R/R patients with SMZL include those who failed local treatment (splenectomy) and those progressing on rituximab monotherapy. Though rituximab-based chemotherapy combinations can be employed in this setting,55,59 treatment, or retreatment in patients who previously receiving rituximab monotherapy is a commonly employed and retains its efficacy in most cases.110,111 BR has also gained popularity as a preferred regimen in R/R SMZL based on the impressive ORR (92%) observed in the BRIGHT study in MZL patients (n=25).112

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Though no studies have specifically looked at R/R NMZL, strategies comparable with similarly staged FL are used, and combination therapies with immunochemotherapy are most typical.50 Good outcomes have been seen in some studies with bortezomib in particular, which has shown promising activity specifically when looking at NMZL.107,113,114

Prognosis of MZL


The natural history of EMZL is indolent, and SEER analysis shows 5-year OS rate of 88.7% and median OS 12.6 years.10 Median time to progression is better for GI compared with non-GI EMZL;74 however, GI and pulmonary involvement had a worse survival compared with other locations, with a 5-year incidence rate of lymphoma-related death of 9.5%–14.3% compared with 4.5%–7.8%, respectively.10For patients not responding to antibiotics, with Stage IE–IIE EMZL treated with IFRT only, OS at 10 years is 79%–87%.74,75 Outcomes for high-dose systemic therapy/autologous hematopoietic stem cell transplantation in disseminated EMZL are similar to those in FL.102,103 Enrollment in clinical trials is highly encouraged given the limited therapeutic options in R/R EMZL.101 Despite frequent relapses, EMZL often maintains a relatively indolent course.35 Relapses most commonly occur in the tissue of origin; however, involvement of other sites (including lymph nodes) can occur.115 Using the data from IELSG-19 trial, Thieblemont et al reported MALT-IPI (International Prognostic Index) as a prognostic tool for risk stratifying patients with MALT. Patient who were ≥70 years, with advanced stage (Ann Arbor Stage III or IV) and elevated lactate dehydrogenase (LDH) conferred poor outcomes in EMZL patients. Based on the presence of 0, 1, and 2 or more risk factors, the patients were stratified into low-, intermediate-, and high-risk groups.116


Though the majority of SMZL run an indolent course similar to EMZL, overall, SMZL has poorer outcomes due to a relatively larger proportion of patients who present with aggressive disease.117 The median OS for SMZL is ~8–10 years;10,43 however, in cases of aggressive disease (~25%–30% of cases), the median survival is <4 years.43,117 In SMZL, the Italian Foundation of Lymphomas prognostication index can be used to risk stratify patients by presence of risk factors, including low hemoglobin, elevated LDH, and reduced albumin level at diagnosis. The 5-year disease-specific survival rate was 88% in the low-risk group, 73% in the moderate-risk group, and 50% in the high-risk group.43 Subsequently, other prognostic models were also developed118,119 to optimize prognostication and can therefore be used. However, these models are based on clinical parameters and are not 100% sensitive or specific. Hence, incorporation of mutational/genetic markers into the current clinical prognostic models may be required in the future to improve risk stratification of SMZL patients.


The overall prognosis for NMZL is worse than EMZL when presenting as disseminated disease120 and more comparable with SMZL and other indolent lymphomas.10,50,121 To date, this disease remains incurable and is characterized a pattern of recurring relapse at nodal sites.50 With the advent of newer therapies, the average 5-year OS of NMZL has reached 70%–90%.122 Both the IPI and the FL International Prognostic Index are used in NMZL to stratify patients into high and low risk.50,122

Role of ibrutinib in MZL – is it ready for primetime?

The importance of the role played by BCR signaling in the development of MZL cannot be undermined.11,13 BTK plays a key role in the BCR signaling pathway and has been shown to be involved in the formation, survival, and proliferation of malignant B cells.123–126 The efficacy of Food and Drug Administration (FDA)-approved ibrutinib in other lymphoid malignancies, including chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia is well known.12 Given the likely importance of BCR, induced by chronic antigenic stimulation, in the development of MZL,4 it was theorized that BTK targeting may play a role in therapy for R/R MZL. A Phase I trial of single-agent ibrutinib in 56 patients with heavily pre-treated B-cell malignancies (median number of prior therapies =3) included 4 patients with R/R MZL; 1 patient sustained a partial response and 3 had stable disease,127 thus opening the window for further studies.

Subsequently, a pivotal, Phase II open-label international study was conducted using ibrutinib in patients with R/R MZL previously treated with rituximab-based therapy.12 The study included 60 evaluable patients who were treated with single-agent ibrutinib (560 mg orally daily) administered until progression or unacceptable toxicity. ORR was 48% and median PFS was 14.2 months. CR was noted in 2 patients (3%). Progression of disease was the main reason for treatment discontinuation, occurring in 32% of study participants. Though AEs occurred in 44% of patients, the rates of treatment discontinuation and dose reduction due to AEs were relatively low at 17% and 10%, respectively. These were comparable with rates of discontinuation due to AE seen in other similar studies with ibrutinib. At a median follow-up of 19.4 months, 38% still remained on ibrutinib, and median OS has not been reached. 

Outcomes were also analyzed by MZL subtype. Median PFS was 13.8 months for EMZL, 19.4 months for SMZL, and 8.3 months for NMZL. Estimated 18-month OS rate was 81%, and of the 8 patients who died during the study, 4 (7%) were attributable to progression of disease. At the time, this study was published (19 months from start date), the median duration of response has not yet been reached. Overall, the rate of disease control based on clinical benefit was 83%, and 78% of patients were shown to have reduced tumor burden. Clinical response to ibrutinib was seen in all subtypes. Response occurred in those treated with prior chemotherapy, immunotherapy, or a combination of the two. Responses were seen in both relapsed and refractory patients as well as those with bulky disease and/or BM involvement.12

Based on these results, FDA granted accelerated approval for ibrutinib for the treatment of R/R MZL requiring systemic therapy and progressing on at least 1 prior anti-CD20-based therapy. It is noteworthy that, prior to ibrutinib, no therapeutic agent had been approved by the FDA specifically for treatment of MZL. Currently, ibrutinib provides a viable alternative treatment option to chemoimmunotherapy for the treatment of R/R MZL.12

Compared with MZL, ibrutinib has shown only modest activity in FLR/R FL. A recent Phase II consortium trial of 40 patients with R/R FL has shown ORR of 37.5% with CR of 12.25, median PFS of 14 months, and 2-year PFS of 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared with those who were rituximab refractory (16.7%). CARD11 mutations were present in 16% (5/31) of patients and predicted resistance to ibrutinib.128 This is in contrast to an ORR of 82% with CR 27% in untreated FL in the Phase II PCYC-1125-CA study that included 80 patients, with the majority having Stage III/IV disease. In that same trial, the median PFS and OS has not been reached as only 5 patients had disease progression.129Ibrutinib was well-tolerated in both trials with low incidence of AEs.

Combination therapies that include BTK inhibition as well as other agents are currently ongoing and have much potential. Currently, a randomized, double-blind, multicenter Phase III trial, SELENE, is underway. This trial is investigating ibrutinib vs placebo in combination with either BR or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with previously treated MZL or FL (NCT01974440). The primary objective is to determine whether ibrutinib vs placebo in combination with BR or R-CHOP will prolong PFS, with secondary objectives, including OS, CR, ORR, safety, and toxicity.130 With the advent of novel combination approaches with more tolerable side effects and improved efficacy, there is hope that optimal and standardized treatment regimens for MZL may soon be around the corner. Ibrutinib is also being investigated in combination with lenalidomide ± rituximab (NCT02532257 and NCT01955499); selinexor (KPT-330), a selective inhibitor of nuclear export (NCT02303392); the check point inhibitor pembrolizumab (NCT02332980); and other target agents in R/R MZL and other B-cell malignancies.