Marginal Zone Lymphoma Patients Research Articles

Transformation risk and associated survival outcome of marginal zone lymphoma: A nationwide study.

Histological transformation into an aggressive B-cell lymphoma indicates a poor survival outcome for patients with indolent marginal zone lymphoma (MZL), which has been less studied. Large-scale data with long-term follow-up to investigate MZL transformation is limited. Here, by reporting a US-Nationwide cohort of 30,619 MZL patients diagnosed between 2000 and 2019, we found that transformation occurred in 2.08% (N = 624) of MZL cases, with the transformation incidence of 3.1 per 1,000 person-years. Advanced Ann Arbor stage, nodal MZL (NMZL) and splenic MZL (SMZL) were associated with an elevated risk of transformation. Certain subtype-specific characteristics, such as non-gastric extra-nodal MZL (vs. gastric, HR, 1.51, 95%CI 1.13-2.04; p = 0.006), and receiving splenectomy for SMZL (HR, 2.04, 95%CI 1.28-3.26; p = 0.003), also indicated a higher risk of transformation. Besides, transformation independently increased the overall mortality risk (HR, 1.38, 95%CI 1.24-1.53, p < 0.001), especially the higher lymphoma-caused mortality risk (HR, 3.21, 95%CI 2.81-3.67, p < 0.001). Transformation was also associated with a higher percentage of lymphoma-caused deaths. The post-transformation prognostic analyses demonstrated that female gender and age ≥ 65 years independently affected patients' mortalities. These findings, based on the largest cohort to date, contribute to a better understanding of transformed MZL, and provide valuable reference points for guidelines and patient counseling.

Impact of Frontline Treatment Strategy on Quality of Life in the First Decade after a Diagnosis of Marginal Zone Lymphoma

Background: Marginal Zone Lymphoma (MZL) is considered indolent but incurable, with a variety of initial treatment strategies including observation. Quality of life (QOL) can be affected by disease burden, side effects of treatment, and psychosocial effects of living with an incurable cancer. However, little is known about long-term QOL in patients with MZL. We investigated QOL at baseline (BL), and up to nine years after a diagnosis of MZL. Methods: Newly diagnosed MZL patients aged 18 years and older were prospectively enrolled within 9 months of diagnosis in the Iowa/Mayo Clinic Molecular Epidemiology Resource from 9/2002 - 6/2015. Pathology was reviewed by a hematopathologist. All MZL participants with both BL and at least one follow-up (FU) QOL questionnaire were eligible for this analysis. QOL was measured at BL and years 1-, 2-, 3-, 6- and 9-year FU with the Functional Assessment of Cancer Therapy-General (FACT-G) scale (range 0-108), which measures 4 QOL domains (range): physical (0-28), social/family (0-28), emotional (0-24), and functional (0-28) well-being (WB). Clinical data were abstracted according to a standard protocol and patients were systematically followed for events (progression, re-treatment, and death). Patients were grouped into initial management with active surveillance (observation), local/antibiotic therapy (including radiation, surgery, and anti- H. pylori therapy), or systemic therapy (including chemotherapy, targeted agents, or antibody therapy). Change in QOL scores over time was analyzed using mixed models for repeated measurements, and comparisons were made according to initial treatment group. Results: Of 324 participants in the analysis, 59% were female, 98% were White and the median age was 63 years. For initial management, 36% (N=118) were observed, 30% (N=96) received local/antibiotic therapy and 34% (N=110) received systemic therapy. Across the initial treatment groups, there were no statistically significant differences by age, gender, or performance status, while there were differences for Ann Arbor Stage IV (observation 50%, local/antibiotic 27%, systemic 67%, p&amp;lt;0.001) and MALT-IPI score 2+ (observation 23%, local/antibiotic 18%, systemic 28%, p&amp;lt;0.001). At BL, mean FACT-G total score was 85.7 (SD 13.1), and physical, social/family, emotional, and functional WB scores were 20.3 (SD 4.2), 24.4 (SD 3.9), 18.9 (SD 3.5), 22.1 (SD 5.3); these scores were similar across initial treatment groups (all p&amp;gt;0.05). FACT-G total score was largely stable over time by treatment group (Panel 1). However, it declined at years 6 (mean -4.0, p&amp;lt;0.05) and 9 (mean -3.7, p&amp;lt;0.05) in the observation group (Panel 2), driven by a decline in functional WB, although this change was not significantly different from the other treatment groups. Further, in comparison with other treatment groups, local therapy was associated with a short-term 1-year improvement of FACT-G total score (mean +2.8, p=0.04), driven by improvements in both functional and emotional WB. For the subscales, we identified two major trends irrespective of treatment group: an overall improvement from BL of emotional WB at years 1 (mean +0.6, p&amp;lt;0.05), 2 (mean +0.7, p&amp;lt;0.05), 3 (+1.3, p&amp;lt;0.05), 6 (+1, p&amp;lt;0.05), and 9 (+1.3, p&amp;lt;0.05) and an overall decline of social/family WB at years 1 (mean -1.1, p&amp;lt;0.05), 2 (mean -1.7, p&amp;lt;0.05), 3 (-2.1, p&amp;lt;0.05), 6 (-2.7, p&amp;lt;0.05), and 9 (-2.2, p&amp;lt;0.05). There was no notable change from BL for physical or functional WB. Conclusions: This analysis is the first to provide prospective real-world QOL data on a longitudinal cohort of MZL patients with long follow-up. At BL, initial treatment was associated with stage and MALT-IPI score, but not QOL. Except for the transient 1-year QOL improvement in patients under local/antibiotic therapy, initial treatment groups had no impact on QOL over time. Irrespective of treatment group, emotional WB showed improvement over time, suggesting psychosocial adaptation by the patient, as it was found in aggressive lymphomas (Thompson et al., 2018). Further, emotional WB over time did not vary across treatment groups, suggesting that being initially observed did not lead to more emotional stress than being actively treated. Finally, decline in social/family WB (support from friends, family, family acceptance of illness, family communication, close to partner) suggests a need to consider interventions to patients and families to address these needs.

Lymphoma-Related Quality of Life (QOL) Is Not Impacted By Initial Treatment Choice in Patients with Marginal Zone Lymphoma (MZL): Results from the Prospective Lymphoma Epidemiology of Outcomes (LEO) Cohort

Background: QOL can be affected by disease burden, side effects of treatment, and psychosocial effects of living with cancer. Although MZL is considered incurable, we previously found that patients diagnosed from 2002-2015 had a good QOL both at baseline (BL) and the first decade after diagnosis, regardless of treatment choice (Bommier et al., submitted). Here, we evaluate whether these findings can be extended to the 2015-2020 treatment era and a more diverse US cohort. Methods: Adults with newly diagnosed MZL from 8 academic centers were prospectively enrolled within 6 months of diagnosis from 2015-2020 in the LEO cohort (NCT02736357). Participants were actively followed for disease progression/relapse, retreatment and death. QOL was measured at BL, and at 1, 2, 3 and 5 years after diagnosis using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) scale (range 0-164), which consists of the FACT-General (FACT-G, range 0-104) plus a lymphoma-specific scale (range 0-60). Total FACT-G measures 4 QOL domains (range): physical (0-28), social/family (0-28), emotional (0-24), and functional (0-28) well-being (WB). We also used the Trial Outcome Index (TOI; range 0-112), which consists of FACT-G physical and functional WB plus the lymphoma-specific scale and is commonly used as an endpoint in treatment trials. All MZL patients with both BL and at least one follow-up QOL questionnaire were eligible for analysis. Patients were grouped by initial management: active surveillance (observation), local/antibiotic therapy (radiation, surgery, or anti- H. pylori therapy), or systemic therapy (chemotherapy, targeted agents, or antibody therapy). Change in QOL scores over time was analyzed using mixed models for repeated measurements, and initial treatment groups were compared. Results: Of 384 patients, 60% were female, 91% were White, 6.6% were Black/African American, and 13% were Hispanic (all races). The median age was 64 years (range 19-94). For initial management, 28% (N=106) were observed, 31% (N=118) received local/antibiotic therapy, and 42% (N=160) received systemic therapy. Across treatment groups, there were no significant differences by age, gender, race, or performance status, while there were differences by Hispanic ethnicity (p=0.006), Ann Arbor stage (p&amp;lt;0.001) and MALT-IPI score (p&amp;lt;0.001) (Table). At BL, patients receiving systemic therapy had lower physical WB (p=0.008), emotional WB (p=0.04), functional WB (p=0.03), FACT-G total score (p=0.008), lymphoma subscale (p&amp;lt;0.001), FACT-Lym (p=0.001) and TOI (p&amp;lt;0.001) compared to observation and local/antibiotic therapy (Table). While FACT-G total scores were largely stable through 5 years after diagnosis, social/family WB declined from BL for patients initially receiving either local/antibiotic therapy (mean at 1-year -1.4, p&amp;lt;0.05; 2-year -2.1, p&amp;lt;0.05; 3-year -1.6, p&amp;lt;0.05; 5-year-2.9, p&amp;lt;0.05) or systemic therapy (mean at 2-year -1.2 , p&amp;lt;0.05; 3-year -1.4, p&amp;lt;0.05; and 5-year -1.2, p&amp;lt;0.05), while this was stable for observed patients. In patients receiving initial systemic therapy, there was a transient improvement in the lymphoma-specific scale (mean +1.7, p&amp;lt;0.05) and TOI (mean +3.7, p&amp;lt;0.05). Otherwise, QOL remained stable over time and global QoL (FACT-G, FACT-Lym), TOI, Lymphoma-specific scale (Figure), and the other FACT-G subscales (physical, emotional, or functional WB) did not differ by initial treatment strategy. Conclusions: In the diverse LEO cohort from the recent treatment era, we confirm our prior findings for newly diagnosed MZL patients that QOL is globally stable over the first 5 years after diagnosis; emotional WB is not associated with initial treatment type, providing evidence that being initially observed does not negatively impact emotional health; and there is a decline in social/family WB (support from friends and family, family acceptance of illness, family communication, close to partner), which supports the need to consider interventions for patients to address these unmet needs. In addition, this study extends these findings to the lymphoma-specific scale, FACT-Lym, and TOI, which all showing largely stable trends in the 5 years after diagnosis and suggest that recent MZL treatment strategies, including systemic therapies, neither impair nor improve QOL.

Real-Life Experience with Lenalidomide Plus Anti-CD20 Antibodies for the Treatment of Patients (pts) with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)

Introduction: The combination of lenalidomide and anti-CD20 antibodies (Ab) is an accepted treatment for R/R iNHL and often used as comparator in registration-directed clinical trials. In pts with R/R marginal zone lymphoma (MZL) or follicular lymphoma (FL) lenalidomide plus rituximab (R2) produced a median PFS of 27.6 months and 5-year OS 83.2% (Leonard, ASH 2022). Similarly, lenalidomide and obinutuzumab (RO) led to high PFS and OS rates in pts with R/R FL (2-year PFS 65% and OS 87%, Morschhauser, Lancet Haematol. 2019). Whether these results are reproducible in clinical practice is unknown. Methods: We retrospectively analyzed our institutional experience in patients with R/R FL or MZL treated at MSK with R2 or RO identified on our electronic lymphoma database. Patients with previous history of histological transformation (HT) or who received R2/RO in combination with other agents were excluded. Planned lenalidomide starting dose was 20 mg orally daily for 21/28 days for twelve 28-day cycles; dose adjustments were considered in case of impaired renal function per standard practice. Rituximab was administered at 375 mg/m2 weekly for 4 weeks, then every 28 days for five 28-day cycles; and obinutuzumab at 1000 mg on D1, 8, and 15 of C1, then on D1 of each 28-day cycle for 6 cycles. Response was assessed according to the 2014 Lugano criteria; for splenic MZL and extranodal MZL patients, the ESMO guidelines were adopted to assess disease response (Zucca, Annals of Onc. 2020). PFS was defined as the time from treatment initiation to disease progression or death, and OS as the time from treatment initiation to death from any cause. Patients undergoing autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) were censored at that time. Results: 85 pts were treated between June 2013 and December 2022. Median age was 65 years (range 39-94); 71 patients (83.5%) had FL and 14 (16.5%) had MZL, and 18 patients (21%) had bulky disease (&amp;gt;7cm). The median number of prior therapies was 2 (range 1-8), 39 pts (46%) had ≥3 prior treatments, and 44 (53%) were refractory to their last regimen; 86% received R2 and 14% RO (Table). At the time of this analysis, pts had received a median of 9 cycles and 8 (10%) received more than 12 cycles. Eight (9%) pts are on therapy, 35 (41%) completed the planned treatment, 17 (20%) discontinued due to progression, 4 (5%) due to adverse events (AEs), 5 (6%) because they underwent auto- or allo-SCT, and 7 (8%) by medical decision, while in 9 cases (11%), treatment was prematurely discontinued in pts who achieved complete response (CR) after 6 cycles. Lenalidomide dose reduction was required in 47 pts (53%) due to non-hematologic AE (20 pts), cytopenia (12), impaired renal function (6), or other reasons (9). AEs of any grade occurred in all but one pt. The most frequent were neutropenia (45%), fatigue (47%), thrombocytopenia (33%), constipation (32%), rash (25%), and anemia (22%). Five patients (6%) developed a second cancer, including myelodysplastic syndrome (1), mucoepidermoid carcinoma (1), and non-melanoma skin cancers (3). The median duration of follow-up is 30.8 months. End of treatment disease response was evaluable in 76 patients; the remaining 8 were still receiving treatment at time of data cutoff and 1 discontinued R2 due to grade 3 colitis before the first disease assessment. The overall response rate (ORR) was 66%, with 55% achieving CR. There were no differences in response rates between pts receiving R2/RO in 2nd line or ≥3rd line, or between pts treated with R2 and RO. The median PFS was 21 months, and the 2-year PFS rate was 44.3% (95% CI: 32.7-60.0%). Seventeen pts died, 10 due to lymphoma and 7 due to other causes. HT occurred in 6 pts. The median OS was not reached, and the 2-year OS rate was 84.4% (95% CI: 75.9-92.6%) (Figure). Conclusion: This is the first real-life study of combined lenalidomide and anti-CD20 Ab for pts with R/R iNHL. Efficacy results were comparable to those reported in clinical trials and we observed no new safety signals. Our findings reaffirm the role of lenalidomide plus anti-CD20 Ab in the management of R/R iNHL and help define the benchmark for registration-directed clinical trials that utilize R2/RO as the control arm.

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.

Prognostic Significance of Monoclonal Paraproteinemia in Marginal Zone Lymphoma

Introduction and aim:Marginal zone lymphoma (MZL) is an indolent lymphoma which can progress with frequent relapses and transform to aggressive lymphoma. Therefore, the factors that affect prognosis are important fields of interest. This study was aimed to investigate the effect of immunoglobulin (Ig) paraproteinemia on MZL prognosis and survival. Material and method: Between January 2000 and June 2022, 73 patients who applied to Dokuz Eylül University Faculty of Medicine Hospital Department of Hematology, diagnosed with MZL, and continued their follow-up in our center were assessed. Patients whose paraproteinemia was investigated by immunofixation (SIFE), serum protein electrophoresis (SPEP), or free kappa and lambda free light chain (FLC) assays were included in the study. Demographic characteristics and laboratory data were retrospectively analyzed. Results: Ig paraproteinemia was ascertained in 20 patients which 11 of 20 was IgM type. The median follow-up was 58 (3-200) months. Median overall survival (OS) and progression free survival (PFS) were not reached. Mean OS and PFS were 169±8.5 and 146±10.6 months, respectively. Serum Ig paraproteinemia was detected in 20 of 73 patients (27.3%). Most were IgM- κ (9, 45%), followed by IgG-κ (7, %35), IgM-λ (2, %10), IgA-λ (1, %5), and IgA-κ (1, %5). The presence of Ig paraproteinaemia was significantly associated with advanced age (p&amp;lt;0.001), advanced disease stage (III-IV) (p=0.023), elevated ß2 microglobulin (ß2MG) level (p=0.001), decreased hemoglobin level (p=0.002), decreased albumin level (p&amp;lt;0.001), and bone marrow involvement (p=.026). Gender, elevated lactate dehydrogenase (LDH) level, and elevated Ki-67 were not significantly associated with the presence of Ig paraproteinaemia. In our cohort Ig paraproteinemia was shown in 35%, 10% and 55% of extranodal MZL, splenic MZL and nodal MZL respectively (p=0,009) which favors nodal MZL dominance. The prognostic value of Ig paraproteinaemia and other clinical outcomes are summarized in Table 1. The OS rate at 5 and 10 years was %87.2 and %81.9, respectively. The PFS rate at 5 and 10 years was %71.5 and %68.3 respectively. Patients with Ig paraproteinaemia has shorter OS compared to patients without any paraproteinemia (73,8 mo. vs 178,8 mo. p&amp;lt;0,05). This survival disadvantage was more pronounced in patients with IgM paraproteinemias. Kaplan-Meier survival curve analysis of PFS according to the occurrence of Ig paraproteinaemia are shown in Figure 1. Conclusion: Although MZL is an indolent lymphoma type and there are many prognostic factors affecting its prognosis, it may show relapsed or refractory disease course or histological transformation. 55% of our nodal MZL cohort had Ig paraproteinemia which is higher than all reported cohorts in the literature so far. Several studies have previously shown that Ig paraproteinemia may be a potential prognostic factor for NHL and MALT lymphoma 1-3. Ren et al. showed that Ig paraproteinemia was an independent prognostic predictor for MALT lymphoma 4. Epperla et al. showed that patients diagnosed with MZL with Ig paraproteinemia had inferior survival in comparation with no-M protein group 5. In conclusion, this study provides evidence that Ig paraproteinaemia and especially of IgM type shortens PFS and OS in patients with MZL. Thus, our study is the first in literature to show survival disadvantage for MZL patients specifically with IgM paraproteinemia and deserves confirmation with further studies.

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.

Phase II, Single Arm, Open Label, Single Center Study of Obinutuzumab and Ibrutinib in the Front Line Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

Background: Anti-CD-20 immunochemotherapy with cytotoxic agents has been the traditional front-line therapy for patients with the advanced stage indolent non-Hodgkin lymphomas (iNHL) such as follicular (FL) and marginal zone lymphoma (MZL) requiring treatment. For patients with medical comorbidities and advanced age at iNHL diagnosis, treatment regimens without cytotoxic chemotherapy may offer an effective but less toxic option. Combination therapies with non-cytotoxic treatments and anti-CD20 antibodies have been developed in FL and MZL, such as lenalidomide and the anti-CD20 antibody obinutuzumab. The combination of Obinutuzumab and ibrutinib was previously reported in first line treatment of follicular lymphoma (Schmidt et al ASH 2018), but not MZL. In a phase II study, we investigated the front line combination of Ibrutinib plus Obinutuzumab in FL and MZL. Methods: Adult patients with untreated, histologically confirmed Ann Arbor Stage II-IV FL (WHO classification grade 1, 2 or 3a) or MZL (nodal, splenic and extranodal) who had an indication for systemic therapy on the basis of symptoms, high tumor burden, cytopenias and/or other evidence of end-organ damage as per standard modified GELF criteria were eligible. In this single-arm study, patients received ibrutinib 560 mg daily and obinutuzumab in 28-day cycles. Obinutuzumab induction was given on days 1, 8 and 15 of cycle 1, and on day 1 of cycles 2-6. Maintenance therapy was administered if there was at least a partial response based on PET-CT after cycle 7 with obinutuzumab every 8 weeks for a total of 12 doses and ibrutinib 560 mg daily until progression. Treatment response was assessed with PET/CT scans after cycle 4 and 7, followed by every 6 months for 2 years and then annually. Overall response rate (ORR) included complete response (CR) and partial response (PR). The primary study endpoint was ORR after 7 cycles of therapy. Results: Twenty-eight patients were enrolled (15 FL, 13 MZL) and 26 patients were evaluable for ORR after 7 cycles of therapy. The median age was 65 years (range 36-84 years), 11 (39%) presented with B symptoms, 23 (82%) had Ann Arbor Stage III-IV disease, and 18 (64%) had bone marrow involvement. For patients with FL, 11 (73%) had a morphologic grade of 1-2, and 4 (27%) had a morphologic grade of 3a. For patients with MZL, 3 (23%) had nodal, 2 (15%) had splenic, and 8 (62%) had extranodal involvement. The median follow-up time was 2.2 years (3.7 years for FL, 2.1 years for MZL). The overall response rate (ORR) following 7 cycles of therapy was 22/26 (85%) with 11/15 (73%) for FL with 10 having a CR and 1 having a PR for patients with FL and 11/11 (100%) for MZL with 8 having a CR and 3 having a PR for patients with MZL. Progression-free survival (PFS) at 24 months was 81% [67% - 97%, 95%CI] with 66% [45% - 95%, 95%CI] for FL and 100% for MZL patients. Six (5 FL, 1 MZL) patients withdrew due to progression. The most common adverse event was grade 1-2 arthralgia (N=21). The most common grade 3-4 adverse event was infection (N=10), including COVID-19 (N=5), pneumonia (N=2), neutropenic fever not otherwise specified (N=1), influenza (N=1), and diverticulitis (N=1). Conclusions: The chemotherapy free combination of Ibrutinib and Obinutuzumab is effective and well tolerated. The regimen was particularly effective in patients in MZL patients with an ORR and PFS of 100 % after median follow up of 2.1 years, and represents an attractive approach for these patients.

Cumulative Incidence, Predictors, and Outcomes of Transformation to Diffuse Large B-Cell Lymphoma in a Prospective Cohort of Patients with Marginal Zone Lymphoma

Background: Although marginal zone lymphoma (MZL) typically exhibits an indolent course, transformation to diffuse large B-cell lymphomas (DLBCL) is associated with a poorer outcome and remains a clinical challenge in managing patients with MZL. The limited existing literature reports various cumulative incidence rates, ranging from 2.5% and 4.7% (Finnish Cancer Registry, 1995-2018) to 6.6% and 8.4% (Florida Cancer Registry, 1995-2016) at 5 and 10-years, respectively, likely in part driven by varying study designs, ascertainment, and study population. Similarly, reported outcomes after transformed MZL (tMZL) have been variable. We evaluated the cumulative incidence of histological transformation (HT) to LBCL in a well-characterized prospective cohort of MZL patients from the upper Midwest, USA, and overall survival (OS) after transformation. Methods: Patients ≥ 18 years old with newly diagnosed MZL were prospectively enrolled in the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) cohort from 2002-2015. Clinical and treatment data were abstracted from medical records using a standard protocol. Patients were actively followed for retreatment, transformation, and death through 2022. Pathology was classified according to WHO 4/4R, including all transformations. The cumulative incidence of HT to LBCL was determined using death as a competing risk. Time to HT (TTHT) was defined as time from the date of MZL diagnosis to the date of transformation. We evaluated potential predictors of HT using a stepwise approach, and derived hazard ratios (HR) and 95% confidence intervals (CI) from Cox proportional hazards models. To assess predictors of OS after HT, patients ≥ 18 years old with newly diagnosed tMZL (into DLBCL) at Mayo Clinic between 1995 and 2002 (N=7) were combined with the MER cases. Results: We identified 524 patients with MZL in the MER cohort: 362 extranodal (EMZL; lung 18%, stomach 16%, orbit 13%, parotid 10%, skin 10%), 84 splenic (SMZL), and 78 nodal (NMZL). The median age at diagnosis was 63 years (range 18-92); 56% were female, and 83% were non-Hispanic white. During a median follow-up of 18.8 years (95% CI 16.7, NA), there were 25 HT (including 8 patients under observation) and 158 deaths. Eight Ten-year OS was 67% and 77% in the groups with and without HT, respectively. The overall cumulative incidence of HT was 1.5% at 2 years after diagnosis, 2.9% at 5 years, 4.5% at 10 years, and 5.7% at 15 years (Panel 1). The cumulative incidence of HT varied by subtype (e.g., at 5 years: 2%, 4% and 6%, in EMZL, NMZL and SMZL, respectively; Panel 2). The median time to HT also varied by subtype: 76 months (interquartile range (IQR) 43, 81) for EMZL, 30 months (IQR 16, 52) for SMZL, and 18 months (IQR 14, 23) for NMZL. In univariable analysis, predictors of HT were Stage III/IV (HR=3.4, 95% CI 1.36-8.53, p=0.009), elevated LDH (HR=2.98, 95% CI 1.25-7.12, p=0.014), and presence of ≥2 extranodal sites (HR=2.69, 95% CI 1.22-5.94, p=0.014). In multivariable analysis, elevated LDH was the only non-composite predictor of HT (HR=2.65, 95% CI 1.08-6.52, p=0.034). MALT-IPI score 2-3 (HR=3.61, 95% CI 1.06-12.25, p=0.040) and FLIPI score 3-5 (HR=2.19, 95% CI 1.22-8.22, p=0.018) also predicted HT. We analyzed OS after HT in 32 cases of tMZL (21 tEMZL, 7 tSMZL, 4 tNMZL). At HT, median age was 68 years (range 39-89); 24 (80%) patients presented with stage III/IV disease, 11 (58%) with elevated LDH, 12 (55%) with hemoglobin &amp;lt;12g/dL, 3 (14%) with platelet count &amp;lt;100x10 9/L and 9 (39%) with biopsy-proven bone marrow involvement. Twenty-six (81%) were treated with a systemic therapy, mainly CHOP-backbone therapy (R-CHOP n=13, CHOP n=4, R-EPOCH n=3, lenalidomide-R-CHOP n=1). Among these patients, the overall response rate was 85% (n=22/26). Three of the 4 non-responders died within 1 year. At last follow-up, 18/32 (56%) patients had died, and 6/13 (46%) alive patients had relapsed (MZL 3/6, DLBCL 3/6). After HT, 2-, 4- and 10-year OS were 76%, 55% and 55%, respectively. In univariable analysis, the only predictor of OS at HT was age ≥70 (HR 3.57 ,95% CI 1.34-9.48, p=0.011). Conclusion: In this North American prospective cohort of mainly non-Hispanic White patients, we found a low cumulative incidence of HT in MZL of 2.9% and 4.5% at 5- and 10-year, which was consistent with the Finnish findings (Kalashnikov et al., 2023). At HT, age was associated with OS and there was a high response rate to CHOP-backbone therapies.

Chemokine Receptor PET/CT Provides Relevant Staging and Management Changes in Marginal Zone Lymphoma.

Because of gastral and extranodal manifestations, guideline-compatible diagnostic work-up of marginal zone lymphoma is challenging. We aimed to determine the diagnostic performance of C-X-C motif chemokine receptor 4 (CXCR4)-directed PET/CT compared with routine diagnostics, along with PET/CT-based retrospective changes in therapeutic management. The predictive potential of the PET signal was also investigated, and the number of patients eligible for CXCR4-directed radioligand therapy in a theranostic setting was determined. Methods: For this study, 100 marginal zone lymphoma patients underwent CXCR4-directed PET/CT. We compared staging results and treatment decisions from molecular imaging with respective results from guideline-compatible work-up (CT, esophagogastroduodenoscopy, and bone marrow-derived biopsy). Prognostic performance of the invivo CXCR4 PET signal for progression-free survival (PFS) was evaluated (using log-rank test and Kaplan-Meier curves). Results: Relative to CT, CXCR4-directed imaging led to Ann Arbor (AA) staging changes for 27 of 100 patients (27.0%). Among those, clinically relevant upstaging from AA I or AA II to AA III or AA IV was observed for 23 patients (85.2%), along with respective changes in therapeutic management (escalation, 6/23 [26.1%]; deescalation, 17/23 [73.9%]). CXCR4 PET/CT yielded diagnostic accuracy of 94.0% relative to esophagogastroduodenoscopy and 76.8% relative to bone marrow-derived biopsy. An increased CXCR4 PET signal was linked to shorter PFS (707 d vs. median PFS not reached; hazard ratio, 3.18; 95% CI, 1.37-7.35; P = 0.01). CXCR4-directed radioligand therapy would have been feasible for 18 of 100 patients (18.0%). Conclusion: Relative to CT, CXCR4-directed PET/CT led to AA changes for 27 of 100 patients. Chemokine receptor PET/CT may improve current diagnostic algorithms and influence management relative to CT alone, potentially obviating some biopsies.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

Recent updates in the indolent lymphomas: Update on marginal zone lymphoma and Waldenström's macroglobulinemia.

Marginal Zone Lymphoma (MZL) and Waldenström's Macroglobulinemia (WM) are indolent lymphomas that both arise from post germinal center lymphocytes. Both can secrete a monoclonal protein but high levels are mostly only seen in WM. The MYD88 L256P somatic mutation that is present in an estimated 95% of patients with WM has helped greatly in differentiating the two lymphomas. Several large clinical studies with new drugs have been performed that have provided new treatment options for both MZL and WM patients. In this short review we will discuss the recent literature published and provide some recommendations.

Orelabrutinib, a new‐generation bruton tyrosine kinase inhibitor, demonstrates safety and efficacy in relapsed/refractory marginal zone lymphoma

Introduction: Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton’s tyrosine kinase (BTK) inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Methods: Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic parameters were evaluated as secondary outcome measures. Results: Between April 2019 and November 2021, 111 Chinese patients with a median age of 60 y/o (range 23–77) were enrolled. Among those, 83 patients who received at least 1 prior therapy with an anti-CD20 antibody-containing regimen were confirmed with MZL by the central pathological review, who were mainly with extranodal MZL of mucosa-associated lymphoid tissue (MALT, 45.8%) and nodal MZL (36.1%). The majority had late-stage diseases, the stage IV accounting for 75.9%. After a median follow-up of 22.3 months, the IRC-assessed ORR was 57.8% (95% CI, 46.5% to 68.6%). Ten patients achieved a complete response (CR, 12%), and 38 achieved a partial response (PR, 45.8%). The IRC-assessed median duration of response (DoR) and median progression-free survival (PFS) was 34.3 months and 36.0 months, respectively, with a 12-month PFS rate of 84.3% (95% CI, 73.9% to 90.8%). The rate of overall survival (OS) was 91.5% (95% CI, 82.9% to 95.8%) at 12 months. Treatment was well tolerated with most treatment-related adverse events (TRAE) being grade 1 or 2. In all the 111 patients, common all-grade TRAEs included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Conclusions: Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL. This trial is registered at ClinicalTrials.gov as NCT03797456. Keyword: Indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

REALMA: Subset of patients with Marginal Zone Lymphomas from the French nationwide REALYSA real‐world prospective cohort.

Background: Marginal Zone Lymphomas (MZL) are a heterogeneous group of lymphomas that include three subtypes: extranodal MZL (EMZL), splenic MZL (SMZL) and nodal MZL (NMZL). Since most of the knowledge comes from clinical trials (with stringent inclusion criteria and limited representativeness), there is a crucial need for real-world evidence in MZL. In 2018 the French REALYSA (Real world dAta in LYmphoma in Adults) study was initiated as a nationwide multicentric prospective cohort of patients newly diagnosed with lymphoma. By Dec 31, 2021, a total of 207 patients with MZL were included in the study. Methods: Patients were recruited in 35 French hematology centers and received routine care. Data were collected from medical records and questionnaires. A first abstraction was performed on Jan 1, 2023, to parse out the available data regarding MZL patients with >1 year of follow-up. Each case was reviewed by medical and pathological experts, and treatments were classified on an intent-to-treat basis. Results: Of the 207 patients with MZL included up to Dec 31, 2021, 111 (53%) presented with EMZL, 47 (23%) with SMZL and 49 (24%) with NMZL. At baseline, median age was of 67 years old (IQR 60,75), 53% of patients were females, 5.5% of patients had a PS of 2–4, 70% were stage III-IV, 19% presented with B-symptoms, 20% had a bulky mass >7 cm and 5.8% had a compressive syndrome. Only 7% of patients reported an auto-immune disease. Diagnosis of MZL was mostly evoked by general practitioners (48%) but patients were finally treated by hematologists (98%). Only 9 patients were referred to an onco-geriatrician. Regarding the initial workup, while at least one imagery was offered in 97% of patients, 18FDG-PET/CT (EMZL 78%, SMZL 62%, NMZL 78%) was performed more frequently than CT-scan at baseline (EMZL 73%, SMZL 62%, NMZL 71%), although 47% patients underwent both procedures. Among the 207 patients, 58 (28%) were not treated. Only 10 patients exclusively received local therapy (radiotherapy n = 6, surgery n = 2, antibiotics n = 2). Regarding systemic therapies, rituximab-chlorambucil was mainly offered in patients with EMZL (40%), while rituximab-monotherapy was preferred in SMZL (60%). For patients with NMZL, physicians mainly offered RCHOP (33%) and rituximab-bendamustine (27%). Only 7 patients with EMZL received the combination of ibrutinib and rituximab. At end of 1st line, 93% of patients had responded to therapy and 75% were in complete response. Among patients assessed with 18FDG-PET/CT, a metabolic complete response was observed in 52/58 (90%) of cases. Conclusion: This is the first analysis describing real-world data of patients with MZL in France. Our cohort features high-quality data both on epidemiological and clinical outcomes. When the total number of patients will increase and data will mature, this dataset will provide insightful information regarding both endpoints and treatment evaluations. Keyword: Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. C. Bommier Research funding: Inserm/AvieSan/ITMO Cancer, LYSA/ELI (Bertrand Coiffier Prize), Philippe Foundation, Institut Servier

MARGINAL ZONE LYMPHOMA INTERNATIONAL PROGNOSTIC INDEX (MZL‐IPI): A PROGNOSTIC SCORE FOR THE ENTIRE SPECTRUM OF MARGINAL ZONE LYMPHOMAS. A FIL AND SPORE‐MER STUDY

Background: Marginal zone lymphomas (MZL) include extranodal (ENMZL), nodal (NMZL), and splenic (SMZL) subtypes. While MZL subtypes have largely been studied as separate entities, most clinical trials evaluate MZL as a single entity. In this setting, a prognostic score for all MZL would be very useful. Methods: We analyzed patients that were prospectively enrolled in the NF10 observational study with the aim to define a prognostic score for all MZL. We included adult patients with MZL who started a systemic therapy. For the purposes of this study, patients were classified as SMZL, ENMZL and NMZL according to pathologic diagnosis. Patients without a clear pattern of organ involvement were categorized as disseminated MZL (dissMZL). The primary study endpoint was progression-free survival (PFS) which was calculated from the date of treatment start. For validation, we applied the same inclusion criteria and model used for the NF10 study to an independent cohort of patients from the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) Molecular Epidemiology Resource (MER). Results: Starting from the NF10 study, we identified 501 eligible patients: 166 SMZL (33%), 197 ENMZL (39%), 60 NMZL (12%) and 78 dissMZL (16%). At presentation, 40% of the patients were >70 years old, 80% were stage III-IV, 31% had elevated LDH, 41% had Hb <12 g/dl, 20% had lymphopenia (absolute lymphocyte count <1 × 109/L), and 14% had platelets <100 × 109/L. After a median follow-up of 61 months, 5-year(y) PFS was 72% (95% CI 68%–76%). In the final multivariate model, elevated LDH, anemia, lymphopenia, thrombocytopenia, and subtype (NMZL or dissMZL) were independently associated with a worse PFS. A prognostic model was then built with those 5 factors, and patients were classified into low (LRG, 0 factors, 27%), intermediate (IRG, 1–2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups. 5y PFS was 85% for the LRG, 66% for IRG, and 37% for HRG (Figure), with c-Harrell = 0.64 and robust internal validation and calibration. Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39–3.80) and HRG (HR = 5.41, 95% CI 3.12–9.38) had inferior PFS. In the validation using the MER cohort of 192 MZL patients, 5y PFS was 57% (95% CI 51–64). Applying the MZL-IPI to the MER, 41(21%), 113 (59%), and 38 (20%) patients were classified as LRG, IRG, and HRG, respectively. The MZL-IPI was associated with PFS (log-rank test p = 0.043; c-Harrell = 0.60, 95% CI 0.55–0.66); compared to the LRG, the IRG (HR = 1.57, 95% CI 0.97–2.54) and HRG (HR = 2.04, 95% CI 1.15–3.62) had inferior PFS. In both the training and the validation studies, MZL-IPI was associated with the best prediction and discrimination performance, as compared to the IPI, FLIPI and MALT-IPI, and was also prognostic for overall survival. Keywords: indolent non-Hodgkin lymphoma, risk models Conflicts of interests pertinent to the abstract S. Luminari Consultant or advisory role: Roche, Jannsen, Incyte, Gilead, Beigene, BMS, Regeneron S. Ferrero Consultant or advisory role: Janssen, EUSA Pharma, Incyte, Clinigen, Italfarmaco Honoraria: Janssen, EUSA Pharma, Servier, Gentili Research funding: Janssen, Gilead, Morphosys, Beigene I. Del Giudice Consultant or advisory role: AstraZeneca B. K. Link Consultant or advisory role: include Genentech/Roche and MEI Inc D. Mannina Consultant or advisory role: GSK, Kyowa Kirin L. Arcaini Consultant or advisory role: Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics Honoraria: EUSA Pharma, Novartis Research funding: Gilead Sciences

Splenic marginal zone lymphoma in Sweden 2000-2020: Increasing rituximab use and better survival in the elderly.

The treatment of splenic marginal zone lymphoma is debated: splenectomy (the old standard-of-care) is better than chemotherapy but maybe not better than rituximab-containing treatment. We examined all 358 patients diagnosed with splenic marginal zone lymphoma in Sweden 2000-2020. The median overall survival was 11.0 years. The median age was 73 years; 61% were women. Age was the only independently prognostic clinical characteristic. Eighty-six patients were started on wait-and-watch, 90 rituximab monotherapy, 47 rituximab-chemotherapy, 88 splenectomy, 37 chemotherapy, and 10 both systemic therapy and splenectomy. Overall survival was inferior in patients treated with chemotherapy, but equal in patients treated with rituximab, rituximab-chemotherapy and splenectomy. Patients treated with both systemic therapy and splenectomy showed good outcome, suggesting that surgery can be safely reserved for nonresponders. After adjustment for age, survival did not differ between patients started on wait-and-watch and those treated with splenectomy or rituximab-containing therapy. Over time, rituximab use and survival increased in patients ≥73 years. This is, to our knowledge, the largest population-based study of splenic marginal zone lymphoma patients treated with upfront rituximab. We conclude that wait-and-watch remains the most reasonable option in asymptomatic splenic marginal zone lymphoma patients. Symptomatic patients should be offered single-agent rituximab in first line.

Estimating the Burden of Illness of Relapsed Follicular Lymphoma and Marginal Zone Lymphoma in Ontario, Canada.

Many patients with advanced follicular lymphoma (FL) and marginal zone lymphoma (MZL) relapse after first-line chemotherapy. To examine healthcare resource utilization (HCRU) and cost, treatment patterns, progression, and survival of patients with FL and MZL who relapse after first-line treatment, in Ontario, Canada. A retrospective, administrative data study identified patients with relapsed FL and MZL (1 January 2005-31 December 2018). Patients were followed for up to three years post relapse to assess HCRU, healthcare costs, time to next treatment (TTNT), and overall survival (OS), stratified by first- and second-line treatment. The study identified 285 FL and 68 MZL cases who relapsed after first-line treatment. Average duration of first-line treatment was 12.4 and 13.4 months for FL and MZL patients, respectively. Drug (35.9%) and cancer clinic costs (28.1%) were major contributors to higher costs in year 1. Three-year OS was 83.9% after FL and 74.2% after MZL relapse. No statistically significant differences were observed in TTNT and OS between patients with FL who received R-CHOP/R-CVP/BR in the first line only versus both the first- and second- line. A total of 31% of FL and 34% of MZL patients progressed to third-line treatment within three years of initial relapse. Relapsing and remitting nature of FL and MZL in a subset of patients results in substantial burden to patients and the healthcare system.

Abstract 394: ERBB4-mediated signaling is a mediator of resistance to BTK and PI3K inhibitors in B cell lymphoid neoplasms

Abstract Background: Marginal zone lymphoma (MZL) is an indolent yet incurable B cell malignancy. Two BTK inhibitors, ibrutinib and zanubrutinib, are FDA approved for relapsed/refractory MZL patients. PI3K inhibitors have also shown clinical activity. The identification of the mechanisms of resistance can provide useful information to optimize the use of the agents. We previously reported an IL6 driven MZL model of PI3K inhibitors resistance developed by prolonged exposure to the PI3Kδ inhibitor idelalisib (Arribas, Haematologica 2022). Here, we present the detailed characterization of a second model with resistance to both BTK and PI3K inhibitors. Methods: MTT assay. RNA-Seq, whole exome sequencing, miRNA and methylation profiling. FACS and ELISA analyses. Results: Resistant cells, developed by continuous exposure of the cell line Karpas1718 to idelalisib, showed resistance to various inhibitors of BTK (ibrutinib, zanubrutinib, acalabrutinib and pirtobrutinib) and PI3K (idelalisib, duvelisib, copanlisib and umbralisib). No mutations affecting BTK, PLCG2 or CXCR4 were identified in resistant cells, which had higher expression of genes involved in ERBB signaling (HBEGF, NRG2, ERBB4), cell proliferation (PBK, MKI67, TCL1A) and DNA recombination (RAG1, RAG2) than parental cells. We confirmed cell surface ERBB4 up-regulation, and the cytoplasmatic expression and secretion of its ligand HBEGF in resistant cells, which led to increased levels of p-AKT and p-ERK. The miRNAs miR-29c and let-7c, known negative regulators of the HBEGF-ERBB axis, were fully methylated and down-regulated in resistant compared to parental cells. ERBB4 genetic silencing improved sensitivity to PI3Kδ inhibitor, and exposure to let-7c or miR-29c mimics decreased secreted HBEGF and recovered sensitivity to PI3K inhibitors in resistant cells. Addition of recombinant HBEGF (rHBEGF) induced resistance to BTK and to PI3K inhibitors in parental cells and in other lymphoma models including mantle cell lymphomas and diffuse large B cell lymphomas (DLBCL). The rHBEGF induced resistance was reverted adding the ERBB inhibitor lapatinib. To extend our findings to the clinical context, using two MZL and one DLBCL expression datasets, we showed HBEGF and ERBB4 expression in clinical specimens. Finally, HBEGF levels appeared elevated in the serum of CLL patients with primary or acquired resistance to PI3Kδ or to BTK inhibitors, compared to patients responding to the drugs and paired for similar clinical features. Conclusions: We characterized a novel B cell lymphoma model of secondary resistance to BTK and PI3K inhibitors. Our results indicate that epigenetic plasticity led to the activation of HBEGF-ERBB signaling sustaining resistance to BTK/PI3K inhibitors, which can be overcome using epigenetic agents and ERBB inhibitors. These therapeutics approaches could be tested in novel clinical trials. AJA, SN: equally contributed. Citation Format: Alberto J. Arribas, Sara Napoli, Luciano Cascione, Laura Barnabei, Giulio Sartori, Eleonora Cannas, Eugenio Gaudio, Chiara Tarantelli, Afua A. Mensah, Filippo Spriano, Antonella Zucchetto, Francesca M. Rossi, Andrea Rinaldi, Manuel Castro de Moura, Anastasios Stathis, Georg Stussi, Valter Gattei, Jennifer R. Brown, Manel Esteller, Emanuele Zucca, Davide Rossi, Francesco Bertoni. ERBB4-mediated signaling is a mediator of resistance to BTK and PI3K inhibitors in B cell lymphoid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 394.

Abstract 913: Engineering allogeneic off-the-shelf CD19-directed CAR-iNKT cells without additional genetic manipulations for the treatment of hematological malignancies

Abstract Despite the approval of three autologous CAR-T cell products, B-cell malignancies still represent an unmet need as several of the relapsed/refractory patients are ineligible for autologous CART cell therapies. Invariant natural killer T (iNKT) cells are a unique subset of immune cells that display properties of both T cells and natural killer cells and bridge the innate and adaptive immune responses upon antigen recognition. Unlike conventional β T cells, iNKT cells express an invariant T cell receptor (TCR) that recognize glycolipids presented in the context of the monomorphic, MHC-class I related molecule, CD1d. iNKT cells are ideal cell types for allogeneic, off the shelf approach as they can target cancers without the risk of graft-versus-host disease (GvHD), circumventing the need to delete or knock out the endogenous TCR. Here, we report the engineering of ‘off-the-shelf’ iNKT cells directed against CD19 and their robust in vitro and in vivo functional profile. Briefly, peripheral blood derived iNKT cells were isolated from healthy donors and were engineered to express a CD19 CAR using a 3rd generation lentiviral vector. To demonstrate the CAR-dependent and independent anti-tumor activity, CAR19-iNKT cells were compared in vitro against non-transduced (NT) iNKT cells in cytotoxicity assays and intracellular cytokine staining assays. Allogeneic CAR19-iNKT cells upregulated activation markers, secreted cytokines, and lysed cancer cell lines and primary tumor cells from chronic lymphocytic leukemia and marginal zone lymphoma patients in an antigen-specific manner. Excellent post thaw recovery and viability was noted in cryopreserved CAR19-iNKT cells. Finally, the anti-tumor activity of cryopreserved CAR19-iNKT cells were evaluated in an established aggressive NSG mice model of SEM-luc, a B cell lymphoblastic leukemia cell line expressing luciferase. Robust antitumor activity by CAR19-iNKT cells was observed without any obvious adverse effects compared to controls (untreated and NT iNKT cells). The persistence of CAR19-iNKT cells in this model is currently being evaluated. These data demonstrate a unique, off the shelf CAR19-iNKT cell platform for targeting hematological malignancies that combines the specificity of CD19 targeting CAR with the innate features of iNKT cells. The data indicates that iNKT cells are a potent cell type for generating allogeneic off the shelf products for treating a broad spectrum of hematological malignancies and solid tumors by targeting different receptors on the respective tumors. Citation Format: Kanagaraju Ponnusamy, Janani Kanagaraju, Yingxin Wang, Bryan Lye, Hongwei Ren, Sandhya Buchanan, Michael J. Baker, Mini Bharathan, Anastasios Karadimitris. Engineering allogeneic off-the-shelf CD19-directed CAR-iNKT cells without additional genetic manipulations for the treatment of hematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 913.

Comparison of histological and molecular features of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma.

Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are pediatric B cell lymphomas with similar clinical characteristics but distinct histological features. We investigated the differences between pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma by comparing their histological and molecular characteristics. A total of 5 pediatric-type follicular lymphoma and 11 pediatric nodal marginal zone lymphoma patients were included in the study. In the histological review, 5 of the 16 cases showed overlapping morphological features of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma; hence, they were reclassified as "mixed type." In molecular analysis, using panel-based massively parallel sequencing, MAP2K1, TNFRSF14, and IRF8 mutations were found in 6, 3, and 2 of the 11 pediatric nodal marginal zone lymphoma patients, respectively, and IRF8 mutation was found in one of the five pediatric-type follicular lymphoma patients. There were no significant differences in genetic alterations established from the histologically reclassified diagnosis as well as the initial diagnosis. Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma showed morphological overlap in some cases, and no difference between the two was found upon molecular analysis. These findings suggest the possibility that pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are single entity pediatric B-cell lymphoma with broad morphological spectrum.