[Current standard treatments and future outlook for follicular lymphoma].

Follicular lymphoma (FL) is the most common subtype of indolent lymphoma. Survival outcomes for FL have improved since the introduction of anti-CD20 monoclonal antibodies, such as rituximab, and median overall survival has reached 15-20 years. However, FL is an incurable disease that subsequently progresses or relapses, and progression-free and overall survival tend to shorten with repeated relapses. For patients with limited-stage disease, radiation therapy is generally the treatment of choice and results in a median survival of approximately nearly 20 years. For advanced-stage patients with low tumor burden, watchful waiting continues to be the appropriate strategy at present. It remains unclear whether rituximab monotherapy might change this watchful waiting approach and result in a benefit from early intervention in patients with low tumor burden. For advanced-stage patients with high tumor burden, chemoimmunotherapy including rituximab or obinutuzumab followed by maintenance therapy is the standard treatment. For relapsed or refractory patients, treatment options such as chemoimmunotherapy, lenalidomide-rituximab, tazemetostat, chimeric antigen receptor T-cell therapies, and CD3/CD20 bispecific antibodies are available or in development. This review presents current standard treatments, recent advances, and future perspectives on the management of FL.

[Chinese expert consensus on the diagnosis and management of elderly patients with follicular lymphoma (2024)].

In the general population of China, the number of older patients with follicular lymphoma (FL) will continue to increase with age. The treatment of elderly patients with FL is based on individual principles, which focuses on the improvement of tumor-related symptoms and quality of life. To improve the diagnosis and treatment of elderly patients with FL in China, several organizations (i.e., Hematology Oncology Committee of China Anti-Cancer Association, etc.) have gathered relevant experts to formulate this consensus.

Preferences of patients and physicians in the United States for relapsed/refractory follicular lymphoma treatments.

BACKGROUND: Patients with follicular lymphoma (FL) often relapse or become refractory to treatment (R/R). While the R/R FL treatment landscape evolves, little is known about the priorities of patients and physicians. This discrete-choice experiment (DCE) study assessed patients' and physicians' treatment preferences, and the trade-offs they would be willing to make between efficacy, tolerability, and administration. METHODS: An online survey was conducted in US-based patients (≥18 years) with R/R FL and FL-treating physicians. The DCE was informed by a targeted literature review, clinical data, expert oncologist input, and pilot interviews. Participants completed eight experimental choice tasks where they chose between two hypothetical treatment profiles defined by six attributes: progression-free survival (PFS), administration/monitoring, risks of laboratory abnormalities requiring intervention, severe infections, diarrhea, and cytokine release syndrome (CRS). Relative attribute importance (RAI) and willingness to trade-off between PFS and other attributes were estimated. RESULTS: Two-hundred patients (mean age 63.5 years; median three prior lines of therapy) and 151 FL-treating physicians participated. Increasing PFS was most important for both groups, although it was relatively less important to patients than physicians (RAI 35.2% vs. 45.7%). Administration/monitoring was three times more important to patients than physicians (RAI 28.8% vs. 9.5%); patients preferred oral treatment and would be willing to tolerate a significant reduction in PFS for oral administration over weekly intravenous infusions. Avoiding CRS was less important to patients than to physicians (RAI 7.7% vs. 15.8%). Both groups would accept shorter PFS for reduced risks of side effects (especially of laboratory abnormalities for patients and of CRS for physicians). CONCLUSION: Although PFS was the most important attribute to patients and physicians, both would tolerate lower PFS for reduced side effects. Patients would also accept a substantial reduction in PFS for oral administration. Differences between the preferences/priorities of patients and physicians highlight the importance of shared decision-making.

[Transformation of Follicular Lymphoma into Composite Lymphoma: A Case Report and Literature Review]. / Transformación de un linfoma folicular a un linfoma compuesto. Reporte de un caso y revisión de la literatura.

Follicular lymphoma is a relatively indolent B-cell lymphoma composed of neoplastic centrocytes and centroblasts. The histologic transformation of follicular lymphoma is a well-described phenomenon with an average risk of 30% at ten years. The occurrence of Hodgkin lymphoma after follicular lymphoma, as well as composite lymphoma, is extremely rare. We report the case of a 79-year-old man with generalized lymphadenopathy who was diagnosed with follicular lymphoma and treated with six cycles of R-CHOP with a complete response. A lymph node biopsy three years later revealed persistent follicular lymphoma, after which the patient received radiotherapy. The patient returned with progressively enlarging axillary lymph nodes five years later. A lymph node biopsy demonstrated a composite lymphoma that was consistent with follicular lymphoma and Hodgkin lymphoma.

The landscape of T-cell engagers for the treatment of follicular lymphoma.

Follicular lymphoma (FL), the second most common subtype of non-Hodgkin lymphoma, relies on interactions with immune elements in the tumor microenvironment, including T-follicular helper cells and follicular dendritic cells, for its survival and progression. Despite its initial responsiveness to chemoimmunotherapy, FL is generally considered incurable. Strategies to improve immune-mediated control of FL could significantly benefit this population, particularly as it includes many elderly and comorbid patients. Immune cell engagers, especially bispecific antibodies (BsAbs), are crucial in targeting FL by bridging tumor and effector cells, thereby triggering T-cell activation and cytotoxic killing. CD3 × CD20 BsAbs have shown the most promise in clinical development for B-NHL patients, with structural variations affecting their target affinity and potency. This review summarizes the current clinical trials of BsAbs for relapsed/refractory FL, highlighting the approval of some agents, their role in first-line treatment or combination therapies, their toxicity profiles, and the future of this therapeutic approach compared to other immune cell therapies.

Impact of positive CD4 cells on event-free survival in follicular lymphoma patients.

OBJECTIVE: Previous results about prognostic value of CD4+ T cells in follicular lymphoma (FL) remain controversial. METHODS: Immunohistochemistry was used to examine expression of positive CD4 cells in 103 patients with FL 1-3A. Early failure was described as failing to achieve event-free survival (EFS) at 12 or 24 months. RESULTS: There were 49 (47.6%) male and 54 (52.4%) females, with a median age of 54 years. Compared to patients with <20% of positive CD4 cells, patients with ≥20% of positive CD4 cells exhibited a significant lower risk of early failure (2-year EFS rate: 56.7% vs 73.5%, p = 0.047). When patients were stratified based on positive CD4 cell combined with FLIPI, the median EFS (p = 0.002) and median OS (p = 0.007) were significantly different. CONCLUSIONS: This study demonstrated that higher expression of positive CD4 cells predicts lower risk of early failure in follicular lymphoma, and combination analysis of CD4 and FLIPI could better predict disease relapse and survival outcome.

[Prognostic value and imaging features of (18)F-FDG PET-CT in follicular lymphoma with different histopathology grade].

Follicular lymphoma (FL) is highly heterogeneous with different histopathologic grades. Its biological characteristics and clinical management are different. This study retrospectively analyzed (18)F-FDG PET-CT metabolic parameters, clinical features, and their relationship with prognosis in 161 FL patients with different histopathological grades (grade 1-2, grade 3A, grade 3B) at the Shanxi Cancer Hospital. There were 93 cases in the grade 1-2 group, 40 cases in the grade 3A group, and 28 cases in the grade 3B group. The expression of LDH, CD10, EZH2, c-Myc, and CD37 proteins was correlated with histological grade (grade 1-2, grade 3A, and grade 3B) (all P values<0.05) . The SUVmax, TLG, TBR, and TLR for the three groups were different (all P values<0.05) . The optimal thresholds of SUVmax, MTV, TLG, TBR, and TLR for predicting FL disease progression were 8.32, 201.31, 2 342.55, 6.56, and 3.52, respectively, and the rate of disease progression increased in patients with higher thresholds (all P value<0.05) . ß(2)-MG (>2.3 µg/L) , Follicular lymphoma international prognostic index-1 (FLIPI-1) score (3-5 points) , negative CD37 expression, positive c-Myc expression, and TLG (>2 342.55 g) were all independent risk factors for PFS in the FL patients (HR=3.609, 2.509, 0.255, 3.506, 13.531, all P value<0.05) . (18)F-FDG PET-CT is a powerful complement to FL histopathological grading and the combination of the two may better predict the prognosis of FL patients.

Aspiration Pneumonia Leading to Clostridium ramosum Bacteremia in a Neutropenic Patient: Case Report and Management Strategy.

BACKGROUND Clostridium ramosum is an anaerobic, spore-producing, gram-positive rod, enteric pathogen that is difficult to identify and is rarely pathogenic. We present a case of Clostridium ramosum bacteremia secondary to aspiration pneumonia in a 65-year-old immunocompromised man on chemotherapy for follicular lymphoma. CASE REPORT We report the case of a 65-year-old man, on active chemotherapy for follicular lymphoma, presenting with a fever of 38.3°C, nonproductive cough, fatigue, and confusion. Physical examination was unremarkable except for +2 lower-extremity pitting edema. CT abdomen pelvis showed left lower-lung consolidation and CT chest angiogram showed that the consolidation was concerning for infarct verses abscess and segmental/subsegmental pulmonary emboli despite anticoagulation use. Blood cultures later grew Clostridium ramosum, which was successfully treated with IV piperacillin-tazobactam. Subsequent outpatient imaging demonstrated resolution of the lung consolidation. CONCLUSIONS Our case highlights the rare diagnosis of Clostridium ramosum bacteremia secondary to aspiration pneumonia in an immunocompromised patient and our approach to management. We highlight the difficulties in identification of Clostridium ramosum, rare pathogenicity, risk factors, and potential sources.

The causal effect of telomere length on the risk of malignant lymphoma: A Mendelian randomization study.

Telomere length (TL) has been implicated in the risk assessment of numerous cancers in observational studies. Nevertheless, the relationship between TL and malignant lymphoma remains unclear, displaying inconsistent patterns across different studies. A summary dataset for genome-wide association study of TL and malignant lymphoma was acquired from the OpenGWAS website. An extensive 2-sample Mendelian randomization (MR) analysis was performed, encompassing various methodologies such as MR-Egger, weighted median, weighted mode, simple mode, and the primary method of inverse-variance weighting (IVW). Sensitivity evaluations were performed using the Cochran Q test, MR-Egger regression, and leave-one-out analysis. The main method IVW revealed that TL substantially increased the risk of Hodgkin lymphoma (HL; odds ratio [OR] = 2.135; 95% confidence interval [CI] = 1.181-3.859; P = .012). Both the IVW and weighted median methods indicated statistical associations between genetically predicted TL and other types of non-HL (OR = 1.671, 95% CI = 1.009-2.768, P = .045; OR = 2.310, 95% CI = 1.033-5.169, P = .042). However, there was no association between TL and diffuse large B-cell lymphoma, follicular lymphoma, or mature T/natural Killer-cell lymphoma, and sensitivity analysis revealed no heterogeneity or horizontal pleiotropy, indicating that the causal effect was robust. Our study shows that TL plays different roles in different types of lymphomas. A longer TL significantly increases the risk of HL and other types of non-HL.

Duodenal-type follicular lymphoma: comprehensive insights into disease characteristics and established treatment strategies.

PURPOSE OF REVIEW: This review aims to detail the characteristics and outcomes of duodenal-type follicular lymphoma (DTFL), a rare lymphoma variant. It focuses on integrating recent reports in treatment modalities and highlights emerging insights into the unique biological features of the disease. RECENT FINDING: Recent studies confirm the indolent nature of DTFL, with extended follow-up periods showing favorable outcomes under watchful waiting strategies and a notable proportion of patients experiencing spontaneous remission. Additionally, advancements in understanding the disease's biology revealed that the tumor microenvironment is marked by specific genomic expressions indicative of chronic inflammation. SUMMARY: The observations of spontaneous resolution and the generally favorable progression of DTFL call for a conservative approach in initiating treatment. Clinical management should judiciously consider the disease's typically benign course against the potential risks of intervention, promoting customized treatment protocols tailored for cases with clinical necessity. Additionally, the discovery of an inflammatory tumor microenvironment and molecular evidence suggesting an antigen-driven process highlight critical areas for future research.

Follicular Lymphoma in Chile in the Adult Public Cancer Program: The Impact of Chemoimmunotherapy.

BACKGROUND: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL) in the United States and Europe. However, data on FL from Latin America are scant. AIMS: This study aims at better understand the clinical features, treatment patterns and outcomes of patients with FL in Chile. Of special interest was to evaluate POD24 as an adverse marker. METHODS AND RESULTS: We collected retrospective data from 722 patients 15 years or older diagnosed with FL and treated in 17 cancer centers in Chile between 2000 and 2019. Time to first treatment (TTFT), progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional-hazard regression models were fitted to investigate prognostic factor. The median age at diagnosis was 62 with a female predominance (63%); 73% of patients had advance stage disease and 68% had bone marrow involvement; 63% had intermediate or high FLIPI scores. The 1-year TTFT rate was 96%, and 30% of patients received chemoimmunotherapy. Adding rituximab to chemotherapy was associated with a higher complete response (69% vs. 60%; p < 0.001) and superior median OS (16 vs. 8 years; p < 0.001). Patients who experience POD24 had an inferior median OS (2.4 vs. 15 years). CONCLUSION: Our study shows a female predominance in patients with FL in Chile and confirms superior response and survival outcomes with adding rituximab to chemotherapy. Our study also confirms a poor OS in patients who experience POD24.

Mosunetuzumab for the treatment of follicular lymphoma.

INTRODUCTION: Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma that shows a progressive increase in relapses and refractory in its natural history and a median survival of approximately 18-20 years. The advent of anti-CD20 monoclonal antibodies has changed the FL therapeutic algorithm, with an increase in progression-free survival. T-cell-dependent bispecific antibodies (BsAbs) represent an emerging drug class against FL. AREAS COVERED: In this review, we selected papers from the principal databases (PubMed, Medline, Medscape, ASCO, ESMO) between January 2021 and June 2024, using the keywords 'mosunetuzumab' and 'follicular lymphoma' to provide an overview of mosunetuzumab-axgb, a pioneering BsAb. Its mechanism of action, efficacy, safety, and future perspectives were analyzed. EXPERT OPINION: Mosunetuzumab grants a directing T-cell mediated cytotoxicity and allows a step-up dosing that reduces adverse events, such as cytokine release syndrome, with promising tolerability. At the same time, it improves outcomes in the evolving landscape of FL management, even in post-CAR-T FL patients. Prognostic factors and targetable mechanisms of resistance need to be explored.

Recent developments in CD19-targeted therapies for follicular lymphoma.

INTRODUCTION: CD19 has emerged as an important and novel therapeutic target in follicular lymphoma. CD19-directed therapies, including monoclonal antibodies, bispecific antibodies, and CAR T-cell therapies, offer promising avenues for treating follicular lymphoma and improving outcomes. AREAS COVERED: We review the role and rationale of targeting CD19 in follicular lymphoma and different interventions of CD19 targeting, such as cell therapy, bispecific antibodies, antibody-drug conjugates, and monoclonal antibodies. We finalize with a discussion on how these therapies may influence the treatment landscape of follicular lymphoma. EXPERT OPINION: CD19 is an attractive target for therapeutic development in follicular lymphoma. Given its effectiveness, it will continue to move forward as a promising therapy for this disease.

Transformed follicular lymphoma with laryngeal edema requiring tracheal intubation after tisagenlecleucel treatment: A case report.

RATIONALE: Cytokine release syndrome (CRS) is a common adverse event of chimeric antigen receptor T (CAR-T) cell therapy. CRS is generally a systemic inflammatory reaction, but in rare cases, it can occur in specific body areas and is referred to as "local CRS (L-CRS)." A case of laryngeal edema due to L-CRS that required tracheal intubation because of the lack of response to tocilizumab (TCZ) and dexamethasone (DEX) is reported. PATIENT CONCERNS: A 67-year-old woman with relapsed transformed follicular lymphoma was treated with CAR-T cell therapy. Although she had been given TCZ and DEX for CRS, neck swelling appeared on day 4 after infusion. DIAGNOSES: Laryngoscopy showed severe laryngeal edema, which was presumed to be due to L-CRS, since there were no other apparent triggers based on history, physical examination, and computed tomography. INTERVENTIONS: Tracheal intubation was performed because of the risk of upper airway obstruction. Ultimately, 4 doses of tocilizumab (8 mg/kg) and 6 doses of dexamethasone (10 mg/body) were required to improve the L-CRS. OUTCOMES: On day 7, laryngeal edema improved, and the patient could be extubated. LESSONS: The lessons from this case are, first, that CAR-T cell therapy may induce laryngeal edema in L-CRS. Second, TCZ alone may be ineffective in cervical L-CRS. Third, TCZ, as well as DEX, may be inadequate. In such cases, we should recognize L-CRS and manage it early because it may eventually progress to laryngeal edema that requires securing the airway.

Association of both BCL2 positive and negative follicular lymphoma to clasical Hodgkin lymphoma and/or gray zone lymphoma.

We present a series of 9 follicular lymphomas that progressed/transformed into classical Hodgkin lymphoma (CHL). Three cases of CHL showed a syncytial pattern (SCHL) making the differential diagnosis to Gray zone lymphoma (GZL) challenging. None of these three cases presented in the mediastinum. Based in all molecular data analyzed (BCL2/BCL6 FISH studies, IgH PCR and TNGS with a customized gene panel) we did find clonal relationship between the BCL2-positive FL cases and their CHL components in all cases. The three SCHL/GZL cases showed an activated phenotype according to Hans algorithm, presented the t(14; 18)(q32; q21), two out of three showed B cell markers and all expressed CD30 and p53. Interestingly, we identified three BCL2-negative FL cases with a further diagnosis of CHL expanding the spectrum of these association. In one of these three cases a different mutational profile was found in both the FL and the CHL components. All this data together suggests that CHL associated to BCL2-positive FL could be originated in a common progenitor cell (CPC) that give rise to both FL and CHL, acquiring this last component further genetic events in a linear fashion. On the other hand, no clonal relationship between CHL and BCL2-negative FL could be found, suggesting a fortuity association. Nevertheless, ample series of cases studied with more sensitive techniques are needed to confirm our hypothesis.

Diagnosis, management and follow-up of follicular lymphoma: a consensus practice statement from the Australasian Lymphoma Alliance.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma subtype, accounting for 15-20% of all lymphoma diagnoses. Although typically slow-growing and responsive to frontline therapies, advanced-stage FL remains incurable with current treatments and typically follows a chronic relapsing/remitting course with increasingly shorter responses to subsequent lines of therapy. Outcomes are highly variable; some patients experience prolonged first remissions that may approximate a 'functional cure'. By contrast, a significant minority of patients experience disease progression shortly after frontline treatment resulting in high rates of lymphoma-related mortality. Reflecting on the heterogeneous natural history of FL, clinical practice varies widely, particularly in controversial areas, including appropriate disease staging, selection of management strategies and duration of clinical follow-up. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice.

Identification of genetic subtypes in follicular lymphoma.

Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma.

Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL.