Management of Marginal Zone Lymphoma

September 15, 2013

MZL comprises three different entities that require integration of clinical and pathologic features to make a diagnosis. Treatment is chosen and initiated on the basis of presentation, symptoms, and underlying subtype.

Marginal zone lymphoma (MZL) is the third most common B-cell non-Hodgkin lymphoma. It consists of three different entities, as defined by the World Health Organization, and arises from post-germinal marginal zone B cells that have similar immunophenotypes. MZL includes extranodal MZL of the mucosal-associated lymphoid tissue (MALT), nodal marginal zone lymphoma (NMZL), and splenic marginal zone lymphoma (SMZL). These entities differ in prognosis and outcomes; therefore, identification of clinical characteristics is important prior to determining treatment. Analysis of the Surveillance, Epidemiology and End Results (SEER) database reveals that prognosis in patients with MALT is statistically significantly better than prognosis in patients with SMZL or NMZL.[1] The 5-year relative survival rate for MALT is estimated to be 88.7%, compared with 79.7% for SMZL and 76.5% for NMZL. In an attempt to be concise, we will focus on SMZL and NMZL in this discussion.

Diagnosis of the MZL Subtypes

Distinguishing between SMZL and NMZL can be difficult and requires integration of clinical and pathologic data. SMZL expresses B-cell antigens (CD19, CD20, CD22) and is typically CD5-negative, CD10-negative, CD43-negative, CD103-negative, and CD25-negative. The lack of CD5 distinguishes SMZL from chronic lymphocytic leukemia and mantle cell lymphoma, and the lack of CD103 and CD25 distinguishes SMZL from hairy cell leukemia. The immunophenotype of NMZL is similar to that of SMZL; thus, clinical features assist with distinguishing between these two.[2] Rinaldi et al performed genome-wide DNA profiling on a large series of MZL tumors in an attempt to assess relationships among the subtypes and evaluate clinical outcomes based on genomic events. They found that SMZL was associated with del(7q31) and del(8p); in addition, del(17p) was often present with del(8p). The presence of either genomic del(17p) or del(8p) had a negative impact on outcomes in those with SMZL.[3] Further studies are still required to better assess the differences in genomic events associated with the subtypes of MZL, and to determine whether a high-risk group can be defined on the basis of genetic features.

Management of SMZL

SMZL is believed to be indolent. It presents primarily as splenomegaly; hepatomegaly can also be present, but lymphadenopathy is rare. The bone marrow is invariably involved upon diagnosis, with many different types of infiltration being reported; however, intrasinusoidal infiltration is considered highly characteristic.[4] Although median overall survival (OS) exceeds 10 years, approximately one-third of patients will have an OS of 4 years, with a clinically more aggressive course. It is difficult to identify these patients at diagnosis, and the International Prognostic Index (IPI) score has not been shown to be of value in SMZL.[5] However, patients with elevated β2-microglobulin, a monoclonal component, leukocyte count > 20,000/µL, and lymphocyte count greater than 9,000/µL have been shown to have shorter survival.[6] The Integruppo Italiano Linfomi performed a multicenter study on clinical features and outcomes in patients with SMZL and created a prognostic model that predicted a negative effect on OS and case-specific survival (CSS). The three parameters that persisted in demonstrating influence following multivariate analysis were hemoglobin level less than 12 g/dL, lactate dehydrogenase level higher than normal, and albumin level less than 3.5 g/dL. Those patients with no risk factors were considered low risk and had a 5-year CSS of 88%. In patients with one risk factor, the intermediate risk group, the CSS decreased to 73%; the CSS decreased even further, to 50%, in those at high risk, defined as having two or more risk factors.[5]

How We Manage Marginal Zone Lymphoma

Marginal zone lymphoma (MZL) consists of 3 different subtypes that are all CD19-positive, CD20-positive, CD22-positive, CD5-negative, CD23-negative, and cyclin D1–negative. Combining clinical and pathologic data is necessary to make a diagnosis.
Splenic marginal zone lymphoma (SMZL) can sometimes be observed for years. When treatment is indicated, we consider first-line rituximab or splenectomy. Maintenance therapy with rituximab should also be considered.
Nodal marginal zone lymphoma (NMZL) is treated similarly to disseminated extranodal MZL of the mucosal-associated lymphoid tissue (MALT) or follicular lymphoma. We initiate treatment with rituximab plus chemotherapy and use bendamustine or chlorambucil upfront.

Many patients with SMZL may be asymptomatic at diagnosis and can be monitored for years prior to treatment. In addition, several studies have noted an association between hepatitis C and SMZL.[7] In our practice, we test for hepatitis C in all patients diagnosed with MZL and initiate antiviral therapy if the result is positive, since data demonstrate response of lymphoma with successful antiviral therapy directed against hepatitis C in this setting.[8] For the more common situation of hepatitis C–negative lymphoma, treatment is considered when nodal disease becomes bulky, cytopenia develops, or the patient becomes symptomatic.

There are several different treatment approaches for SMZL, including single-agent rituximab, splenectomy, and traditional chemotherapy. Tsimberidou et al evaluated rituximab with or without chemotherapy in patients with SMZL[9] Although the sample size was small, the investigators compared rituximab vs chemotherapy alone vs chemotherapy plus rituximab. Response rates were highest in those receiving combined chemotherapy and rituximab or rituximab alone. They reported an 88% response rate in those receiving rituximab alone compared with an 83% response rate in the chemoimmunotherapy group and a 55% response rate in those receiving chemotherapy alone. They also evaluated a subset of patients receiving single-agent rituximab vs those receiving splenectomy alone as initial therapy. They noted that rituximab resulted in resolution of splenomegaly in 92% of patients and was superior to splenectomy in normalizing white blood cell counts and absolute lymphocyte counts. However, splenectomy resulted in higher platelet counts than single-agent rituximab.

The RESORT trial further evaluated rituximab as effective therapy for MZL. In this trial, following induction with rituximab, patients were randomly assigned to either maintenance rituximab (MR) or rituximab retreatment at time of progression (RR). Time to treatment failure in those with indolent lymphoma was 3.74 years for MR vs 1 year for RR. In addition, at 3 years, 100% of MR patients remained free of cytotoxic therapy compared to 70% of RR patients.[10]

In our practice, we will observe patients following diagnosis of SMZL until symptoms from splenomegaly develop, the degree of cytopenia becomes concerning, or significant bulky disease is noted. Depending on the performance status and age of the patient, we will choose between splenectomy and single-agent rituximab as initial therapy. If rituximab is chosen and the patient responds, we then recommend consideration of maintenance rituximab, based on the results of the RESORT trial. If there is inadequate response to rituximab, we consider splenectomy in an interdisciplinary approach that involves our surgical oncology colleagues.

Management of NMZL

NMZL is the least common of the MZL subtypes. It presents with primary nodal involvement without splenomegaly or blood or extranodal involvement. Many believe it most often results from disseminated extranodal MALT. Bone marrow involvement is seen in 30% to 60% of cases but in general is less common than in SMZL. NMZL, too, is believed to be an indolent disease, and the clinical course is similar to that of follicular lymphoma. Prognostic factors for NMZL are not well defined. Two studies evaluating the Follicular Lymphoma International Prognostic Index (FLIPI) in NMZL suggest that a higher FLIPI score correlates with worse prognosis; however, further studies are required to better assess prognosis in this disease.[11,12]

NMZL is commonly treated like follicular lymphoma or disseminated MALT-and approached differently than SMZL. Rituximab, however, continues to be of significant importance in our ability to achieve substantial CR rates and increased survival rates in this disease. In an article published in the Journal of Clinical Oncology this year, Zucca et al reported on a randomized study comparing chlorambucil, chlorambucil plus rituximab, and rituximab alone in patients with extranodal and disseminated extranodal MZL. Rituximab added to chlorambucil significantly reduced event-free survival (EFS) compared with chlorambucil alone (68% vs 50%).[13] In addition, the CR rate was superior, at 78%, in the chemoimmnotherapy group compared with 65% in the chemotherapy group. The update presented at this year’s American Society of Clinical Oncology annual meeting further supported the superiority of chlorambucil plus rituximab over rituximab alone, with EFS of 70% vs 51%.[14] These studies demonstrate that rituximab offers improved survival and CR rates when combined with traditional chemotherapy in patients with NMZL.

Another therapeutic regimen for patients with NMZL is bendamustine plus rituximab (BR). A recent article by Rummel et al evaluated bendamustine and rituximab (BR) vs R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line treatment for indolent lymphoma. A subset of the patients studied included those with MZL. Progression-free survival (PFS) in the MZL patients receiving BR was 57 months compared with 47 months in those receiving R-CHOP, suggesting noninferiority.[15] Because BR has less toxicity than R-CHOP, we prefer to use this combination of agents as first-line therapy in our patients with bulky NMZL or relapsed SMZL following splenectomy.

Experimental Treatments for MZL

More studies are needed to better understand the treatment of MZL. Other possible treatments include combined fludarabine and rituximab. A phase II trial evaluating concurrent fludarabine and rituximab in MZL revealed a CR rate of 54% and PFS of 79.5% at 3 years. However, there was significant toxicity, including hematologic, infectious, and allergic toxicity that resulted in 42% of patients being unable to complete the planned 6 cycles of therapy.[16]

Importantly, novel agents are currently being studied and will likely greatly influence management of MZL in the future. Ibrutinib, a Bruton tyrosine kinase inhibitor, is exciting and is thought to be effective in a wide variety of B-cell lymphomas. A phase I study published in 2013 revealed a response in refractory patients with multiple lymphoma subtypes, including MZL.[17] Phosphoinositide 3-kinase inhibitors are also being studied in refractory indolent non-Hodgkin lymphoma and appear promising, with an interim analysis of a phase II trial by Gilead Sciences (presented this year at the international conference on malignant lymphoma in Lugano, Switzerland) revealing a response rate of 53.6%. Further studies of these novel agents are currently being performed, and their outcomes will likely have an impact on our treatment of refractory and relapsed MZL; these agents may eventually be part of initial treatment regimens.

In summary, MZL comprises three different entities that require integration of clinical and pathologic features to make a diagnosis. Treatment is chosen and initiated on the basis of presentation, symptoms, and underlying subtype. As reviewed above, there have been advances in the past year in our understanding and approach to treatment, and further advances are likely to be made as novel agents are evaluated. However, further studies are needed to better guide treatment choice and sequence of therapy.



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2. Campo E, Miguel R, Krenacs L. Primary nodal marginal zone lymphomas of splenic and MALT type. Am J Surg Pathol. 1999;23: 59-68.

3. Rinaldi A, Mian M, Chigrinova E, et al. Genome-wide DNA profiling of marginal zone lymphomas identifies subtype-specific lesions with an impact on the clinical outcome. Blood. 2011;117:1595-1604.

4. Franco V, Florena AM, Emilio L. Splenic marginal zone lymphoma. Blood. 2003;101:2464-72.

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6. Thieblemont C, Felman P, Berger F, et al. Treatment of splenic marginal zone B-cell lymphoma; an analysis of 81 patients. Clin Lymphoma. 2002;3:41-7.

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8. Saadoun D, Suarez F, Lefrere F, et al. Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood. 2005;105:74-6.

9. Tsimberidou AM, Catovsky D, Schlette E, et al. Outcomes in patients with splenic marginal zone lymphoma and marginal zone lymphoma treated with rituximab with or without chemotherapy or chemotherapy alone. Cancer. 2006;107:125-35.

10. Williams ME, Hong F, Kahl BS, et al. A subgroup analysis of small lymphocytic and marginal zone lymphomas in the Eastern Cooperative Oncology Group protocol E4402 (RESORT): a randomized phase III study comparing two different rituximab dosing strategies for low tumor burden indolent non-Hodgkin lymphoma. J Clin Oncol. 2012;30:(suppl 15):abstr 8007.

11. Heilgeist S, McClanahan F, Ho AD, Witzens-Harig M. Prognositic value of the follicular lymphoma prognostic index score in marginal zone lymphoma: an analysis of clinical presentation and outcome in 144 patients. Cancer. 2013;119:99-106.

12. Arcaini L, Paulli M, Burcheri S, et al. Primary nodal marginal zone B-cell lymphoma: clinical features and prognostic assessment of a rare disease. Br J Haematol. 2007;136:301.

13. Zucca E, Conconi A, Laszlo D, et al. Addition of rituximab to chlorambucil produces superior event-free survival in treatment of patients with extranodal marginal zone lymphoma: 5-year analysis of the IELSG-19 randomization study. J Clin Oncol. 2013;31: 565-72.

14. Zucca E, Conconi A, Martinelli G, et al. Chlorambucil plus rituximab produces better eventfree and progression-free survival in comparison with chlorambucil orrituximab alone in extranodal marginal zone B-cell lymphoma (MALT lymphoma): final results of the IELSG-19 study. Hematol Oncol. 2013;(suppl 1):97-8.

15. Rummel M, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus ritxumab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicenter, randomized, phase 3 non-inferiority trial. Lancet. 2013;381:1203-1210.

16. Brown JR, Friedberg JW, Feng Y, et al. A phase 2 study of concurrent fludarabine and rituximab for the treatment of marginal zone lymphomas. Br J Haematol. 2009;145:741-8.

17. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI- 32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88-94.