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The phase 3 SELENE study evaluated ibrutinib + chemoimmunotherapy (CIT; bendamustine and rituximab [BR]; or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) for patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Adult patients who had received ≥1 prior line of CIT were randomized 1:1 to oral ibrutinib (560 mg) or placebo daily, plus 6 cycles of BR/R-CHOP. The primary end point was investigator-assessed progression-free survival (PFS). Overall, 403 patients were randomized to ibrutinib + CIT (n = 202) or placebo + CIT (n = 201). Most patients received BR (90.3%) and had FL (86.1%). With a median follow-up of 84 months, median PFS was 40.5 months in the ibrutinib + CIT arm and 23.8 months in the placebo + CIT arm (hazard ratio [HR], 0.806; 95% confidence interval [CI], 0.626-1.037; P = .0922). Median overall survival was not reached in either arm (HR, 0.980; 95% CI, 0.686-1.400). Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 85.6% and 75.4% of patients in the ibrutinib + CIT and placebo + CIT arms, respectively. In each arm, 13 patients had TEAEs leading to death. The addition of ibrutinib to CIT did not significantly improve PFS compared with placebo + CIT. The safety profile was consistent with known profiles of ibrutinib and CIT. This trial was registered at www.clinicaltrials.gov as #NCT01974440., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: This dose-escalation part of an ongoing Phase I study assessed the tolerability, safety and pharmacokinetics of mosunetuzumab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL)., Methods: Mosunetuzumab was administered intravenously, with step-up dosing in a 3 + 3 design, on Days 1, 8 and 15 of Cycle 1, and Day 1 of each subsequent 21-day cycle for up to 17 cycles to patients across five cohorts with different target doses (2.8, 6.0, 13.5, 27.0 or 60.0 mg)., Results: As of 5 July 2022, 23 patients had received mosunetuzumab. The median patient age was 63.0 years, 56.5% of patients were male, and 69.6% of patients had diffuse large B-cell lymphoma, 17.4% had transformed follicular lymphoma (FL) and 13.0% had FL. The median number of prior lines of therapy was 4. Mosunetuzumab was well tolerated and there were no deaths. The most common adverse events (any grade) were neutropenia/neutrophil count decreased (47.8%) and cytokine release syndrome (34.8%). Most cytokine release syndrome events were Grade 1/2 (one Grade 3), and most occurred within 24 hours of the first dose of mosunetuzumab. The apparent half-life of mosunetuzumab was 4.1-5.0 days. Two patients achieved a complete response, and 11 patients achieved a partial response., Conclusions: This study demonstrated that mosunetuzumab has an acceptable safety profile and antitumor activity in Japanese patients with relapsed/refractory B-cell NHL. The recommended Phase II dose of 1.0/2.0/60.0/60.0/30.0 mg was tolerable and there were no new or different safety signals compared with the global Phase I study., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Gastrointestinal (GI) follicular lymphoma (FL) is the most frequently diagnosed extranodal FL; however, its pathogenesis is debatable. We investigated the distribution, endoscopic, and histopathologic findings of 366 GI FL samples obtained from 298 patients. FLs were most frequently observed in the small intestine (71%), including the duodenum (52%), but were also commonly found in the stomach (15%) and colon (12%). The proportion of granular lesions in the duodenum, terminal ileum, colon, and stomach was 74%, 39%, 24%, and 0%, respectively. Submucosal or ulcerated tumors were frequently observed in the stomach (48%) and colon (52%). Most GI FL showed grade 1 to 2 histology (89%) as well as CD10 + (93%) and BCL2 + (98%) positivity. There were no significant differences in the endoscopic or histologic findings between primary and secondary GI FLs. As known, the mucosa of the small intestine is thin and villous, while the mucosa of the stomach and colon is thicker and has a smooth surface. Granular lesions corresponding to very small FL were detected in the former but rarely in the latter. Nine (7%) patients with primary GI FL developed histologic transformation to diffuse large B-cell lymphoma (n=8) or high-grade B-cell lymphoma (n=1) 10 months to 14 years after the diagnosis of FL. Two patients died of lymphoma. In conclusion, the incidence and endoscopic findings differed, but the histopathology was similar in FLs in each site. These differences might be attributed to variations in each GI site's mucosal structure and the neoplastic follicles' size. Due to its characteristic structure, very small classic FLs might be detectable mainly in the small intestine., Competing Interests: Conflicts of Interest and Source of Funding: This work was partly supported by the Japan Agency for Medical Research and Development Fund (grant number 22ck0106670h0002). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

BCL2 positivity by immunohistochemistry is helpful for the diagnosis of follicular lymphoma (FL); however, a minority of FL cases are BCL2-negative, and the diagnosis is thus challenging. We retrospectively analyzed the incidence, morphology, immunophenotype, and genetic status of BCL2 1+ (weakly/focally positive by clone 124), BCL2 0 (negative), and BCL2 controversial FLs compared with BCL2 2+ (strongly positive) FLs to clarify diagnostic clues. In 1068 FL cases, 103 (10%) with BCL2 1+ (37 cases, 4%), BCL2 0 (61 cases, 6%), or BCL2 controversial (5 cases, 0.5%) were included in the final analysis. BCL2 1+ and BCL2 0 FLs tended to have limited stage disease, nodal disease, and grades 3A/3B histology and showed a higher complete response rate than BCL2 2+ FLs. Among 103 BCL2 0 , BCL2 1+ , or BCL2 controversial FL cases, 34 (33%) had a diffuse area composed of CD20-positive small-to medium-sized lymphoid cells, a feature of low-grade B-cell lymphoma. Interfollicular dense CD20-positive cells and interfollicular clusters of CD10-positive cells were observed in 59% and 37% of cases, respectively. In remaining 13/40 cases (33%), BCL2 was converted to BCL2 2+ by other clones E17/SP66. CD23 and MUM1 were positive in 10/40 (25%) and 1/40 (3%) cases, respectively. IGH/BCL2 fusion and clonality were detected in 6/37 (16%) and 31/34 (91%) cases, respectively. In conclusion, morphological examination of the distribution of CD20-and/or CD10-positive cells and the presence of diffuse area could be used to diagnose FL in most cases. The majority of the remaining FL cases could be diagnosed using other BCL2 clones and clonality analyses., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Watchful waiting (WW) is one of the standard approaches for newly diagnosed follicular lymphoma (FL) patients with low-tumor burden. However, the impact of WW in FL patients at the first progression, remains unclear. We reviewed 206 FL patients who experienced the first progression after responding to the initial treatment at our institution between 1998 and 2017. Patients were classified into either the WW cohort (132 patients) or the immediate treatment cohort (74 patients). Overall, the median follow-up from the first progression was 79.8 months (range, 2.1-227.0 months). In the WW cohort, the estimated median time to next treatment (TNT) was 19.7 months (95% confidence interval [CI], 13.4-30.2), and 76.5% (95% CI, 68.0-84.1) of the patients subsequently underwent the second-line treatment at 5 years. There was a significant difference in the median time to treatment failure in the WW cohort (72.8 months; 95% CI, 64.6-94.0) compared to the immediate treatment cohort (23.3 months; 95% CI, 13.4-38.8) (HR, 2.13; 95% CI, 1.48-3.06), whereas overall survival and the cumulative incidence of histological transformation were not significantly different between two cohorts. In a multivariate analysis, rituximab refractory status, progression of disease within 24 months from the induction of first-line therapy, and a high Follicular Lymphoma International Prognostic Index score at diagnosis were significantly associated with shorter TNT. Interestingly, 15 patients (11%) of the WW cohort experienced spontaneous tumor regression during WW, and their TNT (median, 82.1 months, 95% CI, 11.7-NA) was longer than that of the remaining patients in the WW cohort (median, 16.5 months, 95% CI, 13.0-25.4), with a significant difference (p = 0.01). The results of the present study suggested that WW could be a safe and reasonable option even at the first progression for the selected FL patients, without a negative impact on clinical outcomes., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The diagnosis of histological transformation of follicular lymphoma can be challenging and ambiguous. We investigated the distribution of the Ki-67 labeling index of histological transformation of follicular lymphoma and determined its cutoff value to predict poor outcomes. The diagnostic criteria for histological transformation were a diffuse pattern of proliferation and a proportion of large lymphoma cells ≥20%. Of the 1121 patients with follicular lymphoma, 171 (15%) showed histological transformation to diffuse large B-cell lymphoma. Of these, 76 patients, whose biopsies were obtained from the sites with the highest maximum standardized uptake values, according to the positron emission tomography findings, were included. The Ki-67 index ranged from 16.8% to 98.4% (median, 60.6%). In patients with histological transformation, the most significant differences were found in progression-free survival (p = 0.087, 58% vs. 87% at 2 years) and overall survival (p = 0.024, 53% vs. 85% at 5 years) when a 70% cutoff was used. Additionally, overall survival was significantly shorter in patients with histological transformation with maximum standardized uptake values of ≥20 (p < 0.0001) and absence of a follicular lymphoma component (p = 0.004). A Ki-67 index of ≥70% was a significant adverse factor for overall survival in patients with histological transformation of follicular lymphoma and may predict poor outcomes., (© 2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Objectives: In this study, we aimed to determine the clinicopathological factors influencing the treatment-free period in patients with follicular lymphoma (FL) using a watch-and-wait (WW) strategy., Methods: We retrospectively assessed histopathological parameters of 82 patients with FL., Results: The median time from diagnosis to WW discontinuation was 62 months (range, 3-138), and median follow-up was 86 months (range, 3-183). Intermediate or high-risk Follicular Lymphoma International Prognostic Index score (P = .012), non-duodenal-type (P = .011), higher numbers of interfollicular CD4 + (P = .038) and intrafollicular FOXP3 + cells (P = .024) in the tumor microenvironment, and Ki-67 index ≥10% (P = .031) were significant adverse factors for WW discontinuation in univariate analyses., Conclusion: Patients with adverse factors for WW discontinuation should be carefully observed during follow-up., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although histologic analysis is the gold standard for diagnosing follicular lymphoma (FL) transformation, many patients are diagnosed with transformation by clinical factors as biopsy specimens often cannot be obtained. Despite the frequency of clinical diagnosis, no clinical assessment tool has yet been established for FL transformation in the rituximab era. We derived and validated a transformation scoring system (TSS) based on retrospective analyses of 126 patients with biopsy-proven FL and histologic transformation (HT) at two hospitals of the National Cancer Center of Japan. In the derivation set (76 patients), the detailed analyses of the clinical characteristics at disease progression showed that lactate dehydrogenase (LDH) elevation, focal lymph nodal (LN) enlargement, hemoglobin <12 g/dl, and poor performance status (PS) (2-4) were associated with HT. The weights of these variables were decided based on the regression coefficients. Next, we constructed a TSS encompassing the above four factors: LDH, (> upper limit of normal [ULN], ≤ULN ×2) (1 point), (≥ULN ×2) (2 points); focal LN enlargement, (≥3 cm, <7 cm) (1 point), (≥7 cm) (2 points); hemoglobin <12 g/dl (1 point); poor PS (2 points). We identified a high positive predictive value (PPV) (96.4%) and negative predictive value (NPV) (85.4%) for diagnosing HT when a cutoff score of 2 was selected for our TSS. In an external validation set (50 patients), the probability of HT was high with scores ≥2 (PPV, 93.3%; NPV, 82.9%). We developed a TSS that offers a simple, yet, valuable tool, for diagnosing HT, especially in patients who cannot undergo biopsy., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Diffuse large B-cell lymphoma (DLBCL) is the most common histological transformation (HT) of follicular lymphoma (FL). Other types of HT are very rare, and their incidence, histopathology, and patient outcomes have not been sufficiently described. Here, we assessed the clinicopathological characteristics of 19 cases of non-DLBCL HT of FL in a single institution in Japan to advance the understanding of the disease. Among 889 consecutive patients diagnosed with FL between 2000 and 2018, 191 suffered HT (21%). The median follow-up period was 94 months (range = 3-225). A total of 172 patients (90%) had DLBCL transformation, whereas the remaining 19 patients (10%) exhibited non-DLBCL transformation. In the latter cases, the following diagnoses were made based on morphology, immunohistochemistry, flow cytometry, and fluorescence in situ hybridization analyses: classic Hodgkin lymphoma (7 patients; 4%); high-grade B-cell lymphoma (HGBL) with MYC and BCL2 rearrangements (4 patients; 2%); HGBL, not otherwise specified (4 patients; 2%); B-cell lymphoblastic leukemia/lymphoma (2 patients; 1%); anaplastic large-cell lymphoma-like lymphoma (1 patient; 0.5%); and plasmablastic lymphoma (1 patient; 0.5%). Epstein-Barr virus-encoded RNA-1 did not associate with HT in any of the cases tested (n = 8). Patients with non-DLBCL transformation showed poor outcomes, with a median overall survival of 13 months (range = 2 days-107 months); 10 of the patients (53%) died of HT. In conclusions, non-DLBCL transformation was observed in 10% of patients with HT from FL. Our data show that timely, accurate, and comprehensive histopathological diagnosis is needed to ensure optimal treatment and improve the outcome of these patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We compared the incidence, esophagogastroduodenoscopy (EGD) findings, and histopathologic characteristics of gastric and duodenal follicular lymphomas (FL). Of 626 FL cases, primary gastric FL and secondary gastric involvement of FL were observed in 1% and 5% of the cases, respectively, which were lower incidences than duodenal FL (10% and 9%, respectively). Gastric FL usually appeared as submucosal tumors (primary, 71%; secondary, 79%), whereas duodenal FL, as granular lesions (primary, 92%: secondary, 87%). In the granular duodenal lesions, the neoplastic follicles were located sparsely on the muscularis mucosa and could be found between villi, whereas in the stomach, similar lesions were hidden within the lamina propria, and only larger lesions such as submucosal tumors could be detected on the mucosal surface. The differences in the incidences and EGD findings were considered to be associated with structural differences of the lamina propria. Typical FL features: grades 1-2 histology, follicularity, and CD10 + and/or BCL6 + and BCL2 + were usually observed in all primary and secondary gastric and duodenal FL. Gastroduodenal and bone marrow involvement were found in 12% and 33% of the cases, respectively, and there was no significant correlation between them (P=.095). Twenty-nine cases (5%) were up-staged by gastroduodenal-positive results. In conclusion, the histopathology of gastric FL was similar to that of duodenal and nodal FL; the differences in the incidence and EGD findings between gastric and duodenal FL were considered to be associated with structural difference of the lamina propria, and EGD was useful as a staging procedure., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We analyzed the effects of the initial approach to patients with follicular lymphoma (FL) on outcomes in order to investigate whether the watch and wait (WW) strategy is still an acceptable approach in the rituximab era. We retrospectively analyzed 348 patients who were initially diagnosed with FL between 2000 and 2012. We compared the clinical outcomes of the WW cohort and immediate treatment cohort. Among 348 patients (median age of 57 years, range: 19-85), 101 were initially managed with WW and 247 were immediately treated. The median follow-up duration was 75 months (range: 7-169). The estimated median time to treatment failure (TTF) in the treatment following WW cohort and immediate treatment cohort were 92 months (95 % CI, 60.1-NA) and 77 months (95 % CI, 65.1-107.6), respectively, which were not significantly different (P = 0.272) . In a multivariate analysis, clinical stage was identified as a predictive factor of TTF (HR 1.19, 95 % CI, 1.03-1.38, P < 0.05). Neither overall survival rate nor cumulative risk of transformation between the WW cohort and immediate treatment cohort was significant. The results of the present study suggested that the WW strategy is still an acceptable approach for selected FL patients in the rituximab era., Competing Interests: Compliance with ethical standards Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standard of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this study, formal consent is not required. Fundings This work was supported in part by the National Cancer Center Research and Development Fund (26-A-4) and a grant for cancer research (Practical Research for Innovative Cancer Control) from the Japan Agency for Medical Research and Development (AMED). Conflict of interest Kensei Tobinai received research funding from Zenyaku Kogyo and Chugai Pharmaceutical.

This study aimed to indicate patient outcomes and pathological characteristics of follicular lymphoma (FL) with peripheral blood (PB) involvement. Of 533 patients with FL, 56 (11%) had PB involvement. Of the patients treated with rituximab, 39 patients with PB involvement had significantly shorter progression-free survival than 107 patients with stage IV disease without PB involvement (p = 0.021), but the overall survival was not different (p = 0.804). The histopathology of the primary sites was usually nodal (95%) low-grade (86%) FL with IGH/BCL2 fusion (75%). Flow cytometric and immunohistochemical analyses revealed that the incidence of CD10 positivity was lower in the bone marrow (55% and 58%) and PB (41% and not available) than in the primary site (86% and 93%) (p = 0.004 and p = 0.0001, respectively). Therefore, even if small lymphoma cells in the bone marrow and PB are negative for CD10, FL cannot be ruled out.

This study aimed to determine the correlations of 7 histopathologic prognostic indicators of follicular lymphoma (follicular lymphoma grade, CD10 expression, Bcl-2 expression, IGH/BCL2 fusion, diffuse area, fibrosis, and marginal zone differentiation) with progression-free survival, overall survival, and follicular lymphoma histologic grade in 255 follicular lymphoma patients who were treated with rituximab-containing therapy. The complete response, overall response, 6-year progression-free survival, and 6-year overall survival rates were 83%, 96%, 56%, and 97%, respectively. Patients with follicular lymphoma grades 3a and 3b showed 100% 6-year and 10-year overall survival, and progression-free survival did not significantly differ between patients with follicular lymphoma grade 3 and those with follicular lymphoma grades 1 and 2. The absence or presence of Bcl-2 expression and intensity of Bcl-2 expression were not significant prognostic indicators of progression-free survival and overall survival. Likewise, the presence of IGH/BCL2 fusion, diffuse area, fibrosis, and marginal zone differentiation were not significantly correlated with progression-free survival and overall survival. Follicular lymphoma grade 3 was correlated with nodal disease and negative or lower intensity of Bcl-2 expression, but not with age, stage, or IGH/BCL2 status. In the prerituximab era, grade 3 disease was reported to be associated with a poor prognosis; however, the opposite was true for patients treated with rituximab-containing therapy, regardless of their age or disease stage. Bcl-2 expression and marginal zone differentiation were not prognostic indicators in follicular lymphoma patients treated with rituximab-containing therapy., (© 2013.)

Recently, a CD20-negative phenotypic change in CD20-positive B-cell non-Hodgkin lymphoma (B-NHL) after rituximab therapy was described. We report the follow-up data of 10 B-NHL patients showing this change after rituximab therapy. Ten patients (4 men and 6 women; median age, 57 y) with B-NHL who were initially CD20 positive and became CD20 negative after rituximab therapy were analyzed. Clinicopathologic features, including clinical course, CD20 expression, and histopathology, were examined. CD20 expression in lymphoma cells was evaluated using immunohistochemistry and/or flow cytometry. Histopathologically, diagnosis at initial presentation was follicular lymphoma (FL) in 7 patients; diffuse large B-cell lymphoma in 1; and chronic lymphocytic leukemia in 2. Six patients (60%, 3 FL, 1 diffuse large B-cell lymphoma, and 2 chronic lymphocytic leukemia patients) showed continuous CD20 negativity until 24 months after the phenotypic change. Three patients (30%) with FL regained CD20 expression within 1 to 7 months after detection of the CD20 change. Two patients (20%) with FL, including 1 who regained CD20 expression, showed heterogenous CD20 expression with a CD20-negative low-grade component and a CD20-positive large cell component. The overall response rate to therapy before the CD20-negative change was 70%. We reported the follow-up data of 10 B-NHL patients with a CD20-negative phenotypic change associated with rituximab-containing therapy. The most common histologic phenotypes were continuous CD20 negativity, recovery of CD20 expression within 7 months, and heterogenous CD20 expression. As the changes in morphology and CD20 expression after rituximab therapy vary widely, careful follow-up and rebiopsy are recommended.