[Modified Premedication of Infusion Reaction with Obinutuzumab Therapy].

Obinutuzumab frequently triggers an infusion reaction(IR). In the GALLIUM study, despite the use of corticosteroids, antipyretic analgesics, and antihistamines to prevent IR, IR occurred at a high frequency of 68.2% for all Grades and 12.4% for Grades 3 or higher. The dose of methylprednisolone was increased from 80 mg administered in the GALLIUM study to 125 mg, and the development of IR was investigated in 30 patients with follicular lymphoma who received the initial dose of obinutuzumab. The incidence of IR was 43.3% for all Grades and 0% for Grades 3 or higher, and no serious IR was observed. It also had no effect on infectious diseases. Increased doses of corticosteroids were well tolerated and suggested as an effective method for reducing the frequency of IR.

Clinical efficacy and safety of subcutaneous rituximab in non-Hodgkin lymphoma: a systematic literature review and meta-analysis.

OBJECTIVES: The role of subcutaneous (SC) rituximab in the efficacy and safety to non-Hodgkin lymphoma (NHL) is not clear enough. The purpose of this study was to conduct a systematic review and meta-analysis, to assess the efficacy and safety of subcutaneous rituximab to NHL. METHOD: A full-scale search was carried out based on the set search terms in PubMed, Web of Science, Embase and Cochrane CENTRAL until 12 October 2022 to identify relevant studies of subcutaneous rituximab for NHL. The efficacy and safety outcomes included complete response (CR) plus unconfirmed complete response (CRu), adverse events (AEs), grade ≥3 AEs, serious adverse events (SAEs), administration-related reactions (ARRs), adverse reaction rates. RESULTS: From a total of 758 studies, 9 trials were eligible. The CR/CRu of patients with NHL receiving SC rituximab was 57%, 55% for Diffuse large B-cell lymphoma (DLBCL) and 54% for Follicular lymphoma (FL). The meta-analysis performed on safety demonstrated that AEs of NHL patients with SC rituximab was 85%, grade ≥3 AEs was 38%, SAE was 27% and ARR was 33%. The result also showed that SC rituximab had a high risk of neutropenia and nausea. CONCLUSION: For NHL patients, there is no significant difference in the efficacy between subcutaneous rituximab and conventional therapy, while subcutaneous injection can shorten exposure time in the hospital and reduce the risk of infection.

Efficacy and safety of rituximab biosimilars or reference product as first-line treatment in patients with low-tumour-burden follicular lymphoma: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: The role of rituximab in the first-line treatment of low-tumour-burden follicular lymphoma (LTB-FL) has been supported by a large number of data. However, whether rituximab biosimilars have the same efficacy and safety as the reference drug (MabThera) is still controversial. METHODS: Electronic databases and the ClinicalTrail.gov website were extensively searched using relevant search criteria. The risk of bias of the included studies was assessed using the RoB 2 assessment scale, and the RevMan 5.4 statistical software was used for meta-analysis. RESULTS AND DISCUSSION: A total of 1223 patients were included in four clinical randomized controlled trials. There was no statistical difference in efficacy between biosimilars and MabThera groups (the objective response rate: RR = 1.00, 95% CI: 0.93-1.08, p = 0.92; the progression-free survival: RR = 1.04, 95% CI: 0.96-1.12, p = 0.30; the overall survival: RR = 1.00, 95% CI: 0.98-1.03, p = 0.76; the serious adverse events: RR = 1.15, 95% CI: 0.69-1.89, p = 0.59; the infusion-related reaction: RR = 0.91, 95% CI: 0.77-1.09, p = 0.32). In terms of safety, there was also no significant difference between two groups. WHAT IS NEW AND CONCLUSION: Our study concluded that the efficacy and safety of rituximab biosimilars in the treatment of LTB-FL are highly similar to those of the original drug.

Ibrutinib, rituximab, and lenalidomide in unfit or frail patients aged 75 years or older with de novo diffuse large B-cell lymphoma: a phase 2, single-arm study.

BACKGROUND: The optimal treatment for older adults with diffuse large B-cell lymphoma (DLBCL) needs to be further explored due to patient comorbidities, standard immunochemotherapy intolerance, and unfavourable genetic features. We did a phase 2 trial of ibrutinib, rituximab, and lenalidomide (iR2) to evaluate the efficacy and safety in older adult patients with de novo DLBCL. METHODS: In this phase 2, single-arm study, unfit or frail patients with de novo DLBCL aged 75 years or older were enrolled at Shanghai Ruijin Hospital, Shanghai, China. During the induction phase from cycle 1 to 6, 560 mg ibrutinib was given orally daily throughout each 21-day treatment cycle, 375 mg/m2 rituximab was given intravenously on day 1, and 25 mg lenalidomide was given orally daily from day 1 to 10 in each cycle. Patients who had a complete response after induction were given another 6 cycles of lenalidomide maintenance (25 mg orally daily from day 1 to 10 every 21 days from cycle 7 to 12). The primary endpoint was complete response rate after 6 cycles or at the end of the induction treatment. This trial is registered with ClinicalTrials.gov, NCT03949062. FINDINGS: Between May 15, 2019, and May 8, 2020, a total of 30 patients were enrolled. The end of induction complete response rate was 56·7% (95% CI 37·4-74·5), and overall response rate was 66·7% (95% CI 47·2-82·7). With a median follow-up of 27·6 months (IQR 23·9-29·6), the 2-year progression-free survival rate was 53·3% (95% CI 34·3-69·1) and the 2-year overall survival rate was 66·7% (95% CI 46·9-80·5). The main grade 3-4 haematological adverse events were neutropenia (seven patients [23%]), thrombocytopenia (three patients [10%]), and anaemia (two patients [7%]). The most common grade 3-4 non-haematological adverse event was pulmonary infection (seven patients [23%]). Atrial fibrillation was observed in three (10%) patients, including one grade 2 and two grade 3. INTERPRETATION: A chemotherapy-free iR2 regimen is clinically effective and safe and warrants further investigation in phase 3 trials as first-line treatment in older adult patients with DLBCL. FUNDING: National Natural Science Foundation of China, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Clinical Research Plan of Shanghai Hospital Development Center, and Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine.

Small intestinal follicular lymphoma induced by methotrexate: a case report.

BACKGROUND: Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a rare but critical complication that develops in patients treated with MTX. Although MTX-LPD has been recently reported, the incidence of follicular lymphoma in the intestine is very low. CASE PRESENTATION: A 73-year-old woman who had been receiving MTX for over 10 years visited our hospital complaining of postprandial abdominal pain and nausea. Upper and lower digestive tract endoscopies did not show any abnormal findings. A patency capsule was stagnated at the proximal part of the ileum with a mild dilation on the oral side. An oral balloon endoscopy revealed shallow ulcerative lesions in the jejunum. She was diagnosed with MTX-LPD based on histopathological findings. The symptoms did not improve with the discontinuation of MTX, and the patient required partial resection of the small intestine. The test result for Epstein-Barr virus-encoded small RNA was negative. She was diagnosed with follicular lymphoma based on the histology findings of a surgical specimen. Postoperative positron emission tomography-computed tomography and bone marrow aspiration did not show any findings of lymphoma. On follow-up, no recurrence was noted four years after the surgery. CONCLUSIONS: Herein, we report the first case of follicular lymphoma that occurred in the small intestine, negative for Epstein-Barr virus-encoded small RNA. If intestinal symptoms occur during MTX administration, it is important to directly observe by endoscopy and perform histological examination.

A systematic review and meta-analysis of occupational exposures and risk of follicular lymphoma.

BACKGROUND: The etiology of follicular lymphoma (FL), a common non-Hodgkin lymphoma subtype, is largely unknown. OBJECTIVE: We performed a systematic review and meta-analysis of observational studies examining the relationship between occupational exposures and FL risk. METHODS: We searched Ovid MEDLINE, Ovid EMBASE, and Web of Science for eligible observational studies examining job titles or occupational exposures prior to January 1, 2020. We performed a narrative synthesis and used random-effects models to generate meta-estimates of relative risk (RR) with 95% confidence intervals (95%CI) for exposures reported by three or more studies. RESULTS: Fifty-eight studies were eligible. Ten cohort and 37 case-control studies quantified FL risk in relation to any exposure to one or more occupational groups or agents. Eight cohort and 19 case-control studies examined dose-response relationships. We found evidence of a positive association with increasing plasma concentration of dichlorodiphenyldichloroethylene (DDE; meta-RR = 1.51, 95%CI = 0.99, 2.31; I2 = 0.0%) and polychlorinated biphenyls (PCBs; meta-RR = 1.47, 95%CI = 0.97, 2.24; I2 = 8.6%). We observed a positive association with exposure to any solvent (meta-RR = 1.16, 95%CI = 1.00, 1.34; I2 = 0.0%) and chlorinated solvents (meta-RR = 1.35, 95%CI = 1.09, 1.68; I2 = 0.0%). Single studies reported a significant positive dose-response association for exposure to any pesticide, hexachlorobenzene, any organophosphate, diazinon, metolachlor, carbaryl, lindane, trichloroethylene, oils/greases, and extremely low-frequency magnetic fields. Job title-only analyses suggested increased risk for medical doctors and spray painters, and decreased risk for bakers and teachers. Overall, studies demonstrated low risk of bias, but most studies examined small numbers of exposed cases. CONCLUSIONS: Current evidence indicates a positive association between FL and occupational exposure to DDE, PCBs, any solvent and chlorinated solvents. Our findings may help guide policies and practices on the safe use of solvents and inform models of lymphomagenesis. Future studies with larger sample sizes and comprehensive quantitative exposure measures may elucidate other avoidable carcinogenic exposures.

Insecticide use and risk of non-Hodgkin lymphoma subtypes: A subset meta-analysis of the North American Pooled Project.

Insecticide use has been linked to increased risk of non-Hodgkin lymphoma (NHL), however, findings of epidemiologic studies have been inconsistent, particularly for NHL subtypes. We analyzed 1690 NHL cases and 5131 controls in the North American Pooled Project (NAPP) to investigate self-reported insecticide use and risk of NHL overall and by subtypes: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and small lymphocytic lymphoma (SLL). Odds ratios (OR) and 95% confidence intervals for each insecticide were estimated using logistic regression. Subtype-specific associations were evaluated using ASSET (Association analysis for SubSETs). Increased risks of multiple NHL subtypes were observed for lindane (OR = 1.60, 1.20-2.10: FL, DLCBL, SLL), chlordane (OR = 1.59, 1.17-2.16: FL, SLL) and DDT (OR = 1.36, 1.06-1.73: DLBCL, SLL). Positive trends were observed, within the subsets with identified associations, for increasing categories of exposure duration for lindane (Ptrend = 1.7 × 10-4 ), chlordane (Ptrend = 1.0 × 10-3 ) and DDT (Ptrend = 4.2 × 10-3 ), however, the exposure-response relationship was nonlinear. Ever use of pyrethrum was associated with an increased risk of FL (OR = 3.65, 1.45-9.15), and the relationship with duration of use appeared monotonic (OR for >10 years: OR = 5.38, 1.75-16.53; Ptrend = 3.6 × 10-3 ). Our analysis identified several novel associations between insecticide use and specific NHL subtypes, suggesting possible etiologic heterogeneity in the context of pesticide exposure.

Follicular lymphoma generating in a patient with non-small cell lung cancer following nivolumab discontinuation.

INTRODUCTION: Immune checkpoint inhibitors have demonstrated the benefit for many cancer types, melanoma, non-small cell lung cancer, urothelial cancer, renal cell cancer, etc. Especially in advanced non-small cell lung cancer, significant improvement in survival results has been shown. CASE REPORT: Here, we report a 66-year-old man with lung adenocarcinoma who received nivolumab for 80 cycles.Management and Outcome: Two months after discontinuing nivolumab, he developed follicular lymphoma. Pneumonitis was also accompanied, which was treated with metilprednisolon, but he died due to progressive respiratory failure. DISCUSSION: Our clinical knowledge with checkpoint inhibitors is increasing day by day, and to the best of our knowledge, this paper presents the first case in the English literature who developed follicular lymphoma after discontinuing nivolumab in non-small cell lung cancer patient.

Transformation of follicular lymphoma to double-hit lymphoma during adjuvant chemotherapy for concurrent ovarian carcinoma.

The frequency of multiple primary malignant neoplasms (MPMN) is increasing due to population aging. Since consensus guidelines for the treatment of MPMN are lacking, treatment strategies are determined by disease status on a per-patient basis. In this report, we describe a case of MPMN with follicular lymphoma (FL) grade 1 that transformed to double-hit lymphoma during adjuvant chemotherapy for concurrent ovarian carcinoma. A 64-year-old woman was diagnosed with MPMN of FL and endometrioid carcinoma by staging laparotomy and lymph node biopsy. She received four cycles of adjuvant chemotherapy (carboplatin and paclitaxel) for endometrioid carcinoma, but during chemotherapy, the FL grade 1 transformed to double-hit lymphoma. We speculate that adjuvant chemotherapy for endometrioid carcinoma may have triggered the transformation of FL in the present case.

A case of lymphoma in a patient on teriflunomide treatment for relapsing multiple sclerosis.

Teriflunomide is an oral therapy approved for relapsing forms of multiple sclerosis which has been shown to reduce relapse rate and disability progression. We report the case of a 54-year -old black woman with multiple sclerosis who developed follicular lymphoma after about 8 months of exposure to teriflunomide. Importantly, apart from age, the patient had none of the established risk factors for follicular lymphoma. Moreover, although this is the first published case of a lymphoma on teriflunomide, it is not the first confirmed case. Ten other cases have so far been reported to pharmacovigilance worldwide, and a further 82 with leflunomide. In conclusion, an association between teriflunomide and a higher risk of lymphoma cannot be ruled out.

Occupational exposure to trichloroethylene and risk of non-Hodgkin lymphoma and its major subtypes: a pooled InterLymph [correction of IinterLlymph] analysis.

OBJECTIVES: We evaluated the association between occupational exposure to trichloroethylene (TCE) and risk of non-Hodgkin lymphoma (NHL) in a pooled analysis of four international case-control studies. METHODS: Overall, the pooled study population included 3788 NHL cases and 4279 controls. Risk of NHL and its major subtypes associated with TCE exposure was calculated with unconditional logistic regression and polytomous regression analysis, adjusting by age, gender and study. RESULTS: Risk of follicular lymphoma (FL), but not NHL overall or other subtypes, increased by probability (p=0.02) and intensity level (p=0.04), and with the combined analysis of four exposure metrics assumed as independent (p=0.004). After restricting the analysis to the most likely exposed study subjects, risk of NHL overall, FL and chronic lymphocytic leukaemia (CLL) were elevated and increased by duration of exposure (p=0.009, p=0.04 and p=0.01, respectively) and with the combined analysis of duration, frequency and intensity of exposure (p=0.004, p=0.015 and p=0.005, respectively). Although based on small numbers of exposed, risk of all the major NHL subtypes, namely diffuse large B-cell lymphoma, FL and CLL, showed increases in risk ranging 2-3.2-fold in the highest category of exposure intensity. No significant heterogeneity in risk was detected by major NHL subtypes or by study. CONCLUSIONS: Our pooled analysis apparently supports the hypothesis of an increase in risk of specific NHL subtypes associated with occupational exposure to TCE.

Personal use of hair dyes--increased risk of non-Hodgkin's lymphoma in Thailand.

The use of hair dyes has been inconsistently associated with an increased risk of lymphomas. To further evaluate this possibility, we examined hair dye use and lymphoma risk in a case-control study in the Thai population. A total of 390 histologically confirmed incident non-Hodgkin's lymphoma (NHL) cases and 422 controls were included. Information on hair dye use was obtained through a personal interview together with information on other known risk factors of lymphoma. Analysis was performed using logistic regression; odds ratios (ORs) estimates and 95% confidence intervals (CI) were calculated. Ever use of hair dyes was not associated with an increase risk of NHL both overall (OR=1.1, 95%CI 0.8-1.5) and in women (OR=1.4, 95%CI 0.9-2.3). However, NHL was significantly higher among persons who began using hair dyes before 1980 (OR=2.1, 95%CI 1.0-4.1). An increased risk was also observed among women who reported use of permanent hair dye product (OR=1.8, 95% CI 1.0-3.1). Analyses by NHL subtype showed an increased risk for diffuse large B-cell lymphoma among users of permanent hair dyes (OR=1.6, 95%CI 1.0-2.5) while follicular lymphoma was associated with the use of dark-colored dyes (OR=3.7, 95%CI 1.1-12.8). No association was observed with duration of use, nor total lifetime applications. These results indicate that personal hair dye use may play role in risks of NHL among person who used hair dyes before 1980.

Oral contraceptives, menopausal hormone therapy use and risk of B-cell non-Hodgkin lymphoma in the California Teachers Study.

We examined oral contraceptive (OC) and menopausal hormonal therapy (MHT) use in relation to risk of B-cell non-Hodgkin lymphoma (NHL). Women under age 85 years participating in the California Teachers Study with no history of hematopoietic cancer were followed from 1995 through 2007. A total of 516 of 114,131 women eligible for OC use analysis and 402 of 54,758 postmenopausal women eligible for MHT use analysis developed B-cell NHL. Multivariable adjusted and age stratified Cox proportional hazards models were fit to estimate relative risks (RRs) and 95% confidence intervals (95% CI). Ever versus never OC use was marginally associated with lower B-cell NHL risk, particularly among women first using OCs before age 25 years (RR=0.72, 95% CI=0.51-0.99); yet, no duration-response effect was observed. No association was observed for ever versus never MHT use among postmenopausal women (RR=1.05, 95% CI=0.83-1.33) overall or by formulation (estrogen alone, ET, or estrogen plus progestin, EPT). Among women with no MHT use, having bilateral oophorectomy plus hysterectomy was associated with greater B-cell NHL risk than having natural menopause (RR=3.15, 95% CI=1.62-6.13). Bilateral oophorectomy plus hysterectomy was not associated with risk among women who used ET or EPT. These results indicate that exogenous hormone use does not strongly influence B-cell NHL risk.

Risk of non-Hodgkin lymphoma and nitrate and nitrite from the diet in Connecticut women.

It has been estimated that 65,980 individuals were diagnosed with non-Hodgkin lymphoma (NHL) and 19,500 died from NHL in the United States in 2009. Although established risk factors such as immunodeficiency and viral infections may be responsible for a portion of the cases, the majority of NHL cases remain unexplained. Dietary nitrate and nitrite intake are exposures of particular interest for NHL risk as they are precursors in the endogenous formation of N-nitroso compounds, which cause lymphomas in animal studies. We investigated NHL risk overall and by histologic type in relation to dietary nitrate and nitrite intake in a population-based case-control study of 1,304 women in Connecticut. Nitrate and nitrite intake were assessed using a 120-item food frequency questionnaire. We found no association between risk of NHL overall and dietary nitrate and a slightly increased risk of NHL with higher dietary nitrite intake (highest vs. lowest intake quartile OR = 1.4; 95% CI: 0.9-2.2). When we evaluated intake by subtype, a significant positive trend was observed for follicular lymphoma and nitrate (p-trend = 0.04) and nitrite (p-trend < 0.01) with an over twofold risk in the highest nitrite intake quartile (OR = 2.3; 95% CI: 1.1-4.9). An increased risk in the highest quartile of nitrite intake was also observed for T-cell lymphoma (OR = 3.4; 95% CI: 1.0-11.9). Animal products containing nitrite were more strongly associated with risk of follicular lymphoma; whereas, both animal and plant sources of nitrite were associated with elevated ORs for T-cell lymphoma. Our results confirm a previous finding for nitrite intake and NHL risk and highlight the importance of evaluating histologic type. We conclude that these results should be replicated in a larger study with data on drinking water as well as dietary sources of nitrate intake.

Agricultural pesticide exposure and the molecular connection to lymphomagenesis.

The t(14;18) translocation constitutes the initiating event of a causative cascade leading to follicular lymphoma (FL). t(14;18) translocations are present in blood from healthy individuals, but there is a trend of increased prevalence in farmers exposed to pesticides, a group recently associated with higher risk of t(14;18)(+) non-Hodgkin's lymphoma development. A direct connection between agricultural pesticide use, t(14;18) in blood, and malignant progression, however, has not yet been demonstrated. We followed t(14;18) clonal evolution over 9 yr in a cohort of farmers exposed to pesticides. We show that exposed individuals bear particularly high t(14;18) frequencies in blood because of a dramatic clonal expansion of activated t(14;18)(+) B cells. We further demonstrate that such t(14;18)(+) clones recapitulate the hallmark features of developmentally blocked FL cells, with some displaying aberrant activation-induced cytidine deaminase activity linked to malignant progression. Collectively, our data establish that expanded t(14;18)(+) clones constitute bona fide precursors at various stages of FL development, and provide a molecular connection between agricultural pesticide exposure, t(14;18) frequency in blood, and clonal progression.

Leukemic phase of follicular lymphoma after treatment with etanercept in a patient with psoriasis.

Etanercept, a fully human soluble recombinant p75 tumor necrosis factor (TNF) receptor that blocks the binding of TNF to cell surface receptors, is approved for the treatment of psoriatic arthritis and other rheumatic conditions in the US and Europe. Ever since the introduction of anti-TNF treatment in patients with inflammatory autoimmune diseases, there have been concerns about a possible tumor-promoting effect of such a measure. We report a rare case of leukemic phase of follicular lymphoma in a 62-year-old man with moderate-to-severe plaque psoriasis receiving long-term treatment with etanercept for 3 years. Although the association is intriguing, no causal relationship is suggested.

Personal use of hair dye and the risk of certain subtypes of non-Hodgkin lymphoma.

Personal use of hair dye has been inconsistently linked to risk of non-Hodgkin lymphoma (NHL), perhaps because of small samples or a lack of detailed information on personal hair-dye use in previous studies. This study included 4,461 NHL cases and 5,799 controls from the International Lymphoma Epidemiology Consortium 1988-2003. Increased risk of NHL (odds ratio (OR) = 1.3, 95% confidence interval (CI): 1.1, 1.4) associated with hair-dye use was observed among women who began using hair dye before 1980. Analyses by NHL subtype showed increased risk for follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) but not for other NHL subtypes. The increased risks of FL (OR = 1.4, 95% CI: 1.1, 1.9) and CLL/SLL (OR = 1.5, 95% CI: 1.1, 2.0) were mainly observed among women who started using hair dyes before 1980. For women who began using hair dye in 1980 or afterward, increased FL risk was limited to users of dark-colored dyes (OR = 1.5, 95% CI: 1.1, 2.0). These results indicate that personal hair-dye use may play a role in risks of FL and CLL/SLL in women who started use before 1980 and that increased risk of FL among women who started use during or after 1980 cannot be excluded.

Association between personal use of hair dyes and lymphoid neoplasms in Europe.

Hair dyes have been evaluated as possibly being mutagenic and carcinogenic in animals. Studies of the association between human cancer risk and use of hair dyes have yielded inconsistent results. The authors evaluated the risk of lymphoid malignancies associated with personal use of hair dyes. The analysis included 2,302 incident cases of lymphoid neoplasms and 2,417 hospital- or population-based controls from the Czech Republic, France, Germany, Ireland, Italy, and Spain (1998-2003). Use of hair dyes was reported by 74% of women and 7% of men. Lymphoma risk among dye users was significantly increased by 19% in comparison with never use (odds ratio (OR) = 1.19, 95% confidence interval (CI): 1.00, 1.41) and by 26% among persons who used hair dyes 12 or more times per year (OR = 1.26, 95% CI: 1.00, 1.60; p for linear trend = 0.414). Lymphoma risk was significantly higher among persons who had started coloring their hair before 1980 (OR = 1.37, 95% CI: 1.09, 1.72) and persons who had used hair dyes only before 1980 (OR = 1.62, 95% CI: 1.10, 2.40). Personal use of hair dyes is associated with a moderate increase in lymphoma risk, particularly among women and persons who used dyes before 1980. Specific compounds associated with this risk remain to be elucidated.