Targeted Therapies Offer New Treatment Options for R/R MZL Across Subtypes

Marginal zone lymphomas (MZLs) are a heterogenous group of B-cell non-Hodgkin lymphomas based on their etiology and clinical presentation, and as such, treatment for these diseases vary by subtype, according to Stephen Douglas Smith, MD.

Smith, who is a physician at Seattle Cancer Care Alliance, an associate professor in the Division of Medical Oncology at University of Washington School of Medicine, and an associate professor in the Clinical Research Division at Fred Hutchinson Cancer Research Center, presented about the standard and emerging treatment options for MZL during the National Comprehensive Cancer Network (NCCN) 2020 Virtual Congress: Hematologic Malignancies.1

Standard therapies have been set in the first-line setting across multiple subtypes of MZL with the use of involved-site radiotherapy (ISRT) and the anti-CD20 monoclonal antibody rituximab (Rituxan) consistent throughout. Historically, few studies have looked specifically at patients with MZL; however, newer approaches using targeted therapies are being investigated and have shown promise in the treatment of subgroups of patients with MZL.

Standardized Therapies Upfront for MZL Subtypes

First Smith explained that it is often necessary to treat related infections before MZL, as in the case of Helicobacter pylori (H. pylori)in gastric mucosa‐associated lymphoid tissue (MALT) lymphoma and hepatitis C virus in splenic MZL. H. pylori is present in about 90% of gastric MALT lymphomas. The infection leads to chronic gastritis which results in lymphoma lesions, according to Smith. However, 70% of patients respond successfully to H. pylori eradication with proton pump inhibition, clarithromycin, and amoxicillin—although the responses do take time, he noted. Treatment of hepatitis C virus has also demonstrated regression of this type of lymphoma.

Generally, in the case of localized disease across subtypes, standard therapy consists of ISRT, especially in the case of MALT lymphoma. For patients with advanced-stage disease or disseminated nodal involvement, treatment typically consists of chemoimmunotherapy consisting of an alkylating chemotherapy agent and rituximab, or rituximab monotherapy. The addition of ISRT or rituximab is also recommended for patients with H. pylori and gastric MALT lymphoma who either do not respond to eradication or have t(11;18) as well.

“In my general practice, [treatment is] non-anthracycline chemoimmunotherapy with an alkylator for first line in the vast majority of patients,” Smith said.

For patients with advanced or relapsed/refractory non-gastric MALT lymphomas, chemoimmunotherapy is more effective than chemotherapy alone as chemoimmunotherapy can be limited. A phase 2 Spanish study of patients with MALT lymphoma treated with response-adapted treatment of bendamustine and rituximab benefitted from only 4 to 6 cycles of therapy.2

The MALT 2008-01 trial enrolled 60 patients who were treated with 3 cycles of bendamustine at 90 mg/m2 on days 1 and 2 plus rituximab at 375 mg/m2 on day 1 given every 4 weeks. Then the patients were restaged and if they had achieved a complete response (CR), they only received 1 more cycle of therapy versus 3 more cycles if the patient had a partial response. Seventy-five percent received 4 cycles and 25% received 6; 13 of these patients went on to achieve a CR. After 2 years, the progression-free survival (PFS) rate was 96% in these patients, and at 4 years the rate was 93%.

The regimen was also well tolerated with grade 3 or higher infections, including 2 cases of cytomegalovirus, observed in 7 patients. The most frequent grade 3/4 adverse events were lymphopenia (33%), neutropenia (20%), and leucopenia (5%).

“For me, this is a nice disease-specific data set which gives justification for 4 cycles of bendamustine/rituximab in marginal zone lymphoma, assuming that you get a [CR] after the first 3,” Smith said.

Patients with nodal MZL similarly benefit from ISRT for limited-stage disease and chemoimmunotherapy for advanced-stage disease. For elderly or unfit patients, though, the NCCN guidelines recommend single-agent rituximab at 375 mg/m2 weekly for 4 doses.3 However, Smith suggested considering extending the dosing for patients who respond based on the results of the phase 3 RESORT/ECOG E4402 study.4

In the trial, patients with MZL and small lymphocytic lymphoma who were responding to weekly rituximab were randomized to either maintenance rituximab of a single dose every 3 months until treatment failure or retreatment of weekly rituximab for 4 doses at the time of progression. Among patients with MZL specifically, the objective response rate (ORR) was 52.1%. The median time to treatment failure in the maintenance rituximab arm was 1.4 years and the median time to first cytotoxic therapy was not reached compared with 4.8 and 6.3 years, respectively, in the retreatment arm.

“We're talking about no overall survival benefit, but it does show that you can delay the need for cytotoxic chemotherapy,” Smith said.

Single-agent rituximab is also effective for splenic MZL, potentially even above splenectomy alone.5 A retrospective analysis of patients with splenic MZL treated with rituximab or rituximab and chemotherapy demonstrated CRs in 90% of patients treated with rituximab monotherapy versus 79% with rituximab and chemotherapy. Additionally, at 3 years, the rate of disease-free survival was 79% with rituximab alone compared with 29% after splenectomy alone (HR, 0.28; 95% CI, 0.12-0.68; P = .003) and versus 25% with rituximab and chemotherapy (HR, 0.21; 95% CI, 0.08-0.51; P = .0004).

However, splenectomy is still necessary if a patient has relapsed or is at risk for transformation.

Targeted Therapies Offer Potential for Relapsed/Refractory Disease

Pathobiology has suggested that there is a potential for targeted therapies in the treatment of MZLs with modulation of the microenvironment using lenalidomide (Revlimid) and through B-cell receptor activation with Bruton tyrosine kinase (BTK) inhibitors and PI3K inhibitors. Each of these agents have demonstrated potential in the treatment of MZL. Other potential approaches that have not been successfully proven yet include the targeting of specific NFkB related pathways, such as the JAK/STAT pathway, and using HDAC inhibitors and other epigenetic modifiers.

“It is my hope that with better understanding of the pathophysiology of this disease, we'll have better treatment targets and emerging paradigms which allow patients a fixed-duration therapy that is very effective and doesn't require chronic administration,” Smith commented.

Ibrutinib (Imbruvica), a first-generation BTK inhibitor, was the first FDA approved treatment for patients with relapsed/refractory MZL who have received at least 1 prior anti-CD20–based therapy.6

In the pivotal trial that led to the approval, 63 patients with previously treated MZL of all subtypes were enrolled and treated with 560 mg ibrutinib orally once daily continually until disease progression or unacceptable toxicity. Among 60 evaluable patients, the ORR was 48% (95% CI, 35%-62%), with CRs in 3%, and the median duration of response (DOR) was not reached. The median PFS was 14.2 months.7

A majority of the patients who responded had extranodal disease. In patients with splenic MZL, the median PFS was 19.4 months versus 13.8 months among patients with MALT MZL and 8.3 months in patients with nodal MZL.

In terms of safety, the most common adverse events of any grade from ibrutinib treatment were fatigue (44%), diarrhea (43%), and anemia (33%). The most frequent events of grade 3 or higher were anemia (14%), pneumonia (8%), and fatigue (5%). Smith mentioned that no atrial fibrillation was reported, which is a known class effect of BTK inhibition and cause for concern in patients with a cardiac history.

Lenalidomide is often given in combination with rituximab. The treatment duration can vary from 8 to 12 months or until CR is achieved. Toxicity with the agent is consistent with other diseases, notably with cases of grade 3/4 neutropenia and common lower-grade rash, anemia, and infections.

In the phase 3 AUGMENT trial of lenalidomide and rituximab versus rituximab alone in patients with relapsed/refractory indolent lymphomas, among patients with MZL specifically, the ORR was 65% with the combination versus 44% with rituximab monotherapy.8 The median PFS, event-free survival, overall survival, and DOR, however, were all greater with rituximab monotherapy.

“This is not a perfect study. But it does suggest that when we use another antibody, we should do so with a grain of salt and make sure that a patient has had a good try at single agent rituximab, at least first or in continuous therapy before trying lenalidomide,” Smith said. “At least that's my approach.”

The NCCN guidelines nonetheless do recommend the use of combination lenalidomide and rituximab as a potential treatment option for patients with MALT lymphoma and other MZL subtypes.3

PI3K inhibitors, including idelalisib (Zydelig), copanlisib (Aliqopa), and duvelisib (Copiktra), have demonstrated potential in the treatment of patients with relapsed/refractory disease, although none have yet been approved. All 3 are included in the NCCN guidelines, however, as potential treatment options for patients with relapsed/refractory disease after 2 prior treatment regimens.3

Smith noted that responses were highest with copanlisib. Of 23 patients with MZL treated with copanlisib in the phase 2 CHRONOS-1 trial, the ORR was 78% with CRs in 13% of patients, all of whom had splenic MZL. The median PFS was 24.2 months among the responding patients and the median DOR was 17.4 months.9

He recommended choosing between the 3 based on their different off-target effects due to the various isoforms they hit, as the efficacy in MZL was comparable between the agents. Adverse events typically seen with copanlisib included fatigue, hyperglycemia, and diarrhea. Alternatively, duvelisib leads to more neutropenia and nausea as well as diarrhea and fatigue, and idelalisib is associated with neutropenia, diarrhea, colitis, and ALT/AST increases.

_References:

_{1. Smith SD. Challenges and opportunities in marginal zone lymphoma: implications of biology on treatment. Presented at: NCCN 2020 Virtual Congress: Hematologic Malignancies; October 9-10, 2020; Virtual.}

_{2. Salar A, Domingo-Domenech E, Panizo C, et al. 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 Hematol. 2014;1(3):E104-E111. doi:10.1016/S2352-3026(14)00021-0}

_{3. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas; version 4.2020. August 13, 2020. Accessed October 9, 2020. https://bit.ly/3iHUnCY}

_{4. 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. B J Haematol. 2016;173(6):867-875. doi:10.1111/bjh.14007}

_{5. Else M, Marín-Niebla A, de la Cruz F, et al. Rituximab, used alone or in combination, is superior to other treatment modalities in splenic marginal zone lymphoma. Br J Haematol. 2012;159(3):322-328. doi:10.1111/bjh.12036}

_{6. U.S. FDA approves IMBRUVICA® (ibrutinib) as first treatment specifically indicated for relapsed/refractory marginal zone lymphoma (MZL) - a rare type of non-hodgkin's lymphoma. News release. Abbvie. January 19, 2017. Accessed October 9, 2020. https://bit.ly/3lu0lcr}

_{7. 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}

_{8. 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}

_{9. Dreyling M, Panayiotidis P, Follows GA, et al. Long-term efficacy and safety of copanlisib in multiply relapsed or refractory patients with marginal zone lymphoma. Blood. 2019;134(suppl 1):1351. doi:10.1182/blood-2019-121932}