Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma: a phase Ib/II study.

Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Despite treatment advances that have improved outcomes for patients with relapsed or refractory (R/R) FL, many patients still die from progressive disease or treatment-related toxicities. In the phase Ib/II GO29365 study (clinicaltrials.gov 02257567), the safety and efficacy of polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) versus bendamustine and rituximab (BR) alone, and polatuzumab vedotin plus bendamustine and obinutuzumab (Pola-BG) as a single-arm cohort were evaluated in patients with R/R FL. Following the phase Ib safety run-in, patients were randomized 1:1 to receive Pola-BR or BR alone in the phase II stage; a separate non-randomized Pola-BG cohort was examined in the phase Ib/II expansion stage. Primary endpoints included safety and tolerability (phase Ib) and positron emission tomography complete response (PET-CR) rate by independent review committee (phase II). Overall, 112 patients were enrolled (phase Ib safety run-in: Pola-BR, N=6; phase II randomized cohort: Pola-BR, N=39; BR, N=41; phase Ib/II expansion cohort: Pola-BG, N=26). PET-CR rates were 66.7% (phase Ib safety run-in, Pola-BR); 69.2% (phase II randomized, Pola-BR); 63.4% (phase II randomized, BR); and 65.4% (phase Ib/II expansion Pola-BG). There was a higher occurrence of cytopenias with Pola-BR and Pola-BG than with BR; serious adverse events were more frequent with Pola-BR (61.4%) and Pola-BG (46.2%) than with BR (29.3%). Overall, this analysis does not demonstrate a benefit of adding Pola to BR or BG regimens for patients with R/R FL.

A Population-Based Family Case-Control Study of Sun Exposure and Follicular Lymphoma Risk.

BACKGROUND: Epidemiologic evidence suggests an inverse association between sun exposure and follicular lymphoma risk. METHODS: We conducted an Australian population-based family case-control study based on 666 cases and 459 controls (288 related, 171 unrelated). Participants completed a lifetime residence and work calendar and recalled outdoor hours on weekdays, weekends, and holidays in the warmer and cooler months at ages 10, 20, 30, and 40 years, and clothing types worn in the warmer months. We used a group-based trajectory modeling approach to identify outdoor hour trajectories over time and examined associations with follicular lymphoma risk using logistic regression. RESULTS: We observed an inverse association between follicular lymphoma risk and several measures of high lifetime sun exposure, particularly intermittent exposure (weekends, holidays). Associations included reduced risk with increasing time outdoors on holidays in the warmer months [highest category OR = 0.56; 95% confidence interval (CI), 0.42-0.76; Ptrend < 0.01], high outdoor hours on weekends in the warmer months (highest category OR = 0.71; 95% CI, 0.52-0.96), and increasing time outdoors in the warmer and cooler months combined (highest category OR = 0.66; 95% CI, 0.50-0.91; Ptrend 0.01). Risk was reduced for high outdoor hour maintainers in the warmer months across the decade years (OR = 0.71; 95% CI, 0.53-0.96). CONCLUSIONS: High total and intermittent sun exposure, particularly in the warmer months, may be protective against the development of follicular lymphoma. IMPACT: Although sun exposure is not recommended as a cancer control policy, confirming this association may provide insights regarding the future control of this intractable malignancy.

Occupational exposure to extremely low-frequency magnetic fields and follicular lymphoma risk: a family case-control study.

OBJECTIVES: We aimed to examine the relationship between occupational exposure to extremely low-frequency magnetic fields (ELF-MFs) and follicular lymphoma (FL) risk. METHODS: We conducted a family case-control study between 2011 and 2016 in Australia and included 681 cases. Controls were either a family member of cases (related (n=294), unrelated (n=179)) or were unrelated recruited for a similarly designed Australian multiple myeloma study (n=711). We obtained detailed job histories using lifetime work calendars. We assigned exposure to ELF-MFs using an enhanced job exposure matrix, with a lag period of 10 years. We examined associations with FL risk using logistic regression accounting for relatedness between cases and controls. We performed sensitivity analyses including by control type, by sex, complete case analyses, ELF-MF exposure percentiles in addition to quartiles, ELF-MF exposure in the maximum exposed job, a shorter lag period (1 year) and the cumulative exposure in the most recent time period (1-9 years). RESULTS: We observed no association with the average intensity, duration or lifetime cumulative exposure to occupational ELF-MF exposure in the primary or sensitivity analyses. CONCLUSIONS: Our findings do not support an association between occupational ELF-MF exposure and FL risk. Although the inclusion of family members as part of the larger control group may have biased our risk estimates towards the null, findings were similar in sensitivity analyses restricted to cases and unrelated controls. Further research incorporating enhanced exposure assessment to ELF-MF is warranted to inform occupational safety regulations and any potential role in lymphomagenesis.

Efficacy and safety-related factors of BTK inhibitors as a bridge to CAR-T therapy in R/R FL.

Although anti-CD19 chimeric antigen receptor (CAR) T cell therapy has achieved satisfactory results in relapsed/refractory (R/R) follicular lymphoma (FL), patients with R/R FL and high-risk disease characteristics, previous hematopoietic stem cell transplantation, bulky disease, and progression of disease within 2 years (POD24) had a low complete response (CR). Twenty-seven patients with R/R FL, later disease stages, higher tumor burden, or higher previous treatment lines who had received Bruton tyrosine kinase (BTK) inhibitors before anti-CD19 CAR T cell therapy, or received BTK inhibitors as combination therapy, were included in this study. The clinical response and adverse events (AEs) in anti-CD19 CAR T cell therapy were observed. All patients with R/R FL who received BTK inhibitors combined with anti-CD19-CAR T cell therapy had later disease stages, higher tumor burden, and higher treatment lines than those who did not receive BTK inhibitor combination therapy. However, no difference in the clinical response was found between the two groups. The clinical response in the POD24 group was lower than that in the non-POD24 group; however, no difference in the clinical response was found between the FL and transformed FL (tFL) groups, between the follicular lymphoma international prognostic index (FLIPI) 1 1-2 and FLIPI 1 3-5 groups, and between the FLIPI 2 1-2 and FLIPI 2 3-5 groups. The mean anti-CD19 CAR T cell peak was higher in the CAR-T group with BTK inhibitor than in the CAR-T group without BTK inhibitor. Meanwhile, a higher proportion of patients in the non-POD24 group, FL group, and PR group achieved CR after 2 months. No difference in cytokine secretion was found between the CAR-T group with and without BTK inhibitors. It was higher in the non-POD24 group, FLIPI 1 3-5 group, and FLIPI 2 3-5 group. No difference in cytokine release syndrome and immune effector cell-associated neurotoxic syndrome grades was found between the CAR-T groups with or without BTK inhibitors and between the other groups. Poor prognostic factors, other than POD24, did not affect the clinical response to BTK inhibitors in combination with anti-CD19 CAR T cell therapy in patients with R/R FL. Therefore, BTK inhibitors combined with anti-CD19 CAR-T therapy may be an effective and safe approach for patients with R/R FL and high-risk factors.Trial registration: The study was registered at http://www.chictr.org.cn/index.aspx as ChiCTR-ONN-16009862 and http://www.chictr.org.cn/index.aspx as ChiCTR1800019622.

Early efficacy and safety of obinutuzumab with chemotherapy in previously untreated patients with follicular lymphoma: A real-world retrospective report of the Polish Lymphoma Research Group.

BACKGROUND: The first-line obinutuzumab-based immunochemotherapy improves the outcome of patients with follicular lymphoma (FL) compared with rituximab-based regimens. However, infusion-related reactions occur in almost half of patients during the 1st obinutuzumab administration. OBJECTIVES: The study aimed to evaluate the early effectiveness and safety of obinutuzumab-based induction regimens in a real-world setting. MATERIAL AND METHODS: Outcomes of patients diagnosed with FL and treated with obinutuzumab between January 2020 and September 2021 were analyzed. RESULTS: The study group included 143 treatment-naïve patients with FL. The median age was 52 years (range: 28-89 years); 45.1% of patients had a high-risk disease as assessed using the Follicular Lymphoma International Prognostic Index (FLIPI). Induction chemotherapy included: O-CVP (obinutuzumab, cyclophosphamide, vincristine, prednisolone) in 49.0% of patients, O-CHOP (O-CVP plus doxorubicin) in 28.7% and O-BENDA (obinutuzumab, bendamustine) in 22.4%. Complete response (CR) and partial response (PR) rates were 69.9% and 26.5%, respectively. There was no difference in response rates between different regimens (p = 0.309). Maintenance was started in 115 patients (85.2%). In the 1st cycle, obinutuzumab was administered as a single 1000-milligram infusion in 47.9% of patients, whereas in 52.1%, initial infusions were split over 2 days (100 mg/900 mg). Infusion-related reactions were reported only during the 1st administration of obinutuzumab in 9.1% of patients, with a similar incidence in those receiving the total dose on a single day or split over 2 days (p = 0.458). The most common adverse events were hematological. Five patients died from coronavirus disease 2019 (COVID-19). CONCLUSION: The early responses to induction regimens and adverse events profile were similar for every type of induction treatment. The infusion-related reactions were rare and limited to the 1st dose of obinutuzumab.

Follicular lymphoma: The long and winding road leading to your cure?

Follicular lymphoma, the most common indolent lymphoma, though highly responsive to therapy is coupled with multiple relapses for the majority of patients. Advances in biologic understanding of molecular events in lymphoma cells and the tumor microenvironment, along with novel cellular and targeted therapies, suggest this may soon change. Here we first review the development of the molecular concepts and classification of follicular lymphoma, along with therapeutic development of treatments based on chemotherapy plus monoclonal antibodies targeting CD20. We then focus on developments over the last decade in further defining follicular lymphoma pathophysiology, leading to targeted therapeutics, as well as novel immunotherapeutic strategies effective against B cell lymphomas including follicular, particularly patients with advanced stage disease. Additional alterations beyond the hallmark t(14;18) translocation are necessary for development of follicular lymphoma. Epigenetic mutations are almost universally identified in follicular lymphoma, most commonly involving histone-lysine N-methyltransferase 2D (KMT2D, the histone acetyltransferases, cAMP response element-binding protein binding protein (CREBBP) and E1A binding protein P300 (EP300) and the histone methyltransferase enhancer of zeste homologue 2 (EZH2). Mutations are also commonly identified in other proliferation/survival pathways such as B-cell receptor, RAS, mTOR and JAK-STAT pathways, as well as immune escape mutations. The host immune response plays a key role as well, based on studies correlating various immune cell subsets and gene expression signatures with outcomes. Over the last decade, many therapeutic options beyond the commonly used bendamustine-rituximab induction regimen have become available or are being investigated. We focus on these newer agents in the relapsed setting. New antibody-based agents include the naked CD19 directed antibody tafasitamab, the CD79b directed antibody drug conjugate (ADC) polatuzumab vedotin and the CD47 directed antibody magrolimab that targets macrophages rather than FL cells directly. Immune modulation by lenalidomide has moved to earlier lines of therapy and in combinations. Several small molecule inhibitors of proliferation signal pathways involving PI3kinase and BTK have activity against FL. Apoptotic pathway modulators also have activity. With increasing recognition of the high rate of epigenetic mutations in FL, HDAC inhibition has a role. More importantly, the EZH2 inhibitor tazemetostat is FDA approved for FL after 2 prior lines of therapy. The most exciting data currently involve immune attack against follicular lymphoma by chimeric antigen receptor T-cells (CART) or bispecific antibody constructs. Given these multiple potentially non-crossreactive mechanisms, studies of rationally designed combination strategies hold the promise of improving outcomes and possibly cure of follicular lymphoma.

Physical activity and the risk of non-Hodgkin lymphoma subtypes: A pooled analysis.

Non-Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case-control studies to examine the association between moderate-to-vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T-cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study-specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case-control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.

Ultra-low-dose radiotherapy in the treatment of ocular adnexal lymphoma: a prospective study.

PURPOSE: This single-arm, prospective, exploratory study investigated the effectiveness of ultra-low-dose radiotherapy in the treatment of ocular adnexal lymphoma (OAL). PATIENTS AND METHODS: Patients with pathologically confirmed ocular adnexal low-grade non-Hodgkin lymphoma (predominantly mucosa-associated lymphoid tissue, MALT or follicular lymphoma) were included and treated with ultra-low-dose radiotherapy consisting of 2 successive fractions of 2 Gy at our institution between 2019 and 2021. Disease response was assessed clinically and radiographically within 4 months and at 3 to 6-month intervals after treatment. Data collected included rates of overall response, complete response (CR), partial response (PR), lesion size, and acute/chronic ocular toxic effects. RESULTS: Sixteen patients with median age of 63 years (range 23-86 years) were included in the study. The histological subtypes included MALT (11 patients; 69%); follicular lymphoma (2 patients; 12%); Lymphoid hyperplasia (3 patient, 19%). At a median follow-up time of 15.5 months (range 5.0-30.0 months), the overall response rate was 88%, with a CR rate of 75% (n = 12) and a PR rate of 13% (n = 2). The average lesion area was reduced from 117.9 ± 60.4 mm2 before radiation therapy to 38.7 ± 46.0mm2 at initial evaluation post radiation therapy (P = 0.002, n = 16), and to 8.5 ± 21.2 mm2 (P < 0.001 compared with postoperative lesion area) in patients with response at one year (n = 11). Disease progression was noted in 2 patients (12%). The 1-year rates of local progression-free survivals (LPFS) and overall survival (OS) were 85% and 100%, respectively. No distant relapses were observed in any of the patients. No acute or late toxic effects were noted. CONCLUSION: Ultra-low-dose radiotherapy in patients with OAL is associated with excellent local disease control and long-term survival with no significant acute or late toxicities.

Complete responses to odronextamab in two patients with diffuse large B-cell lymphoma refractory to chimeric antigen receptor T-cell therapy.

Outcomes remain poor for patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). While chimeric antigen receptor (CAR) T-cell therapy has revolutionised treatment, a significant proportion of patients relapse or fail to respond. Odronextamab is a CD20 × CD3 bispecific antibody that has demonstrated durable responses and a manageable safety profile in patients with R/R B-NHL in a first-in-human trial (NCT02290951). Here, we document two patients with diffuse large B-cell lymphoma refractory to CART-cell therapy. Both achieved complete responses that remain ongoing for ≥2 years following odronextamab. Neither patient experienced Grade ≥3 cytokine release syndrome or Grade ≥3 neurological adverse events during treatment.

Severity of Cytokine Release Syndrome Influences Outcome After Axicabtagene Ciloleucel for Large B cell Lymphoma: Results from the US Lymphoma CAR-T Consortium.

BACKGROUND: The majority of patients with large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, develop cytokine release syndrome (CRS). Whether the lack of development of CRS with axi-cel is associated with inferior lymphoma outcomes is unknown. Additionally, relationship between CRS grade and lymphoma outcome is not well established. METHODS: The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data independently of manufacturers. We analyzed the modified intent-to-treat population of 275 patients receiving axi-cel in two different ways: 1) Two group analysis comparing no CRS with any grade CRS; 2) Three group analysis comparing grade 0 CRS with grade 1 to 2 CRS, and grade 3-5 CRS. RESULTS: In this large multi-center observational cohort of 275 patients receiving axi-cel, 9% (n = 24) did not develop CRS, 84% (n = 232) developed grade 1-2 CRS, and 7% (n = 19) developed grade 3 to 5 CRS. Patients without CRS, compared with those having any grade CRS, had similar overall response rates (ORR), lower complete response (CR) rates and inferior progression free survival (PFS) with no statistically significant difference in overall survival (OS). Patients experiencing grade 1 to 2 CRS had superior CR rate and PFS, as compared to those without CRS or with grade 3 to 5 CRS. Grade 3 to 5 CRS was associated with a worse OS. CONCLUSION: Overall, durable responses were seen in patients that did not develop CRS, however grade 1 to 2 CRS was associated with better outcomes while those with grade 3 to 5 experienced the worse outcomes.

Predictors of cytopenias after treatment with axicabtagene ciloleucel in patients with large B-cell lymphoma.

Cytopenias are important but less studied adverse events following chimeric antigen receptor-engineered T cell (CAR-T) therapy. In our analysis of patients with large cell lymphoma who received axicabtagene ciloleucel (axi-cel), we sought to determine the rate and risk factors of clinically significant short term cytopenias defined as grade ≥3 neutropenia, anemia, or thrombocytopenia, or treatment with growth factors or blood product transfusions between days 20-30 after axi-cel. Fifty-three pts received axi-cel during the study period and severe cytopenias were observed in 32 (60%) pts. Significant cytopenias were more common in non-responders (stable or progressive disease) vs. responders (partial or complete response) (100% vs. 70%; p = .01). In the multivariable model, platelet transfusion within a month before leukapheresis, number of red blood cell and platelet transfusions between leukapheresis to lymphodepletion, pre-lymphodepletion absolute neurophil count, pre-lymphodepletion lactate dehydrogenase, and number of dexamethasone treatments after CAR-T were significantly associated with severe cytopenias after axi-cel.

Toxicity and efficacy of chimeric antigen receptor T-cell therapy in patients with diffuse large B-cell lymphoma above the age of 70 years compared to younger patients - a matched control multicenter cohort study.

Data regarding efficacy and toxicity of chimeric antigen receptor T (CAR-T) cell therapy in the elderly, geriatric population are insufficient. In 2019, tisagenlecleucel and axicabtagene-ciloleucel were commercially approved for relapsed/refractory diffuse large B-cell lymphoma. From May 2019 onwards, 47 relapsed/refractory diffuse large Bcell lymphoma patients, ≥70 years underwent lymphopharesis in three Israeli centers. Elderly (n=41, mean age 76.2 years) and young (n=41, mean age 55.4 years) patients were matched based on ECOG performance status and lactose dehydrogenase levels. There were no differences in CD4/CD8 ratio (P=0.94), %CD4 naive (P=0.92), %CD8 naive (P=0.44) and exhaustion markers (both HLA-DR and PD-1) between CAR-T cell products in both cohorts. Forty-one elderly patients (87%) received CAR-T cell infusion. There were no differences in the incidence of grade ≥3 cytokine-release-syndrome (P=0.29), grade≥3 neurotoxicity (P=0.54), and duration of hospitalization (P=0.55) between elderly and younger patients. There was no difference in median D7-CAR-T cell expansion (P=0.145). Response rates were similar between the two groups (complete response 46% and partial response 17% in the elderly group, P=0.337). Non-relapse mortality at 1 and 3 months was 0 in both groups. With a median follow-up of 7 months (range, 1.3-17.2 months), 6- and 12-months progression-free and overall survival in elderly patients were 39% and 32%, and 74% and 69%, respectively. EORTC QLQ-C30 questionnaires, obtained at 1 month, showed worsening of disability and cancer-related-symptoms in elderly versus younger patients. We conclude that outcomes of CAR-T cell therapy are comparable between elderly, geriatric and younger patients, indicating that age as per se should not preclude CAR-T cell administration. Longer rehabilitation therapy is essential to improve disabilities and long-term symptoms.

A randomized phase II study comparing consolidation with a single dose of 90Y ibritumomab tiuxetan vs. maintenance with rituximab for two years in patients with newly diagnosed follicular lymphoma responding to R-CHOP. Long-term follow-up results.

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to 90Y-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m2 every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving 90Y-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.

Follicular lymphoma: is there an optimal way to define risk?

Follicular lymphoma (FL) has a long natural history and typically indolent behavior. In the present era, there are a plethora of prognostic factors combining clinical, biological, and genetic data to determine patient prognosis and help develop treatment strategies over the course of a patient's lifetime. The rapid pace of tumor-specific and clinical advances in FL has created a challenge in the prioritization and implementation of these factors into clinical practice. Developing a comprehensive understanding of existing prognostic markers in FL will help select optimal ways of utilization in the clinical setting and investigate opportunities to define and intervene upon risk at FL diagnosis and disease recurrence.

Newly diagnosed follicular lymphoma during pembrolizumab treatment for lung cancer.

Malignant lymphoma developing during anti-PD-1 antibody treatment is extremely rare. A 74-year-old female was admitted with left hypochondrial pain. She was diagnosed with squamous cell carcinoma of the right upper lobe of the lung, and had undergone surgery and postoperative chemotherapy three years prior. Needle biopsy of a mediastinal lymph node revealed recurrent lung cancer (LC). Pembrolizumab (PEM) monotherapy was started as salvage treatment. Although her lymphadenopathy improved, thrombocytopenia and splenomegaly developed during treatment with nine doses of PEM. Laboratory findings included anemia, increased lactate dehydrogenase, and soluble interleukin-2 receptor levels of 6379 U/mL. Flow cytometry of peripheral blood and bone marrow showed CD20+, κ ≪ λ cell populations. IGH-BCL2 fusion was detected by fluorescence in situ hybridization in bone marrow. Positron emission tomography showed abnormal uptake in tonsils, both cervical lymph nodes, mediastinum (different location from the recurrent LC), spleen, and abdominal cavity. Follicular lymphoma (FL) grade 1/2 was histologically diagnosed by tonsillar biopsy. She achieved a complete metabolic response (CMR) after rituximab monotherapy on PEM discontinuation. Relapsed FL was diagnosed by submandibular gland biopsy four months after restarting PEM and she achieved a second CMR after rituximab-containing chemotherapy. We describe the first case of newly diagnosed FL during PEM treatment.

Pathological and molecular analysis of a composite lymphoma of mantle cell lymphoma and Epstein-Barr virus-positive follicular lymphoma.

Composite lymphoma (CL) is a very rare clinical entity defined by the presence of two or more different subtypes of lymphoma in the same lymph node. We report a case of CL in a 78-year-old male presenting with leukocytosis and swelling of multiple lymph nodes. A left axillary node biopsy showed atypical lymphocytes in both the interfollicular and follicular areas. Immunohistochemistry revealed that mantle cell lymphoma (MCL) was mainly present in the interfollicular area and follicular lymphoma (FL) was present in the follicular area. Polymerase chain reaction analysis of immunoglobulin heavy chain gene rearrangements confirmed that they were clonally related neoplasms. However, Epstein-Barr virus (EBV) DNA was detected in only FL cells, suggesting that MCL and FL had split into two clones in the early steps of pathogenesis. This is the first reported case of CL with EBV-negative B-cell non-Hodgkin lymphoma (NHL) and EBV-positive B-cell NHL with a clonal relationship. We discuss the developmental processes of these two lymphomas.

How to manage early-stage follicular lymphoma.

INTRODUCTION: Early-stage follicular lymphoma (FL) is characterized by good prognosis and can be cured with involved-field radiotherapy (IF-RT) in most cases. PET scan is a milestone of diagnostic work-up, with the aim of identifying a truly localized disease; however, staging in most of the studies was without PET. AREAS COVERED: We have searched in MEDLINE (inclusive dates 1994-2020) data about localized FL management. While high-quality evidence is lacking, current guidelines recommend IFRT or involved-site RT as first-line treatment in limited stages FL. Since a significant proportion of disease relapse occurred in non-irradiated areas, it has been hypothesized that occult disease could be present at diagnosis and could persist after RT, contributing to relapse. Available treatment options include watch-and-wait, chemotherapy, RT plus chemo- or chemo-immunotherapy, and RT combined with rituximab (R). EXPERT OPINION: RT combined with chemotherapy could increase PFS, but a clear OS benefit is lacking and toxic effects could be unacceptable. A promising strategy is represented by R combined with IF-RT, with low relapse rate outside the radiation fields and without the toxicity reported with chemotherapy. The study of prognostic factors in PET-staged patients, the reduction of RT fields and doses, and a response-adapted strategy represent new perspectives to investigate.

Mediating effect of soluble B-cell activation immune markers on the association between anthropometric and lifestyle factors and lymphoma development.

Sustained B-cell activation is an important mechanism contributing to B-cell lymphoma (BCL). We aimed to validate four previously reported B-cell activation markers predictive of BCL risk (sCD23, sCD27, sCD30, and CXCL13) and to examine their possible mediating effects on the association between anthropometric and lifestyle factors and major BCL subtypes. Pre-diagnostic serum levels were measured for 517 BCL cases and 525 controls in a nested case-control study. The odds ratios of BCL were 6.2 in the highest versus lowest quartile for sCD23, 2.6 for sCD30, 4.2 for sCD27, and 2.6 for CXCL13. Higher levels of all markers were associated with increased risk of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). Following mutual adjustment for the other immune markers, sCD23 remained associated with all subtypes and CXCL13 with FL and DLBCL. The associations of sCD23 with CLL and DLBCL and CXCL13 with DLBCL persisted among cases sampled > 9 years before diagnosis. sCD23 showed a good predictive ability (area under the curve = 0.80) for CLL, in particular among older, male participants. sCD23 and CXCL13 showed a mediating effect between body mass index (positive) and DLBCL risk, while CXCL13 contributed to the association between physical activity (inverse) and DLBCL. Our data suggest a role of B-cell activation in BCL development and a mediating role of the immune system for lifestyle factors.