Most patients with extranodal marginal zone lymphoma (MZL) are overtreated, according to Emanuele Zucca, MD, of the Oncology Institute of Southern Switzerland and Institute of Oncology Research in Bellinzona and the Università della Svizzera Italiana in Lugano. “Aggressive therapy is not needed in most cases,” he told attendees at the 2024 Pan Pacific Lymphoma Conference, sponsored by the University of Nebraska.1
Emanuele Zucca, MD
MZL is a group of related clinical entities whose differential diagnosis is not always straightforward. Extranodal MZL lacks a genetic “hallmark”; rather, it is characterized by site-specific genetic heterogeneity. The etiology of these lymphomas is chronic infection (Helicobacter pylori and related species, Chlamydia psittaci, and possibly Borrelia burgdorferi) or autoimmune (Sjögren’s syndrome, Hashimoto’s thyroiditis).
Treatment varies by etiology. For patients with limited disease, there are three main approaches that are selective for H pylori–positive gastric lymphoma, H pylori–negative gastric lymphoma, and nongastric extranodal MZL.
H Pylori–Positive Localized Gastric Lymphoma
“The saying ‘First do no harm’ is particularly valid for this type of lymphoma,” Dr. Zucca said. “In my everyday second-opinion consultations, the most frequent issue is overtreatment of these patients. Keep in mind: Treatment may not always be needed; cure is usually not the aim, and most patients will survive a long time despite relapsing on any type of treatment you offer.”
For localized gastric disease, H pylori eradication must be the initial approach, according to several published studies including almost 2,000 patients. Although lymphocytes may “wax and wane” in repeat biopsies, without a frank macroscopic relapse, these patients do not require therapy, he emphasized.
Another setting in which antibiotics (eg, doxycycline) might be warranted is for ocular adnexa lymphoma. Their benefit, especially with prolonged treatment, has been shown in this subtype, both in patients with and without infection with Chlamydia psittaci.2
For patients with hepatitis C positivity, analogous to the setting of concomitant chronic bacterial infection, virus eradication with direct-acting antivirals should be the initial treatment.
H Pylori–Negative Localized Gastric Lymphoma
Of note, H pylori–negative gastric lymphoma may also respond to antibiotics in about 15% of cases, though 85% of this subtype will require oncologic treatment at some point. Local radiation to the stomach can be effective in treating gastric MZL; a dose of 24 Gy is appropriate for most gastric and nongastric MZLs with localized disease when not contraindicated.
Although 24 Gy represents the standard dose for all indolent lymphomas, as shown in the FoRT trial, there is also some evidence that ultra-low–dose radiotherapy—4 Gy total given on a 2+2 basis—controls disease in up to 70% of patients.3 This approach is increasingly used in select patients (such as the elderly or those with orbital and salivary gland lymphomas) because of its reduced toxicity and sustained activity.4-6 With local treatment for stage I disease, a Memorial Sloan Kettering Cancer Center study showed overall survival to be nearly identical to that of the U.S. population, around 60% at 15 years.7 At this point, he added, low-dose radiotherapy (24 Gy) should remain the benchmark.
Treatment of Advanced-Stage MZL
The patient with advanced-stage disease is the one who needs systemic therapy, according to Dr. Zucca. Such decisions are generally made on the same basis as for those with follicular lymphomas. “If the disease is not symptomatic, you can wait—sometimes for a long time—until therapy is needed,” he noted.
The IELSG19 randomized trial of three systemic approaches in extranodal MZL,8 led by Dr. Zucca, showed clinical synergism for chlorambucil plus rituximab. In 405 patients, this combination led to a 46% reduction in events compared with chlorambucil plus rituximab (P = .0009), though overall survival was identical, approximately 80% at 10 years. “Rituximab alone may be enough for the majority of these patients, who are usually older than 70,” he said.
In the subsequent IELSG38 study, subcutaneous rituximab maintenance after chlorambucil plus rituximab resulted in a 5-year progression-free survival rate of 87% (95% confidence interval [CI] = 78%–92%), whereas it was 72% (95% CI = 63%–79%) in the IELSG19 study. However, overall survival (93% at 5 years with 95% CI = 86%–96%) was very close to the one observed in the previous trial (90%; 95% CI = 83%–94%).9 “Maintenance seems to add something in terms of better control of disease but not overall survival,” he commented.
In the real world, bendamustine has replaced chlorambucil in the first-line treatment of extranodal MZL.— Emanuele Zucca, MD
Tweet this quote
“Irrespective of the lack of a specific randomized study, in the real world, bendamustine has replaced chlorambucil in the first-line treatment of extranodal MZL,10” he noted. The first study to prompt this change was done by the GELTAMO Spanish Cooperative Group, which evaluated bendamustine plus rituximab in a response-adapted strategy.11 The combination achieved a complete response rate of 75% after three cycles; 25% who had not achieved a complete response after three cycles went on to receive a total of six cycles. The estimated 7-year progression-free survival rate was 93% (95% CI = 82%–97%).
“The important message of this trial was that four cycles are enough. If you get disease remission, you don’t need to give prolonged therapy. You can give the minimum possible treatment to these patients,” stated Dr. Zucca. He acknowledged that in the “real world,” patients are often treated longer,10 and many receive maintenance rituximab, which is not affecting overall survival, and it is prolonging immune suppression,” he said. In addition, the monoclonal antibody obinutuzumab does not appear to be more effective than rituximab and is more toxic, based on the GALLIUM trial.12
Treatment of Relapsed or Refractory MZL
Multiple studies have shown that relapse within 2 years—as occurs in 20% of patients—heralds a particularly poor outcome and represents an unmet clinical need in extranodal MZL.13 When deciding upon treatment, Dr. Zucca advised, one should consider the treatment aim, whether treatment is really needed, whether the disease is localized, whether CD20 is still being expressed, and whether transformation is suspected.
Transformation is rarer in MZL than in follicular lymphoma and is most likely to occur with the splenic location. “Nevertheless, if you have any suspicion of transformation—because the disease is clinically more aggressive, LDH [lactate dehydrogenase] is elevated, or the patient is sick—then a biopsy is recommended to guide second-line therapy,” Dr. Zucca advised, and a positron-emission tomography scan may help to determine the optimal biopsy site.13
If you have any suspicion of transformation, then a biopsy is recommended to guide second-line therapy.— Emanuele Zucca, MD
Tweet this quote
Potential targeted treatments have not panned out well yet, and clinical trials evaluating them have included few patients with the extranodal subtype. Among these targets is the PI3K signaling pathway, which seems to be involved in pathogenesis; however, in indolent lymphoma, all PI3K-targeted agents ultimately have not been effective and have been withdrawn from consideration. A second approach is rituximab plus lenalidomide (so-called R2). Although early studies with this approach were promising, the randomized phase III AUGMENT trial did not meet its endpoints.14
Some data suggest a benefit with Bruton’s tyrosine kinase (BTK) inhibitors in MZL. However, the phase III SELENE study showed no significant benefit of adding ibrutinib to immunochemotherapy.15 The approval of ibrutinib in MZL after at least one prior anti-CD20–based therapy has been withdrawn.
“Nevertheless, we have data suggesting this class of agents is quite active,” Dr. Zucca continued. In the phase II ACE-LY-003 trial, monotherapy with the BTK inhibitor acalabrutinib in relapsed or refractory MZL led to a median progression-free survival of 27 months.16 In the MAGNOLIA trial, monotherapy with the BTK inhibitor zanubrutinib led to a 40% complete response rate in extranodal disease.17
Dr. Zucca and his team are conducting a phase II trial of ibrutinib plus rituximab in patients with MZL, including 130 with extranodal MZL, 30 with splenic MZL, and 15 with nodal MZL. The data are currently incomplete and are not available for the extranodal subset, but 97% of patients with splenic disease responded (48% complete responses), as did 93% with nodal disease (57% complete responses).18 Based on these promising findings, the IELSG48 front-line study of zanubrutinib plus rituximab in splenic MZL has been initiated, and he predicted that “BTK inhibitors might become a novel chemotherapy-free option.”
DISCLOSURE: Dr. Zucca has received honoraria from AstraZeneca, BeiGene, Celgene, Incyte, Janssen, Merck, Roche AbbVie, Miltenyi Biomedicine, Celltrion HealthCare, and Kite Pharma.
REFERENCES
1. Zucca E: Is there a right management of extranodal marginal zone lymphoma? 2024 Pan Pacific Lymphoma Conference. Presented July 18, 2024.
2. Ferreri AJM, Sassone MC, Cangi MG, et al: The IELSG39 trial: Efficacy of first-line Chlamydia psittaci eradication with a 6-month regimen of doxycycline in patients with stage 1 MALT lymphoma of the ocular adnexae. 17th International Congress on Malignant Lymphoma. Abstract 066. Presented June 13, 2023.
3. Hoskin P, Popova B, Schofield O, et al: 4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): Long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial. Lancet Oncol 22:332-340, 2021.
4. Gunther JR, Park C, Dabaja BS, et al: Radiation therapy for salivary gland MALT lymphoma: Ultra-low dose treatment achieves encouraging early outcomes and spares salivary function. Leuk Lymphoma 61:171-175, 2020.
5. Pinnnix CC, Dabaja BS, Gunther JR, et al: Response-adapted ultralow-dose radiation therapy for orbital indolent B-cell lymphoma: A phase 2 nonrandomized controlled trial. JAMA Oncol 11:e242112, 2024.
6. Gunther JR, Xu J, Bhutani MS, et al: Response-adapted ultra-low-dose 4 Gy radiation as definitive therapy of gastric MALT lymphoma: A single-centre, pilot trial. Lancet Haematol 11:e521-e529, 2024.
7. Qi S, Liu X, Noy A, et al: Predictors of survival in patients with MALT lymphoma: A retrospective, case-control study. Blood Adv 7:1496-1506, 2023.
8. Zucca E, Conconi A, Martinelli G, et al: Final results of the IELSG19 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 35:1905-1912, 2017.
9. Stathis A, Pirosa MC, Orsucci L, et al: IELSG38: Phase II trial of front-line chlorambucil plus subcutaneous rituximab induction and maintenance in mucosa-associated lymphoid tissue lymphoma. Haematologica 109:2564-2573, 2024.
10. Alderuccio JP, Arcaini L, Watkins MP, et al: An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma. Blood Adv 6:2035-2044, 2022.
11. 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 130:1772-1774, 2017.
12. Herold M, Hoster E, Janssens A, et al: Immunochemotherapy and maintenance with obinutuzumab or rituximab in patients with previously untreated marginal zone lymphoma in the randomized GALLIUM trial. Hemasphere 6:e699, 2022.
13. Rossi D, Bertoni F, Zucca E: Marginal-zone lymphomas. N Engl J Med 386:568-581, 2022.
14. Leonard JP, Trneny M, Izutsu K, et al: AUGMENT: A phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 37:1188-1199, 2019.
15. Nastoupil LJ, Hess G, Pavlovsky MA, et al: Ibrutinib plus BR or R-CHOP in previously treated patients with follicular or marginal zone lymphoma: The phase 3 SELENE study. 17th International Congress on Malignant Lymphoma. Abstract LBA2. Presented June 13, 2023.
16. Strati P, Coleman M, Champion R, et al: A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma. Br J Haematol 199:76-85, 2022.
17. 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 27:6323-6332, 2021.
18. Thieblemont C, Lamy T, Tani M, et al: Rituximab and ibrutinib combination is safe and effective in untreated splenic and nodal marginal zone lymphomas: Planned subset analysis of the IELSG47/MALIBU phase II study. 17th International Congress on Malignant Lymphoma. Abstract 065. Presented June 13, 2023.
