Marginal Zone Lymphoma Subtypes Research Articles

Matching-adjusted indirect comparisons of zanubrutinib (MAGNOLIA, BGB-3111-AU-003) versus ibrutinib (PCYC-1121) and rituximab (CHRONOS-3) in relapsed/refractory marginal zone lymphoma.

In the absence of head-to-head randomized trials, unanchored matching-adjusted indirect comparisons were conducted to estimate the relative efficacy of zanubrutinib versus ibrutinib and zanubrutinib versus rituximab in relapsed or refractory marginal zone lymphoma (MZL). Logistic propensity score models were used to estimate weights for the patient-level data from two phase II single-arm trials, MAGNOLIA and BGB-3111-AU-003, such that their characteristics matched the ibrutinib and rituximab aggregate-level data from PCYC-1121 and CHRONOS-3, respectively. The base case model for each comparison incorporated four key prognostic factors: prior lines of therapy, MZL subtype, response to prior therapy, and age. A sensitivity analysis incorporating additional prognostic factors was also conducted for the ibrutinib comparison. The impact of each covariate was explored via a leave-one-out analysis. Compared with ibrutinib and rituximab, zanubrutinib demonstrated significant benefits in terms of both overall response and progression-free survival in patients with previously treated MZL.

Delphi consensus recommendations on treatment for advanced-stage marginal zone lymphoma in South Korea

Due to the lack of treatment guidelines for the management of advanced-stage marginal zone lymphoma (MZL), only one chemoimmunotherapy—cyclophosphamide, vincristine, and prednisone plus rituximab (R-CVP)—is reimbursed in the first-line setting in South Korea. The aim of this study was to develop a consensus-based recommendation for the treatment of patients with advanced-stage MZL. Twelve hematologist oncologists participated in a two-round Delphi process to identify consensus on the management of patients with advanced-stage MZL in South Korea. Physicians rated their level of agreement with each statement on a four-point Likert scale. Statements were divided into two sections: definitions used in clinical practice and clinical management of patients with advanced-stage MZL. Consensus was reached for 23 of 33 (69.7%) and 5 of 13 statements (38.5%) in rounds 1 and 2, respectively. There was strong consensus (91.7%) that advanced-stage MZL subtypes are defined according to the Lugano staging system. First-line systemic treatment should be prescribed for patients with symptomatic advanced-stage MZL. Although there was unanimous agreement that R-CVP is the standard first-line treatment for advanced-stage MZL, physicians also agreed that bendamustine with rituximab (BR) has greater efficacy than R-CVP as first-line treatment (91.7%). For the treatment of relapsed/refractory advanced-stage MZL, BR and R-CVP can be repeated in patients with short (< 24 months) and long remission periods (≥ 24 months), respectively. This study provides insights on the management of patients with advanced-stage MZL in South Korea. This may enhance clinical decision-making, thus improving patient outcomes.

Risk of transformation by frontline management in follicular and marginal zone lymphomas: a US population–based analysis

AbstractFollicular lymphoma (FL) and marginal zone lymphoma (MZL) often have long overall survival (OS), however, high-grade transformation (HGT) to diffuse large B-cell lymphoma markedly reduces survival. The roles of upfront treatment vs observation on the incidence and outcome of HGT remain unclear. Thus, we analyzed a Surveillance, Epidemiology, and End Results database to address this question. Patients diagnosed with FL grades 1 to 2 or MZL between 2000 and 2020 were included. Fine-Gray models estimated the impact of covariates on HGT cumulative incidence and lymphoma-specific survival (LSS) and Cox regression on OS. HGT occurred in 4.2% of 23 384 patients with FL and 2.5% of 20 530 patients with MZL. The 5- and 10-year HGT cumulative incidence rates were 2.80% and 4.87% for FL, and 1.74% and 2.95% for MZL, respectively, which are notably lower than in earlier studies. The annual HGT incidence rate peaked in the first 2 years, then steadily declined over 2 decades for FL and all MZL subtypes. In FL, upfront observation vs treatment increases HGT risk (sub-distribution hazard ratio [SHR], 1.23; 95% confidence interval [CI], 1.09-1.40; P < .001) and barely affects OS (hazard ratio [HR], 0.95; 95% CI, 0.90-0.99; P = .03). Conversely, upfront observation was associated with lower HGT risk in nodal (SHR, 0.71; 95% CI, 0.53-0.94; P = .01) and extranodal (SHR, 0.64; 95% CI, 0.48-0.86; P = .003) MZL and did not affect survival in extranodal disease (HR, 0.94; 95% CI, 0.97-1.02; P = .15). HGT was associated with decrease in LSS across all histologies. Upfront treatment reduced the risk of HGT only in FL but not MZL.

Splenic Marginal Zone Lymphoma complicated with cold autoimmune haemolytic anaemia

Splenic Marginal Zone Lymphoma (SMZL) is a distinct subtype of Marginal Zone Lymphoma (MZL) which is categorized under Non-Hodgkin Lymphoma. It is usually benign with the potential to transform into diffuse large B-cell lymphoma. Comorbid cold Autoimmune Haemolytic Anaemia(cAHA) is rare with SMZL. A case of a 53-year-old woman is presented here. She presented with fever and anaemic symptoms. Biochemical, radiological and histological investigations were done, and a diagnosis of SMZL complicated with cAHA was made.

Impact of Maintenance Rituximab Following First-Line Systemic Therapy on Outcomes in Patients with Marginal Zone Lymphoma: Real-World Evidence from 10 US Centers

Introduction First-line treatment options for patients (pts) with marginal zone lymphoma (MZL) include rituximab monotherapy (R) and immunochemotherapy (IC), such as bendamustine with rituximab (BR) or RCHOP/RCVP. The efficacy of maintenance rituximab (M-R) has been studied in splenic (SMZL) and nodal (NMZL) MZL, showing a benefit in progression-free survival (PFS) when M-R is administered after BR (Rummel et al., ASCO 2018). However, the role of M-R in pts with extranodal MZL (EMZL) of the mucosa-associated lymphatic tissue (MALT), or those receiving R or RCHOP/RCVP, remains uncertain. In this study, we analyzed the outcomes of pts with MZL who received M-R after their first-line systemic therapy (R or IC) using data from a large multi-institutional retrospective cohort. Methods Adult pts with MZL (SMZL, NMZL, or EMZL) who were treated at 10 US medical centers from 2010 onwards were included. Pts who had received first-line treatment with either R or IC and achieved a partial (PR) or complete (CR) response to the initial therapy were divided into groups based on whether they subsequently received M-R or not. To avoid immortal-time bias, we required a minimum follow-up of 6 months from diagnosis. Outcomes included PFS, overall survival (OS) and cumulative incidence of histologic transformation (HT). Because of non-proportional hazards, Wilcoxon test was used to compare survival curves, and Cox models (augmented by multiple imputation to account for missing data) were bounded by 6 years of follow up. Multivariable models adjusted for prognostic factors including age, sex, performance status, stage, baseline hemoglobin, albumin, LDH, type of IC and CR/PR status at the end of therapy. Results The study included 427 pts with a median age of 63 years. Of these pts, 53% were women, and 49% had EMZL, 27% had NMZL, and 23% had SMZL. The first-line therapies received were R (54%), BR (36%), RCHOP (7%), or RCVP (3%). A CR was achieved by 70% (n=298) of pts after the initial therapy. Overall, 33% (n=140) received M-R with a median of 8 cycles. Among pts who initially had PR, 39% converted to a CR during M-R therapy. The median follow-up period was 5 years. Factors associated with a higher likelihood of receiving M-R included achieving a PR instead of a CR after the first-line therapy (41% vs 29% receiving M-R, respectively; p=0.02) and having the SMZL subtype (p=0.03, Fig 1A). Pts treated with RCHOP were less likely to receive M-R compared to those receiving other regimens (p=0.049). There was also evidence of hospital-level preference to either prescribe M-R or not. We analyzed survival outcomes separately for pts who received first-line IC or R monotherapy, stratified further by MZL subtype and the type of IC regimen. Among pts who received IC (n=197), M-R was associated with longer PFS (median of 9.0 vs. 6.8 years, p=0.008, Fig 1B). However, the statistical significance was lost in the multivariable model (adjusted HR=0.52, 95%CI=0.25-1.10). When evaluated by MZL subtype, pts with EMZL had a significantly longer PFS with M-R (p=0.01), while those with NMZL and SMZL did not (p=0.41 and 0.10, respectively). When examining the type of first-line IC, pts receiving RCHOP/RCVP had a prolonged PFS with M-R (p=0.03), whereas the difference was not statistically significant after BR (p=0.12). There was no difference in OS overall (p=0.09; adjusted HR=0.55, 95%CI=0.12-2.60) or in any subgroup. Among pts who received first-line R, there were no statistically significant differences in PFS (p=0.70; adjusted HR=0.99, 95%CI=0.59-1.66) or OS (p=0.17) based on the receipt of M-R, either in the entire cohort or any subset. A total of 14 transformation events occurred during the study, including 3 in the M-R group. The cumulative incidence of HT did not significantly differ between the two groups (sub-HR=0.76, 95%CI=0.21-2.82, p=0.68). Discussion In this large retrospective cohort study, the use of M-R in MZL was primarily influenced by local preferences, the quality of response after initial treatment, and the type of IC regimen. Receipt of M-R was associated with a longer PFS for pts receiving first-line IC, especially for those with EMZL and those receiving RCHOP/RCVP. These findings suggest a PFS advantage of M-R in EMZL, which is a novel observation. However, this advantage was not observed in terms of OS or the rate of HT. M-R after initial R did not show any significant differences in outcomes for MZL.

Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Relapsed / Refractory Marginal Zone Lymphoma: Results from Phase 1/2 BRUIN Study

Background: Marginal zone lymphoma (MZL) is an indolent lymphoma that is typically treated with chemoimmunotherapy, but often requires sequential therapy. Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) are increasingly being used in the relapsed or refractory (R/R) setting, but options for pts with MZL after cBTKi therapy may be limited. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable once daily oral pharmacology that enables continuous BTK inhibition throughout the dosing interval, regardless of intrinsic rate of BTK turnover. Pirtobrutinib has demonstrated promising efficacy and tolerability in pts with poor-prognosis B-cell malignancies following prior therapy, including prior cBTKi. Pirtobrutinib is approved in the USA to treat R/R mantle cell lymphoma after at least two lines of systemic therapy including prior BTKi treatment. Here we report the safety and efficacy of pirtobrutinib in pts with MZL from the BRUIN study (NCT03740529). Methods: Pts with previously treated B-cell malignancies, including MZL, were eligible for pirtobrutinib monotherapy treatment in either the dose escalation or expansion portion of the multicenter, phase 1/2 BRUIN study. MZL diagnosis required local pathologic review of an adequate biopsy. Endpoints include overall response rate (ORR) assessed by investigator per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. A 05 May 2023 data cut was used. Results: Among the 36 pts with MZL, 34 (94%) received the recommended phase 2 dose of pirtobrutinib, 200mg once daily.Pts had a median age of 68 (range 22-83), a majority were female (56%, n=20), and median prior lines of systemic therapy were 3 (range 1-10). Pts had nodal (47%, n=17), splenic (36%, n=13), and extranodal (17%, n=6) MZL subtypes. Most pts had Ann Arbor stage III/IV disease (81%, n=29). Most pts were in high risk MALT-IPI group (53%, n=19), 10 (28%) were intermediate, 1 (3%) was low, and missing in 6 (17%) pts. Baseline LDH was elevated in 15 (42%) pts and hemoglobin was &amp;lt;12 g/dL in 29 (81%) pts. All 36 MZL pts were previously treated with an anti-CD20 antibody, and 31 (86%) pts had received prior chemotherapy. Of the 26 pts (72%) with MZL who received a prior cBTKi, 20 (77%) pts discontinued due to progressive disease (PD) and 6 (23%) discontinued due to toxicity/other. Median time on treatment was 9 months (range 1.1-40.8), with 15 (47.1%) pts still receiving pirtobrutinib. The ORR of the MZL cohort was 50% (95% confidence interval [CI], 32.9- 67.1), including 1 (2.8%) complete response, 17 (47.2%) partial responses ( Figure). There were 15 (41.7%) pts with stable disease. The ORR in pts with nodal, splenic, and extranodal MZL were 58.8% (95%CI, 32.9-81.6), 30.8% (95%CI, 9.1-61.4), and 66.7% (95%CI, 22.3-95.7), respectively. The ORR for MZL pts with prior cBTKi therapy was 46.2% (95%CI, 26.6-66.6). With a median follow-up time of 17.6 months, median DOR was 12.7 months (95%CI, 5.6-non-estimable [NE]). Median PFS was 16.5 months (95%CI, 7.43-22.1) with a median follow up of 15.8 months. With a median follow up of 21.5 months, the median OS was NE (95%CI, 27.6-NE) and the 24-mo OS rate was 77.5% (95%CI, 56.3-89.3). In the MZL cohort, the most frequent treatment-emergent adverse events (TEAE) of any grade regardless of attribution were diarrhea (36.1%, n=13), fatigue (33.3%, n=12), and contusion (30.6%, n=11). Grade ≥3 hemorrhage/hematoma was not observed, and any grade hypertension (5.6%, n=2) was infrequent. No atrial fibrillation/flutter was observed. The most frequent grade ≥3 TEAE was neutropenia/neutrophil count decreased (27.8%, n=10) and anemia (13.9%, n=5). Treatment-related AE led to dose reductions in 4 pts (11.1%) and pirtobrutinib discontinuation in 2 (5.6%) pts (diarrhea and platelet count decreased/neutropenia). No fatal TEAEs were observed. Conclusions: In this cohort of heavily pre-treated R/R MZL pts, pirtobrutinib showed preliminary efficacy and was well tolerated with low rates of discontinuation.Pirtobrutinib appears to be a promising therapeutic option after cBTKi treatment in R/R MZL pts.

Impact of Diagnosis to Treatment Interval on Outcomes in Patients with Newly Diagnosed Marginal Zone Lymphoma - a US Multisite Study

Introduction Diagnosis to treatment interval (DTI) is an important prognostic factor in patients with newly diagnosed diffuse large B-cell lymphoma (Maurer M et al, JCO 2018) and mantle cell lymphoma (Epperla N et al, Blood Adv 2023) where patients with shorter DTI consistently show inferior survival. In marginal zone lymphoma (MZL), the use of first-line bendamustine and rituximab (BR) therapy may enhance progression-free survival (PFS) compared to cyclophosphamide-based regimens such as RCHOP/RCVP. However, the differences in outcomes may be influenced by other factors, such as the DTI, especially in observational studies. Until now, the prognostic significance of DTI in MZL has not been explored. Therefore, our objective was to assess the impact of DTI on outcomes for patients with newly diagnosed MZL. Methods This is a substudy of a previously reported multicenter, retrospective cohort that included adult MZL patients treated at 10 US medical centers on or after 1/1/2010. In this substudy, we included patients who initiated first-line BR, RCHOP, or RCVP within 120 days of diagnosis. Patients who were on observation or received antibiotics, local therapy (surgery or radiation therapy), or rituximab monotherapy were excluded. DTI was defined as the number of days from the MZL diagnosis to the start of immunochemotherapy (IC). Using concordance statistics for different DTI cutoffs, we determined 60 days as optimal for analysis. Patients who received treatment within 60 days from their diagnosis were classified into the short DTI group. To compare clinical characteristics between the two groups, univariable and multivariable (MV) logistic regression analyses were performed, accounting for missing data through multiple imputations. The primary endpoint of this analysis was PFS, while secondary endpoints included overall survival (OS) and the cumulative incidence of histologic transformation (HT). Predictors of PFS and OS were identified using Cox regression analysis. Results Of the 900 patients with newly diagnosed MZL included in the main study, 177 patients met the inclusion criteria and were included in this analysis, including 144 (81%) in the short DTI group and 33 (19%) in the long DTI group. The median time to treatment initiation was 27 days (range: 1-60) for the short DTI group and 81 days (range: 61-112) for the long DTI group. The median age was 61 years with 43% EMZL (n=77), 38% NMZL (67), and 19% SMZL (33) patients. Among the patients, 75% received BR as first-line treatment followed by R-CHOP (15%), and R-CVP (10%). A higher proportion of patients in the short DTI group had B symptoms compared to long DTI group (27% vs 3%, p=0.03, respectively). No significant differences were observed between the two groups in regard to MZL subtype, ECOG performance status, stage, LDH, or the choice of first-line IC. In the MV model, presence of B symptoms remained significantly associated with short DTI (OR=12.63, p=0.02). Short DTI was not associated with a statistically different PFS in a univariable assessment (HR=0.86, 95%CI=0.47-1.56), or in the MV model, adjusting for other prognostic factors (aHR=0.87, 95%CI=0.47-1.61, p=0.65, Figure 1A), while high LDH (aHR=2.07, 95%CI=1.06-4.07, p=0.034) and low albumin (aHR=2.31, 95%CI=1.10-4.85, p=0.027) at diagnosis were associated with significantly inferior PFS in the MV model. Additionally, the MV model indicated that patients who received BR had significantly better PFS compared to those who received R-CHOP/RCVP (aHR=0.50, 95% CI=0.29-0.86, p=0.01, Figure 1B). Short DTI was not associated with inferior OS in either univariable or MV models (MV: aHR=0.74, 95%CI=0.26-2.08, p=0.57). There were 12 transformation events in the study: 8 in the short DTI group and 4 in the long DTI group. The cumulative incidence of HT was not significantly different between the two groups (10-year CIF 13% versus 12%, respectively, p=0.22). Conclusion In MZL, a short DTI does not correlate with an inferior prognosis, despite being associated with certain unfavorable characteristics such as the presence of B symptoms. This lack of prognostic utility of DTI in newly diagnosed MZL, in contrast to aggressive B-cell lymphomas, may be intrinsically linked to the underlying biology of the disease. Furthermore, the observed improvement in PFS with BR compared to RCHOP/RCVP, as demonstrated in clinical trials like STiL and BRIGHT, cannot be attributed to differences in DTI.

Chemokine receptor–targeted PET/CT provides superior diagnostic performance in newly diagnosed marginal zone lymphoma patients: a head-to-head comparison with [18F]FDG

BackgroundIn patients with marginal zone lymphoma (MZL), [18F]FDG PET/CT provided inconsistent diagnostic accuracy. C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in MZL and thus, may emerge as novel theranostic target. We aimed to evaluate the diagnostic performance of CXCR4-targeting [68Ga]Ga-PentixaFor when compared to [18F]FDG PET/CT in MZL.MethodsThirty-two untreated MZL patients (nodal, n = 17; extranodal, n = 13; splenic, n = 2) received [68Ga]Ga-PentixaFor and [18F]FDG PET/CT within median 2 days. We performed a visual and quantitative analysis of the total lymphoma volume by measuring maximum/peak standardized uptake values (SUVmax/peak), and calculating target-to-background ratios (TBR, defined as lesion-based SUVpeak divided by SUVmean from blood pool). Visual comparisons for both radiotracers were carried out for all target lesions (TL), and quantitative analysis of concordant TL evident on both scans. Last, MZL subtype analyses were also conducted.ResultsOn a patient-based level, [68Ga]Ga-PentixaFor identified MZL manifestations in 32 (100%) subjects (vs. [18F]FDG, 25/32 [78.1%]). Of the 256 identified TL, 127/256 (49.6%) manifestations were evident only on CXCR4-directed imaging, while only 7/256 (2.7%) were identified on [18F]FDG but missed by [68Ga]Ga-PentixaFor. In the remaining 122/256 (47.7%) concordant TL, [68Ga]Ga-PentixaFor consistently provided increased metrics when compared to [18F]FDG: SUVmax, 10.3 (range, 2.53–37.2) vs. 5.72 (2.32–37.0); SUVpeak, 6.23 (1.58–25.7) vs. 3.87 (1.54–27.7); P < 0.01, respectively. Concordant TL TBR on [68Ga]Ga-PentixaFor (median, 3.85; range, 1.05–16.0) was also approximately 1.8-fold higher relative to [18F]FDG (median, 2.08; range, 0.81–28.8; P < 0.01). Those findings on image contrast, however, were driven by nodal MZL (P < 0.01), and just missed significance for extranodal MZL (P = 0.06).ConclusionsIn newly diagnosed MZL patients, [68Ga]Ga-PentixaFor identified more sites of disease when compared to [18F]FDG, irrespective of MZL subtype. Quantitative PET parameters including TBR were also higher on [68Ga]Ga-PentixaFor PET/CT, suggesting improved diagnostic read-out using chemokine receptor-targeted imaging.

Transformation to diffuse large B-cell lymphoma and its impact on survival in patients with marginal zone lymphoma: A population-based study.

Some patients with marginal zone lymphoma (MZL) experience histological transformation to diffuse large B-cell lymphoma (DLBCL). Because of the paucity of long-term data on transformation, we conducted a population-based study to estimate the risk of transformation and its impact on survival in MZL. Using the Surveillance, Epidemiology and End Results database, we identified 23 221 patients with histology-proven MZL between 2000 and 2018. Competing risk method, Kaplan-Meier and Cox proportional hazards regression were performed to analyze time-to-event outcomes. Based on 420 events of transformation, the 10-year cumulative incidence rate of transformation is 2.23% (95% CI: 2.00%-2.46%) in MZL, 1.5% (95% CI: 1.3%-1.8%), 2.7% (95% CI: 2.3%-3.2%) and 5.8% (95% CI: 4.6%-7.1%) in extranodal, nodal and splenic MZL (EMZL, NMZL and SMZL), respectively. Patients with SMZL (subdistribution hazard ratio [SHR], 2.96; 95% CI: 2.21-3.96) or NMZL (SHR, 1.49; 95% CI: 1.17-1.90) have a higher risk of transformation than those with EMZL. For each MZL subtype, patients with transformation had a significantly shorter overall survival. Patients with transformation >18 months since MZL diagnosis had longer OS than those who presented within 18 months (5-year rate, 87.4% [95% CI: 83.7%-91.2%] vs 47.9% [95% CI: 38.8%-59.0%]; P < .001). Compared to patients with matched de novo DLBCL, those whose DLBCL was transformed from MZL had a shorter OS (5-year rate, 56.6% [95% CI: 51.9%-61.8%] vs 46.1% [95% CI: 40.9%-51.9%]; P < .001). We concluded that patients with SMZL had the highest risk of transformation. Regardless of MZL subtype, transformation resulted in significantly increased mortality.

Comparative efficacy of zanubrutinib (ZANU) versus rituximab (RTX) in relapsed marginal zone lymphoma (MZL): Matching-adjusted indirect comparison (MAIC).

e19526 Background: ZANU is a Bruton tyrosine kinase inhibitor that has been evaluated for relapsed/refractory MZL in two phase 2, single-arm (MAGNOLIA, n=66, NCT03846427; BGB-3111-AU-003, n=20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. Here, we conducted an unanchored MAIC to estimate relative treatment effects of ZANU vs RTX, a commonly used treatment for patients with relapsed MZL. Note the comparison was restricted to the relapsed population because RTX refractory patients would not be retreated with RTX. Methods: The MAIC was performed using pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. Study level-data of RTX in relapsed patients were used from CHRONOS-3 (Özcan et al., Ann Oncol 2021) which was identified as the most suitable comparator study via a systematic literature review. A logistic propensity score model was used to estimate weights for patients in ZANU trials such that their weighted mean baseline characteristics matched those of CHRONOS-3. The following characteristics were identified as key prognostic factors and included in the base case propensity score model: prior lines of therapy, MZL subtype, relapse after prior therapy, and age. Sensitivity analyses incorporating additional characteristics were not possible owing to a lack of reporting from CHRONOS-3, but the impact of each covariate in the base model was explored via a leave-one-out analysis. Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models, with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% CIs. Results: After applying weights estimated from the base case propensity score model, the effective sample size (ESS) for ZANU was 39. ZANU reduced the risk of progression (HR 0.29; 95% CI 0.13–0.65) and had a higher probability of response (OR 5.09; 95% CI: 1.84–14.08) when compared with RTX (Table). OS was comparable for ZANU and RTX, which is consistent with the survival expectancy for indolent lymphomas. The leave-one-out analysis showed that removing any of the characteristics from the propensity score model yielded comparable results. Conclusions: MAIC results suggest ZANU is associated with improved PFS and ORR compared with RTX in relapsed MZL. [Table: see text]

Transformation and survival in marginal zone lymphoma: a Finnish nationwide population-based study

Marginal zone lymphoma (MZL) is an indolent B-cell malignancy with heterogeneous anatomical and clinical presentation. While MZLs are generally associated with long survival, some patients experience histological transformation to aggressive large B-cell lymphoma. Population-based long-term data on the transformation of MZL is limited. We conducted a nationwide population-based study to estimate the risk of transformation and relative survival in patients diagnosed with MZL in Finland from 1995–2018. We identified a total of 1454 patients with MZL from the Finnish Cancer Registry (FCR). The cumulative incidence of transformation was 4.7% (95% CI, 3.6−6.2) at 10 years. The highest incidence of transformation was observed in the patients with splenic MZL (14.0%; 95% CI, 8.6−22.7). The transformation was associated with a substantially increased risk of death (HR, 5.18; 95% CI, 3.58–7.50). Ten-year relative survival was 79% (95% CI, 73‒83%). Transformation, nodal MZL subtype, and older age at diagnosis were associated with increased excess mortality, whereas patients diagnosed at a later calendar period had a lower excess risk of death. We conclude that transformation resulted in a substantially increased mortality irrespective of MZL subtype compared with the patients without transformation. Our results also suggest a reduction in excess mortality in recent years.

Study of the Utility of Myeloid Cell Nuclear Differentiation Antigen (MNDA) in the Diagnosis of Marginal Zone Lymphoma.

Myeloid cell nuclear differentiation antigen (MNDA) is normally expressed on myelomonocytic cells and a subset of B lymphocytes. It was found to be differentially expressed between nodal marginal zone lymphoma (MZL) and follicular lymphoma (FL). However, MNDA has not been widely used as a diagnostic marker in clinical practice. To validate its utility, we studied the expression of MNDA by immunohistochemistry in 313 cases of small B-cell lymphomas. Our results showed that MNDA was positive in 77.9% of MZL, 21.9% of mantle cell lymphoma, 28.9% of small lymphocytic lymphoma/chronic lymphocytic leukemia, 2.6% of FL, and 25% of lymphoplasmacytic lymphoma. MNDA positivity varied from 68.0% to 84.0% among the 3 MZL subtypes, with extranodal MZL having the highest percentage. There was a statistically significant difference in MNDA expression between MZL and FL, mantle cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, or lymphoplasmacytic lymphoma. CD43 expression was slightly more frequent in MNDA-negative MZL than in MNDA-positive MZL. Combined use of CD43 and MNDA improved the diagnostic sensitivity for MZL from 77.9% to 87.8%. There was a trend of positive correlation between MNDA and p53 in MZL. In conclusion, MNDA is preferentially expressed in MZL among small B-cell lymphomas and it is a useful marker for the differentiation of MZL and FL.

Predictive Value of Staging PET/CT to Detect Bone Marrow Involvement in Marginal Zone Lymphoma (MZL): An Analysis from LEO MZL Working Group

Introduction: Bone marrow (BM) involvement impacts stage and prognosis in lymphoma, remaining an important factor in risk-stratification scores, including the MALT-IPI. PET/CT is routinely implemented in the staging and response assessment of patients with lymphoma. However, FDG avidity to detect marginal zone lymphoma (MZL) remains debatable. In this study we aimed to assess the predictive value of PET/CT to detect BM involvement and survival implications in MZL using prospectively collected data from the Lymphoma Epidemiology of Outcomes (LEO) cohort. Methods: The LEO cohort is a prospective cohort from 8 academic cancer centers in which patients are enrolled within 6 months of lymphoma diagnosis and followed. We extracted baseline data of MZL patients enrolled in the LEO cohort between 5/2015 and 2/2020. BM biopsy was used as a gold standard for BM involvement. In addition, radiology reports were reviewed for PET/CT-suggested BM involvement. Event-free survival (EFS) defined as time from diagnosis to relapse/progression, retreatment, or death due to any cause and overall survival (OS) defined as time from diagnosis to death due to any cause were estimated by Kaplan-Meier. Results: Of 706 MZL patients enrolled in LEO, 311 (44%) with data on BM status by both biopsy and PET/CT were included in the analysis. Patients’ characteristics were median age 64 (range 24-89) years with most <70 years (n=217, 69.8%), non-Hispanic (n=264, 84.9%) white (n=276, 88.7%), without B symptoms (n=246, 79.1%), and normal LDH (n=185, 59.5%). The most common MZL subtype was extranodal (EMZL, n=208, 66.9%) followed by nodal (NMZL, n=61, 19.6%) and splenic (SMZL, n=42, 13.5%). Stage distribution was as follows: early-stage (I-II; n=134, 43.1%), advanced-stage (III-IV; n=159, 51.1%), and unknown (n=18, 5.8%). BM biopsy was positive in 99 (31.8%) and negative in 212 (68.2%) patients. Across all MZL subtypes, biopsy-proven and PET/CT-suggested BM involvement was present in 11.6% (n=36/311), and positive BM biopsy with negative PET/CT was observed in 20.3% (n=63/311) (EMZL=9.6%, n=20/208; NMZL=31.1%, n=19/61; and SMZL=57.1%, n=24/42). For EMZL, 15.9% (n=33) demonstrated pathologically confirmed BM involvement, and among those patients PET/CT was positive in 39.4% (n=13) and negative in 60.6% (n=20). For NMZL, 50.8% (n=31) demonstrated pathologically confirmed BM involvement, and among those patients PET/CT was positive in 38.7% (n=12) and negative in 61.3% (n=19). Most patients (83.3%, n=35) with SMZL demonstrated pathologically confirmed BM involvement, with positive PET/CT in 31.4% (n=11) and negative in 68.6% (n=24). Considering BM result from biopsy as the standard, PET/CT-based sensitivity and specificity in EMZL, NMZL, and SMZL were 39.4% & 98.9%, 38.7% & 100%, and 31.4% & 100%, respectively. PET/CT-based positive and negative predictive values in EMZL, NMZL, and SMZL were 86.7% & 89.6%; 100% & 61.2%; and 100% & 22.6%, respectively. With a median follow up of 35.4 months there were 70 EFS events and 18 OS events across all MZL subtypes. The 2-year EFS and OS were 81.7% (95%CI 76.8-85.7%) and 96.8% (95%CI 93.9-98.3%), respectively. The 2-year EFS and OS by histology were EMZL= 84.7% (95%CI 78.7-89.1%) & 97.2% (95%CI 93.5-98.8%); NMZL= 69.6% (95%CI 56.1-79.6%) & 96.5% (95%CI 86.9-99.1%); and SMZL= 85.6% (95%CI 70.7-93.3%) & 95.2% (95%CI 82.3-98.8%), respectively. Acknowledging the low number of events and unspecific criteria for treatment selection, those patients exhibiting pathological BM involvement (n= 99) did not show significantly different EFS (p=0.097) (EMZL p=0.48; NMZL p=0.68; and SMZL p=0.75, respectively) or OS (p=0.978) (EMZL p=0.46; NMZL=0.53; and SMZL=0.21, respectively) compared to those without BM disease. Conclusions: While PET/CT may be positive in nodal and some extranodal locations, assessment of BM involvement by PET/CT is characterized by a low sensitivity across all MZL subtypes and low negative predictive value in SMZL, underscoring the limitations of current Lugano criteria in staging MZL. With currently relatively limited follow-up, we did not observe significantly different survival based on BM status.

Assessing the Epidemiology, Treatment Patterns, and Economic Impact of Marginal Zone Lymphoma: A Review of the Literature

Background Marginal zone lymphoma (MZL) is a heterogenous group of lymphomas caused by malignant transformation of marginal zone B-cells, further classified into three subtypes: extra-nodal marginal zone lymphoma (EMZL), splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL). In 2013, 5-year relative survival rates were reported at 88.7%, 79.7% and 76.5% for EMZL, SMZL and NMZL, respectively (US SEER database). Aims and objectives Evidence regarding incidence, treatment pattern, and associated cost for MZL is lacking. This study aims to evaluate the current evidence for epidemiology, treatment patterns, and economic burden associated with MZL. Methods Epidemiology and treatment pattern searches were conducted in Embase and Medline-in-process databases (January 2011-February 2022), by a single reviewer and validated by an independent reviewer; STROBE checklist used for critical appraisal. The economic search also included the Cochrane database (up to February 2022), conducted by two reviewers with a third to resolve discrepancies; Adapted Drummond's checklist used for critical appraisal. Relevant conferences websites were also searched. Reviews focused on adult patients with treatment naïve or relapsed/refractory (r/r) MZL. Results Of the 9089 records retrieved, 91 studies for epidemiology, 32 studies for treatment patterns (RWE: 20, treatment guidelines: 12), and 10 economic studies were included. The studies showed that MZL incidence varied by geographic location (0.5-2.6 per 100,000); and overall incidence of MZL increased over time. The incidence rate was reportedly higher for developing countries vs. western developed countries, older vs. younger patients, and patients of white race vs. other races. Among the MZL population, incidence rate per 100,000 was highest for EMZL/MALT (1.1-1.59), followed by NMZL (0.12-0.83) and SMZL (0.13-0.25). Site-specific incidence per 100,000 was highest for stomach MALT (0.13-0.44). The 5-year relative survival rates for MZL ranged from 61.2-92% and were generally higher in EMZL/MALT patients vs. other subtypes/overall MZL population. Guideline recommendations for patients with MZL consist of a combination of different therapies including radiotherapy, chemotherapy, immunotherapy and surgery. BTK inhibitors (ibrutinib, zanubrutinib), and rituximab-based combinations are recommended in r/r MZL. Analysis of real-world treatment patterns revealed rituximab±chemotherapy was the most prescribed systemic treatment across all lines of therapy. Common 1L non-systemic treatments included surgical resection (17-100%) and radiation therapy (1.2-86.8%). H. pylori eradication therapy was the most common 1L approach for H. pylori +ve gastric MALT patients. Treatment patterns for patients in subsequent lines were sparsely reported. A large US study (n=1162) reported that MZL patients not receiving an NCCN-recommended agent increased by LOT: 1L (11%), 2L (25%), and 3L (29%); 51% of MZL patients also received no systemic therapy. Studies reporting OS/PFS outcomes (n=4) and response rates (n=6) in real-world patients were limited and predominantly in the 1L setting (Table 1). Economic studies covered North America and APAC, assessing different measures of economic burden, in MZL sub-populations. No clear trends were observed for costs or resource use by the line of therapy. Overall cost of treatment and AE management was low for BTKi vs. immunotherapy/chemotherapy. Rituximab+bendamustine was shown to be a cost-effective treatment for MZL in Canada, but in the US it incurred greater costs and healthcare resource utilization vs. rituximab monotherapy - potentially indicative of their differing AE profiles. Conclusion Whilst MZL incidence varies by geography, incidence rates over time indicate a growing patient population, where the disease and economic burden will continue to increase. The 5-year relative survival rates are highest in EMZL/MALT patient subpopulations, but novel treatments are required across sub-types of MZL. Treatment patterns appear generally reflective of current guidelines, but systemic therapy was heavily reliant on rituximab-based treatment options. Evidence from the US reported that the need for novel therapies increases by LOT, but to further characterize real-world outcomes and treatment pathways in MZL (in particular r/r patients), additional studies are required. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epidemiology and Prognostic Index of Ocular Adnexal Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT) in Thailand: Results from the Thai Lymphoma Study Group (TLSG)

Introduction Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is the most common subtype of marginal zone lymphoma (MZL) in Thailand. Results from the TLSG showed that almost half of the patients were ocular adnexal subtype (49.2%). However, there has been no validated prognostic index to predict outcome in these patients. Objectives This study aimed to describe epidemiology and develop prognostic index for ocular adnexa MALT lymphoma in Thai population. Methods Data from the TLSG were collected during January 2007 to March 2022. Patients who were diagnosed with ocular adnexa MALT lymphoma were enrolled. Demographic data including age, performance status (Eastern Cooperative Oncology Group; ECOG), stage of disease, lactate dehydrogenase (LDH), number of extranodal sites, presence of B symptoms and hepatitis profile were collected. Univariate and multivariate analyses were performed by using Cox regression. Parameters found to be associated with progression-free survival (PFS) and overall survival (OS) in multivariate analysis were used to perform prognostic index. Kaplan-Meier survival curves were analyzed to predict PFS and OS stratified by this prognostic index. Results Two hundred twenty-five patients were enrolled to this study. Male was predominantly affected (60.4%). Median age at diagnosis was 59 years (range: 28-87). Most of the patients (216, 96%) had good performance status (ECOG 0-1). Thirty-three patients (14.3%) had more than 1 extranodal sites. Thirty-five patients (15.6%) had high LDH at first diagnosis of lymphoma. Approximately half of the patients (116, 51.6%) were treated with chemotherapy. Twenty-three patients (10.2%) received immunotherapy (rituximab). Seventy-eight patients (34.7%) were radiated alone but only 3 patients (1.3%) in this registry underwent only surgery for treatment of ocular adnexa MALT lymphoma. Three parameters (age >65 years, ECOG 2-4, and advanced stage) were found to be potentially affecting survival in multivariate analysis. The prognostic index was categorized into low, intermediate, and high risk, according to the number of these parameters (0, 1, ≥ 2, respectively). Estimated 4-year OS for low-, intermediate- and high-risk groups were 97.4%, 90.9% and 77.9%, respectively, as shown in figure 1A (p-value=0.011). Estimated 4-year PFS for low-, intermediate- and high-risk groups were 82.5%, 69.2% and 55.4%, respectively (p-value=0.053), as shown in figure 1B. Conclusions This prognostic index can statistically discriminate among patients with ocular adnexa MALT lymphoma into low-, intermediate- and high-risk groups by OS. Although PFS can be stratified into 3 groups from this prognostic index, it has no statistical significance. Longer time of follow-up and more numbers of patients may result in statistical significance in near future. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Circulating Lymphoma at Diagnosis on Outcomes in Patients with Marginal Zone Lymphoma

Introduction Marginal zone lymphoma (MZL) is an indolent B-cell non-Hodgkin lymphoma that includes 3 subtypes: extranodal marginal zone lymphoma (EMZL) of the mucosa-associated lymphatic tissue (MALT), splenic MZL (SMZL), and nodal MZL (NMZL). Although flow cytometry can detect circulating lymphoma cells in many cases of MZL, outside of case reports and small case series, the relevance of this circulating lymphoma (CL) in patients with MZL at diagnosis is largely unknown. Hence, we sought to evaluate the impact of CL at diagnosis on outcomes in patients with MZL. Methods This multicenter, retrospective cohort study of MZL patients treated at 3 US medical centers included patients who were ≥18 years old, diagnosed with MZL from 2010-2020, and had peripheral blood flow cytometry performed at diagnosis. Patients who never received therapy for MZL were excluded. Patients were classified according to positive or negative flow cytometry results as CL+ and CL-, respectively. The primary endpoint was progression-free survival (PFS) defined as the time from the start of first-line therapy until lymphoma relapse/progression or death from any cause, censoring at the last clinical assessment. Secondary endpoints were overall survival (OS, from the start of first-line therapy until death or last follow-up) and time from diagnosis to systemic therapy in CL+ and CL- groups. Results Among 294 eligible patients with newly diagnosed MZL, 75 (25%) had detectable CL at diagnosis. The CL+ group had a higher median age (66 vs 63 years), advanced-stage disease (100% vs 53%), bone marrow involvement (91% vs 35%), elevated LDH (49% vs 22%), lower albumin (24% vs 13%), and less often received R-chemotherapy (39% vs 41%) compared to the CL- group. SMZL constituted the predominant subtype (52%, n=39) in the CL+ group with NMZL and EMZL constituting 24% each (n=18). The median PFS was not significantly different between the CL+ (6.2 years, 95%CI=3.6-NR) and CL- (5.9 years, 95%CI=4.3-8.4), p=0.73 (Figure 1) groups. Similar results were noted across the MZL subtypes with no significant difference in median PFS in EMZL (p=0.51), NMZL (p=0.51), or SMZL (p=0.38) according to the CL status. The median PFS was not significantly different between CL+ and CL- groups among patients treated with rituximab monotherapy (median PFS 4.1 vs 3.2 years, respectively, p=0.69) or immunochemotherapy (median PFS NR vs 8.7 years, respectively, p=0.84, Figure 2). After adjusting for factors associated with PFS in multivariate cox regression (age, B symptoms, albumin level, LDH>ULN, and type of first-line treatment regimen), there was no difference in PFS between CL+ and CL- groups (HR=0.73, 95%CI=0.45-1.20, p=0.22). We did not observe a significant difference in OS between the CL+ and CL- groups with a 5-year rate of OS being 89% vs 82% in the CL+ and CL- groups (p=0.31). Furthermore, the time from diagnosis to systemic therapy initiation did not significantly differ between the CL+ and CL- groups with % of patients who started treatment at 1, 3, and 5 years from diagnosis being 83% vs 92%, 95% vs 96%, and 97% vs 99%, respectively (p=0.42). Conclusions This is the first study to compare the outcomes of patients with CL+ and CL- groups in newly diagnosed MZL. In this largest study to date evaluating the prognostic relevance of CL in patients with MZL, we found that CL at diagnosis was not associated with shorter PFS, OS, or time from diagnosis to first-line therapy. Further studies should evaluate whether the presence of CL is associated with specific molecular or other clinically relevant markers that were not available in our patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Monoclonal Protein at Diagnosis on Outcomes in Patients with Marginal Zone Lymphoma: A Multicenter Cohort Study

Introduction Marginal zone lymphoma (MZL) is an indolent B-cell non-Hodgkin lymphoma that includes 3 subtypes: extranodal marginal zone lymphoma (EMZL) of the mucosa-associated lymphatic tissue (MALT), splenic MZL (SMZL), and nodal MZL (NMZL). Outside of case reports and small case series, the relevance of monoclonal protein (M-protein) in patients with MZL at diagnosis is largely unknown. Hence, we sought to evaluate the impact of M-protein at diagnosis on outcomes in patients with MZL. Methods This multicenter, retrospective cohort study of MZL patients treated at 8 US medical centers included patients who were ≥18 years old, diagnosed with MZL from 2010-2020, and had information on M-protein at diagnosis. Patients who were on observation or received antibiotics only were excluded. Patients were grouped according to the presence or absence of M-protein detectable by serum protein electrophoresis or immunofixation. The primary endpoint was progression-free survival (PFS). Secondary endpoints were time from diagnosis to systemic therapy, cumulative incidence of relapse in stage 1 disease after local treatment (surgery or radiation therapy), and cumulative incidence of transformation in M-protein versus no M-protein groups. PFS was defined as the time from the start of first-line therapy until lymphoma relapse/progression or death from any cause, censoring at the last clinical assessment. Results Among 501 eligible patients with newly diagnosed MZL, 152 (30%) had detectable M-protein at diagnosis and 349 (70%) did not. Among those with M-protein, 59% (n=90) had IgM, 29% (n=44) had IgG, 3% (n=4) had both IgM and IgG, and 9% (n=14) had non-IgM/non-IgG M-protein and light chains. Patients in the M-protein group had a higher median age (66 vs 61 years), more advanced stage disease (76% vs 53%), lower albumin (27% vs 15%), and were more likely to receive R-chemotherapy (39% vs 23%) compared to no M-protein group. The median PFS was 3.2 years (95%CI=2.1-5.6) in the M-protein group compared to 6.6 years (95%CI=5.4-NR) in the no M-protein group (log-rank p<0.001; Figure 1) with a 3-year and 5-year PFS rates of 51% and 44% in the M-protein gp versus 74% and 59% in the no M-protein groups. In order to determine if the M-protein was independently associated with PFS, we performed Cox regression analysis in only those who received systemic therapy at diagnosis (n=377). After adjusting for factors associated with PFS in univariate analysis (age, MZL subtype, ECOG PS, albumin level, LDH>ULN, and first-line treatment regimen), M-protein remained associated with significantly inferior PFS (HR=1.80, 95%CI=1.24-2.62, p=0.002) in the multivariable analysis. There was no difference in PFS based on the type of M-protein at diagnosis (IgM vs IgG, p=0.88). M-protein group treated with rituximab monotherapy had significantly shorter PFS compared to no M-protein group (1.9 years versus 4.3 years, p<0.001, Figure 2), however, there was no significant difference in PFS among patients treated with bendamustine and rituximab (BR, 6.1 years versus NR, p=0.14). In the EMZL subset (n=101) treated with local therapy (surgery or radiation), PFS did not significantly differ by presence/absence of M-protein at diagnosis (p=0.53). There was no difference in the time from diagnosis to systemic therapy initiation between the M-protein and no M-protein groups with % of patients who started treatment at 1, 3, and 5 years being 89% vs 86%, 96% vs 94%, and 99% vs 98%, respectively (p=0.21). The cumulative incidence of relapse in stage 1 disease (n=144) among the recipients of local therapy was not significantly different between the M-protein and no M-protein groups (p=0.10). The cumulative incidence of transformation was significantly higher in the M-protein group compared to no M-protein group with 3-, 5-, and 10-year rate of transformation being 5.6% vs 0.6%, 8.9% vs 1.3%, and 14% vs 1.3%, respectively (p=0.001). Conclusions In this study (to our knowledge, the largest to date) of the prognostic relevance of M-protein in MZL, we found that M-protein at diagnosis was associated with shorter PFS and a higher risk of histologic transformation. Because the PFS difference was not observed after BR, immunochemotherapy may be a preferred approach over rituximab monotherapy in this group and needs to be explored further. M-protein in stage 1 EMZL was not associated with shorter PFS after standard local therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Relapse within 24 Months after Frontline Systemic Therapy (POD24) Is Associated with Worse Survival in Patients with Marginal Zone Lymphoma: A US Multisite Study

Introduction Marginal zone lymphoma (MZL) is an indolent B-cell non-Hodgkin lymphoma with heterogeneous practice patterns. Early relapse after diagnosis in MZL has been associated with poor outcomes in one European study (Luminari et al, Blood 2019) which included only patients requiring immediate therapy for MZL and defined early relapse as lymphoma progression within 24 months (POD24) from diagnosis rather than from the initiation of systemic therapy. In contrast, many patients with MZL do not require immediate therapy, and time from diagnosis to treatment may be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse (POD24) defined as relapse/progression within 24 months from systemic therapy initiation in a large US cohort. Methods This multicenter, retrospective cohort study of MZL patients treated at 8 US medical centers included patients who were ≥18 years old, diagnosed with MZL from 2010-2020, and had information on treatment at diagnosis. Patients who never received systemic therapy, or those who received only antibiotics, radiation, and surgery were excluded. Patients were grouped into POD24 and non-POD24 groups. The primary endpoint was overall survival (OS). Secondary endpoints were determining the predictive factors for POD24 and cumulative incidence of histologic transformation in POD24 vs non-POD24 groups. Survival analysis according to POD24 was only calculated for patients with events within 24 months (early progressors). For patients without early progression, OS was computed starting from the time of systemic therapy. Patients who were censored or expired before 24 months were excluded from analysis. Results Among the 364 eligible patients with newly diagnosed MZL, 103 (28%) were in the POD24 group and 261 (72%) in the non-POD24 group. Patients in the POD24 group had a higher median age (66 vs 61 years), LDH >ULN (39% vs 25%), lower albumin (26% vs 16%), presence of monoclonal protein (49% vs 29%), and received rituximab monotherapy (R, 67% vs 52%) compared to non-POD24 group. The median OS was not reached in either group, however, the 3- and 5-year OS estimates were 80% and 73% in POD24 group compared to 97% and 91% in the non-POD24 groups, respectively (p<0.001, Figure 1). In order to determine if the POD24 was independently associated with OS, we performed Cox regression analysis. After adjusting for factors associated with OS in the multivariate analysis (age, ECOG PS, MZL subtype, LDH >ULN, first-line treatment regimen), POD24 remained associated with significantly inferior OS (HR=3.69, 95%CI=1.93-7.04, p<0.0001). Regardless of the type of first line systemic therapy (R or immunochemotherapy), POD24 group had significantly inferior OS compared to non-POD24 groups. The 3- and 5-year OS estimates for those receiving R were 80% and 75% in POD24 compared to 96% and 88% in non-POD24 (p=0.007), while the 3- and 5-year OS estimates for those receiving immunochemotherapy were 81% and 69% in the POD24 compared to 97% and 94% in the non-POD24 groups, respectively (p<0.0001, Figure 2). To determine the factors associated with POD24, we performed multinomial logistic regression analysis and found that advanced age (continuous, OR=1.03, 95%CI=1.00-1.05, p=0.04) and elevated LDH (compared to normal LDH, OR=1.96, 95%CI=1.05-3.67, p=0.03) were associated with increased odds of POD24, while those who received immunochemotherapy had lower odds of POD24 (compared to R, OR=0.46, 95%CI=0.25-0.87, p=0.02). The cumulative incidence of transformation was significantly higher in the POD24 group compared to non-POD24 group with 3- and 5-year rate of transformation being 18% vs 0% and 32% vs 1%, respectively (p<0.0001). Conclusions In this study (to our knowledge, the largest dataset to date), we show the prognostic relevance of POD24 in MZL in US patient population. Patients with POD24 regardless of the type of systemic therapy received (R or immunochemotherapy) have poor outcomes. These patients represent a high-risk subset of MZL and need to be prioritized for cellular and experimental therapies. Patients with POD24 have a significantly higher risk for histologic transformation and should be considered for a repeat biopsy at relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A roadmap for clinical trial design in marginal zone lymphoma.

Marginal zone lymphoma (MZL) is commonly underrepresented in clinical trials collectively studying mostly nodal indolent lymphomas.In this manuscript we propose new inclusion and response criteria defined by MZL subtype and disease location for those with extranodal MZL. Progression of disease within 24 months is associated with poor outcomes in MZL and future studies should assess the efficacy of novel agents in this population.

Acalabrutinib in patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL): Results of a phase 2, multicenter, open-label trial.

7549 Background: MZL is a rare indolent B-cell malignancy considered incurable at recurrent stage. Bruton tyrosine kinase (BTK) inhibitors have produced durable responses in patients (pts) with R/R MZL. Acalabrutinib (acala) is a potent next-generation BTK inhibitor with high selectivity for BTK. We report data for acala monotherapy from the R/R MZL cohort (phase 2) of a phase 1b/2 clinical trial (NCT02180711). Methods: Pts with histologically confirmed MZL, ECOG performance status ≤2, and ≥1 prior therapy (including ≥1 CD20-directed regimen) received oral acala 100 mg twice daily until disease progression or unacceptable toxicity ± R. The primary objective was overall response rate (ORR; Lugano criteria as assessed by the investigator). Secondary objectives were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively (no formal hypothesis testing). Results: Forty-two pts received acala (median age 69 y [range 42–84]; median 2 prior systemic regimens [range 1–4]). MZL subtypes were extranodal (43%), nodal (31%), and splenic (26%). At data cutoff (Oct 15, 2021), median follow-up duration was 10.7 mo (range 0.4–42.8). Sixteen (38%) pts discontinued acala, most commonly due to disease progression (26%). Among pts evaluable for response (n = 37; 3 pts had not reached the first assessment timepoint and 2 pts exited the study without response assessment), ORR was 54% (95% CI 37%–71%) with 6 complete (16%) and 14 partial (38%) responses; 17 (46%) pts had stable disease. ORRs in extranodal, nodal, and splenic subtypes were 65%, 44%, and 45%, respectively. Median time to initial response was 3.0 mo; median DOR was 19.3 mo (95% CI 8.4–not estimable). Median PFS was 27.4 mo with a 12-mo PFS rate of 66%. Four pts died (disease progression, n = 2; transformation to diffuse large B-cell lymphoma after stopping treatment, n = 1; adverse event [AE], n = 1 [septic shock unrelated to treatment]); median OS was not reached. Treatment was well tolerated with most AEs being grade 1 or 2. Sixteen pts (38%) had grade ≥3 AEs, most commonly (in ≥2 pts) anemia, dyspnea, neutrophil count decrease (n = 3 each), fatigue, thrombocytopenia, and neutropenia (n = 2 each). AEs led to treatment discontinuation in 2 pts (grade 3 hypotension and grade 1 myalgia). Among AEs of clinical interest, hypertension was reported in 2 pts (both grade 2); no cases of atrial fibrillation/flutter or major hemorrhage were reported. Conclusions: These early results indicate that acala is efficacious and well tolerated in pts with R/R MZL. The AE profile is consistent with the known safety profile of acala. Clinical trial information: NCT02180711.