PURPOSE: The presence of MYC and BCL2 translocations (ie, double-hit lymphoma, DHL) in large B-cell lymphoma (LBCL) is associated with reduced chemosensitivity, but less is known on its impact on radiotherapy (RT) efficacy. METHODS AND MATERIALS: Patients with LBCL who received their first course of RT for relapsed/refractory disease between 2008 and 2020 were eligible if there was adequate pathologic evaluation to be categorized as DHL versus non-DHL as per the World Health Organization (fifth edition). Separate analyses were conducted by treatment intent. Predictors for response (complete and partial) and local recurrence (LR) were evaluated using Cox regression analysis. LR analysis was restricted to curative-intent patients to ensure adequate follow-up. RESULTS: Three hundred and eighty-three patients (102 DHL, 281 non-DHL, and 44% curative) were treated at 447 sites. Median time from diagnosis to RT was 11.6 months, with 38.7% of patients having primary chemorefractory disease, 37.4% having received >2 lines of systemic therapy, and 24% status post-stem cell transplant. Median biological equivalent dose (alpha/beta: 10) was 28 Gy (range: 3.2-60.0) for palliative and 46.9 Gy (range: 6.4-84.0) for curative-intent patients. With a median follow-up of 41.1 and 41.5 months among curative and palliative patients, respectively, the response was high (81.1% curative, 60.1% palliative). On univariate analysis, DHL pathology was not associated with RT response in either curative or palliative patients. Among curative patients, 2-year LR rate was 38.8%. On multivariable analysis, DHL pathology was associated with a 2 times higher risk of LR (95% CI: 1.05-3.67, P = .03), with a crude LR rate of 42.9% (DHL) versus 28.9% (non-DHL). RT was well tolerated with low rates of grade 3 or higher acute toxicity (1.8% curative, 2.9% palliative). CONCLUSIONS: Relapsed/refractory LBCL remains radioresponsive with a 60%-80% response rate to RT. Although DHL pathology does not appear to influence RT response, its presence is associated with higher rates of LR, suggesting that it may be more radioresistant.
- MeSH
- Lymphoma, Large B-Cell, Diffuse * radiotherapy pathology genetics MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local * pathology MeSH
- Young Adult MeSH
- Proto-Oncogene Proteins c-bcl-2 genetics MeSH
- Proto-Oncogene Proteins c-myc genetics MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Translocation, Genetic MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
Patients with testicular lymphoma are at an increased risk of central nervous system (CNS) disease. Optimal strategy for CNS relapse prevention is unknown. We analyzed treatment strategies, cumulative incidence of CNS relapse and prognosis in 229 patients with diffuse large B-cell lymphoma (DLBCL) and testicular involvement: 157 primary testicular lymphomas (PTL) in clinical stages IE/IIE and 72 patients in advanced stages (T-DLBCL) IIIE/IV. Treatments for PTL vs. T-DLBCL included: rituximab-based chemotherapy (80.9% vs. 90.3%), orchiectomy (94.3% vs. 65.3%) and contralateral testicular irradiation (59.8% vs. 44.4%). Majority (84.3%) received CNS prophylaxis with similar rates of prophylactic methotrexate (intravenous 19.1% vs. 16.6%, intrathecal 40.8% vs. 40.4%, or both 24.2% vs. 27.8%) between PTL and T-DLBCL (p = 0.89). Median follow-up was 51.8 months. CNS relapses occurred in 14 (6.1%) of 63 relapsing patients. The 5-year cumulative incidence of CNS relapse in PTL was 4.5% and in T-DLBCL 12.1%. Median time to CNS relapse was 21.9 months. In univariate analyses, orchiectomy was the single significant factor associated with lower risk of CNS relapse in PTL (HR = 0.11 [95% CI, 0-0.124], p = 0.001). Rituximab significantly reduced CNS relapse risk in T-DLBCL (HR = 0.1002, p = 0.0005). Median progression-free survival (PFS) and overall survival (OS) following CNS relapse was dismal in T-DLBCL compared to PTL (PFS 1.6 vs. 37.8 months, p = 0.04 and OS 2.3 vs. 37.8 months, p = 0.05). This study confirmed a favorable impact of rituximab in prevention of CNS relapse in T-DLBCL. Methotrexate prophylaxis did not alter CNS relapse risk. Prognosis of CNS relapse is particularly poor in T-DLBCL.
- MeSH
- Lymphoma, Large B-Cell, Diffuse * therapy epidemiology MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Methotrexate therapeutic use MeSH
- Young Adult MeSH
- Central Nervous System Neoplasms * therapy epidemiology prevention & control mortality MeSH
- Follow-Up Studies MeSH
- Orchiectomy MeSH
- Prognosis MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Retrospective Studies MeSH
- Rituximab * therapeutic use MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Testicular Neoplasms * therapy pathology epidemiology MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
Although chronic inflammation is implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), the mechanisms responsible are unknown. We demonstrate that the overexpression of the collagen receptor, DDR1, correlates with reduced expression of spindle checkpoint genes, with three transcriptional signatures of aneuploidy and with a higher frequency of copy number alterations, pointing to a potential role for DDR1 in the acquisition of aneuploidy in DLBCL. In support of this, we found that collagen treatment of primary germinal centre B cells transduced with DDR1, not only partially recapitulated the aberrant transcriptional programme of DLBCL but also downregulated the expression of CENPE, a mitotic spindle that has a crucial role in preventing chromosome mis-segregation. CENPE expression was also downregulated following DDR1 activation in two B-cell lymphoma lines and was lost in most DDR1-expressing primary tumours. Crucially, the inhibition of CENPE and the overexpression of a constitutively activated DDR1 were able to induce aneuploidy in vitro. Our findings identify a novel mechanistic link between DDR1 signalling and chromosome instability in B cells and provide novel insights into factors driving aneuploidy in DLBCL.
- MeSH
- Aneuploidy * MeSH
- B-Lymphocytes metabolism MeSH
- Chromosomal Instability * genetics MeSH
- Lymphoma, Large B-Cell, Diffuse * genetics pathology metabolism MeSH
- Collagen pharmacology MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Discoidin Domain Receptor 1 * genetics metabolism MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Signal Transduction MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: Pathogenesis of large B-cell lymphomas (LBCL) and follicular lymphomas (FL) is a multistep process associated with the development of diverse DNA alterations and consequent deregulation of critical cellular processes. Detection of tumor-associated mutations within non-tumor compartments (mainly plasma) is the basis of the 'liquid biopsy' concept. Apart from tumor mutational profiling, quantitative analysis of circulating tumor DNA (ctDNA) allows longitudinal assessment of tumor burden. ctDNA-based technologies provide a new tool for tumor diagnostics and treatment personalization. AREAS COVERED: Our review provides a comprehensive overview and summary of available ctDNA studies in LBCL and FL. The accuracy of ctDNA-based detection of lymphoma-associated DNA alterations is correlated to known LBCL and FL molecular landscape. Additionally, we summarized available evidence that supports and justifies the clinical use of ctDNA for lymphoma risk stratification, treatment response evaluation, and treatment response-adapted therapy. Lastly, we discuss other clinically important ctDNA applications: monitoring of lymphoma clonal evolution within resistance and/or relapse development and utilization of ctDNA for diagnostics in non-blood fluids and compartments (e.g. cerebrospinal fluid in primary CNS lymphomas). EXPERT OPINION: Despite certain challenges, including methodological standardization, ctDNA holds promise to soon become an integral part of lymphoma diagnostics and treatment management.
- MeSH
- Circulating Tumor DNA * blood genetics MeSH
- Lymphoma, Large B-Cell, Diffuse * diagnosis genetics therapy blood MeSH
- Lymphoma, Follicular * diagnosis genetics therapy blood MeSH
- Humans MeSH
- Mutation MeSH
- Biomarkers, Tumor * blood genetics MeSH
- Prognosis MeSH
- Liquid Biopsy methods MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
INTRODUCTION: Central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) is a rare but serious condition requiring accurate diagnostics. Cerebrospinal fluid (CSF) analysis plays a crucial role, particularly in cases where biopsy is not feasible, and imaging is inconclusive. AREAS COVERED: Chemical markers have limitations, particularly in low-cellularity samples. Novel molecular techniques, including circulating tumor DNA (ctDNA) analysis and microRNAs (miRNAs), are gaining prominence for their ability to detect gene mutations at diagnosis and monitor minimal residual disease during follow-up. The sensitivity and specificity of genetic mutations, particularly MYD88 L265P, in combination with interleukin-10 (IL-10) levels, are discussed. The literature search methodology involved reviewing relevant studies and clinical data.This review examines both traditional and emerging methods for CSF analysis in diagnosing CNS involvement in DLBCL. Conventional approaches such as cytomorphology, flow cytometry, and biochemical markers have limitations, particularly in low-cellularity samples. Novel molecular techniques, including ctDNA analysis and miRNAs, are gaining prominence for their ability to detect gene mutations at diagnosis and monitor minimal residual disease during follow-up. The sensitivity and specificity of genetic mutations, particularly MYD88 L265P, in combination with interleukin-10 (IL-10) levels, are discussed. The literature search methodology involved reviewing relevant studies and clinical data. EXPERT OPINION: Advancements in CSF biomarker analysis are improving the diagnosis of CNS lymphoma, aiding early detection and personalized treatment approaches. However, further research and broader clinical validation are necessary for their routine implementation.
- MeSH
- Circulating Tumor DNA cerebrospinal fluid genetics MeSH
- Molecular Diagnostic Techniques methods MeSH
- Lymphoma, Large B-Cell, Diffuse * diagnosis cerebrospinal fluid genetics pathology MeSH
- Interleukin-10 genetics cerebrospinal fluid MeSH
- Humans MeSH
- Meningeal Neoplasms * diagnosis cerebrospinal fluid genetics MeSH
- MicroRNAs genetics cerebrospinal fluid MeSH
- Mutation MeSH
- Myeloid Differentiation Factor 88 genetics MeSH
- Biomarkers, Tumor * cerebrospinal fluid genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes (complete response [CR] rates with standard salvage therapy gemcitabine plus oxaliplatin [GemOx], ∼30%; median overall survival [OS], 10 to 13 months). Patients with refractory disease fare worse (CR rate with salvage therapy, 7%; median OS, 6 months). Epcoritamab, a CD3×CD20 bispecific antibody approved for R/R DLBCL after ≥2 therapy lines, has shown promising safety and efficacy in various combinations. We report results from the phase 1b/2 EPCORE NHL-2 trial evaluating epcoritamab plus GemOx in autologous stem cell transplant (ASCT)-ineligible R/R DLBCL. Patients received 48 mg subcutaneous epcoritamab after 2 step-up doses until progression or unacceptable toxicity; GemOx was given once every 2 weeks for 8 doses. The primary end point was overall response rate (ORR). As of 15 December 2023, 103 patients were enrolled (median follow-up, 13.2 months; median age, 72 years). Patients had challenging-to-treat disease: ≥2 prior therapy lines, 62%; prior chimeric antigen receptor T-cell therapy, 28%; primary refractory disease, 52%; refractory to last therapy, 70%. ORR and CR rate were 85% and 61%, respectively. Median duration of CR and OS were 23.6 and 21.6 months, respectively. Common treatment-emergent adverse events were cytopenias and cytokine release syndrome (CRS). CRS events had predictable timing, were primarily low grade (52% overall, 1% grade 3), and resolved without leading to discontinuation. Epcoritamab plus GemOx yielded deep, durable responses and favorable long-term outcomes in ASCT-ineligible R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT04663347.
- MeSH
- Deoxycytidine * analogs & derivatives administration & dosage adverse effects therapeutic use MeSH
- Lymphoma, Large B-Cell, Diffuse * drug therapy mortality pathology MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Oxaliplatin administration & dosage adverse effects MeSH
- Antibodies, Bispecific * administration & dosage adverse effects therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use adverse effects administration & dosage MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Salvage Therapy MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase I MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
Histological transformation (HT) in Waldenström's macroglobulinemia (WM) is a rare complication and despite growing literature in the last years, no consensus recommendations exist. Consensus Panel 6 (CP6) of the 12th International Workshop on Waldenström's Macroglobulinemia (IWWM-12) was convened to review the current data on transformed WM and make recommendations on its diagnosis and management. The key recommendations from IWWM-12 CP6 included: (1) in case of suspected HT, tissue biopsy is the gold standard for diagnosis; (2) the initial work-up should comprise 18FDG-PET/CT for the evaluation of disease extent and, for patients with clinical suspicion or for high-risk patients (CNS-IPI, multiple and/or specific extranodal involvements), cerebrospinal fluid examination and brain MRI; (3) standard dose chemoimmunotherapy (CIT) such as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) or R-CHP + polatuzumab vedotin are the preferred front-line regimen; (4) CNS prophylaxis and consolidation with autologous stem cell transplantation (SCT) can be considered according to de novo diffuse large B-cell lymphoma (DLBCL) guidelines; (5) T-cell-engaging therapies (CAR T-cells, bispecific antibodies) should be used in the relapse/refractory setting according to international guidelines for DLBCL and local access to these therapies. Key unanswered questions include the role of TP53 abnormalities and CXCR4 mutations on the risk of HT, the prognostic role of clonal relationship between WM and HT, the optimal front-line therapy (addition of novel agents to CIT, dose-intensive CIT, consolidation with autologous SCT), and the sequence of T-cell-engaging therapies. International collaboration and consideration of and inclusion in clinical trials is critical to address these issues in a rare patient population.
Terapie bispecifickými protilátkami se v hematoonkologii dostává do popředí zájmu, a to zejména u B lymfoproliferací. Jedná se o léčbu využívající imunitní systém pacienta k eliminaci nádorových buněk. Epkoritamab je podkožně podávaná anti-CD20/CD3 bispecifická protilátka, která prokázala významnou účinnost v léčbě relabujících nemocných s difuzním velkobuněčným B lymfomem po selhání dvou a více linií léčby. Na základě výsledků registrační studie fáze 1b/2 EPCORE NHL-1 byla prokázána léčebná odpověď u 63,1 % pacientů, z toho 38,9 % dosáhlo kompletní remise. Medián doby do dosažení kompletní remise byl 2,7 měsíce. Medián doby do progrese onemocnění byl 4,4 měsíce. Toxicita léku je přijatelná, dobře predikovatelná a při dodržení preventivních opatření není při podávání léku problémem. Epkoritamab je podáván do progrese nemoci a/nebo toxicity. Epkoritamab je aktuálně registrován v USA a EU, v rámci České republiky je očekávána úhrada pro nemocné po dvou a více předchozích liniích léčby na přelomu roku 2024/2025. Do budoucna bude zajímavé sledovat, zda se lék posune do časnějších linií léčby difuzního velkobuněčného B lymfomu nemocných - je nutno vyčkat výsledků klinických studií, které v této oblasti probíhají, a to i v celé řadě center v České republice. Zkušenosti, které jsme dosud nabyli s tímto lékem v rámci klinických studií, jsou velmi slibné.
Therapy with bispecific antibodies is gaining prominence in hemato-oncology, particularly in B-lymphoproliferative disorders. This treatment utilizes the patient’s immune system to eliminate cancer cells. Epcoritamab is a subcutaneously administered anti-CD20/CD3 bispecific antibody that has demonstrated significant efficacy in treating relapsed patients with diffuse large B-cell lymphoma after the failure of two or more lines of therapy. Based on the results of the phase 1b/2 registration trial, EPCORE NHL-1, a therapeutic response was observed in 63.1% of patients, with 38.9% achieving complete remission. The median time to complete remission was 2.7 months. The median time to progression was 4.4 months. The drug’s toxicity is acceptable, well predictable, and, with proper preventive measures, is not a challenge during administration. Epcoritamab is administered until disease progression and/or toxicity. It is currently approved in the USA and the EU, and in the Czech Republic, reimbursement for patients after two or more prior lines of therapy is expected around the turn of the year 2024/2025. In the future, it will be interesting to see if the drug moves into earlier lines of treatment for diffuse large B-cell lymphoma patients, though the results of ongoing clinical trials, including those at many centers in the Czech Republic, will need to be awaited. The experience we have gained so far with this drug in clinical trials is very promising.
Cíle: Deficit vitaminu D je spojen u řady chorob s horší prognózou. V naší práci jsme analyzovali hladiny vitaminu D u pacientů s Nehodgkinovými lymfomy (NHL) v České republice. Metody: Retrospektivní analýza nově diagnostikovaných pacientů, kteří měli před zahájením léčby stanoveny plazmatické hladiny vitaminu D, vybraných mikronutrientů (selen, zinek), albuminu a IgG. Analýza zahrnovala asociaci vitaminu D s demografickými, klinickými a vybranými laboratorními parametry a dopad hypovitaminózy D na přežití. Výsledky: Celkem bylo analyzováno 1 196 pacientů (medián věku 65 let, 49,5 % mužů), medián koncentrace vitaminu D byl 43,5 nmol/l. Pacientů s deficitem (≤ 50 nmol/l) bylo 717/1196 (59,9 %), hladinu v normě (≥ 75 nmol/l) mělo pouze 14,1 % nemocných. Medián sledování byl 3,9 roku. Ženské pohlaví (p < 0,000001), špatný celkový stav PS ≥ 2 (p < 0,0001), LDH > normu (p = 0,0063) a hypoalbuminémie (p < 0,000001) byly asociovány s deficitem vitaminu D. U agresivních lymfomů byly pozorovány signifikantně nižší hladiny vitaminu D (p = 0,000002). Deficit vitaminu D koreloval u difuzního velkobuněčného B-lymfomu s kratší dobou do progrese a celkovým přežitím (5,16 roku vs. nedosažen a 8,9 roku vs. nedosažen; p < 0,01), u folikulárního lymfomu nebyl rozdíl v PFS; nicméně 5leté celkové přežití bylo 80 vs. 95 %; p = 0,0007). Závěr: Deficit vitaminu D před zahájením léčby je problém většiny pacientů s NHL. Deficit je sdružen s dalšími negativními prognostickými faktory (hypoalbuminémie, vyšší LDH, horší klinický stav) a je rovněž asociován s kratším přežitím.
Objectives: Vitamin D deficiency is associated with worse prognosis in several diseases. In our study, we analysed vitamin D levels in patients with non-Hodgkin lymphomas (NHL) in the Czech Republic. Methods: A retrospective analysis of newly diagnosed patients who had their plasma levels of vitamin D, selected micronutrients (selenium, zinc), albumin, and IgG measured before initiating treatment. The analysis included the association of vitamin D with demographic, clinical, and selected laboratory parameters, as well as the impact of vitamin D deficiency on survival. Results: A total of 1,196 patients were analysed (median age 65 years, 49.5% male). The median vitamin D concentration was 43.5 nmol/L. Vitamin D deficiency (≤ 50 nmol/L) was observed in 717/1,196 patients (59.9%), while only 14.1% had normal levels (≥ 75 nmol/L). The median follow-up period was 3.9 years. Female gender (P < 0.000001), poor performance status (PS ≥ 2; P < 0.0001), elevated LDH levels (P = 0.0063), and hypoalbuminemia (P < 0.000001) were associated with vitamin D deficiency. Significantly lower vitamin D levels were observed in aggressive lymphomas (P = 0.000002). In diffuse large B-cell lymphoma, vitamin D deficiency correlated with shorter progression-free survival and overall survival (5.16 years vs. not reached and 8.9 years vs. not reached; P < 0.01). For follicular lymphoma, there was no difference in progression-free survival; however, 5-year overall survival was 80% vs. 95% (P = 0.0007). Conclusion: Vitamin D deficiency prior to treatment is a concern for the majority of patients with NHL. It is associated with other negative prognostic factors (hypoalbuminemia, elevated LDH, poorer clinical status) and with shorter survival.
Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs' expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs' expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL.
- Publication type
- Journal Article MeSH
- Review MeSH
