Treatment of splenic marginal zone lymphoma

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Abstract

Splenic marginal zone lymphoma (SMZL) is a distinct lymphoma entity characterized by an indolent clinical course and prolonged survival. Treatment is not standardized, since there are no prospective randomized trials in large series of SMZL patients. Splenectomy and rituximab represent the most effective treatment strategies used so far. The addition of chemotherapy to rituximab has not further improved the outcome, although this issue requires further investigation. Rituximab monotherapy has been associated with high response rates (∼90%), with approximately half of these responses being complete, even at the molecular level. More importantly, many of these responses are long-lasting, with a reported 7-year progression-free survival (PFS) at the rate of 69%. Maintenance rituximab treatment has been associated with further improvement of the quality of response as well as longer response duration in studies derived from one group of investigators. Based on its high efficacy and the good safety profile, rituximab represent one of the best treatment options for SMZL patients. Moreover, rituximab retains its efficacy in the relapse setting in most cases. Splenectomy is a meaningful alternative to rituximab in patients with bulky splenomegaly and cytopenias, without extensive bone marrow infiltration, who are fit for surgery. However splenectomy cannot completely eradicate the disease and it is also associated with greater morbidity or even mortality compared to rituximab. The choice of one of these two treatment approaches (rituximab or splenectomy) should mainly be based on patient's characteristics and on the disease burden. Novel agents are currently testing in low grade lymphomas including a small number of SMZL patients with promising results.

Introduction

Splenic marginal zone lymphoma (SMZL) is a distinct lymphoma entity in the WHO (World Health Organization) classification [1]. During the last years several biological and clinical features of SMZL have been clarified. SMZL is rare, accounting for less than 2% of the lymphoid malignancies. It mainly affects elderly patients without gender predilection. The disease is typically characterized by splenomegaly without lymphadenopathy besides splenic hilum [1]. Lymphocytosis is commonly present, while anaemia and thrombocytopenia are found in approximately 20% and 10%, respectively [2], [3], [4], [5], [6], [7], [8]. A serum paraprotein, mainly of the IgM type is evident in less than one third of the cases. B symptoms are rare. LDH may be moderately elevated in more than one third of the patients. A markedly raised LDH may indicate disease transformation. Autoimmune phenomena include autoimmune haemolytic anaemia (AIHA) and thrombocytopenia (ITP) as well as autoantibodies against several tissue antigens with or without clinical manifestations which may be present in ∼20% of the patients [3], [4].

Hepatitis C virus (HCV) has been implicated in the pathogenesis of a subgroup of SMZL cases, albeit with a great geographic heterogeneity [9], [10]. In African patients, a concomitant malaria infection may be present [11].

The immunoglobulin heavy variable (IGHV) genes show evidence of somatic hypermutation in the majority of the cases ranging from minimal to pronounced [12], [13], [14], [15], [16], [17], [18], [19]. However approximately 15% of cases carry truly unmutated IGHV genes. Interestingly almost one third of SMZL cases utilize the IGHV1-2*04 allele, strongly suggesting an antigen selection process [19]. Complex chromosomal aberrations are common (80% of cases display an abnormal karyotype) [20], [21], [22], [23]. The most frequent cytogenetic aberrations are gains of 3q and 12q and deletion of 7q22–36, mostly at band 7q31–32. Recently, mutations in various genes have been documented in SMZL. Among them somatic mutations clustered in NOTCH2 and KLF2 (Kruppel-like factor 2) appear to be the most common [24], [25], [26], [27], [28], [29], [30].

SMZL usually runs an indolent and chronic clinical course. The median survival is around 10 years [5], [6], [7], [8]. Interestingly more than one third of deaths are lymphoma unrelated [31], [32]. Histologic transformation to diffuse large B-cell lymphoma may occur during the course of the disease, although the exact incidence is not well documented, ranging for <5%–12% in various reports [33], [34], [35]. Several clinical and biological prognostic factors have been reported, without however reproducible results [5], [6], [7], [8], [36], [37]. Recently the Splenic Lymphoma Study Group (SLSG) proposed a risk stratification system based on the assessment of 4 variables: presence of extrahilar lymphadenopathy, elevated LDH, low haemoglobin levels and low platelet counts and separated three risk groups with significantly different lymphoma specific 5-year overall survival [38], [39]. This stratification system has been recently validated in an independent series [40]. SMZL diagnosis is based on the integration of clinical features, immunophenotype, molecular genetics and when available spleen histology, although splenic tissue is no longer necessary for the establishment of SMZL diagnosis [1], [41]. Differential diagnosis from lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) and the provisional entities hairy cell-variant (HCLv) and splenic diffuse red pulp lymphoma (SDRLP) may be difficult and require either splenectomy or detailed molecular analysis [41], [42].

Section snippets

Management of SMZL

Due to its rarity, management of SMZL is mainly based on the experience from other low grade B-cell lymphomas as well as on data provided by relatively small retrospective series of SMZL patients. The SLSG tried to summarize the existing data on all aspects of SMZL and provided a consensus review in the form of guidelines [41]. An updated form is in process. According to the above mentioned guidelines, treatment should be considered in patients with active disease: presence of B-symptoms, bulky

Discussion

Many novel clinical and biological aspects of SMZL have been recently recognised and much knowledge has been gathered regarding treatment approaches. Due to its rarity, there are no prospective randomized studies in large series of SMZL patients. Thus, the selection of treatment is mainly based on the results derived from retrospective studies, as well as on the experience from other low grade B-cell lymphomas. Currently, the most effective treatment options include splenectomy and rituximab

Summary

SMZL treatment is not standardized due to the lack of prospective randomized studies. Based on the data gathered until now from retrospective studies as well as from the experience on other low grade lymphomas, currently the main treatment options include splenectomy and rituximab. Both of them are effective with high response rates and long duration of response. Given the toxicity profile and the fact that responses to splenectomy are not complete, splenectomy should be probably a good option

Conflict of interest

There is no conflict of interest.

References (91)

  • A. Conconi et al.

    Histologic transformation in marginal zone lymphomas

    Ann Oncol

    (2015)
  • A.H. Meyer et al.

    Transformation and additional malignancies are leading risk factors for an adverse course of disease in marginal zone lymphoma

    Ann Oncol

    (2014)
  • E. Ruiz Ballesteros et al.

    Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis

    Blood

    (2005)
  • L. Arcaini et al.

    Splenic marginal zone lymphoma: a prognostic model for clinical use

    Blood

    (2006)
  • L. Arcaini et al.

    Splenic marginal zone lymphoma:from genetics to management

    Blood

    (2016)
  • G. Cervetti et al.

    Significant efficacy of 2-chlorodeoxyadenosine±rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up

    Ann Oncol

    (2013)
  • E. Orciuolo et al.

    2CdA chemotherapy and rituximab in the treatment of marginal zone lymphoma

    Leuk Res

    (2010)
  • M.J. Rummel et al.

    Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial

    Lancet

    (2013)
  • I.W. Flinn et al.

    Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study

    Blood

    (2014)
  • B.D. Cheson et al.

    Bendamustine produces durable responses with an acceptable safety profile in patients with rituximab-refractory indolent non-Hodgkin lymphoma

    Clin Lymphoma Myeloma Leuk

    (2010)
  • M. Dreyling et al.

    ESMO Consensus conferences: guidelines on malignant lymphoma. Part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma

    Ann Oncol

    (2013)
  • L. Arcaini et al.

    Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi

    Ann Oncol

    (2014)
  • A. Fabbri et al.

    Activity of rituximab monotherapy in refractory splenic marginal zone lymphoma complicated with autoimmune hemolytic anemia

    Clin Lymphoma Myeloma

    (2006)
  • L.H. Sehn et al.

    Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial

    Lancet Oncol

    (2016 Aug)
  • J.R. Brown et al.

    Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia

    Blood

    (2014)
  • N.H. Fowler et al.

    Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial

    Lancet Oncol

    (2014)
  • A. Conconi et al.

    International Extranodal Lymphoma Study Group (IELSG). Clinical activity of bortezomib in relapsed/refractory MALT lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group (IELSG)

    Ann Oncol

    (2011)
  • N. Di Bella et al.

    Results of a phase 2 study of bortezomib in patients with relapsed or refractory indolent lymphoma

    Blood

    (2010)
  • P.G. Isaacson et al.

    Splenic B-cell marginal zone lymphoma

  • D. Catovsky et al.

    Splenic lymphoma with circulating villous lymphocytes/splenic marginal-zone lymphoma

    Semin Hematol

    (1999)
  • X. Troussard et al.

    Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d’Hematologie Cellulaire (GFHC)

    Br J Haematol

    (1996)
  • N. Parry-Jones et al.

    Prognostic features of splenic lymphoma with villous lymphocytes: a report on 129 patients

    Br J Haematol

    (2003)
  • E. Iannitto et al.

    Splenic marginal zone lymphoma with or without villous lymphocytes. Hematologic findings and outcomes in a series of 57 patients

    Cancer

    (2004)
  • L. Arcaini et al.

    Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles

    Cancer

    (2004)
  • I. Bates et al.

    Chronic malaria and splenic lymphoma: clues to understanding lymphoma evolution

    Leukemia

    (1997)
  • A. Traverse-Glehen et al.

    Analysis of VH genes in marginal zone lymphoma reveals marked heterogeneity between splenic and nodal tumors and suggests the existence of clonal selection

    Haematologica

    (2005)
  • K. Stamatopoulos et al.

    Immunoglobulin heavy- and light-chain repertoire in splenic marginal zone lymphoma

    Mol Med

    (2004)
  • C. Kalpadakis et al.

    Mutation analysis of IgVH genes in splenic marginal zone lymphomas: correlation with clinical characteristics and outcome

    Anticancer Res

    (2009)
  • V. Bikos et al.

    Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

    Leukemia

    (2012)
  • X. Troussard et al.

    Genetic analysis of splenic lymphoma with villous lymphocytes: a Groupe Francais d’Hematologie Cellulaire (GFHC) study

    Br J Haematol

    (1998)
  • F. Sole et al.

    Splenic marginal zone B-cell lymphomas: two cytogenetic subtypes, one with gain of 3q and the other with loss of 7q

    Haematologica

    (2001)
  • E. Callet-Bauchu et al.

    Cytogenetic analysis delineates a spectrum of chromosomal changes that can distinguish non-MALT marginal zone B-cell lymphomas among mature B-cell entities: a description of 103 cases

    Leukemia

    (2005)
  • D. Rossi et al.

    The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development

    J Exp Med

    (2012)
  • M.J. Kiel et al.

    Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma

    J Exp Med

    (2012)
  • Q. Yan et al.

    BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas

    Haematologica

    (2012)
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