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C.Y. Cheah et al.
with nodal MZL, an IgM paraprotein may occur and MYD88 mutation testing can help distinguish splenic MZL from Waldenström macroglobulinemia.58 Hepatitis C infection should be treated if present as treatment can result in lymphoma regression.48 Splenic hilar lym- phadenopathy occurs in 25% of cases of splenic MZL but peripheral lymphadenopathy is rare.59,60 Most patients present with splenomegaly, lymphocytosis and cytope- nias.59 Autoimmune hemolytic anemia and other autoim- mune phenomena can occur. Computed tomography (CT) scan is adequate for staging; positron emission tomography (PET) with CT can be reserved for patients in whom histological transformation is suspected.55
Current treatment approaches
Asymptomatic patients can be managed with observa- tion. Symptomatic splenomegaly, cytopenia, systemic symptoms or progressive nodal disease are indications for treatment.55,56 Frontline treatment options include splenec- tomy, rituximab monotherapy, and chemo-immunother- apy.55 While these three approaches have not been direct- ly compared, rituximab monotherapy or chemo- immunotherapy are typically preferred.
Splenectomy
Splenectomy was the mainstay of therapy before ritux- imab monotherapy was adopted, and its role in modern management is now often in the second-line setting or beyond. Nonetheless, splenectomy removes disease bulk, abdominal discomfort and improves cytopenias due to splenic sequestration which is more common than heavy marrow involvement.55 Splenectomy typically results in durable disease control and facilitates a definitive diagno- sis of splenic MZL.55 Short-term perioperative complica- tions may be reduced with a laparoscopic approach and prophylaxis against venous thromboembolism. The late risk of infections with encapsulated bacteria can be mini- mized with vaccinations at least 2 weeks before elective splenectomy and, potentially, prophylactic antibiotics.55
Chemo-immunotherapy
Chemo-immunotherapy is appropriate for fit patients with disseminated disease, constitutional symptoms, and/or high-grade transformation.55 R-CVP and R-CHOP, both commonly used in follicular lymphoma, can be delivered to patients with splenic MZL; however, in a prospective phase II trial R-COMP (rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone) resulted in an objective response rate (ORR) of 84% and a 6-year PFS of 54%.55 Bendamustine and rituximab resulted in durable respons- es in the BRIGHT61 and STiL51 studies, and the use of rit- uximab maintenance for 2 years following initial treat- ment with bendamustine and rituximab in both nodal and splenic MZL prolonged PFS (but not OS) relative to no maintenance (hazard ratio=0.35, 95% confidence interval: 0.17-0.76, P=0.008) in the STiL NHL7-2008 MAINTAIN trial.62
Single-agent rituximab
Rituximab monotherapy resulted in an ORR of 92% and 10-year freedom from progression of 64% in a large retrospective series.63 The RESORT trial treated patients with 375 mg/m2 weekly for 4 weeks and then random- ized patients to observation versus maintenance ritux-
imab.64 There was a significant improvement in time to treatment failure and PFS in the maintenance therapy arm. Single-agent rituximab (with short or protracted administration) has become the preferred approach in most patients, so that splenectomy or chemo- immunotherapy is reserved for patients not responding to single-agent treatment.65 Recent single institution data showed that CD5 expression, although rare in MZL, was associated with a lower ORR following rituximab monotherapy but not bendamustine and rituximab, sug- gesting the latter combination might be preferred if sys- temic therapy is required.66
Histological transformation
Histological transformation to diffuse large B-cell lym- phoma is associated with a poor outcome and inferior overall survival. Histological transformation occurs with an annual incidence of approximately 1% per year.11 Failure to achieve complete remission, elevated lactate dehydrogenase concentration, more than four nodal sites involved at diagnosis,11 involvement of multiple mucosal sites,66 CD5 expression65 and in splenic MZL, complex karyotype, are associated with greater risk of histological transformation.67
Mantle zone lymphoma assessment criteria and response evaluation
Several classifications are used for treatment response assessment in MZL. CT-scan response assessment is not well defined in MZL, which is primarily an extranodal disease. Splenic MZL and gastric MZL, or MZL from other extranodal sites prove difficult to assess based on CT-scan criteria. Various response assessment criteria for these diseases, such as the Lugano,68 Matutes69 and GELA70 classifications need to be homogenized, to facili- tate better comparison of the results between different clinical trials. In localized gastric MZL, serial endoscopy and gastric biopsy are recommended, and responses can take up to 12 months. The presence of residual micro- scopic lymphoma prior to that time should not prompt initiation of another treatment if the patient has improved clinically and macroscopically.8
There is a wide range of endpoints that are currently used in clinical trials and in routine practice.71-73 However, the endpoints currently validated by the Food and Drug Administration (FDA) for use in phase II clinical trials are the ORR and complete response rate, which may not fully capture patients’ outcomes in MZL. Surrogate end- points in MZL may include PET-CT, minimal residual dis- ease, and progression of disease within 2 years.74 The value of PET-CT and minimal residual disease criteria in assessing response to treatment in MZL requires further characterization.
The value of PET-CT in routine evaluation of MALT lymphoma remains unestablished.75 The sensitivity of PET-CT is highly variable in the disease, ranging from 50- 80% in various studies.76 Furthermore, fluorodeoxyglu- cose avidity in MZL is strongly dependent on the histopathological subtype.77 Nevertheless, PET-CT is use- ful because CT-based staging is of limited utility in the evaluation of extranodal disease.75 PET-CT is useful in
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haematologica | 2022; 107(1)