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Marginal zone lymphoma
staging MZL to confirm localized disease and ensure effective radiotherapy. However, gastric and ocular MALT possess low fluorodeoxyglucose avidity. In histo- logically transformed MZL, PET-CT is necessary to con- firm transformation and PET-CT-based response criteria are also used in the Lugano classification to identify trans- formed MZL.78 Site-specific imaging is required to moni- tor response in MZL (for example, magnetic resonance imaging in ocular adnexal MALT).
Novel agents in mantle zone lymphoma
Bruton tyrosine kinase inhibitors
The covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib was approved for patients with relapsed/refrac- tory MZL on the basis of the results of a phase II trial.79 Noy et al. treated 63 patients with a median age of 66 years and median of two prior lines of therapy. MALT lymphoma (51%) was the most common subtype of MZL, followed by nodal MZL (27%) and splenic MZL (22%). Among the 60 patients in whom efficacy could be evaluated, the ORR was 48% (complete responses, 3%) and consistent across disease subtypes. The median dura- tion of response was not reached, while the median PFS
was 14.2 months. The safety profile of ibrutinib was con- sistent with that following its use in other settings, with anemia (14%), pneumonia (8%) and fatigue (6%) being the most common grade ≥3 treatment-emergent adverse events (TEAE). Bleeding events occurred in 59% of patients and were all grade 1-2 apart form one grade 5 cerebral hemorrhage that occurred in a patient therapeu- tically anticoagulated with dalteparin. Atrial fibrillation occurred in four patients (6%). The long-term follow-up of this study was recently published, and after a median follow-up of 33.1 months the ORR was 58%, the median duration of response was 27.6 months, the median PFS 15.7 months and the median OS had not been reached.80 The ORR for extranodal, nodal and splenic MZL was 63%, 47% and 62%, respectively. Mutations in KMT2D and CARD11 were associated with shorter duration of response.
The B-cell lymphoma-2 (BCL2) inhibitor venetoclax showed activity in a phase I study of patients with relapsed/refractory lymphoma, including MZL.81 Although this agent has not been further explored as monotherapy in MZL, the combination of ibrutinib and venetoclax was investigated in a small phase II study.82 An interim analysis demonstrated an ORR of 84% (complete responses, 42%) at week 16.
Figure 1. Mechanism of action of selected novel agents for the treatment of marginal zone lymphoma. Bold type indicates approved agents, normal type indicates agents under investigation. IgH: immunoglobulin heavy chain; CD: cluster of differentiation; Syk: spleen tyrosine kinase; Btk: Bruton tyrosine kinase; PLCγ2: phospho- lipase Cγ2; PKCb: protein kinase Cb; PI3K: phosphatidylinositol-3-kinase; Akt: protein kinase B; bax: B-cell lymphoma-2 associated X protein; Bcl2: B-cell lymphoma protein-2; CAR: chimeric antigen receptor; PD-1, programmed cell death-1. Adapted from Cheah et al. J Clin Oncol 2016.
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