A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma)

251

198

• Single-agent ibrutinib induced durable remissions (ORR 48%) with a favorable benefit-risk profile in patients with previously treated MZL.• Inhibition of BCR signaling with ibrutinib provides a treatment option without chemotherapy for an MZL population with high unmet need.Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ‡1 prior therapy with an anti-CD20 antibody-containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ‡1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ‡3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628. (Blood. 2017;129(16):2224-2232

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma

Noy

Vos

Thiéblemont

et al. 2017

251

198

“…125 The significant hematological and infectious toxicity observed with the latter regimen, both during and after therapy, was deemed too high in this patient population. 125 As shown in Table 4, [126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144] new targeted agents have been poorly studied in MALT lymphomas: only 3 studies 127,129,133 were restricted to this entity and included .10 patients.…”

Section: Treatment Of Malt Lymphoma Patients With Advanced-stage Disementioning

confidence: 99%

The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance

Zucca

Bertoni

2016

240

205

Extranodal marginal zone (MZ) B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The best evidence of an etiopathogenetic link is provided by the association between Helicobacter pylori–positive gastritis and gastric MALT lymphoma. Indeed, successful eradication of this microorganism with antibiotics can be followed by gastric MALT lymphoma regression in most cases. Other microbial agents have been implicated in the pathogenesis of MZ lymphoma arising at different sites. Apart from gastric MALT lymphoma, antibiotic therapies have been adequately tested only in ocular adnexal MALT lymphomas where upfront doxycycline may be a reasonable and effective initial treatment of patients with Chlamydophila psittaci–positive lymphoma before considering more aggressive strategies. In all other instances, antibiotic treatment of nongastric lymphomas remains investigational. Indeed, there is no clear consensus for the treatment of patients with gastric MALT lymphoma requiring further treatment beyond H pylori eradication or with extensive disease. Both radiotherapy and systemic treatments with chemotherapy and anti-CD20 antibodies are efficacious and thus the experience of individual centers and each patient’s preferences in terms of adverse effects are important parameters in the decision process.

“…78,79 The first-generation immunomodulatory drug, thalidomide, showed a lack of efficacy when administered as monotherapy in a small pilot study, 80 however, the second-generation molecule lenalidomide, administered either alone at 25 mg per day or combined with rituximab in MALT lymphoma, showed a 70% ORR in a phase 2 trial as monotherapy and an impressive 86% when combined with rituximab. 64,81 Importantly, these biological insights and knowledge of the toxicity profiles of the novel available drugs provide guidance to physicians when deciding whether or not to combine these agents with classical chemotherapy. In addition, there is no doubt that, as in all cancers, the microenvironment is of major importance and targeting it with anti-PD1 or anti-PDL1/2 may be an important next step.…”

Section: Disseminated Diseasementioning

confidence: 99%

Optimizing therapy for nodal marginal zone lymphoma

Thiéblemont

Molina

Davi

2016

Nodal marginal zone lymphoma (NMZL) is a rare form of indolent small B-cell lymphoma which has only been clearly identified in the last 2 decades and which to date remains incurable. Progress in therapeutic management has been slow, largely due to the very small number of patients treated and the heterogeneity of treatments administered; thus, standard-of-care treatment is currently nonspecific for this lymphoma entity. In this review, treatments routinely used to manage adult NMZL patients are presented, principally based on immunochemotherapy (when treatment is needed). Biological research behind the key axes of agents currently under development is described; development of novel agents is heavily based on data from gene profiling and genome-wide sequencing research, uncovering a number of critical deregulated pathways specific to NMZL tumors. These include B-cell receptor, JAK/STAT, NF-κB, NOTCH, and Toll-like receptor signaling pathways, as well as intracellular processes such as the cell cycle, chromatin remodeling, and transcriptional regulation in terms of epigenetic modifiers, histones, or transcriptional co-repressors, along with immune escape via T-cell–mediated tumor surveillance. These pathways are examined in detail and a projection of how the field may evolve in the near future for an efficient personalized treatment approach for NMZL patients is presented.