Current Treatments in Marginal Zone Lymphoma

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Oncology, ONCOLOGY Vol 36, Issue 4, Volume 36, Issue 4
Pages: 206-215

This review provides an updated analysis of the literature and discusses the authors' approach to the diagnosis and treatment of patients with marginal zone lymphoma.

ABSTRACT: Marginal zone lymphoma (MZL) is a heterogenous group of indolent non-Hodgkin lymphomas (NHLs). Three subtypes are recognized based on the site of involvement: extranodal MZL, splenic MZL, and nodal MZL. MZL represents 7% of all mature NHLs that exhibit geographical variability in their incidence and association with infectious agents. Each MZL subtype is characterized by unique biology, clinical presentation, therapeutic approach, and natural history. Recent findings have improved risk stratification of patients at diagnosis and after frontline therapy; however, these data are not incorporated into treatment decisions or selections of therapeutic agents. Moreover, a limited number of patients with MZL have been enrolled in randomized clinical trials, and all subtypes have been analyzed as a single group. This approach precludes a full characterization of the efficacy of treatment platforms, and current recommendations are largely derived from experience with follicular lymphoma. Emerging data have demonstrated that novel agents have higher efficacy and safety, expanding the landscape of treatment options. However, despite recent advances, several unmet needs remain in this field, including the discovery of prognostic biomarkers, utility of PET/CT at different extranodal sites, and appropriate sequence of therapies. There is a significant need to design clinical trials with the power to establish standard therapies as well as to assess their effects on patient-reported outcomes. In this review, we will provide an updated analysis of the literature and discuss our approach to the diagnosis and treatment of patients with MZL.

Introduction

Marginal zone lymphoma (MZL) is an indolent disease that represents 7% of all non-Hodgkin lymphomas (NHLs).1 The World Health Organization classification recognizes 3 subtypes according to primary site of involvement: extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT), nodal MZL (NMZL), and splenic MZL (SMZL).2 In the United States, EMZL is the most common subtype (60.8%), followed by NMZL (30.3%) and SMZL (8.9%).1 A similar immunophenotype marks all MZLs, but they exhibit unique clinical features that have therapeutic implications.3,4 However, few clinical trials have enrolled a significant number of patients with MZL, and current recommendations are largely borrowed from treatments of follicular lymphoma and other indolent NHLs. In this manuscript, we will review recent advances in MZL and describe current evidence supporting the appropriate management for each subtype.

Current Standards for Diagnosis and Molecular Testing

EMZL has been described in nearly all tissues. The most common extranodal sites include the stomach (30%), ocular adnexal (OA; 12%), skin (10%), lung (9%), and salivary gland (7%).1 Clinical manifestations are variable and depend on the site of origin. EMZL arises as a consequence of chronic inflammation within extranodal sites, with the strongest evidence associated with Helicobacter pylori and gastric EMZL.5,6 Chlamydia psittaci infection was associated with OA EMZL in Europe,7 although this association remains unclear in the United States.8-10 In addition, chronic inflammation caused by autoimmune conditions such as Sjögren syndrome or Hashimoto thyroiditis were seen in salivary gland and thyroid EMZL, respectively.11-13

EMZL is diagnosed based on the histopathologic identification of an abnormally expansile population of marginal zone B cells, usually with diffuse or nodular extension into interfollicular zones with associated follicular colonization. Neoplastic cells are small- to medium-sized lymphoid cells with round to slightly irregular nuclei, moderately dispersed chromatin, and inconspicuous nucleoli with relatively abundant pale cytoplasm.2 Neoplastic cells have an immunophenotype similar to that of normal marginal zone B cells, including expression of pan B-cell markers (CD19, CD20, CD79a, PAX5) and general lack of expression of CD5, CD10, LEF1, and cyclin D1. Some EMZLs coexpress CD43 and show plasmacytic differentiation with a monotypic plasma cell component. Recent reports highlighted IRTA1 as a possible specific biomarker for EMZL, although integration in clinical practice remains limited.14,15

NMZL is characterized by pathologic lymphadenopathy without evidence of extranodal or splenic involvement.2,16 A minority of patients experience B symptoms (drenching night sweats, unintentional weight loss of >10% of body weight over the past 6 months or fever defined as temperature >100.4 °F) or demonstrate bone marrow or peripheral blood involvement.17 Diagnosis is based on the histology of the lymph node and it requires the exclusion of secondary nodal involvement by EMZL and SMZL. Lymph nodes demonstrate partial or total nodal architectural effacement by a small- to medium-sized lymphoid proliferation that surrounds reactive follicles and expands into the interfollicular areas. Follicular colonization is commonly identified and is a useful feature in making this diagnosis. Neoplastic cells are composed of variable numbers of marginal zone (centrocyte-like and monocytoid) B cells with occasional plasma cells and scattered transformed B cells.2 The antigen expression profile is similar to that of other MZLs.16 There are no specific recurrent cytogenetic abnormalities associated with NMZL; as in other MZLs, there are gains of chromosomes 3, 7, 12, and
18, and losses of 6q23-24.18 MYD88 L265P mutation is usually absent but has been occasionally reported.19,20

In contrast with EMZL and NMZL, SMZL is characterized by splenomegaly with bone marrow involvement and variable presence of peripheral blood villous lymphocytes. Peripheral lymphadenopathy is uncommon.2 Cytopenias may be present, and these are secondary to hypersplenism, autoimmune phenomena, or bone marrow infiltration. An increased risk of SMZL has been reported in patients with chronic hepatitis C (HCV) infection.21,22 To establish a definitive diagnosis of SMZL, a bone marrow biopsy is frequently required, because the aspirate is not always sufficient for an accurate diagnosis.23 The combination of atypical and expansile interstitial nodular involvement with prominent intrasinusoidal infiltration is typical of SMZL.18,24 When spleen histology is not available, SMZL diagnosis relies on the integration of clinical features and lymphocyte immunophenotype coupled with the histopathologic evaluation of the bone marrow.25 Although no ancillary biomarker exists, deletion 7q22-36 (seen in 30%-40% of cases of SMZL), mutations in KLF2 (12%-42%) and NOTCH2 (10%-25%) are frequently seen, facilitating the diagnosis.26-28 Nonmutated IGHV as well as mutations in NOTCH2, KLF2, and TP53 have been associated with inferior outcomes.26,29,30 Importantly, mutations in MYD88 L265P can be also observed in 7% to 15% of SMZL cases, underscoring the need for an appropriate clinicopathological diagnosis to avoid an erroneous diagnosis of lymphoplasmacytic lymphoma.19

CT with contrast remains the preferred imaging for staging and for assessing treatment response in MZL.31,32 MRI is valuable in specific locations such as dural, OA, salivary gland, and breast.11,33-36 The Lugano Classification considers MZL to be a nonfluorodeoxyglucose (FDG)–avid disease without
recommending PET/CT, although the National Comprehensive Cancer Network (NCCN) guidelines list PET/CT as useful in selected patients.31,37 The role of PET/CT in EMZL remains questionable because of variable FDG-avidity in extranodal sites. Better detection rates were described in certain locations, such as lung (50%-100%) and head and neck (50%-100%), compared with OA (22%-100%) and stomach (0%-100%).38,39 In SMZL and NMZL, the reported FDG-avidity is above 76%, supporting its clinical implementation.40,41 PET/CT sensitivity to detected bone marrow involvement in MZL was described in 36%, underscoring the need for bone marrow biopsy in those patients where specific kinds of disease involvement has implications for therapeutic selections.42 Nevertheless, in patients with stage I EMZL that has been established by physical examination and imaging, then treated with frontline involved site radiation therapy (ISRT), bone marrow status does not affect lymphoma specific-survival (LSS).43

Stratification for Treatment Selection

Gastric EMZL

The stomach remains the most common EMZL disease location; it is typically associated with chronic gastritis induced by H pylori. However, a declining frequency in H pylori–associated gastric EMZL has been observed in Italy; it remains unclear whether this association is also decreasing in other regions globally.44 Using endoscopic ultrasound to determine involvement of submucosa or regional lymph nodes may help predict a potentially lower success rate of H pylori eradication therapy, which underlines the value of this test in the initial work-up.31 The presence of t(11;18) confers low probability of response to H pylori eradication therapy; patients with this characteristic should be considered for ISRT (Figure 1).31,45 The presence of t(11;18) is observed in about 40% of gastric cases; such cases usually present at an advanced stage but they have a lower frequency of higher-grade transformation than patients without this abnormality.45-47 Eradicating the infection is still recommended, in the attempt to decrease the risk of other H pylori–associated complications as well as eliminate a source of chronic antigen stimulation that may contribute to lymphoma recurrence.47 H pylori eradication should be confirmed by urea breath or stool antigen tests at least 6 weeks after starting eradication therapy and at least 2 weeks after the withdrawal of proton pump inhibitors.32 If initial treatment fails to eradicate H pylori, a second-line treatment is recommended. After frontline therapy, upper endoscopy with biopsy is repeated in 3 months to assess response. In those who achieve endoscopic lymphoma remission but have persistent asymptomatic microscopic disease, current guidelines recommend observation for at least 12 months before starting a new line of therapy,
because most patients achieve subsequent complete response (CR).32,48,49 After eradication therapy, detection of monoclonal rearrangement of the IgVH gene in patients with histological response can persist for years without increasing risk for lymphoma relapse.50 Still, the risk of gastric adenocarcinoma remains higher in patients with gastric EMZL, so it remains unclear whether these patients should undergo regular endoscopic surveillance.51,52

Alterations in NF-κB signaling, with frequent TNFAIP3 inactivating mutations and translocations in MALT1/IGH, are characteristics of H pylori–negative gastric EMZL.53 Compared with H pylori–associated gastric EMZL, patients without H pylori appear to have more advanced-stage disease at diagnosis.54,55 ISRT remains the preferred treatment modality in H pylori–negative gastric EMZL; it is associated with long-term disease control.56 Consensus guidelines recommend a dose of 30 Gy; however, lower doses (23.5-27 Gy) seem to achieve comparable results.31,57 Importantly, eradication therapy in H pylori–negative gastric EMZL may still benefit a subset of patients.58,59

Nongastric EMZL

Stratification for treatment selection in nongastric EMZL is less well established, but in those with localized disease who are treated with ISRT, the primary extranodal site does not affect survival.43 The most common EMZL location after the gastrointestinal tract is OA. In a large (n = 182) single-center retrospective analysis, Desai et al identified age greater than 60 years and ISRT dose less than 30.6 Gy as independent factors associated with shorter progression-free survival (PFS) in OA EMZL.34 However, consensus guidelines recommend a dose of 24 Gy; clearly, the appropriate dose in EMZL remains under debate.31 Cutaneous EMZL is commonly localized to the skin; relatively few patients (6%) demonstrate extracutaneous spreading.60 Most patients exhibit a single skin lesion (58%), and treatment with ISRT is the preferred approach.60,61 In patients with asymptomatic widespread cutaneous involvement, the watch-and-wait approach is acceptable. In symptomatic patients, however, single-agent rituximab (Rituxan) is preferred, given the indolent course of the disease.

Pulmonary EMZL is commonly associated with a smoking history. Rarely, there are presenting B symptoms, elevated lactate dehydrogenase (LDH), or bone marrow involvement. Cavitary and large lesions, multifocal parenchymal disease, concomitant extrapulmonary disease, thrombocytopenia, and elevated LDH are features associated with shorter PFS.39,62 Regardless of the features of initial presentation, watch-and-wait is suitable in a significant proportion of patients.62

Colorectal EMZL can present during colonoscopy as subepithelial tumors, mucosa granularity, polyps, exophytic lesions, and enlarged folds. In asymptomatic patients without evidence of advanced-stage disease, watch-and-wait after complete endoscopic resection is a valid option.63,64

Therapy Selection

Although molecular data and prognostic factors have been recently described (Table 1), these features are not incorporated into clinical practice for treatment initiation or for selection of a specific regimen. Similarly, no studies have been done regarding therapies for patients with EMZL who progress within 24 months. Based on expert opinion, current guidelines recommend therapy initiation in patients with lymphoma-related symptoms, gastrointestinal bleeding, deep organ invasion, threatened end-organ function, bulky disease, and rapid disease progression; patient preference must be considered as well.31,32 The Groupe d’Etude des Lymphomes Folliculaires (GELF)65 criteria correlate with those for high-tumor-burden follicular lymphoma (FL) and are commonly included in the treatment decision for patients with MZL. However, the applicability of those criteria in MZL remains to be determined.

EMZL

EMZL typically remains localized within the tissue of origin for a prolonged period, making ISRT the preferred approach in limited-stage disease (Figure 1). This has been shown to achieve long-term remissions across studies.34,66-69 One exception to this recommendation is salivary gland EMZL, in which ISRT can be associated with significant long-term toxicities. Patients with Sjögren syndrome have a higher risk for future contralateral gland EMZL; therefore, other approaches, including single-agent rituximab, should be considered.70 Although surgery is not recommended in the management of EMZL, it can provide long-term remission in patients who have had a complete resection for diagnostic purposes, with subsequent watch-and-wait usually advised.39,62,71

In symptomatic patients experiencing advanced-stage disease, who have relapsed after H pylori therapy or ISRT, immunotherapy and chemoimmunotherapy are established options in EMZL. Several regimens were tested across indolent NHL (including a small number of patients with MZL), which prevents the selection of 1 platform as the standard of care. We will discuss the most common therapeutic platforms.

Bendamustine with rituximab (BR). Work by the Study group indolent Lymphomas (StiL) and the BRIGHT study established BR as the preferred regimen for indolent lymphomas.72,73 These 2 randomized noninferiority
clinical trials tested BR vs R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride [Adriamycin], vincristine, and prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) in mantle cell lymphoma and indolent NHL. The studies differed in their primary end points: PFS in the StiL trial (NCT00991211) and CR rate in the BRIGHT study (NCT00877006). BR was associated with better tolerance. The efficacy of BR was comparable with that of R-CHOP and R-CVP, with favorable response rates (CR; 31% vs 25%, respectively; P = .0225). The median PFS approached 5 years for patients treated with BR.

The MALT2008-01 trial (NCT01015248) demonstrated the efficacy of BR in 57 patients with EMZL.74 The trial tested a response-adapted strategy, and most patients achieved CR or unconfirmed CR (CRu) after 3 cycles with only 14 (25%) patients requiring more than 4 cycles of treatment. Responses did not differ by primary site or t(11;18) status, and the reported 7-year event-free survival (EFS) rate was 88%.75

Through studies, BR demonstrated acceptable safety. The main grade ≥3 adverse events (AEs) were lymphopenia (34%-74%) and neutropenia (5%-49%). The most common all-grade nonhematological toxicity was drug hypersensitivity (6%-15%); only 4% developed alopecia.72,73,75 Notably, bendamustine leads to prolonged T-cell depletion, which increases the risk for opportunistic infections.76 Prophylaxis for Pneumocystis jirovecii and varicella-zoster virus is recommended. In a recent 5-year update of the BRIGHT study,77 authors reported a higher incidence of nonmelanoma skin carcinomas in patients treated with bendamustine-based regimens, underscoring the need for regular dermatologic surveillance of such individuals.

R-CVP and R-CHOP. As previously described, R-CVP and R-CHOP demonstrated efficacy similar to that of BR, although both regimens were associated with more frequent AEs. In the StiL trial, R-CHOP exhibited more hematological toxicity (68% vs 30%; P <.0001), infections (50% vs 27%; P = .0025), peripheral neuropathy (29% vs 7%; P <.0001), and stomatitis (19% vs 6%; P <.0001) compared with BR. Further, all patients developed alopecia.72 The most common AEs associated with R-CVP were neutropenia (56%), infections (50%), peripheral neuropathy (47%), and constipation (44%).73 NCCN guidelines list R-CHOP and R-CVP as preferred first-line therapy regimens for MZL. However, based on comparable efficacy with improved toxicity, we favor the selection of BR as frontline therapy in EMZL.

Lenalidomide with rituximab (R2). Lenalidomide (Revlimid) at a dose of 25 mg on days 1 to 21 demonstrated efficacy in EMZL, with an overall response rate (ORR) of 61.1% (CR rate, 33.3%).78 Commonly, lenalidomide is combined with rituximab to enhance single-agent activity. In a single-institution study, the combination of lenalidomide (20 mg on days 1 to 21) with rituximab (day 1 of each cycle) was tested in patients with advanced-stage indolent NHL; GELF criteria were not required for enrollment.79,80 The study enrolled 30 patients with MZL (NMZL, 60%; EMZL, 37%; SMZL, 3%), and the ORR was 93% with a CR rate of 70% and a median PFS of 59.8 months. Responses were similar across MZL subtypes. The most common all-grade AEs were fatigue (93%) and nausea/vomiting (73%). R2 demonstrated similar efficacy (ORR, 80%; CR rate, 54%) in a multicenter EMZL study with no new safety concerns.81

Single-agent rituximab. Rituximab demonstrated efficacy in the treatment of indolent lymphomas and was associated with an acceptable safety profile. Conconi et al proved clinical activity (n = 23) of frontline rituximab in EMZL; patients’ ORR was 87% (CR rate, 48%) with a median time to treatment failure (TTF) of 22 months.82 Similar results were seen in patients with gastric EMZL (n = 27) who were refractory to H pylori eradication therapy
or not eligible for this approach.83 However, these results were not reproduced in subsequent studies, which frequently saw PR or stable disease as best responses and shorter median TTFs.84-86 Single-agent rituximab is a reasonable approach in patients who are not candidates for combination chemotherapy regimens. It has a favorable safety profile, but the trade-off is a low likelihood of durable remissions.

Chlorambucil with rituximab. A total of 454 patients participated in IELSG-19 (NCT00210353), the only randomized clinical trial exclusively focused on untreated EMZL; its primary end point was EFS.87 The combination arm with chlorambucil and rituximab resulted in significantly longer 5-year EFS (68%) compared with single-agent chlorambucil (51%) or single-agent rituximab (50%; P = .0009). Despite proven efficacy, this combination is not commonly selected in the United States. The NCCN guidelines suggest this approach for elderly or infirm patients.31

90Y-Ibritumomab tiuxetan. 90Y-Ibritumomab tiuxetan (90Y-IT) is a radio-conjugated murine monoclonal antibody approved for certain patients with FL: those with relapsed/refractory (R/R) CD20-positive disease or as consolidation following induction therapy in untreated patients.88 Its use encompasses a single treatment plan and induces cell death via antibody-stimulated cytolysis and apoptosis caused by emitted ionizing radiation.89 Two single-institution studies tested this approach in untreated indolent NHL including MZL (n=11 and 17, respectively).90,91 Although baseline characteristics differed between the patients in the studies, both studies reported an ORR above 88.4%, with most patients achieving CR/CRu (59%-96.7%). The 5-year PFS rate was between 41.2% and 82%, with grade 3 or greater neutropenia (53%-61.3%) and thrombocytopenia (35% in both studies) as common toxicities. One case of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) occurred after 90Y-IT. In the FDA Adverse Event Reporting System database analysis, this treatment approach has yielded incidence rates of MDS and AML of 6.9% and 3.6%, respectively.89 The selection of this treatment by clinicians has been limited by concerns about secondary myeloid malignancies as well as by significant logistic considerations that are involved in delivering this compound. It is currently unclear where 90Y-IT fits into the MZL landscape, but this approach can be considered in patients with appropriate marrow cellularity who request a short treatment program.

SMZL

There is no full agreement regarding the treatment of SMZL; watch-and-wait is an acceptable approach in asymptomatic patients.32 Consensus guidelines support treatment initiation in those with symptomatic splenomegaly, systemic symptoms, and cytopenias (hemoglobin <10 g/dL, platelets <80,000/mm3, and neutrophils <1000/mm3). In patients with chronic HCV infection, antiviral therapy is recommended.32,92 Patients with concomitant autoimmune cytopenias should receive conventional treatments for these diseases prior to lymphoma therapy.23 Treatment options include splenectomy, chemoimmunotherapy, and single-agent rituximab; none has a clear survival benefit over the others (Figure 2).93-96

Single-agent rituximab. Rituximab is the preferred approach in patients with SMZL requiring therapy. In a retrospective analysis, patients (n = 106) received an induction phase of 6 weekly doses of rituximab 375 mg/m2 followed by maintenance every 2 months for up to 2 years or follow up in responders.94,97 The ORR at the end of induction was 92%, with 44% CR, 21% CRu, and 27% partial response (PR) rates. Clinical splenomegaly resolved in a median of 4 weeks (range, 1-48) and hematologic response was seen in a median of 2 weeks (range, 1-32). The 5-year freedom from
progression (FFP), overall survival (OS), and LSS rates were 71%, 93%, and 99%, respectively. Among responders, maintenance therapy was associated with better 5-year FFP rates (79% vs 52%; P = .0006) without difference by maintenance duration (P = .90). The role of rituximab maintenance was also tested in the E4402 study (NCT01406782) in patients with asymptomatic, low-tumor-burden, non-FL indolent lymphomas.85 Maintenance was associated with longer median TTF compared with retreatment (4.8 vs 1.4 years; P = .012) without OS benefit.95 As a result, maintenance treatment can be considered optional and should be only considered after a careful evaluation of potential infectious complications.

Bendamustine with rituximab. The BRISMA/IELSG 36 trial (NCT02853370) tested BR in 56 patients with untreated SMZL or who relapsed after splenectomy.98 The ORR was 91% (CR rate, 73%) with estimated 3-year PFS and OS rates of 90% and 96%, respectively. Notably, treatment discontinuation occurred in 9% due to toxicity; 68% experienced grade 3 or greater toxicity, largely hematological; and 1 patient died from infection. BR is an effective platform in patients with SMZL; however, the toxicity profile appears worse than in other indolent NHL, preventing its generalization as preferred frontline therapy.

Splenectomy. Splenectomy facilitates SMZL diagnosis; it also provides quick symptom control associated with splenomegaly, resolution of cytopenias, and prolonged disease control.99 However, while this approach was once popular, the practice of splenectomy has steadily declined in the United States.96 Splenectomy does not address disease in bone marrow and/or blood and it is associated with potential perioperative and infectious complications. It should be reserved for symptomatic patients who are refractory to systemic agents.100

NMZL

Few data exist on the management of NMZL, and there is no standard of care.16 Consensus guidelines recommend the same treatment as for other MZL subtypes, with ISRT in patients with limited-stage disease. In those patients with advanced-stage disease that is asymptomatic and has a low-tumor-burden, a watch-and-wait approach, similar to that used in FL, is reasonable. In patients who are symptomatic or presenting with a high-tumor-burden, single-agent rituximab or BR are appropriate options (Figure 2).

Relapsed/Refractory MZL

Obinutuzumab. Obinutuzumab (Gazyva) is a recombinant type II glycoengineered anti-CD20 and immunoglobulin G Fc-optimized monoclonal antibody. It has the potential to generate an effect in the recipient more potent than that of rituximab.101 In the GAUGUIN study (NCT00517530), 40 patients with indolent NHLs (MZL, n = 3) were randomly assigned to receive 8 cycles of obinutuzumab at 400 mg on days 1 and 8 of cycle 1 and day 1 of cycles 2 to 8 (400/400 mg arm) or 1600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8 (1600/800 mg arm). In patients with rituximab-refractory indolent NHL (n = 22; 55%), obinutuzumab achieved an ORR of 50% (CR/CRu rate, 22.7%) in the 1600/800 mg arm compared with 8.3% (CR/CRu rate, 11.1%) in the 400/400mg arm.102 The most common AEs included infusion-related reactions, infection, asthenia, and nausea.

Bendamustine with obinutuzumab. The randomized phase 3 GADOLIN trial (NCT01059630) tested bendamustine with obinutuzumab followed by obinutuzumab maintenance (n = 194; MZL = 27) vs bendamustine monotherapy (n = 202; MZL = 19) in rituximab-refractory indolent NHL.103 Median PFS was significantly longer in the combination cohort (not reached vs 14.9 months; P = .0001) with common grade 3 or greater AEs including neutropenia (33%), thrombocytopenia (11%), anemia (8%), and infusion-related reactions (11%). In an updated analysis,104 authors confirmed initial observations of longer median PFS in the combination arm (25.8 vs 14.1 months) with an HR for progression or death of 0.57 (P <.001) associated with OS benefit (HR, 0.67; P = .027). However, 51.3% experienced infections during maintenance. Cardiac toxicity was more common in the combination arm with grade 3 or greater atrial fibrillation (n=2) and heart failure (n=2).

Lenalidomide with rituximab (R2). R2 is an active combination in MZL, currently FDA approved after 1 line of therapy. The AUGMENT trial (NCT01938001) randomly enrolled 358 patients who required treatment per investigator assessment to R2 (n = 178) vs placebo with rituximab (n = 180).105 The treatment schedule was lenalidomide 20 mg, or placebo, on days 1 through 21 of a 28-day cycle, for 12 cycles, with rituximab 375 mg/m2 weekly in cycle 1 and on day 1 of cycles 2 through 5. As in prior trials, most patients enrolled in this study had FL (n = 295; 82%); in those with MZL (n = 63; 18%), EMZL (n = 30) was the most common (NMZL, n = 18; SMZL, n = 15). ORR at 78% (CR, 34%) vs 53% (CR, 18%; P = .001) and the primary study end point of median PFS (HR, 0.46; P <.0001) favored R2. Common AEs associated with R2 were neutropenia (58%; grade ≥3, 50%), diarrhea (31%), constipation (26%), cough (23%), and fatigue (22%). A subgroup analysis in MZL demonstrated a trend toward better ORR (65% [CR, 29%] vs 44% [CR, 13%]; P = .1313) in the R2 arm without improving PFS (unstratified HR, 1.00). Although no PFS benefit was observed in the AUGMENT trial, the results of several other studies support the incorporation of lenalidomide-based programs in MZL.78-81

Emerging and Novel Therapies for Relapsed/Refractory MZL

Ibrutinib. Ibrutinib (Imbruvica) is a potent and irreversible inhibitor of Bruton tyrosine kinase (BTK), an integral component of the B-cell receptor pathway. Ibrutinib was evaluated in a single-arm phase 2 study in patients with MZL treated with at least 1 prior therapy.106 Patients received ibrutinib 560 mg daily until progression or unacceptable toxicity, for up to 3 years. Most had EMZL (n = 32; 51%) followed by NMZL (n = 17; 27%) and SMZL (n = 14; 22%). In 60 evaluable patients, the ORR (primary end point) was 48% (95% CI, 35%-62%) with only 3% (n = 2) achieving CR. ORRs by MZL subtype were 47% in EMZL (CR, 6%), 50% in SMZL (no CRs), and 41% in NMZL (no CRs). There was a median PFS of 15.7 months.107 Common grade 3 or greater AEs included anemia (14%), pneumonia (8%), and fatigue (6%). Importantly, 62% of the patients discontinued treatment, with disease progression (32%) and AEs (17%) as common causes. Atrial fibrillation occurred in 6% (all grade 1-2). Exploratory biomarker analysis demonstrated shorter response in cases with mutations in KMT2D and CARD11.

Zanubrutinib. The MAGNOLIA trial (NCT03846427) demonstrated safety and efficacy of the second-generation BTK inhibitor zanubrutinib (Brukinsa) in MZL.108,109 Investigators provided zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The study enrolled 68 patients (EMZL, 38%; NMZL, 38%; SMZL, 18%; and unknown, 6%) with R/R MZL; the ORR (primary end point) was 68.2% (CR rate, 25.8%). Median duration of response and PFS were not reached. Most common cause of treatment discontinuation (41.2%) was disease progression, observed in 23.5%. Frequent AEs included diarrhea (22.1%), bruising (20.6%), and constipation (14.7%). Neutropenia (7.3%) was the most common grade ≥3 AE. Atrial fibrillation/flutter occurred in 2 patients. Based on these data, zanubrutinib is the BTK inhibitor of choice in MZL.

Phosphatidylinositol 3-kinase (PI3K) inhibitors. The PI3K family is classified into 3 distinct classes. Class I is most relevant to cell growth and survival and has been the target for drug development. The class I PI3K pathway includes 4 isoforms—α, β, δ, and ɣ—with the last 2 isoforms largely expressed in leukocytes.110 Several PI3K inhibitors have been tested in R/R indolent NHL after at least 2 prior lines of therapy. Idelalisib is a potent, small molecule inhibitor of PI3Kδ, and it was the first agent of this group evaluated in clinical trials. Duvelisib is a dual inhibitor of PI3K-δ and -ɣ; copanlisib is an intravenous pan-class I PI3K inhibitor, with predominant activity against PI3K-α and -δ isoforms; and umbralisib is a dual inhibitor of PI3Kδ/casein kinase-1ε. Table 2 summarizes the safety and efficacy of these agents.

Idelalisib. In a single-group, open-label, phase 2 study, the response rate (primary end point) to idelalisib (Zydelig) 150 mg twice daily was 57%, with only 6% achieving CR. The median PFS was 11 months, with similar results across MZL subtypes. The most common AEs (all grades) included diarrhea (43%), fatigue (30%), nausea (30%), cough (29%), and pyrexia (28%).111 Idelalisib was voluntarily withdrawn for R/R FL and small lymphocytic lymphoma from the United States market in January 2022.

Duvelisib. In the phase 2 DYNAMO trial (NCT01882803), duvelisib (Copiktra) 25 mg twice daily demonstrated an ORR of 47.3% (95% CI, 38%-56%) largely based on PRs (45.7%).112 With a median follow-up of 32.1 months, the median PFS was 9.5 months (95% CI, 8.1-11.8). Frequent all-grade AEs included diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%).

Copanlisib. In the CHRONOS-1 trial (NCT01660451), copanlisib (Aliqopa) at a dosage of 60 mg on days 1, 8, and 15 of a 28-day cycle achieved an objective response rate of 59%, with 12% attaining CRs. Common AEs included hyperglycemia (50%), diarrhea (34%), hypertension (30%), fatigue (30%), neutropenia (30%), and fever (25%).113 Most AEs decreased in incidence and grade after 6 months, except for grade 3 diarrhea, which increased from 4.9% to 10.8% after 1 year.114 To improve single-agent efficacy, rituximab was incorporated with copanlisib in the randomized CHRONOS-3 trial (NCT02367040). The combination arm demonstrated a better PFS compared with placebo with rituximab (HR, 0.52; 95% CI, 0.39-0.69; P <.0001). Similar to effects seen with single-agent copanlisib, hyperglycemia and hypertension were substantial: 64% and 37% of the patients enrolled in the combination arm required medications to address these AEs, respectively.115

Umbralisib. In the phase 2b UNITY-NHL trial (NCT02793583), treatment consisted of umbralisib (Ukoniq) 800 mg once daily. Across all indolent NHLs, the ORR was 47.1%. Umbralisib achieved higher CR rates (Table 2) compared with other single-agent PI3K inhibitors. Furthermore, with a median follow-up of 27.8 months, the median PFS (95% CI, 12.1 months to not estimable) was not reached in the MZL subgroup. Common AEs included diarrhea (59.1%), nausea (39.4%), fatigue (30.8%), vomiting (23.6%), and cough (20.7%). These observations encouraged the selection of umbralisib over other agents, but in February 2022, the FDA released a notice with information regarding a possible increased risk of death associated with umbralisib. The agency suspended the enrollment of new patients in clinical trials while the investigation is undergoing.116

Conclusions

MZL is commonly characterized by an indolent course, with patients experiencing long survival. Patients with limited-stage EMZL can achieved prolonged remissions with ISRT, and that treatment remains the preferred approach. Patients with SMZL are best managed with single-agent rituximab. For patients with advanced-stage but asymptomatic, low-tumor-burden NMZL, watch-and-wait is a reasonable approach, with a significant number of patients not needing therapy for years. Patients with symptoms and/or a high-tumor-burden appear best served by the BR regimen. Several treatment platforms have demonstrated efficacy in R/R MZL, but potential toxicities should be carefully considered before treatment selection. The current therapeutic landscape in MZL allows clinicians to limit the use of cytotoxic chemotherapy, and future studies should delineate the appropriate sequence of novel agents in MZL.

AUTHOR AFFILIATIONS:

Juan pablo Alderuccio, MD1; and Brad S. Kahl, MD2

1Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.

2Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO.

Correspondence: Brad S. Kahl, MD, Division of Oncology, Campus Box 8056, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO 63110. Phone: 314-747-7402. Fax: 314-747-5123. email: bkahl@wustl.edu

Conflict of interest:

JPA reports consulting fees and research funding from ADC Therapeutics; and has an immediate family member who has reported consulting fees from Puma Biotechnology, Inovio Pharmaceuticals, Agios Pharmaceuticals, Forma Therapeutics, and Foundation Medicine.

BSK reports consulting fees from AbbVie, Acerta, Celgene, Genentech, Roche, Pharmacyclics, Gilead, Bayer, AstraZeneca, and Beigene; and research funding from Acerta, Celgene, Genentech, and Beigene.

REFERENCES

  1. Cerhan JR, Habermann T. Epidemiology of marginal zone lymphoma. Ann Lymphoma. 2021;5:1. doi:10.21037/aol-20-28
  2. Swerdlow SH, Campos E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th edition. IARC Press; 2017.
  3. Alderuccio JP, Lossos IS. Prognostic factors and risk of transformation in marginal zone lymphoma. Ann Lymphoma. 2020;4. doi:10.21037/aol-20-8
  4. Bertoni F, Rossi D, Zucca E. Recent advances in understanding the biology of marginal zone lymphoma. F1000Res. 2018;7:406. doi:10.12688/f1000research.13826.1
  5. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991;338(8776):1175-1176. doi:10.1016/0140-6736(91)92035-z
  6. Zucca E, Bertoni F, Roggero E, et al. Molecular analysis of the progression from Helicobacter pylori–associated chronic gastritis to mucosa-associated lymphoid-tissue lymphoma of the stomach. N Engl J Med. 1998;338(12):804-810. doi:10.1056/NEJM199803193381205
  7. Ferreri AJ, Guidoboni M, Ponzoni M, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst. 2004;96(8):586-594. doi:10.1093/jnci/djh102
  8. Ruiz A, Reischl U, Swerdlow SH, et al. Extranodal marginal zone B-cell lymphomas of the ocular adnexa: multiparameter analysis of 34 cases including interphase molecular cytogenetics and PCR for Chlamydia psittaci. Am J Sur Pathol. 2007;31(5):792-802. doi:10.1097/01.pas.0000249445.28713.88
  9. Vargas RL, Fallone E, Felgar RE, et al. Is there an association between ocular adnexal lymphoma and infection with Chlamydia psittaci? the University of Rochester experience. Leuk Res. 2006;30(5):547-551. doi:10.1016/j.leukres.2005.09.012
  10. Rosado MF, Byrne GE Jr, Ding F, et al. Ocular adnexal lymphoma: a clinicopathologic study of a large cohort of patients with no evidence for an association with Chlamydia psittaci. Blood. 2006;107(2):467-472. doi:10.1182/blood-2005-06-2332
  11. Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. Blood. 2016;127(17):2082-2092. doi:10.1182/blood-2015-12-624304
  12. Royer B, Cazals-Hatem D, Sibilia J, et al. Lymphomas in patients with Sjögren’s syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses. Blood. 1997;90(2):766-775.
  13. Troch M, Woehrer S, Streubel B, et al. Chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) in patients with MALT lymphoma. Ann Oncol. 2008;19(7):1336-1339. doi:10.1093/annonc/mdn049
  14. Falini B, Agostinelli C, Bigerna B, et al. IRTA1 is selectively expressed in nodal and extranodal marginal zone lymphomas. Histopathology. 2012;61(5):930-941. doi:10.1111/j.1365-2559.2012.04289.x
  15. Wang Z, Cook JR. IRTA1 and MNDA expression in marginal zone lymphoma: utility in differential diagnosis and implications for classification. Am J Clin Pathol. 2018;151(3):337-343. doi:10.1093/ajcp/aqy144
  16. Thieblemont C, Molina T, Davi F. Optimizing therapy for nodal marginal zone lymphoma. Blood. 2016;127(17):2064-2071. doi:10.1182/blood-2015-12-624296
  17. van den Brand M, van Krieken JHJM. Recognizing nodal marginal zone lymphoma: recent advances and pitfalls. a systematic review. Haematologica. 2013;98(7):1003-1013. doi:10.3324/haematol.2012.083386
  18. Mollejo M, Piris MA. The complex pathology and differential diagnosis of splenic and nodal marginal zone lymphoma. Ann Lymphoma. 2020;4. doi:10.21037/aol-20-17
  19. Martinez-Lopez A, Curiel-Olmo S, Mollejo M, et al. MYD88 (L265P) somatic mutation in marginal zone B-cell lymphoma. Am J Surg Pathol. 2015;39(5):644-651. doi:10.1097/PAS.0000000000000411
  20. Hamadeh F, MacNamara SP, Aguilera NS, Swerdlow SH, Cook JR. MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma. Mod Pathol. 2015;28(4):564-574. doi:10.1038/modpathol.2014.120
  21. Arcaini L, Vallisa D, Rattotti S, 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;25(7):1404-1410. doi:10.1093/annonc/mdu166
  22. Hermine O, Lefrère F, Bronowicki J-P, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347(2):89-94. doi:10.1056/NEJMoa013376
  23. Matutes E, Oscier D, Montalban C, et al. Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria. Leukemia. 2008;22(3):487-495. doi:10.1038/sj.leu.2405068
  24. Audouin J, Le Tourneau A, Molina T, et al. Patterns of bone marrow involvement in 58 patients presenting primary splenic marginal zone lymphoma with or without circulating villous lymphocytes. Br J Haematol. 2003;122(3):404-412. doi:10.1046/j.1365-2141.2003.04449.x
  25. Rodrigues CD, Peixeiro RP, Viegas D, et al. Clinical characteristics, treatment and evolution of splenic and nodal marginal zone lymphomas – retrospective and multicentric analysis of Portuguese centers. Clin Lymphoma Myeloma Leuk. 2021;21(11):e839-e844. doi:10.1016/j.clml.2021.06.013
  26. Alderuccio JP, Lossos IS. NOTCH signaling in the pathogenesis of splenic marginal zone lymphoma – opportunities for therapy. Leuk Lymphoma. 2022;63(2):279-290. doi:10.1080/10428194.2021.1984452
  27. Rossi D, Trifonov V, Fangazio M, et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012;209(9):1537-1551. doi:10.1084/jem.20120904
  28. Jaramillo Oquendo C, Parker H, Oscier D, Ennis S, Gibson J, Strefford JC. Systematic review of somatic mutations in splenic marginal zone lymphoma. Sci Rep. 2019;9(1):10444. doi:10.1038/s41598-019-46906-1
  29. Parry M, Rose-Zerilli MJ, Ljungström V, et al. Genetics and prognostication in splenic marginal zone lymphoma: revelations from deep sequencing. Clin Cancer Res. 2015;21(18):4174-4183. doi:10.1158/1078-0432.CCR-14-2759
  30. Campos-Martín Y, Martínez N, Martínez-López A, et al. Clinical and diagnostic relevance of NOTCH2-and KLF2-mutations in splenic marginal zone lymphoma. Haematologica. 2017;102(8):e310-e312. doi:10.3324/haematol.2016.161711
  31. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 5.2021. Accessed October 1, 2021. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf.
  32. Zucca E, Arcaini L, Buske C, et al; ESMO Guidelines Committee. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(1):17-29. doi:10.1016/j.annonc.2019.10.010
  33. de la Fuente MI, Haggiagi A, Moul A, et al. Marginal zone dural lymphoma: the Memorial Sloan Kettering Cancer Center and University of Miami experiences. Leuk Lymphoma. 2017;58(4):882-888. doi:10.1080/10428194.2016.1218006
  34. Desai A, Joag MG, Lekakis L, et al. Long-term course of patients with primary ocular adnexal MALT lymphoma: a large single-institution cohort study. Blood. 2017;129(3):324-332. doi:10.1182/blood-2016-05-714584
  35. Kato H, Kanematsu M, Goto H, et al. Mucosa-associated lymphoid tissue lymphoma of the salivary glands: MR imaging findings including diffusion-weighted imaging. Eur J Radiol. 2012;81(4):e612-e617. doi:10.1016/j.ejrad.2011.12.035
  36. Iyer SG, Kuker R, Florindez JA, et al. A single-center analysis of patients with extranodal marginal zone lymphoma of the breast. Leuk Lymphoma. Published online October 21, 2021. doi:10.1080/10428194.2021.1992764
  37. Cheson BD, Fisher RI, Barrington SF, et al; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin’s Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano Classification. J Clin Oncol. 2014;32(27):3059-3067. doi:10.1200/JCO.2013.54.8800
  38. Albano D, Durmo R, Treglia G, Giubbini R, Bertagna F. 18F-FDG PET/CT or PET role in MALT lymphoma: an open issue not yet solved – a critical review. Clin Lymphoma Myeloma Leuk. 2020;20(3):137-146. doi:10.1016/j.clml.2019.10.006
  39. Husnain M, Kuker R, Reis IM, et al. Clinical and radiological characteristics of patients with pulmonary marginal zone lymphoma: a single center analysis. Cancer Med. 2020;9(14):5051-5064. doi:10.1002/cam4.3096
  40. Albano D, Giubbini R, Bertagna F. 18F-FDG PET/CT in splenic marginal zone lymphoma. Abdom Radiol (NY). 2018;43(10):2721-2727. doi:10.1007/s00261-018-1542-z
  41. Vaxman I, Bernstine H, Kleinstern G, et al. FDG PET/CT as a diagnostic and prognostic tool for the evaluation of marginal zone lymphoma. Hematol Oncol. 2019;37(2):168-175. doi:10.1002/hon.2578
  42. Strouse C, Rutherford SC, Smith BJ, et al. Utility and patterns of use of PET/CT and bone marrow biopsy for staging in non-Hodgkin lymphoma in the clinical setting: a retrospective analysis using the LEO database. Blood. 2019;134(suppl 1):1610. doi:10.1182/blood-2019-126068
  43. Alderuccio JP, Isrow D, Reis IM, et al. Diagnostic bone marrow biopsy in patients with stage I EMZL treated with radiation therapy: needed or not? Blood. 2020;135(15):1299-1302. doi:10.1182/blood.2019003236
  44. Luminari S, Cesaretti M, Marcheselli L, et al. Decreasing incidence of gastric MALT lymphomas in the era of anti-Helicobacter pylori interventions: results from a population-based study on extranodal marginal zone lymphomas. Ann Oncol. 2010;21(4):855-859. doi:10.1093/annonc/mdp402
  45. Liu H, Ye H, Ruskone-Fourmestraux A, et al. T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H pylori eradication. Gastroenterology. 2002;122(5):1286-1294. doi:10.1053/gast.2002.33047
  46. Starostik P, Patzner J, Greiner A, et al. Gastric marginal zone B-cell lymphomas of MALT type develop along 2 distinct pathogenetic pathways. Blood. 2002;99(1):3-9. doi:10.1182/blood.v99.1.3
  47. Kahl BS. Update: gastric MALT lymphoma. Curr Opin Oncol. 2003;15(5):347-352. doi:10.1097/00001622-200309000-00001
  48. Wündisch T, Thiede C, Morgner A, et al. Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol. 2005;23(31):8018-8024. doi:10.1200/JCO.2005.02.3903
  49. Broccoli A, Zinzani PL. How do we sequence therapy for marginal zone lymphomas? Hematology Am Soc Hematol Educ Program. 2020;2020(1):295-305. doi:10.1182/hematology.2020000157
  50. Montalban C, Santón A, Redondo C, et al. Long-term persistence of molecular disease after histological remission in low-grade gastric MALT lymphoma treated with H. pylori eradication. lack of association with translocation t(11;18): a 10-year updated follow-up of a prospective study. Ann Oncol. 2005;16(9):1539-1544. doi:10.1093/annonc/mdi277
  51. Capelle LG, de Vries AC, Looman CWN, et al. Gastric MALT lymphoma: epidemiology and high adenocarcinoma risk in a nation-wide study. Eur J Cancer. 2008;44(16):2470-2476. doi:10.1016/j.ejca.2008.07.005
  52. Wündisch T, Dieckhoff P, Greene B, et al. Second cancers and residual disease in patients treated for gastric mucosa-associated lymphoid tissue lymphoma by Helicobacter pylori eradication and followed for 10 years. Gastroenterology. 2012;143(4):936-942;quiz e13-e14. doi:10.1053/j.gastro.2012.06.035
  53. Kiesewetter B, Copie-Bergman C, Levy M, et al. Genetic characterization and clinical features of Helicobacter pylori negative gastric mucosa-associated lymphoid tissue lymphoma. Cancers. 2021;13(12):2993. doi:10.3390/cancers13122993
  54. Ishikawa E, Nakamura M, Satou A, Shimada K, Nakamura S. Mucosa-associated lymphoid tissue (MALT) lymphoma in the gastrointestinal tract in the modern era. Cancers. 2022;14(2):446. doi:10.3390/cancers14020446
  55. Choi YJ, Kim N, Paik JH, et al. Characteristics of Helicobacter pylori-positive and Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma and their influence on clinical outcome. Helicobacter. 2013;18(3):197-205. doi:10.1111/hel.12033
  56. Yahalom J, Xu AJ, Noy A, et al. Involved-site radiotherapy for Helicobacter pylori–independent gastric MALT lymphoma: 26 years of experience with 178 patients. Blood Adv. 2021;5(7):1830-1836. doi:10.1182/bloodadvances.2020003992
  57. Saifi O, Lester SC, Rule W, et al. Comparable efficacy of reduced dose radiation therapy for the treatment of early stage gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Adv Radiat Oncol. 2021;6(4):100714. doi:10.1016/j.adro.2021.100714
  58. Jung K, Kim DH, Seo HI, Gong EJ, Bang CS. Efficacy of eradication therapy in Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma: a meta-analysis. Helicobacter. 2021;26(2):e12774. doi:10.1111/hel.12774
  59. Cheah CY, Zucca E, Rossi D, Habermann TM. Marginal zone lymphoma: present status and future perspectives. Haematologica. 2022;107(1):35-43. doi:10.3324/haematol.2021.278755
  60. Zinzani PL, Quaglino P, Pimpinelli N, et al; Italian Study Group for Cutaneous Lymphomas. Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol. 2006;24(9):1376-1382. doi:10.1200/JCO.2005.03.6285
  61. Dalle S, Thomas L, Balme B, Dumontet C, Thieblemont C. Primary cutaneous marginal zone lymphoma. Crit Rev Oncol Hematol. 2010;74(3):156-162. doi:10.1016/j.critrevonc.2009.09.003
  62. Joffe E, Leyfman Y, Drill E, et al. Active surveillance of primary extranodal marginal zone lymphoma of bronchus-associated lymphoid tissue. Blood Adv. 2021;5(2):345-351. doi:10.1182/bloodadvances.2020003213
  63. Trabolsi A, Alderuccio JP, Florindez J, et al. Marginal zone lymphoma of the colon: case series from a single center and SEER data review. Leuk Lymphoma. Published online December 19, 2021. doi:10.1080/10428194.2021.2015766
  64. Jeon MK, So H, Huh J, et al. Endoscopic features and clinical outcomes of colorectal mucosa-associated lymphoid tissue lymphoma. Gastrointestinalendosc. 2018;87(2):529-539. doi:10.1016/j.gie.2017.08.027
  65. Brice P, Bastion Y, Lepage E, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1997;15(3):1110-1117. doi:10.1200/JCO.1997.15.3.1110
  66. Alderuccio JP, Florindez JA, Reis IM, Zhao W, Lossos IS. Treatments and outcomes in stage I extranodal marginal zone lymphoma in the United States. Cancers (Basel). 2021;13(8):1803. doi:10.3390/cancers13081803
  67. Teckie S, Qi S, Chelius M, et al. Long-term outcome of 487 patients with early-stage extra-nodal marginal zone lymphoma. Ann Oncol. 2017;28(5):1064-1069. doi:10.1093/annonc/mdx025
  68. Platt S, Al Zahrani Y, Singh N, Hill B, Cherian S, Singh AD. Extranodal marginal zone lymphoma of ocular adnexa: outcomes following radiation therapy. Ocular Onc Pathol. 2017;3(3):181-187. doi:10.1159/000453615
  69. Tsai HK, Li S, Ng AK, Silver B, Stevenson MA, Mauch PM. Role of radiation therapy in the treatment of stage I/II mucosa-associated lymphoid tissue lymphoma. Ann Oncol. 2007;18(4):672-678. doi:10.1093/annonc/mdl468
  70. Jackson AE, Mian M, Kalpadakis C, et al. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue of the salivary glands: a multicenter, international experience of 248 patients (IELSG 41). Oncologist. 2015;20(10):1149-1153. doi:10.1634/theoncologist.2015-0180
  71. Thieblemont C, Dumontet C, Bouafia F, et al. Outcome in relation to treatment modalities in 48 patients with localized gastric MALT lymphoma: a retrospective study of patients treated during 1976-2001. Leuk Lymphoma. 2003;44(2):257-262. doi:10.1080/1042819021000035680
  72. Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). 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;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2
  73. Flinn IW, van der Jagt R, Kahl BS, 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;123(19):2944-2952. doi:10.1182/blood-2013-11-531327
  74. Salar A, Domingo-Domenech E, Panizo C, et al; Grupo Español de Linfomas/Trasplante de Médula Ósea (GELTAMO). First-line response-adapted treatment with the combination of bendamustine and rituximab in patients with mucosa-associated lymphoid tissue lymphoma (MALT2008-01): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2014;1(3):e104-e111. doi:10.1016/S2352-3026(14)00021-0
  75. Salar A, Domingo-Domenech E, Panizo C, et al. Long-term results of a phase 2 study of rituximab and bendamustine for mucosa-associated lymphoid tissue lymphoma. Blood. 2017;130(15):1772-1774. doi:10.1182/blood-2017-07-795302
  76. Martínez-Calle N, Hartley S, Ahearne M, et al. Kinetics of T-cell subset reconstitution following treatment with bendamustine and rituximab for low-grade lymphoproliferative disease: a population-based analysis. Br J Haematol. 2019;184(6):957-968. doi:10.1111/bjh.15722
  77. Flinn IW, van der Jagt R, Kahl B, et al. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019;37(12):984-991. doi:10.1200/JCO.18.00605
  78. Kiesewetter B, Troch M, Dolak W, et al. A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma). Haematologica. 2013;98(3):353-356. doi:10.3324/haematol.2012.065995
  79. Fowler NH, Davis RE, Rawal S, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014;15(12):1311-1318. doi:10.1016/S1470-2045(14)70455-3
  80. Becnel MR, Nastoupil LJ, Samaniego F, et al. Lenalidomide plus rituximab (R2) in previously untreated marginal zone lymphoma: subgroup analysis and long-term follow-up of an open-label phase 2 trial. Br J Haematol. 2019;185(5):874-882. doi:10.1111/bjh.15843
  81. Kiesewetter B, Willenbacher E, Willenbacher W, et al; AGMT Investigators. A phase 2 study of rituximab plus lenalidomide for mucosa-associated lymphoid tissue lymphoma. Blood. 2017;129(3):383-385. doi:10.1182/blood-2016-06-720599
  82. Conconi A, Martinelli G, Thiéblemont C, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003;102(8):2741-2745. doi:10.1182/blood-2002-11-3496
  83. Martinelli G, Laszlo D, Ferreri AJM, et al. Clinical activity of rituximab in gastric marginal zone non-Hodgkin’s lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol. 2005;23(9):1979-1983. doi:10.1200/JCO.2005.08.128
  84. Lossos IS, Morgensztern D, Blaya M, Alencar A, Pereira D, Rosenblatt J. Rituximab for treatment of chemoimmunotherapy naive marginal zone lymphoma. Leuk Lymphoma. 2007;48(8):1630-1632. doi:10.1080/10428190701457949
  85. Williams ME, Hong F, Gascoyne RD, et al. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016;173(6):867-875. doi:10.1111/bjh.14007
  86. Ferreri AJM, Ponzoni M, Martinelli G, et al. Rituximab in patients with mucosal-associated lymphoid tissue-type lymphoma of the ocular adnexa. Haematologica. 2005;90(11):1578-1579.
  87. Zucca E, Conconi A, Martinelli G, et al. Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy. J Clin Oncol. 2017;35(17):1905-1912. doi:10.1200/JCO.2016.70.6994
  88. Lolli G, Argnani L, Broccoli A, et al. 90Y-ibritumomab tiuxetan in patients with extra-nodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) – The Zeno Study. Br J Haematol. 2020;189(1):e6-e9. doi:10.1111/bjh.16404
  89. Sachpekidis C, Jackson DB, Soldatos TG. Radioimmunotherapy in non-Hodgkin’s lymphoma: retrospective adverse event profiling of zevalin and bexxar. Pharmaceuticals (Basel). 2019;12(4):141. doi:10.3390/ph12040141
  90. Samaniego F, Berkova Z, Romaguera JE, et al. 90Y-ibritumomab tiuxetan radiotherapy as first-line therapy for early stage low-grade B-cell lymphomas, including bulky disease. Br J Haematol. 2014;167(2):207-213. doi:10.1111/bjh.13021
  91. Lossos IS, Reis IM, Rosenblatt JD, Alderuccio JP. Long-term outcomes of frontline 90Y-ibritumomab tiuxetan in marginal zone lymphoma. Leuk Lymphoma. 2020;61(13):3234-3238. doi:10.1080/10428194.2020.1802449
  92. Arcaini L, Rossi D, Paulli M. Splenic marginal zone lymphoma: from genetics to management. Blood. 2016;127(17):2072-2081. doi:10.1182/blood-2015-11-624312
  93. 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(1):125-135. doi:10.1002/cncr.21931
  94. Kalpadakis C, Pangalis GA, Sachanas S, et al. Rituximab monotherapy in splenic marginal zone lymphoma: prolonged responses and potential benefit from maintenance. Blood. 2018;132(6):666-670. doi:10.1182/blood-2018-02-833608
  95. Bennett M, Sharma K, Yegena S, Gavish I, Dave HP, Schechter GP. Rituximab monotherapy for splenic marginal zone lymphoma. Haematologica. 2005;90(6):856-858.
  96. Florindez JA, Alderuccio JP, Reis IM, Lossos IS. Splenic marginal zone lymphoma: a US population-based survival analysis (1999-2016). Cancer. 2020;126(21):4706-4716. doi:10.1002/cncr.33117
  97. Kalpadakis C, Pangalis GA, Dimopoulou MN, et al. Rituximab monotherapy is highly effective in splenic marginal zone lymphoma. Hematol Oncol. 2007;25(3):127-131. doi:10.1002/hon.820
  98. Iannitto E, Bellei M, Amorim S, et al. Efficacy of bendamustine and rituximab in splenic marginal zone lymphoma: results from the phase II BRISMA/IELSG36 study. Br J Haematol. 2018;183(5):755-765. doi:10.1111/bjh.15641
  99. Lenglet J, Traullé C, Mounier N, et al. Long-term follow-up analysis of 100 patients with splenic marginal zone lymphoma treated with splenectomy as first-line treatment. Leuk Lymphoma. 2014;55(8):1854-1860. doi:10.3109/10428194.2013.861067
  100. Bennett M, Schechter GP. Treatment of splenic marginal zone lymphoma: splenectomy versus rituximab. Semin Hematol. 2010;47(2):143-147. doi:10.1053/j.seminhematol.2010.01.004
  101. Cartron G, Watier H. Obinutuzumab: what is there to learn from clinical trials? Blood. 2017;130(5):581-589. doi:10.1182/blood-2017-03-771832
  102. Salles GA, Morschhauser F, Solal-Céligny P, et al. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23):2920-2926. doi:10.1200/JCO.2012.46.9718
  103. Sehn LH, Chua N, Mayer J, 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;17(8):1081-1093. doi:10.1016/S1470-2045(16)30097-3
  104. Cheson BD, Chua N, Mayer J, et al. Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol. 2018;36(22):2259-2266. doi:10.1200/JCO.2017.76.3656
  105. Leonard JP, Trneny M, Izutsu K, et al; AUGMENT Trial Investigators. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi:10.1200/JCO.19.00010
  106. Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017;129(16):2224-2232. doi:10.1182/blood-2016-10-747345
  107. Noy A, de Vos S, Coleman M, et al. Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis. Blood Adv. 2020;4(22):5773-5784. doi:10.1182/bloodadvances.2020003121
  108. Opat S, Tedeschi A, Linton K, et al. Efficacy and safety of zanubrutinib in patients with relapsed/refractory marginal zone lymphoma: initial results of the MAGNOLIA (BGB-3111-214) trial. Blood. 2020;136(suppl 1):28-30. doi:10.1182/blood-2020-134611
  109. Opat S, Tedeschi A, Linton K, et al. The magnolia trial: zanubrutinib, a next-generation Bruton tyrosine kinase inhibitor, demonstrates safety and efficacy in relapsed/refractory marginal zone lymphoma. Clin Cancer Res. 2021;27(23):6323-6332. doi:10.1158/1078-0432.CCR-21-1704
  110. Batlevi CL, Younes A. Revival of PI3K inhibitors in non-Hodgkin’s lymphoma. Ann Oncol. 2017;28(9):2047-2049. doi:10.1093/annonc/mdx392
  111. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018. doi:10.1056/NEJMoa1314583
  112. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922. doi:10.1200/JCO.18.00915
  113. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905. doi:10.1200/JCO.2017.75.4648
  114. Dreyling M, Santoro A, Mollica L, et al. Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study. Am J Hematol. 2020;95(4):362-371. doi:10.1002/ajh.25711
  115. Matasar MJ, Capra M, Özcan M, et al. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(5):678-689. doi:10.1016/S1470-2045(21)00145-5
  116. FDA investigating possible increased risk of death with lymphoma medicine Ukoniq (umbralisib). FDA. February 3, 2022. Updated February 11, 2022. AccessedMarch 3, , 2022. https://bit.ly/3HgB6ov
  117. Thieblemont C, Cascione L, Conconi A, et al. A MALT lymphoma prognostic index. Blood. 2017;130(12):1409-1417. doi:10.1182/blood-2017-03-771915
  118. Conconi A, Thieblemont C, Cascione L, et al. Early progression of disease predicts shorter survival in MALT lymphoma patients receiving systemic treatment. Haematologica. 2020;105(11):2592-2597. doi:10.3324/haematol.2019.237990
  119. Montalban C, Abraira V, Arcaini L, et al; Splenic Marginal Zone Lymphoma Study Group (SMZLSG). Simplification of risk stratification for splenic marginal zone lymphoma: a point-based score for practical use. Leuk Lymphoma. 2014;55(4):929-931. doi:10.3109/10428194.2013.818143
  120. Montalbán C, Abraira V, Arcaini L, et al; Splenic Marginal Zone Lymphoma Study Group. Risk stratification for splenic marginal zone lymphoma based on haemoglobin concentration, platelet count, high lactate dehydrogenase level and extrahilar lymphadenopathy: development and validation on 593 cases. Br J Haematol. 2012;159(2):164-171. doi:10.1111/bjh.12011
  121. Phillips TJ, Corradini P, Gurion R, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory marginal zone lymphoma (CITADEL-204). Blood. 2020;136(suppl 1):27-28. doi:10.1182/blood-2020-134451
  122. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol. 2021;39(15):1609-1618. doi:10.1200/JCO.20.03433