL, Stein H, Isaacson PG. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood. 2008;112:4384–99. doi: 10.1182/blood-2008-07-077982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zucca E, Dreyling M. ESMO Guidelines Working Group. Gastric marginal zone lymphoma of MALT type: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v175–176. doi: 10.1093/annonc/mdq182. [DOI] [PubMed] [Google Scholar]
- 8.Economopoulos T, Psyrri A, Fountzilas G, Tsatalas C, Anagnostopoulos A, Papageorgiou S, Xiros N, Dimopoulos MA. Phase II study of low-grade non-Hodgkin lymphomas with fludarabine and mitoxantrone followed by rituximab consolidation: promising results in marginal zone lymphoma. Leuk Lymphoma. 2008;49:68–74. doi: 10.1080/10428190701784714. [DOI] [PubMed] [Google Scholar]
- 9.Brown JR, Friedberg JW, Feng Y, Scofield S, Phillips K, Dal Cin P, Joyce R, Takvorian RW, Fisher DC, Fisher RI, Liesveld J, Marquis D, Neuberg D, Freedman AS. A phase 2 study of concurrent fludarabine and rituximab for the treatment of marginal zone lymphomas. Br J Haematol. 2009;145:741–748. doi: 10.1111/j.1365-2141.2009.07677.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Orciuolo E, Buda G, Sordi E, Baraté C, Galimberti S, Ciancia E, Petrini M. 2CdA chemotherapy and rituximab in the treatment of marginal zone lymphoma. Leuk Res. 2010;34:184–189. doi: 10.1016/j.leukres.2009.04.003. [DOI] [PubMed] [Google Scholar]
- 11.Cervetti G, Galimberti S, Sordi E, Buda G, Orciuolo E, Cecconi N, Petrini M. Significant efficacy of 2-CdA with or without rituximab in the treatment of splenic marginal zone lymphoma (SMZL) Ann Oncol. 2010;21:851–854. doi: 10.1093/annonc/mdp395. [DOI] [PubMed] [Google Scholar]
- 12.Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M. International harmonization project on lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–586. doi: 10.1200/JCO.2006.09.2403. [DOI] [PubMed] [Google Scholar]
- 13.Kovács L, Szodoray P, Kiss E. Secondary tumours in Sjögren’s syndrome. Autoimmun Rev. 2010;9:203–206. doi: 10.1016/j.autrev.2009.07.002. [DOI] [PubMed] [Google Scholar]
- 14.Troch M, Woehrer S, Streubel B, Weissel M, Hoffmann M, Müllauer L, Chott A, Raderer M. Chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) in patients with MALT lymphoma. Ann Oncol. 2008;19:1336–1339. doi: 10.1093/annonc/mdn049. [DOI] [PubMed] [Google Scholar]
- 15.Inagaki H, Chan JK, Ng JW, Okabe M, Yoshino T, Okamoto M, Ogawa H, Matsushita H, Yokose T, Matsuno Y, Nakamura N, Nagasaka T, Ueda R, Eimoto T, Nakamura S. Primary thymic extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue type exhibits distinctive clinicopathological and molecular features. Am J Pathol. 2002;160:1435–1443. doi: 10.1016/S0002-9440(10)62569-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Zinzani PL, Magagnoli M, Galieni P, Martelli M, Poletti V, Zaja F, Molica S, Zaccaria A, Cantonetti AM, Gentilini P, Guardigni L, Gherlinzoni F, Ribersani M, Bendandi M, Albertini P, Tura S. Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients. J Clin Oncol. 1999;17:1254. doi: 10.1200/JCO.1999.17.4.1254. [DOI] [PubMed] [Google Scholar]
- 17.Oh SY, Kim WS, Kim SJ, Kim JS, Kim SH, Lee DH, Won JH, Hwang IG, Kim MK, Lee SI, Kim JG, Yang DH, Kang HJ, Choi CW, Park J, Choi YJ, Kim HJ, Kwon JH, Suh C, Kim HJ. Relapsed or refractory nongastric marginal zone B-cell lymphoma: multicenter retrospective analysis of 92 cases. Am J Hematol. 2009;84:826–829. doi: 10.1002/ajh.21557. [DOI] [PubMed] [Google Scholar]
- 18.Matutes E. Splenic marginal zone lymphoma with and without villous lymphocytes. Curr Treat Options Oncol. 2007;8:109–116. doi: 10.1007/s11864-007-0026-0. [DOI] [PubMed] [Google Scholar]
- 19.Bennett M, Schechter GP. Treatment of splenic marginal zone lymphoma: splenectomy versus rituximab. Semin Hematol. 2010;47:143–147. doi: 10.1053/j.seminhematol.2010.01.004. [DOI] [PubMed] [Google Scholar]
- 20.Coiffier B. State-of-the-art therapeutics: diffuse large B-cell lymphoma. J Clin Oncol. 2005;23:6387–6393. doi: 10.1200/JCO.2005.05.015. [DOI] [PubMed] [Google Scholar]
- 21.Hiddemann W, Buske C, Dreyling M, Weigert O, Lenz G, Unterhalt M. Current management of follicular lymphomas. Br J Haematol. 2007;136:191–202. doi: 10.1111/j.1365-2141.2006.06378.x. [DOI] [PubMed] [Google Scholar]
- 22.Zinzani PL, Tani M, Pulsoni A, Gobbi M, Perotti A, De Luca S, Fabbri A, Zaccaria A, Voso MT, Fattori P, Guardigni L, Ronconi S, Cabras MG, Rigacci L, De Renzo A, Marchi E, Stefoni V, Fina M, Pellegrini C, Musuraca G, Derenzini E, Pileri S, Fanti S, Piccaluga PP, Baccarani M. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ) Lancet Oncol. 2008;9:352–358. doi: 10.1016/S1470-2045(08)70039-1. [DOI] [PubMed] [Google Scholar]
- 23.Salar A, Domingo-Domenech E, Estany C, Canales MA, Gallardo F, Servitje O, Fraile G, Montalbán C. 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. 2009;115:5210–5217. doi: 10.1002/cncr.24605. [DOI] [PubMed] [Google Scholar]
- 24.Lam CC, Ma ES, Kwong YL. Therapy-related acute myeloid leukemia after single-agent treatment with fludarabine for chronic lymphocytic leukemia. Am J Hematol. 2005;79:288–290. doi: 10.1002/ajh.20340. [DOI] [PubMed] [Google Scholar]
- 25.Ahmadi T, Schuster SJ. Variations on the fludarabine, cyclophosphamide, and rituximab combination in chronic lymphocytic leukemia therapy: what have we learned? J Clin Oncol. 2009;27:479–480. doi: 10.1200/JCO.2008.18.8698. [DOI] [PubMed] [Google Scholar]