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Splenic marginal zone lymphoma: disease features and management Expert Rev. Hematol. 6(6), 735–745 (2013)

Estella Matutes Haematopathology Unit, Hospital Clinic. Barcelona University, Villarroel, 170, 08036 Barcelona, Spain Tel.: +34 663 109 312 Fax: +34 932 275 717 [email protected]

Splenic marginal zone lymphoma (SMZL) is a lymphoma recognized as a distinct entity in the WHO classification of the lymphoid tumors. SMZL probably results from the expansion of a marginal zone B-cell driven by persistent antigen stimulation. SMZL is clinically and biologically heterogeneous. The SMZL Working Group has published guidelines for the diagnosis, workup and treatment of SMZL. There are no standard criteria to initiate treatment. A policy of watch and wait in asymptomatic patients is recommended. In symptomatic patients, data from retrospective studies suggest that rituximab with or without chemotherapy is the best strategy for SMZL. It is uncertain which is the optimal type of chemotherapy and whether patients may benefit from splenectomy prior chemoimmunotherapy. In the future, we may see progress with agents targeting known molecular lesions in SMZL. KEYWORDS: prognosis • purine analog • rituximab • splenectomy • splenic marginal zone lymphoma • survival • therapy

Splenic marginal zone lymphoma (SMZL) had been already described in the literature in the late 1970s and 1980s under different designations such as lymphoma-simulating reticuloendotheliosis, splenomegalic immunocytoma with circulating hairy cells, CD11c+ B-cell disorder with intermediate features between chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL) and splenic lymphoma with villous lymphocytes. Following the designation of SMZL by Schmid et al. [1], there have been a number of reports referring to the diagnostic aspects and pathogenesis as well as management of the patients with this lymphoma. Despite of early uncertainties as to whether SMZL represented a disease entity and, for this reason, was not considered as such in the REAL lymphoma classification, subsequently became apparent that SMZL is a lymphoma with distinct features and in the WHO classification of the hemopoietic and lymphoid tumors in 2001 [2] was included as a definitive category. In the revised updated WHO classification published in 2008 [3], in addition to the classical SMZL, a form of lymphoma perhaps related to SMZL and designated splenic diffuse red pulp small B-cell lymphoma (SDRPBCL) has been included as

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10.1586/17474086.2013.845522

a provisional entity [4]. It is not known whether the latter may represent a variant form of SMZL and it should be considered within the spectrum of SMZL. Although progress has been made over the last decade regarding the main disease manifestations, biology, pathogenesis and management of SMZL, the heterogeneity in clinical features, the paucity of prospective trials and lack of randomized clinical studies have conspired on which is the optimal treatment for this disease. This review is primarily addressed to describe the management of patients with SMZL but also will briefly describe the pathogenesis, diagnosis and prognosis of this lymphoma as these may influence the treatment choice. Epidemiology & pathogenesis

SMZL is the most common lymphoma that affects primarily the spleen. It is an infrequent form of low-grade lymphoma accounting for 98% homology to the germ line). However, despite of this heterogeneity in the level of mutations, there is a biased usage of the IGHV chain genes with IGHV1-2*04 present in up to a third of the cases [16]. This and the existence of cases sharing almost identical antigen-binding sites (stereotyped B-cell receptors [BCRs]) [17] support the role of antigen stimulation driving the lymphoma. Further SMZL occurs in carriers of the hepatitis C virus particularly in endemic areas such as Southern Italy, Japan and Southern of USA, and treatment directed to eradicate this virus may result in the remission of the lymphoma [18–23]. The antigen stimulation might first induce a polyclonal proliferation of B cells in the splenic marginal zone and later an independent clone may emerge following second hits involving deregulation of genes [19]. This model although not yet definitively proven in SMZL has been well documented in a variety of mucosa-associated lymphoid tissue (MALT) lymphomas, particularly but not exclusively gastric MALT lymphomas, which is driven by Helicobacter pylori. SMZL is a lymphoma poorly defined at a genomic level and has a high genomic complexity [24]. Deletions of 7q31–32 and gains of 3q are frequent and the smallest overlapping region of imbalance in chromosome 7 is 7q32.1–q32.2. Other genes or pathways shown to be disrupted are TP53 (~15% of cases) [25] and several genes of the NF-kB signaling pathway required for normal marginal zone B-cell differentiation and maintenance (~30% of cases) [26]. These abnormalities are not unique to SMZL, but are also seen in other B-cell malignancies. Two recent reports using whole-genome DNA sequencing have documented the presence of NOTCH2 mutations in 20–25% of SMZL cases [27,28]. Since NOTCH2 mutations appear to be very rare in other B-cell lymphomas except for diffuse large Bcell lymphoma (DLBCL) (5% of cases), the authors considered the high specificity of these mutations for SMZL. The NOTCH2 gene is known to play a role in normal marginal zone cell fate determination and therefore mutations of this gene may well be involved on SMZL pathogenesis. The lesions of the NOTCH2 and those of the NF-kB pathway could provide the rationale for targeted therapy in SMZL. Clinical manifestations

SMZL is a disease of adults without sex predominance. Main clinical features are those derived from splenomegaly such as abdominal discomfort and/or cytopenias often related to hypersplenism or autoimmune phenomena rather than bone marrow infiltration [29–34]. Systemic B symptoms and palpable lymph nodes are rare. Autoimmune manifestations and involvement of extranodal sites may be seen. Some patients may be 736

asymptomatic and the disease is discovered by chance on a routine checkup blood count that shows lymphocytosis. These patients may not have organomegaly at diagnosis and only a Bcell clone in the blood. This early form of SMZL may represent what are the monoclonal gammopathy of uncertain origin and monoclonal B-cell lymphocytosis that precede myeloma and CLL, respectively [30]. Diagnostic features & staging

The establishment of the diagnosis of SMZL and rule out other low-grade lymphomas is important because of the different response to treatment, prognosis and outcome of these lymphomas. Spleen histology is the hallmark for the diagnosis of SMZL [35]. However, in a substantial proportion of patients, such as these in whom splenectomy is not indicated on clinical grounds or those who do not or have mild splenomegaly, the diagnosis may be difficult. In such patients, it is important to compound the results of the various laboratory investigations to establish the diagnosis of SMZL. These include lymphocyte morphology if circulating lymphoma cells are present, immunophenotype, bone marrow histology and molecular genetics. Although SMZL does not have a recurrent chromosomal abnormality as it is the case of follicular or mantle cell lymphomas, trisomy 3 or iso3q and deletions or less often translocations involving chromosome 7q22–34 are present in approximately 20 and 40% of cases, respectively, and their presence might support the diagnosis of SMZL. Still these are not unique to SMZL neither found in all SMZL cases and for this reason results from cytogenetics should not be taken in isolation. In addition, cytogenetics and/or fluorescence in situ hybridization will help to distinguish SMZL from follicular and mantle cell lymphomas by allowing to rule out the presence of the t(14;18) and t(11;14). To this end, the SMZL working group provided guidelines aimed to establish the diagnosis of SMZL when information on the spleen histology is not available [36]. This was an important step since the diagnosis of SMZL could be broadened to patients with early-stage disease, a subgroup in which studies may give some clues on the first events involved in the pathogenesis of the lymphoma. Still some diagnostic problems may arise between SMZL and other low-grade lymphomas particularly with lymphoplasmacytic lymphoma in SMZL cases that have a serum monoclonal paraprotein and/or manifest lymphoplasmacytic differentiation, the variant form of HCL-v and the SDRPBCL, the latter two diseases considered as provisional entities in the WHO classification [4]. Concerning staging, the laboratory and imaging investigations that need to be carried out for a workup in a patient with SMZL are not as well defined as they are in other lymphomas such as follicular lymphoma or CLL. The SMZL working group addressed this issue too. Laboratory investigations should include full blood cell counts, renal and liver biochemistry, serum lactate dehydrogenase (LDH), B-2 microglobulin and serum and urine immunoglobulins [36]. In addition, screening for hepatitis C virus needs to be performed Expert Rev. Hematol. 6(6), (2013)

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SMZL: disease features & management

to identify the patients who are carriers of this virus and could benefit from therapy targeting the hepatitis C virus (see below) and if positive the genotype analysis should be done; an autoimmune screen including a search for autoantibodies to different tissues such as thyroid, muscle, ANA, anti-DNA and rheumatoid factor, cryoglobulins and a direct antiglobulin test is recommended on the baseline investigations as it will help to disclose patients with an autoimmune background. As in other lymphomas, testing for HIV and hepatitis B should be considered. The SMZL working group guidelines recommended a bone marrow trephine biopsy with immunohistochemistry to be carried out in all patients for diagnostic purposes. However, the need for this could be entertained in asymptomatic patients in whom treatment is not planned, and the diagnosis has already been established by the other investigations. A CT scan to estimate more precisely the spleen size and rule out the presence of lymphadenopathy is recommended particularly in patients with a need of treatment. A summary of the diagnostic and staging/disease evaluation is shown in FIGURE 1. Clinical & biological prognostic factors

SMZL is a low-grade lymphoma with a favorable prognosis. Median survivals are reported to be >10 years and a proportion of deaths are unrelated to the lymphoma but due to cardiovascular disease, solid tumors or lung disease. Transformation to large cell lymphoma has been documented and its incidence is estimated to be around 10% [30]. A recent report recorded on the Surveillance, Epidemiology and End Results (SEER) database analyzing the survival rates in 1,298 patients with SMZL during the periods of 1995 through 2000, 2001 through 2004 and 2005 through 2009 showed a 5-year relative survival rate of 79.7% and a 10-year relative survival rate of 57.9% [37]. There were no differences in survival according to the stage of the disease and, unlike in nodal marginal zone lymphomas (NMZL) and MALT lymphomas, there was no improvement in survival along all these years. Hopefully, this scenario will change with the use of new treatments. Considering clinical variables, single center studies have shown in multivariate analysis that older age, anemia, lymphocytosis, high LDH, low albumin level, no response (NR) to treatment and/or involvement of nonhemopoietic sites predict for a shorter survival in SMZL patients [31,34,38]. Risk stratification has been proposed in a few studies. Considering that a third of the patients die from causes unrelated to the lymphoma, all information available needs to be taken with caution. A report by the Italian group in 309 patients suggested three variables predictors for a shorter cause-specific survival: hemoglobin 70 years), anemia and IGHV genes truly unmutated (100% homology to the germ line) predicted for shorter survival [15]. TP53 mutations and IGHV family gene usage had no prognostic impact in multivariate analysis. The combination of cases positive for one or more of these three adverse prognostic factors for survival compared with those without a risk factor allowed to stratify patients into two risk groups with survival of 72% in the high-risk group versus 100% in the low-risk group (p = 0.0004) [15]. The prognostic impact of NOTCH2 mutations in SMZL is controversial too. In one study the presence of NOTCH2 mutations were not correlated with IGHV mutations, IGHV usage, abnormalities of chromosome 3 or hepatitis C virus status, but preferentially associated with deletions of 7q and a favorable prognosis. OS at 5 years for patients with NOTCH2 mutations was 93 versus 74.3% for those with wild-type 737

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improving the cytopenias. However, infiltration of the bone marrow will persist and therefore all responses are partial. Different reports have documented Diagnostic tests Staging responses in 75–100% of patients, and at 4–5 years, a PFS of approximately 80% and OS ranging from 72 to 88% [31,32,42– 44]. Some of these studies suggested that Full blood cell count Spleen histology patients who had splenectomy had a betRenal and liver biochemistry Cytology of blood and bone marrow Serum and urine Ig and B-2 microglobulin Immunophenotype ter OS than those treated with chloramLDH Bone marrow aspirate and biopsy bucil and the difference was higher Hepatitis C and B serology, HIV Cytogenetics/FISH when nonlymphoma-related deaths were Autoimmune screen excluded [31,32]. An alternative to splenecDAT, cryoglobulins CT scan of chest, abdomen and pelvis tomy is splenic irradiation with a dose of Bone marrow biopsy 6–8 grays given in one or two fractions in patients with surgical risk. Responses are seen in most patients and around half Figure 1. Diagnosis and staging in a patient with splenic marginal zone of them may not require further treatlymphoma. Note that not all the investigations may be needed. ment in a long-term follow-up [31,32]. NOTCH2 [27]. In contrast, in another study, patients with A recent analysis on 1251 SMZL cases recorded in the SEER NOTCH2 mutations had an adverse outcome with shorter database concluded that there was no evidence of a beneficial PFS, transformation and survival [28]. or detrimental effect of the splenectomy on patients survival [45]. Of these 1251 cases, 52.1% underwent splenectomy and 1.2% Management & treatment splenic irradiation; 203 (16.2%) died from lymphoma that There is no evidence that asymptomatic patients with mild accounted for 54% of the deaths. However, this study has limisplenomegaly, no cytopenias and absence of systemic symptoms tations since there was no information on clinical factors, would benefit from early intervention. Single center studies on which may have had influence in the outcome, for instance, a a large number of patients support the strategy of watch and higher tumor burden and more active disease in patients who wait in these patients who indeed have a favorable outcome [31– underwent splenectomy. 33]. The issue is whether patients who have a poor prognostic profile on the basis of biological factors should be treated ear- IFN-a plus or not ribavirin lier. One exception is the subset of patients with hepatitis C Hermine et al. first reported the remarkable activity of IFN virus positive serology who likely would benefit from treatment alone or in combination with ribavirin in nine SMZL patients with IFN-a plus or not ribavirin, even if they have low tumor with hepatitis C virus infection [22]. IFN was given at a dose of burden. 3 MU/thrice a week subcutaneously and ribavirin at a dose of Treatment is indicated in patients with symptomatic disease 1,000–1,200 mg/daily/po for a period of 10 month. Seven out often manifested with bulky splenomegaly, cytopenias, rapidly of nine patients responded to IFN alone. The two nonrespondprogressive lymphocyte counts and/or systemic B symptoms. It ers achieved a response (one partial and one complete) when is uncertain which is the optimal treatment for SMZL due to ribavirin was added to IFN. Complete responses (CRs) correthe lack of prospective randomized clinical trials. Therefore, the lated with loss of detectable hepatitis C virus RNA load. The clinician should be guided by the disease manifestations and efficacy of IFN and ribavirin has been subsequently confirmed the patient’s characteristics. For instance, splenectomy can still in other studies. Kelaidi et al. documented a response to IFN be considered and indicated in patients with very bulky spleens, and ribavirin in five out of eight SMZL, but this only correminimal bone marrow involvement and who are fit for surgery lated with virological responses in few patients [23]. Similarly while this option is not considered in those with mild spleno- Arcaini et al. [18] reported a response in three out of four megaly and with the bulk of the lymphoma in the bone mar- patients treated with IFN and ribavirin [2] and IFN alone [1]. row and/or extranodal sites. The response rate and outcome of SMZL patients treated Purine analogs with different strategies are described below. The three purine analogs fludarabine, 2´chlorodeoxyadenosine (CDA) and 2´deoxycoformycin (DCF) are cytotoxic drugs that have a chemical structure similar to adenosine or deoxyadenoSplenectomy Splenectomy has been traditionally the treatment of choice for sine. They act as antimetabolites competing with natural SMZL patients since the quality and duration of responses to nucleosides and as inhibitors of critical enzymes involved in the alkylating agents in this lymphoma are suboptimal. Splenec- metabolism of purine nucleosides. These drugs that are cytotomy is effective by debulking tumor and correcting or toxic to quiescent and proliferating cells have a significant

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SMZL. Diagnosis and staging

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SMZL: disease features & management

efficacy in low-grade B-cell lymphoproliferative disorders such as CLL and HCL. Therefore, there is a rationale for these agents to be used in SMZL.

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Fludarabine

Boland et al. [46] first reported the efficacy of fludarabine in four SMZL patients who had relapsed or were refractory to chlorambucil [3] and IFN-a and splenectomy [1]. Fludarabine was given intravenously (i.v.) as a single agent at a dose of 25 mg/m2/day/5 days/3–5 monthly courses. All four patients responded with resolution of the splenomegaly and/or improvement of the blood cell counts. Responses were durable (‡2 years) in the two cases with a long-term follow-up; the other two died from causes unrelated to the lymphoma. Subsequently, Lefrere et al. treated 10 patients with fludarabine alone, two of whom had not been previously treated [47]. Eight patients received 4 monthly courses and two had 2 and 6 courses, respectively. The overall response rate (ORR) was 100%. Seven patients achieved a good response as defined by the resolution of the splenomegaly, absence of lymphocytosis and levels of Hb >10 g/dl, neutrophils >1  109/l and platelet count >100  109/l; the remaining three achieved a partial response (PR). An update of this study showed that 30% of the patients remain alive and progression free 6–7 years after treatment [48]. The median event-free survival was 4.7 years and median OS from diagnosis was not reached. Lower doses of fludarabine have shown to have efficacy in single case reports. Yasukawa et al. documented a case of SMZL resistant to splenic irradiation and chemotherapy that responded to fludarabine given at a dose of 15 mg/m2/i.v./day/3 days [49]. A retrospective study from the MD Anderson has shown that chemotherapy namely using fludarabine-based regimens is effective but inferior to rituximab monotherapy and chemoimmunotherapy [43]. In this study, 43 out of the 70 patients with SMZL required systemic treatment, 10 were splenectomized and 17 on a watch-and-wait policy. Out of the 43 patients who were treated, 11 received chemotherapy only: fludarabine (2), fludarabine plus prednisolone (1), fludarabine plus cyclophosphamide (4), CDA (2) and a regimen of fractionated cyclophosphamide, vincristine, liposomal doxorubicin and dexamethasone (1). The ORR to chemotherapy alone was 54% with a CR rate of 18% and a PR rate of 36%. At a median follow-up of 2.7 years, 15 patients have died. Survival rates were lower in the chemotherapy group, 8 out of 11 (73%) patients died at a median follow-up of 6.8 years compared with the rituximab group (12% of patients died at a median follow-up of 2.5 years) and to the 6 patients who received chemoimmunotherapy whom all of them are alive. The median failure-free survival of the 70 patients was 5.7 years. Treatment failure occurred in 26 patients and this included all 11 who were treated with chemotherapy alone. 2´ CDA

Wirchis and colleagues first reported the efficacy of CDA in a patient who was refractory to alkylating agents and progressed www.expert-reviews.com

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following splenectomy [50]. CDA was given at a dose of 0.1 mg/kg/i.v./day/7 days for a total of four courses. The patient achieved a long-lasting response without major toxicity. Subsequently Lefrere et al. documented the short-lived responses and toxicity of CDA in seven SMZL [51]. The schedule was that outlined above and the median number of courses was one (range 1–2). Two of the seven patients achieved a CR lasting for 9–20+ months and four had a short-lived PR and relapsed at 3.5 months (1–4). Hematological toxicity was a matter of concern. The authors concluded on the lack of efficacy and major toxicity of CDA in patients with SMZL. In contrast, Riccioni et al. [52] documented a response rate to CDA of 80% in 10 patients and 4 of these patients had been previously treated with chemotherapy (3) or splenectomy (1). Two (20%) patients achieved a CR including one with molecular remission and 60% PR. The schedule used in this study was 5 mg/m2/week/6 weeks. Survival at 48 months was 60% and PFS at 24 months was 37%. Unlike in Lefrere’s study, the treatment was well tolerated with no significant toxicity; this might be related to the different schedule used. A recent study by the same group in 50 patients treated with CDA alone or with rituximab confirmed the efficacy of CDA although the CR rate was higher when rituximab was given in combination or subsequently to chemotherapy [53] (see below rituximab plus chemotherapy). A retrospective study by Orciulo et al. in 89 patients with marginal zone lymphoma treated with CDA plus or not rituximab confirmed the above results [54]. The 89 patients included 26 SMZL, 16 MALT and 47 NMZL. All patients were not previously treated except four that had splenectomy. The schedule of CDA was that used by Riccioni et al. [52] and rituximab was given either concomitantly or after the end of therapy. Out of the 26 SMZL included in the study, 16 received the combination of CDA and rituximab and 9 CDA alone. The ORR and CR rate in patients treated with CDA alone were 66.7 and 22%, respectively, and the median time to treatment failure (TTF) was 38 months. Addition of rituximab resulted too in a higher ORR, CR rate and longer median TTF (see below rituximab plus chemotherapy). The treatment with CDA alone or in combination with rituximab was well tolerated and main side effects were neutropenia and infections that particularly occurred in patients with SMZL (36%) compared with NMZL (2.1%) and MALT lymphomas (12.5%). 2´ DCF

There is scanty experience with this drug in SMZL. A Phase II trial on 16 patients, 3 of whom were untreated and 13 had relapsed following splenectomy (1) or alkylating agents (12) showed an ORR of 68% (11/16) [55]. Out of the 11 responders, 3 (2 previously untreated) achieved a CR and 8 a minimal hematological response. DCF was administered at a dose of 4 mg/m2/i.v. every other week for 5–10 weeks. The toxicity, particularly hematological was manageable. At a median followup of 35 months, the median PFS was 18 months and the median OS 40 months. 739

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Table 1. Response and outcome of splenic marginal zone lymphoma treated with single agent rituximab. Study (year)

Patients (n)

ORR (%)

CR/CRu (%)

PFS (years)

OS (years)

Ref.

Bennett et al. (2010)

11

91

73

60% (4)

81% (6.4)

Tsimberidou et al. (2006)

25

88

31

86% (3)

95% (3)

[43]

Kalpadakis et al. (2013)

58

95

71

73% (5)

92% (5)

[59]

Else et al. (2012)

10

100

90

79% (3)

98% (3)

[60]

[44,56,57]

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CR/CRu: Complete response/unconfirmed complete response; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival.

Rituximab monotherapy

There have been a number of reports documenting the efficacy of single agent rituximab in SMZL. Rituximab is a humanized monoclonal antibody (McAb) that targets the CD20 antigen expressed in normal B cells and in cells from the vast majority of B-cell lymphomas. It is possible that the activity of rituximab in SMZL relates in part to the high number of CD20 molecules in the surface of the lymphoma cells. The schedule most commonly used is 375 mg/m2/i.v. weekly for 4– 6 weeks. Bennett et al. used rituximab in 11 elderly patients, 10 of whom had been previously treated with chemotherapy and another that had been splenectomized [56]. The ORR was 91% and 5 of the 10 responders were in continuous remission at a median follow-up of 73 months. The other five responders relapsed but again achieved a second response when retreated with rituximab. The OS from the rituximab treatment with a median follow-up of 77 months was 81% [44,57]. Tsimberidou et al. used rituximab in 25 untreated SMZL and reported an ORR of 88% with 31% unconfirmed complete responses (CRu) as defined by minimal stable radiological changes and/ or persistent lymphoid aggregates in the bone marrow without atypia; with a median follow-up of 36 months, the PFS at 3 years was 86% [43]. Kalpadakis et al. documented an ORR of 100% to rituximab given weekly for 6 weeks in 16 patients naı¨ve of treatment [58]. The CR rate was 69% and CRu 19%. Twelve of the 16 patients went into a maintenance schedule and received rituximab every 2 months for 1 year. At a median follow-up of 25.5 months, 3 of the 16 patients had relapsed and these were 1 out of 12 that received maintenance and 2 out of 4 that did not receive maintenance. The study by Kalpadakis et al. has been recently updated and extended to 58 patients, 43 of whom received maintenance for 1–2 years. The ORR was 95% with 45% CR and 26% CRu [59]. Interestingly, of the 43 who had maintenance, 27 maintained the response and in 15 there was a further improvement in the quality of response. This suggests that rituximab maintenance may have a role in maintaining or improving responses in SMZL. At 5 years, the PFS was 73% and the OS 92%. Like in Bennett series, 4 out of 6 patients that relapsed responded for a second time to rituximab indicating that the efficacy of rituximab is maintained in a relapse setting. Data reported by Else et al. [60] in 10 patients, 5 of whom had been previously treated and another splenectomized showed similar results with an ORR of 100% with a CR rate of 90% [60]. A summary of 740

the ORR, CR rate, PFS and OS in SMZL patients treated with rituximab single agent is shown in TABLE 1. Rituximab plus chemotherapy

Rituximab with different forms of chemotherapy has been used in several studies. Arcaini et al. first reported the efficacy of rituximab combined with cyclophosphamide and vincristine (R-CV) in three patients previously treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) [61]. All three responded and at a median follow-up of 1.3 years, the PFS and OS were 100%. In a prospective Phase II study, Brown et al. documented the high efficacy but significant toxicity of fludarabine in combination with rituximab (FR) in 26 patients with marginal zone lymphomas [62]. These included 14 NMZL, 8 MALT and 4 SMZL. Three of the four SMZL had been previously splenectomized. Fludarabine was given at a dose of 25 mg/m2/i.v./day for 5 days and rituximab 375 mg/ m2/i.v./day for 1. Patients received prophylaxis with cotrimoxazole for Pneumocystis jiroveci pneumonia and acyclovir for herpes zoster. Six cycles were planned, but only 58% of the patients were able to complete the six cycles due to toxicity. The ORR for 26 patients was 85% with a CR and CRu rates of 54%. At 3.1 year, PFS was 79.5% and OS 87.4% with all the deaths being unrelated to the lymphoma including two patients who developed myelodysplasia. Although the schedule was highly effective, 77% of patients experienced hematological toxicity, infections and severe allergic reactions [62]. In the report by Tsimberidou et al. six patients were treated with rituximab in combination with chemotherapy: fludarabine, cyclophosphamide and rituximab (5) and fludarabine mitoxantrone dexamethasone and ritucximab (1). The ORR was 83% with a CR rate of 17% and a CRu of 17% [43]. At 4 years, the PFS was 66% and the OS at 3 years 100%. Two studies combining CDA and rituximab have also shown the superiority of this combination compared to CDA alone [53,54]. The retrospective study by Orciulo et al. [54] included 89 patients with marginal zone lymphomas: 26 SMZL, 47 NMZL and 16 MALT. All patients were treatment naı¨ve and four SMZL had previously splenectomy. Patients received CDA alone or in combination with rituximab. CDA was given at a dose of 5 mg/m2/i.v./ week per six cycles. Rituximab was given concomitantly for six cycles (15 patients) or in a sequential manner following the treatment with CDA for 4 consecutive weeks at a dose of 375 mg/m2/i.v./week. A total of 85 patients were evaluable for

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SMZL: disease features & management

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Table 2. Response and outcome of splenic marginal zone lymphoma treated with rituximab in combination with chemotherapy. Study (year)

Patients (n)

Chemotherapy

ORR (%)

CR/CRu (%)

PFS (years)

OS (years)

Ref.

Arcaini et al. (2004)

3

CV

100

NA

100% (1.3)

100% (1.3)

[61]

Brown et al. (2009)

26

F

85

54

79.5% (3)

87.4% (3)

[62]

Tsimberidou et al. (2006)

6

FC (5) FMD (1)

83

34

66% (4)

100% (3)

[43]

Orciulo et al. (2010)

16

CDA

100

75

NA

NA

[54]

Cerveti et al. (2013)

32

CDA

87

62

80% (5)

86% (5)

[53]

Else et al. (2012)

33

F, FC. CVP, CHOP

100

79

79% (3)

98% (3)

[60]

Ianitto et al. (2007)

19

COMP

100

63

NA

NA

[63]

Ianitto et al. (2011)

6

Bendamustine

100

66

NA

NA

[64]

†

†

Included 4 splenic marginal zone lymphoma, 14 nodal marginal zone lymphoma and 8 mucosa-associated lymphoid tissue lymphoma. CDA: Chlorodeoxyadenosine; CHOP: Cyclophosphamide, doxorubicin, vincristine, prednisolone; COMP: Cyclophosphamide, nonpegylated liposomal doxorubicin, vincristine, prednisolone; CR/CRu: Complete response/unconfirmed complete response; CV: Cyclophosphamide, vincristine; CVP: Cyclophosphamide, vincristine, prednisolone; F: Fludarabine; FC: Fludarabine, cyclophosphamide; FMD: Fludarabine, mitoxantrone and dexametasone; NA: Not available; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival.

response. The ORR in 58 patients who received the combination of CDA plus rituximab was 96% with a CR rate of 60.3% and a PR rate of 36.2%. This compares very favorable with the 26 patients who received CDA alone (ORR of 73% and CR rate of 38.5%). Considering the group of SMZL, 25 out of 26 were evaluable for response and 16 of those received the combination of CDA plus Rituximab. The ORR was 100% with a 75% CR rate and median TTF of 60 months. Treatment was well tolerated with main side effects neutropenia, infections and infusional reactions to rituximab that were more common in SMZL (36.4%) compared with NMZL (2.1%) and MALT lymphomas (12.5%). In the retrospective study by Cervetti et al. [53], 32 out of 50 patients were treated with CDA plus Rituximab either concomitantly or sequentially like in Orciulo’s study. All patients received prophylaxis with cotrimoxazole, acyclovir and fluconazole. The ORR for 46 patients who were evaluable for response was 87% with a CR rate of 52% and NR of 6%. The CR rate was significantly higher in the patients who had received CDA plus rituximab (62%) versus those that received CDA alone (11%). Out of 31 patients who underwent minimal residual disease (MRD) assessment by molecular studies, 48% achieved a CR with MRD negativity. Toxicity was manageable with few patients developing neutropenia, chills or rigors. At a median follow-up of 5 years, PFS was 80% and the OS was 86%. Interestingly, all seven relapsed patients responded again to rituximab plus or no chemotherapy achieving a PR. In the study by Else et al. [60], 33 patients were treated with rituximab in combination with chemotherapy (fludarabine-based regimens, CVP or CHOP). The ORR and CR rates were 100 and 79%, respectively, similar to that of patients treated with rituximab alone in the same study [60]. Toxicity was higher in patients treated with chemoimmunotherapy compared with those treated with rituximab alone. In this study, 10 of the patients had been previously treated with chemotherapy alone. The CR rate following chemotherapy was 30%, significantly www.expert-reviews.com

lower than the CR rate of 79% following chemoimmunotherapy even when this was used as second line. This emphasizes the efficacy of rituximab in patients with SMZL. Of interest was that the CR rate was significantly higher in patients who had been previously splenectomized versus those whose spleens had not been removed (100 vs 67%). The PFS and OS at 3 years for the series of 33 patients were of 79 and 98%, respectively. A prospective study with a combination of nonpegylated liposomal doxorubicin, cyclophosphamide, prednisolone and rituximab has been used as front-line therapy in 20 patients with SMZL with an ORR in the 19 evaluable patients of 100% and a CR rate of 63%. However, toxicity was a matter of concern with grade III/IV neutropenia (42%) and peripheral neuropathy (25%). A follow-up from this study has not been documented [63]. Bendamustine, an agent that has alkylating and purine analog like properties, is currently used in several clinical trials for lowgrade lymphomas and CLL. Iannitto et al. treated six SMZL patients with the combination of Bendamustine plus rituximab. All six patients responded and four of them achieved a CR. The duration of response and toxicity was not detailed [64]. A summary of the responses, PFS and OS to chemotherapy in combination with rituximab is shown in TABLE 2. At present, there is a multicenter prospective trial for patients with SMZL using bendamustine and rituximab (BRISMA study) with main endpoints: response, duration of response and significance of MRD. Results are awaited. Future potential treatments

Over the last decade, a number of new agents have been developed and/or used in patients with low-grade B-cell lymphomas including those derived from the marginal zone [65], particularly in the relapsed or refractory setting. Among these are: • Novel McAb targeting, the CD20 antigen with greater activity than rituximab such as the humanized anti-CD20 antibodies ofatumumab and obinutuzumab (GA-101), an 741

Review

Matutes

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Management of SMZL

Expert commentary

In asymptomatic SMZL patients, there is no evidence that early intervention could be of benefit and a policy of Asymptomatic Symptomatic patients Hepatitis C+ watch and wait is recommended. The No cytopenias or optimal and more effective treatment bulky spleen for SMZL remain controversial due to the lack of prospective randomized clinInterferon-alpha+/Watch and wait Rituximab + ribavirin ical trials. With the present available Rituximab +/chemotherapy information, rituximab either alone or splenectomy +/- splenectomy Progression in combination with chemotherapy with or without splenectomy are the treatFigure 2. Treatment of splenic marginal zone lymphoma. ments of choice for symptomatic patients with SMZL. Splenectomy is anti-CD22 McAb and bispecific antibodies such as Blini- still possibly indicated in patients fit for surgery who present tumomab an anti-CD3/CD19 antibody that engages neo- with bulky spleens, no lymphadenopathy and little bone marplastic B cells to cytotoxic T cells facilitating and row disease. Splenectomy will remove tumor burden and can increasing the lysis of the tumor cells; be followed by rituximab that might clear the residual disease • Bruton’s tyrosine kinase inhibitors that block the BCR- in the bone marrow [Matutes E, Unpublished Data] (personal experistimulated activation of the NF-kB pathway; ence in a few patients). It is uncertain whether rituximab • Proteasome inhibitors such as Bortezomib, an inhibitor of with chemotherapy is superior to rituximab single agent, the NF-kB pathway used alone or in combination with which type of chemotherapy has a higher efficacy with less rituximab; toxicity and whether rituximab maintenance has a role in • Drugs targeting microenvironment such as lenalidomide. prolonging PFS and OS as prospective randomized trials have not been conducted. Decisions should be made on an Considering the success of these agents in low-grade lympho- individual patient basis and possibly tailored according to the mas, they could be considered in the future in SMZL patients risk scores proposed by the SMZL working group. Chemowith advanced disease and who are refractory to the standard immunotherapy may be indicated in patients with high risk, immunochemotherapy. while rituximab single agent in those with intermediate or In addition, NOTCH inhibitors are in the phase of develop- low risk and less tumor burden. FIGURE 2 illustrates the treatment and since approximately 25% of SMZL have mutations ment pathways in SMZL. of NOTCH2, these molecularly targeted agents to NOTCH2 could in future be used in SMZL. Five-year view Hopefully in the next years, the role of rituximab maintenance Management of transformation Like in other low-grade B-cell lymphoproliferative disorders, in SMZL will be established if this agent is included as consolitransformation may occur in SMZL either in the spleen, dation therapy in future clinical studies. New agents particubone marrow, lymph nodes or at extranodal sites. In few larly but not only McAbs such as ofatumumab possibly will be patients, it occurs in the spleen at diagnosis following sple- tested in patients who had short-lived responses or are refracnectomy. Information on the risk factors for transformation, tory to rituximab plus chemotherapy. It is still uncertain how response to treatment and outcome is scanty as only a few the potential new molecularly targeted drugs such as NOTCH2 single case reports and retrospective small series have been inhibitors could be integrated with the present therapy as they documented. Features at diagnosis that have been reported to are in its infancy for development and clinical use. We may see be associated with transformation are a high Ki-67, presence therapeutic advances by incorporating the genomic features of of a monoclonal band and lymphadenopathy [66,67]. In terms SMZL in the routine practice that could allow moving to a of treatment, these patients should be managed as those with patient-tailored treatment. DLBCL with an antracycline-based regimen combined with Rituximab. One study on nine patients suggested that the site of transformation influenced the outcome. All five patients that transformed in the lymph nodes responded to treatment achieving a CR while only one out of four with transformation in the bone marrow responded [67]. The median OS for the former group was 54 months compared with 9 months for the second group.

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Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Expert Rev. Hematol. 6(6), (2013)

SMZL: disease features & management

Review

Key issues • Splenic marginal zone lymphoma (SMZL) is a low-grade B-cell lymphoma with diverse clinical and biological features. The diagnosis may sometimes be difficult when information on the spleen histology is not available since lacks a cytogenetic hallmark. • The prognosis is favorable with a median overall survival of approximately 12 years and a proportion of deaths being unrelated to the lymphoma. • Risk stratification is based on clinical and laboratory manifestations as data are controversial on the prognostic impact of biological parameters.

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• A policy of watch and wait is recommended in asymptomatic patients. • In the past, splenectomy had been the standard therapeutic approach for SMZL. There is now evidence from retrospective studies that Rituximab alone or in combination with chemotherapy with or without splenectomy is highly effective in SMZL and at present is the gold standard treatment. • Relapsed patients who achieved a response to rituximab may respond again to this agent. • The role of rituximab maintenance or consolidation is not yet established, but there are suggestions that it may prolong response. • Therapeutic options that include new McAb and molecularly targeted agents to NOTCH2 may become available in future in a relapse or refractory setting.

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