Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma: additional evidence to support they are a single disease with variation in the histologic spectrum.

Pediatric-type follicular lymphoma (PTFL) and pediatric nodal marginal zone lymphoma (PNMZL) are two rare indolent B-cell lymphomas with overlapping features. Recently, cases showing hybridizing features of PTFL and PNMZL have been reported. Herein, we retrospectively analyzed the clinicopathologic features of 59 patients, including 39 with PTFL, 5 with PNMZL, and 15 with mixed-type tumors (MTT). And next-generation sequencing analysis was performed on 3 PTFL, 2 PNMZL, and 2 MTT cases. In addition, previously published mutational data of 96 PTFLs, 25 PNMZLs, and 46 MTTs were also analyzed. There were 52 male and 7 female patients, with a median age of 17 years. Most patients (96.6%) had lymph node involvement in the head and neck region and were diagnosed with stage I disease. Among the 50 patients (85%) with telephone follow-up, 44 (88%) adopted a watch-and-wait strategy after surgical resection of the lesions. Only one PTFL patient experienced a relapse 6 months after diagnosis. Microscopically, not only the MTT cases showed a composite form of enlarged follicles and interfollicular lymphocytic proliferation producing a progressively transformed germinal center (PTGC) pattern, but also focal follicles with a PTGC-like pattern were observed in PTFL cases. Genetically, the most frequently mutated genes were TNFRSF14 (in 3 PTFLs and 2 MTTs), MAP2K1 (in 2 PTFLs, 1 PNMZL and 1 MTT), and IRF8 (in 2 MTTs and 1 PNMZL). Based on the similar or overlapping clinical, pathologic, and genetic features, PTFL and PNMZL are likely to represent two different histologic patterns of the same disease.

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.

A case of grade1 follicular lymphoma diagnosed by laparoscopic lymph node resection: differentiating from late lymph node recurrence of endometrial cancer.

Follicular lymphoma is a common hematologic malignancy; however, it is less common among all malignant diseases and is difficult to suspect in advance due to the lack of specific clinical findings. Here, we report a case in which a late recurrence of corpus cancer was first suspected and finally diagnosed as follicular lymphoma. A 67-year-old female presented to our department with enlarged pelvic lymph nodes. She was diagnosed with breast cancer (HER2-posiotive with lymph node metastasis) and corpus cancer (endometrioid carcinoma grade 2, stage IA) 16 years prior, received definitive therapy and was followed up. A positron emission tomography scan was performed, and an accumulation of 18F-fluorodeoxyglucose (FDG) was detected in multiple lymph nodes, including the lymph nodes with no change in size or enlargement. We performed laparoscopic resection of the enlarged and FDG-accumulated lymph nodes and a pathological examination. The patient was diagnosed with follicular lymphoma (FL) grade 1 and is currently under observation at the Department of Hematology. FL can be considered when there is a discrepancy between the change in lymph node size and the degree of FDG accumulation. A pathological examination is useful for accurate diagnosis. Therefore, it is important to consider tissue collection; however, care must be taken to minimize the invasiveness of the procedure for the patient.

Complete response using the EZH2 inhibitor tazemetostat against multiple relapsed follicular lymphoma in the leukemic phase.

Though multiple relapses and serial shortening of remission is one of the characteristics of follicular lymphoma (FL), standard third- and later-line treatments with clear evidence have not yet been established. Tazemetostat, the first oral enhancer of zester homolog 2 (EZH2) inhibitor, showed a favorable clinical outcome and safety profile against relapsed mutant EZH2 FL in a clinical trial and was applied to this clinical setting. Peripheral blood involvement, known as the leukemic phase, was observed in approximately 10% of patients with FL and reported as a poor prognostic factor. However, because of the infrequency of EZH2-activating mutations, clinical data on tazemetostat against FL in the leukemic phase is lacking. Herein, we report a case of multiple relapsed FL in the leukemic phase for which tazemetostat was administered as a sixth-line treatment. Tazemetostat monotherapy showed a slow and sustained clinical efficacy in the leukemic phase as shown by nodal involvement. Circulating lymphoma cells gradually decreased and disappeared in counts after 4 months of treatment. However, circulating lymphoma cells were still detected by flow cytometry up to 6 months of treatment and finally undetected after 9 months. Extended-interval dosing of tazemetostat transformed a partial response into a complete response. Thus, tazemetostat is effective for the treatment of multiple relapsed FL in the leukemic phase.

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.

The value of semiquantitative PET features and end-of-therapy PET in grade 3B follicular lymphoma.

Grade 3B follicular lymphoma (G3BFL) is a rare lymphoma thought to sit on a continuum between low-grade FL and diffuse large B-cell lymphoma (DLBCL). The prognostic impact of quantitative positron emission tomography (PET) metrics such as total metabolic tumour volume (TMTV), total lesion glycolysis (TLG), and maximum standard uptake value (SUVmax) have been extensively analysed in FL and DLBCL, but G3BFL data are lacking. Here, we describe PET outcomes and radiomic characteristics in 46 G3BFL cases uniformly treated with R-CHOP (like) chemotherapy. Central semi-automated PET TMTV, TLG, and SUVmax analyses, using MIM software, were correlated with clinical outcomes and compared with published results in low-grade FL and DLBCL. In G3BFL, the end-of-treatment complete metabolic response was associated with improved progression-free survival (PFS; p = 0.002) and overall survival (OS; p = 0.04). G3BFL median TLG (1455) and SUVmax (16.50) sit between published values for low-grade FL (TLG: 1112, SUVmax: 11.3) and DLBCL (TLG: 3004, SUVmax: 24.35). No association between TMTV (>350 cm3) and survival was seen (PFS: p = 0.24; OS: p = 0.40). High SUVmax (>19.2) and TLG (>2760) both conferred inferior PFS but not OS (PFS: SUVmax p = 0.004; TLG p = 0.05). These data support the routine incorporation of PET radiomics at baseline and treatment response for G3BFL.

Patient-reported outcomes in patients with relapsed or refractory follicular lymphoma treated with zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy: results from the ROSEWOOD trial.

OBJECTIVE: We report patient-reported outcomes (PROs) measuring health-related quality of life (HRQoL) from the ROSEWOOD trial (NCT03332017), which demonstrated superior efficacy and a manageable safety profile with zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) in patients with heavily pretreated relapsed/refractory follicular lymphoma (R/R FL). METHODS: PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) and EQ-5D-5L questionnaires at baseline and subsequently every 12 weeks. All QLQ-C30 domains and EQ-5D-5L visual analog scale (VAS) scores were analyzed descriptively. At the key clinical timepoints (weeks 12 and 24), a mixed model for repeated measures (MMRM) analysis was used to evaluate the key PRO endpoints, including global health status, physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting. Clinically meaningful change was defined as a ≥ 5-point mean difference from baseline and between the ZO and O arms. RESULTS: Patients were randomized to ZO (n = 145) or O (n = 72). By week 48, descriptive analysis results indicated that patients in the ZO arm demonstrated improved outcomes in role functioning and fatigue and nausea/vomiting symptoms, compared with those in the O arm. Both groups experienced improvements in pain symptoms. EQ-5D-5L VAS scores showed no observable differences between treatment arms through week 48. MMRM analysis revealed that the global health status/quality of life of patients treated with ZO improved, as did fatigue, at week 12. At week 24, patients in the ZO arm experienced a clinically meaningful improvement in role functioning, pain, and fatigue. CONCLUSIONS: In patients with R/R FL, ZO was associated with improved PROs compared with O. These findings suggest that zanubrutinib contributed clinically meaningful benefits to patient HRQoL when added to obinutuzumab. TRIAL REGISTRATION: The ROSEWOOD trial is registered on ClinicalTrials.gov (BGB-3111-212; ClinicalTrials.gov identifier: NCT03332017).

Follicular lymphoma (or FL) is a common blood cancer where abnormal white blood cells form lumps in organs and glands in the body that normally help fight infection (lymph nodes). Zanubrutinib selectively blocks Bruton tyrosine kinase, which can prevent cancer cells growing and lead to their death. Obinutuzumab binds to a protein called CD20 on cancer cells, facilitating their removal using the body's natural defense system. Previous results from the ROSEWOOD trial showed that zanubrutinib plus obinutuzumab had improved cancer-fighting effects versus obinutuzumab alone, with manageable side effects in patients whose cancer returned after treatment or when treatment had failed. This study examined how these two cancer treatments impacted the patients' wellbeing and day-to-day functioning as reported directly by them (patient-reported outcomes). Researchers found that by week 48 of the trial, patients who received zanubrutinib plus obinutuzumab found it easier to manage daily activities (role functioning) and had fewer symptoms of feeling exhausted all the time (fatigue) and nausea/vomiting versus those who received obinutuzumab alone. Further analysis showed that the patients who received zanubrutinib plus obinutuzumab had noticeable improvements from the start of treatment in role functioning, pain, and fatigue versus patients receiving obinutuzumab alone at week 24 of the trial. In conclusion, this study showed that zanubrutinib plus obinutuzumab was associated with improved patient-reported outcomes versus obinutuzumab alone in patients with relapsed or refractory FL.

[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.

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.

Clinical characteristics and outcomes of Brazilian patients with duodenal-type follicular lymphoma: a multicenter retrospective study.

Duodenal-type follicular lymphoma (DFL) is a rare subtype classified by the 5th edition of the WHO and international consensus classifications of lymphoid neoplasms, typically presenting as localized disease with favorable outcomes. This multicenter retrospective study examines 53 Brazilian DFL patients with a median age of 58.2 years (33-85), with males comprising 50% (n = 27). According to Lugano GI tract classification, 40 patients (75%) were stage I. Median follow-up was 2.9 years (range 0.1-11). Incidental diagnosis occurred in 28 patients (52.8%) during routine endoscopy; 24 patients (45%) presented mild gastrointestinal symptoms. Treatments included watchful waiting (32 patients, 60.4%), rituximab monotherapy (15 patients, 28.3%), radiotherapy (three patients, 5.7%), and chemoimmunotherapy (three patients, 5.7%). Three patients experienced disease progression; watchful waiting showed three spontaneous remissions. No deaths occurred during follow-up. This study, the first from Latin America, demonstrates a good prognosis across treatments, highlighting Watchful waiting's effectiveness.

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.

In the SARS-CoV-2 era, do we need to be afraid of obinutuzumab?

In their paper, Pinto et al. report findings from the Italian URBAN study; an ambispective, observational, multicentre study evaluating the safety and efficacy of obinutuzumab-based therapy for advanced stage follicular lymphoma (FL) in routine practice. The URBAN substudy reported here examined severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcomes in 299 patients with treatment-naïve advanced stage FL, treated with obinutuzumab-based chemoimmunotherapy and maintenance. The study began enrolling in September 2019, continuing enrolment throughout the pandemic, with cut-off for the current analysis of 31 January 2022; thus, it provides unique insights into various pandemic phases, including the impact of administration of SARS-CoV-2 vaccination. Commentary on: Pinto et al. Exposure to obinutuzumab does not affect outcomes of SARS-CoV-2 infection in vaccinated patients with newly diagnosed advanced-stage follicular lymphoma. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19661.

Is radiotherapy still the optimal initial choice for patients with early-stage low-grade follicular lymphoma in the modern era? A population-based study.

Despite radiotherapy (RT) is recognized as preferred initial therapy for early-stage low-grade follicular lymphoma (FL) by many international practice guidelines, the medical oncologist has improperly underutilized RT, and diverse management strategies, including systemic therapy (ST), combined modality (CM) and watch and wait (WW), are still used. Except survival outcomes, previous studies concerned little about the treatment-related toxicity, which is also important factor in choosing initial management strategy, especially second primary malignancies (SPMs). The aim of this study was to compare the overall survival (OS) and the SPMs risk between different management strategies, which can provide guidance for the choice of optimal initial management strategy. Data was acquired from the Surveillance, Epidemiology, and End Results (SEER) database. Finally, A total 10,900 patients were identified, in which 930 cases developed SPMs. The use of radiotherapy (RT) has remained consistently low, with a utilization rate of around 20%, while most patients have received watchful waiting (WW) and systemic therapy (ST). In the rituximab era, multivariate analysis indicated that RT exhibited significantly superior OS and did not increase SPMs risk in comparison with ST and WW. At the same time, although there were no significant differences in OS between CM and RT, RT had significantly lower SPMs risk in comparison with CM. The use of RT improved the OS and did not increase the SPMs risk in comparison with other management strategies. Considering the low application rate of RT, oncologists should emphasize and increase the use of RT as an initial management strategy in patients with early-stage low-grade FL.

Time to lymphoma treatment within 24 months in 'watch and wait' follicular lymphoma is associated with inferior outcomes: A multicentre analysis.

Some 'watch and wait' (W&W) FL patients suffer from rapid progression in a short term. Herein, we sought to identify these patients and also develop a risk score to screen them at diagnosis. Between 2008 and 2022, a total of 411 FL patients managed by the W&W strategy from 16 cancer centres were retrospectively enrolled in this study, and their time to lymphoma treatment (TLT) and progression-free survival (PFS) were evaluated. Thirty-five percent of W&W FL patients experienced TLT within 24 months (TLT24) after diagnosis. Their 5-year PFS rate was significantly lower than those without treatment at 24 months (62.3% vs. 89.5%). In multivariable analysis, five factors were identified as independent predictors of TLT24: stages III-IV, ß2 microglobulin ≥3 mg/L, lymphocyte-to-monocyte ratio <3.8, bone marrow involvement and spleen enlargement (above umbilical line). Their AUCs for TLT24 were 0.76 (95% CI, 0.70-0.82) in the training cohort and 0.76 (95% CI, 0.67-0.85) in the validation cohort respectively. Risk groups were also associated with PFS (p < 0.001). In FL patients initially managed by W&W, TLT24 was associated with poor outcomes. This multivariable model helps screening for predicting TLT24, which may be useful to identify candidates for early interventional treatment.

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.

Concurrent identification of follicular lymphoma and papillary thyroid carcinoma.

INTRODUCTION: PTC has high lymph node metastasis, affecting central and lateral lymph nodes. On the other hand, follicular lymphoma is the second most frequent non-Hodgkin lymphoma in the West and affects cervical lymph nodes. CASE PRESENTATION: A 66-year-old Saudi man with type 2 diabetes and hypertension presented with neck lumps on both sides of his neck. The swelling was progressive, with no apparent cause, no history of hypothyroidism or hyperthyroidism, and no constitutional symptoms. Physical examination revealed multiple lymph node enlargements and a hard, firm mass on his thyroid gland. CLINICAL DISCUSSION: Multiple malignant neoplasms are rare, but secondary primary cancers have been documented in patients with PTC. The occurrence of both cancers is commonly detected during follow-up and aided by modern imaging techniques. The main treatment for PTC is surgery, usually with a good prognosis. CONCLUSION: A 66-year-old male was diagnosed with follicular lymphoma during a papillary thyroid carcinoma workup, emphasizing the importance of careful lymph node dissection and microscopic examination for rare cases.

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.