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Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5–9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7–7·6). We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31–57·95) versus 77·21% (95% CI 69·21–86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47–6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10–6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71–0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50–49·99) versus 68·24% (58·84–79·15) in the low-risk group (HR 3·58, 95% CI 2·00–6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69–0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21–3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12–3·67). Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Deutsche Krebshilfe, Terry Fox Research Institute.

Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

In this Research Ethics Board-approved retrospective study, we evaluated pre-infusion [ 18 F]FDG PET/CT prognostic value in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients undergoing chimeric antigen T-cell (CAR-T) therapy. A total of 159 Patients treated with CAR-T between 2018 and 2023 were reviewed. Deauville scores 4 and 5 were considered to be a significant residual disease at baseline. Standardized uptake values (SUVs), whole-body metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were calculated. Additionally, the furthest distance between tumoral lesions throughout the body (Dmax) and from the spleen (spleen Dmax) were measured. Survival analyses evaluated the predictive value of the clinical and imaging-derived variables for progression-free survival (PFS) and overall survival (OS) prognostication. Of 129 DLBCL patients with pre-infusion [ 18 F]FDG PET/CT, 117/129 (91%) had significant residual disease. The median PFS and OS post-CAR-T were six and nine months, respectively. For PFS, variables that remained significant in the multivariate analysis were serum LDH (HR = 1.68) and TLG (HR = 4.31), being independent predictors of PFS. Considering OS, the only variable which retained its significance in the multivariate analysis was [ 18 F]FDG PET/CT-derived standardized Dmax (HR = 3.28). Pre-infusion [ 18 F]FDG PET/CT can provide valuable prognostic information in CAR-T candidates, enhancing patient management.

CNS relapse occurs in about 5% of patients during the course of diffuse large B-cell lymphoma and entails a dismal prognosis. This consideration has led to the adoption of CNS prophylaxis, although known risk factors do not allow for an accurate prediction of CNS recurrences because they have insufficient sensitivity and specificity. Here, we review the reports of CNS events in major studies of diffuse large B-cell lymphoma before and after the introduction of rituximab, and probe the evidence that underlies prophylactic strategies such as intrathecal or high-dose intravenous chemotherapy. Now that rituximab is available, CNS prophylaxis relies on little—if any—evidence and should not be routinely administered. Nonetheless, several patient subgroups probably have a high risk of systemic and CNS relapses, and how to manage their treatment is a challenge. These subgroups include patients with testicular lymphoma or those who have more than one extranodal site involved plus at least one additional risk factor. For such patients, we recommend against prophylactic intrathecal chemotherapy because of the rare occurrence of isolated leptomeningeal relapses, the absence of evidence-based efficacy, and the potential harmful side-effects that are associated with this procedure. Because many CNS events are a result of primary resistance to treatment or accompany systemic relapses, high-dose intravenous methotrexate has been suggested as an alternative approach that needs to be validated in prospective controlled trials.

Christian Steidl and colleagues identify recurrent somatic mutations in the PTPN1 gene in primary mediastinal B cell lymphoma and Hodgkin lymphoma. They show that mutant PTPN1 leads to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Classical Hodgkin lymphoma and primary mediastinal B cell lymphoma (PMBCL) are related lymphomas sharing pathological, molecular and clinical characteristics. Here we discovered by whole-genome and whole-transcriptome sequencing recurrent somatic coding-sequence mutations in the PTPN1 gene. Mutations were found in 6 of 30 (20%) Hodgkin lymphoma cases, in 6 of 9 (67%) Hodgkin lymphoma–derived cell lines, in 17 of 77 (22%) PMBCL cases and in 1 of 3 (33%) PMBCL-derived cell lines, consisting of nonsense, missense and frameshift mutations. We demonstrate that PTPN1 mutations lead to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Moreover, silencing of PTPN1 by RNA interference in Hodgkin lymphoma cell line KM-H2 resulted in hyperphosphorylation and overexpression of downstream oncogenic targets. Our data establish PTPN1 mutations as new drivers in lymphomagenesis.

Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and ‘eat-me’ signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A- knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A- knockout cell lines and TMEM30A -mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A- knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation—a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited. Integrative analysis in patients with diffuse large B-cell lymphoma uncovers that biallelic mutations on TMEM30A are associated with a favorable outcome and enhanced sensitivity to CD47 blockade.

The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.

Purpose To evaluate the prognostic value of early post-treatment 18 F-FDG PET/CT in diffuse large B-cell lymphoma (DLBCL) patients undergoing chimeric antigen receptor T-cell (CAR-T) therapy. Methods In this retrospective study, 159 patients referred for imaging prior to CAR-T therapy between January 2018 and May 2023 were reviewed. Of those, 51 with both baseline pre-infusion and one-month post-treatment 18 F-FDG PET/CTs were included. 18 F-FDG PET/CT parameters were derived, including standard uptake values (SUVs), metabolic tumour volume (MTV), total lesion glycolysis (TLG), and Dmax. Additionally, the delta changes from the baseline were calculated. Time to progression/death was documented. For progression-free survival (PFS) and overall survival (OS), univariate analysis was performed using the Kaplan-Meier method. The significance of the difference was measured using the Mantel-Cox log-rank test. Significant parameters entered the multiple Cox regression. Results Overall, 51 patients (mean age = 56y) entered the study. All had Deauville scores of 4 (14/51; 28%) or 5 (37/51; 72%) at baseline. At one month, 28% of patients showed a complete metabolic response, while 72% had 18 F-FDG-avid significant residual disease. Investigating those with residual disease, SUVmax, SUVpeak, SUVmax-to-Liver ratio and MTV were significantly lower in the one-month post-treatment scan. For PFS evaluation, serum LDH, one-month post-treatment SUVmax-to-liver ratio, one-month post-treatment TLG, and baseline Dmax entered the multivariate analysis. The one-month post-treatment SUVmax-to-liver ratio (Hazard ratio [HR] = 5.21; p  = 0.004) and baseline Dmax (HR = 13.8; p  = 0.013) retained significance, being independent predictors of PFS. For OS, serum LDH, delta SUVmean-to-liver ratio, delta percentage TLG, and one-month post-treatment Dmax were included in the multivariate analysis. The delta percentage TLG (HR = 4.37; p  = 0.023) remained significant as an independent predictor of OS. Conclusion Early post-treatment 18 F-FDG PET/CT can provide valuable prognostic information for DLBCL patients receiving CAR-T. The most significant predictors of outcomes would be the baseline extent of the disease, one-month post-treatment avidity, and changes in the metabolic burden from baseline.

Lymphoid cancers are among the most frequent cancers diagnosed in adolescents and young adults (AYA), ranging from approximately 30%–35% of cancer diagnoses in adolescent patients (age 10–19) to approximately 10% in patients aged 30–39 years. Moreover, the specific distribution of lymphoid cancer types varies by age with substantial shifts in the subtype distributions between pediatric, AYA, adult, and older adult patients. Currently, biology studies specific to AYA lymphomas are rare and therefore insight into age‐related pathogenesis is incomplete. This review focuses on the paradigmatic epidemiology and pathogenesis of select lymphomas, occurring in the AYA patient population. With the example of posttransplant lymphoproliferative disorders, nodular lymphocyte‐predominant Hodgkin lymphoma, follicular lymphoma (incl. pediatric‐type follicular lymphoma), and mediastinal lymphomas (incl. classic Hodgkin lymphoma, primary mediastinal large B cell lymphoma and mediastinal gray zone lymphoma), we here illustrate the current state‐of‐the‐art in lymphoma classification, recent molecular insights including genomics, and translational opportunities. To improve outcome and quality of life, international collaboration in consortia dedicated to AYA lymphoma is needed to overcome challenges related to siloed biospecimens and data collections as well as to develop studies designed specifically for this unique population.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease and represents the most common subtype of lymphoma. Although 60–70% of all patients can be cured by the current standard of care in the frontline setting, the majority of the remaining patients will experience treatment resistance and have a poor clinical outcome. Numerous efforts have been made to improve the efficacy of the standard regimen by, for example, dose intensification or adding novel agents. However, these results generally failed to demonstrate significant clinical benefits. Hence, understanding treatment resistance is a pressing need to optimize the outcome of those patients. In this Review, we first describe the conceptual sources of treatment resistance in DLBCL and then provide detailed and up-to-date molecular insight into the mechanisms of resistance to the current treatment options in DLBCL. We lastly highlight the potential strategies for rationally managing treatment resistance from both the preventive and interventional perspectives.