Recurrent Diffuse Large B-cell Lymphoma Research Articles

High-Dose Chemotherapy and Autologous or Allogeneic Transplantation in Aggressive B-Cell Lymphoma—Is There Still a Role?

Novel therapies such as CAR-T, BTK inhibitors and PD-1 inhibitors have changed the management of aggressive B-cell lymphomas. Nonetheless, these novel therapies have their own risk of late toxicities including second malignancies. They also create a subgroup of patients with relapse, treatment failure, or indefinite maintenance. We discuss the current role of autologous and allogeneic stem cell transplantation in this context. In patients with recurrent diffuse large B-cell lymphoma, CAR-T cell treatment has largely replaced autologous transplant. Autologous transplant should be considered in patients with late relapses and in selected patients with T-cell-rich B-cell lymphoma, where CAR-T cell therapy may be less effective. It also remains the treatment of choice for consolidation of patients with primary CNS lymphoma. In mantle cell lymphoma, intensive chemotherapy combined with BTK inhibitors and rituximab results in excellent outcomes, and the role of autologous transplantation is declining. In Hodgkin’s lymphoma, autologous transplant consolidation remains the standard of care for patients who failed initial chemotherapy. Allogeneic transplantation has lower relapse rates but more complications and higher non-relapse mortality than autologous transplantation. It is usually reserved for patients who fail autologous transplantation or in whom autologous stem cells cannot be collected. It may also have an important role in patients who fail CAR-T therapies. The increasing complexity of care and evolving sequencing of therapies for patients with aggressive B-cell lymphomas only emphasizes the importance of appropriate patient selection and optimal timing of stem cell transplantation.

TCP1 expression alters the ferroptosis sensitivity of diffuse large B-cell lymphoma subtypes by stabilising ACSL4 and influences patient prognosis

Diffuse large B-cell lymphoma (DLBCL), an invasive lymphoma with substantial heterogeneity, can be mainly categorised into germinal centre B-cell-like (GCB) and non-GCB subtypes. DLBCL cells are highly susceptible to ferroptosis, which offers an effective avenue for treating recurrent and refractory DLBCL. Moreover, various heat shock proteins are involved in regulating the sensitivity of tumour cells to ferroptosis. Among these proteins, tailless complex polypeptide 1 (TCP1), a subunit of chaperonin-containing T-complex protein-1 (CCT), plays a role in tumour proliferation and survival. Therefore, we explored the role of TCP1 in different DLBCL subtypes, the sensitivity of GCB and non-GCB subtypes to the ferroptosis inducer RAS-selective lethal small molecule 3 (RSL3), and the underlying molecular mechanism. In GCB cells, TCP1 promoted RSL3-induced ferroptosis. Notably, TCP1 could bind with acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme regulating lipid composition and facilitating ferroptosis, to reduce its ubiquitination and degradation. This interaction activated the ACSL4/LPCAT3 signalling pathway and promoted ferroptosis in the GCB subtype. However, in the non-GCB subtype, TCP1 did not act as a positive regulator but served as a predictor of an unfavourable prognosis in patients with non-GCB. In conclusion, our results suggest that in DLBCL, high TCP1 expression enhances the sensitivity of GCB tumour cells to ferroptosis and serves as a marker of poor prognosis in patients with non-GCB DLBCL.

Higher Mortality in Patients With Diffuse Large B-cell Lymphoma Pre-Existing Arterial Hypertension—Real World Data of the Polish Lymphoma Research Group

Arterial hypertension is mentioned as a risk factor in cardio-oncology. This study aimed to assess the long-term prognostic value of arterial hypertension (AH) in diffuse large B-cell lymphoma (DLBCL). We analysed data collected by the Polish Lymphoma Research Group for the evaluation of the outcomes associated with the use of first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy in patients with DLBCL with coexisting AH. Patients with other cardiovascular comorbidities or premature chemotherapy discontinuation due to cardiovascular toxicity were excluded. Pre-existing AH was diagnosed in 65 of 232 patients with DLBCL (28%) included in the study, and was associated with significantly shorter overall survival values (p<0.00001). The rates of DLBCL recurrence, administration of second-, third-, or fourth-line chemotherapy, and lymphoma-related deaths were similar in patients with and those without AH. Cardiovascular deaths were significantly more frequently observed in patients with pre-existing AH (38.5% vs 3.6%, p<0.0001). In the univariate analysis, AH (p=0.000001), older age (p<0.000001), and diabetes (p=0.0065) were identified as significant predictors of all-cause mortality; however, cardiovascular mortality was associated with AH (p<0.000001), older age (p=0.000008), and dyslipidaemia (p=0.03). Multivariate analysis revealed AH as an age-independent significant predictor of all-cause (p=0.00045) and cardiovascular mortality (p<0.000001). In the long-term follow-up of patients with DLBCL, the role of AH, as an important age-independent predictor of premature cardiovascular mortality, was so strong that it may have value for use in close surveillance in cardio-oncology clinics.

Unraveling the enigma of B cells in diffuse large B-cell lymphoma: unveiling cancer stem cell-like B cell subpopulation at single-cell resolution.

Diffuse large B-cell lymphoma (DLBCL) represents the most prevalent form of aggressive non-Hodgkin lymphoma. Despite receiving standard treatment, a subset of patients undergoes refractory or recurrent cases, wherein the involvement of cancer stem cells (CSCs) could be significant. We comprehensively characterized B cell subpopulations using single-cell RNA sequencing data from three DLBCL samples and one normal lymph tissue. The CopyKat R package was employed to assess the malignancy of B cell subpopulations based on chromosomal copy number variations. CIBERSORTx software was utilized to estimate the proportions of B cell subpopulations in 230 DLBCL tissues. Furthermore, we employed the pySCENIC to identify key transcription factors that regulate the functionality of B cell subpopulations. By employing CellphoneDB, we elucidated the interplay among tumor microenvironment components within the B cell subpopulations. Finally, we validated our findings through immunofluorescence experiments. Our analysis revealed a specific cancer stem cell-like B cell subpopulation exhibiting self-renewal and multilineage differentiation capabilities based on the exploration of B cell subpopulations in DLBCL and normal lymph tissues at the single-cell level. Notably, a high infiltration of cancer stem cell-like B cells correlated with a poor prognosis, potentially due to immune evasion mediated by low expression of major histocompatibility complex molecules. Furthermore, we identified key transcription factor regulatory networks regulated by HMGB3, SAP30, and E2F8, which likely played crucial roles in the functional characterization of the cancer stem cell-like B cell subpopulation. The existence of cancer stem cell-like B cells in DLBCL was validated through immunofluorescent staining. Finally, cell communication between B cells and tumor-infiltrating T cell subgroups provided further insights into the functional characterization of the cancer stem cell-like B cell subpopulation. Our research provides a systematic description of a specific cancer stem cell-like B cell subpopulation associated with a poor prognosis in DLBCL. This study enhances our understanding of CSCs and identifies potential therapeutic targets for refractory or recurrent DLBCL patients.

Results of consolidative radiotherapy for relapsed diffuse B-cell lymphoma.

Recurrent diffuse large B-cell lymphoma (DLBCL) is a disease with high mortality. The standard of care involves autologous stem-cell transplantation (ASCT), which is not always feasible. We investigated the impact of radiotherapy as part of the salvage treatment for patients with relapsed disease. Retrospective study of patients with recurrent DLBCL after chemotherapy and consolidative radiotherapy at a single institution. All patients were included if radiation was part of the first treatment. Of 359 patients assessed between 2010 and 2017, 65 (18.1%) presented a recurrence, but only 62 received further treatment and were included in the study. Mean overall survival was 18.6 months since diagnosis and progression-free survival after first progression (PFS2) was 7.7 months. Patients were divided into two groups according to whether they did (24.8%) or did not (75.8%) receive radiation as part of their salvage treatment. Patients that did not receive R-CHOP (rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) in the first line were treated more with radiation in the second line (p = 0.02). Six patients with in-field relapse were re-irradiated. Only 4 patients received ASCT as part of their treatment for relapsed disease. There was no difference in outcomes. There is a place for radiotherapy in the treatment of relapsed DLBCL, particularly when patients do not receive ASCT. Radiotherapy is well-tolerated. More trials to assess the role of radiotherapy for these patients are needed.

Lymphoma recurrence presenting as vocal cord fixation.

Lymphomas of the larynx are a rare finding. Those with lymphoma of the larynx often present with symptoms such as vocal hoarseness, throat pain, dysphagia, and weight loss. This is a case of a 74-year-old man who presents with new onset of hoarseness and dysphagia. He has a previous history of diffuse large B-cell lymphoma (DLBCL) but was thought to be in remission at the time of presentation. On nasolaryngoscopy, there was a large, right sided, sub-mucosal mass with right vocal cord fixation. Physical exam and computed topography of the neck did not identify any adenopathy. Biopsy confirmed the recurrence of DLBCL isolated to the larynx at the time of diagnosis. The patient was treated with chemotherapy and fully recovered his vocal cord motion with resolution of his hoarseness and dysphagia. Physicians should consider lymphoma in patients presenting with laryngeal complaints especially in patients with a history of lymphoma.

Construction and Validation of a Novel Nomogram for Predicting the Recurrence of Diffuse Large B Cell Lymphoma Treated with R-CHOP.

To explore recurrence-risk factors of diffuse large B cell lymphoma (DLBCL) and construct a risk nomogram for predicting recurrence. A retrospective analysis was performed on 228 DLBCL patients who achieved complete remission after R-CHOP treatment between January 2015 and December 2019. Univariate and multivariate analyses were applied to identify recurrence-related risk factors from the pretreatment evaluation factors covering patients' demographic characteristics, clinical manifestations, serological indicators, pathological and immunohistochemical results. A nomogram was developed based on the above results and validated by the concordance index (C-index), the receiver operating characteristic (ROC) curve, and the calibration curve. The training and validation cohorts consisted of 160 and 68 patients (randomized by 7:3). Of the whole cohort, 50 of 228 (21.9%) cases recurred during follow-up. Three recurrence-risk factors including BCL2 expression (P = 0.027), CD10 expression (P = 0.021), LDH level (P = 0.004) were identified from multivariate analysis and entered the final nomogram. The C-index of the nomogram was 0.815 in training cohort and 0.797 in the validation cohort, higher than that of IPI system (0.699) and NCCN-IPI system (0.709). And the 1-year, 2-year, 3-year, and 4-year areas under ROC (AUC) were 0.812, 0.850, 0.837, and 0.801, respectively. The calibration curves also showed a good discrimination capability and accuracy. The novel nomogram incorporating the three independent risk factors (BCL2 expression, CD10 expression and LDH level) provided a valuable tool for predicting DLBCL recurrence.

Molecular classification and therapeutics in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) encompasses a wide variety of disease states that have to date been subgrouped and characterized based on immunohistochemical methods, which provide limited prognostic value to clinicians and no alteration in treatment regimen. The addition of rituximab to CHOP therapy was the last leap forward in terms of treatment, but regimens currently follow a standardized course when disease becomes refractory with no individualization based on genotype. Research groups are tentatively proposing new strategies for categorizing DLBCL based on genetic abnormalities that are frequently found together to better predict disease course following dysregulation of specific pathways and to deliver targeted treatment. Novel algorithms in combination with next-generation sequencing techniques have identified between 4 and 7 subgroups of DLBCL, depending on the research team, with potentially significant and actionable genetic alterations. Various drugs aimed at pathways including BCR signaling, NF-κB dysfunction, and epigenetic regulation have shown promise in their respective groups and may show initial utility as second or third line therapies to patients with recurrent DLBCL. Implementation of subgroups will allow collection of necessary data to determine which groups are significant, which treatments may be indicated, and will provide better insight to clinicians and patients on specific disease course.

Clinical Application and Research Progress of Circulating Tumor DNA in Diffuse Large B-Cell Lymphoma--Review

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, its diagnosis and prognosis evaluation mainly depends on tissue biopsy and imaging examination. As a part of liquid biopsy, circulating tumor DNA (ctDNA) is a novel noninvasive and real-time tumor-specific biomarker, which can reliably reflect the comprehensive tumor genetic profiles, and it plays an important role in assisting early diagnosis, monitoring the curative effect, prognosis evaluation and prediction of recurrence of DLBCL. This review summarized recent research progress of ctDNA in DLBCL.

HDAC inhibitor chidamide synergizes with venetoclax to inhibit the growth of diffuse large B-cell lymphoma via down-regulation of MYC, BCL2, and TP53 expression.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin's lymphoma. A total of 10%‒15% of DLBCL cases are associated with myelocytomatosis viral oncogene homolog(MYC) and/or B-cell lymphoma-2 (BCL2) translocation or amplification. BCL2 inhibitors have potent anti-tumor effects in DLBCL; however, resistance can be acquired through up-regulation of alternative anti-apoptotic proteins. The histone deacetylase (HDAC) inhibitor chidamide can induce BIM expression, leading to apoptosis of lymphoma cells with good efficacy in refractory recurrent DLBCL. In this study, the synergistic mechanism of chidamide and venetoclax in DLBCL was determined through in vitro and in vivo models. We found that combination therapy significantly reduced the protein levels of MYC, TP53, and BCL2 in activated apoptotic-related pathways in DLBCL cells by increasing BIM levels and inducing cell apoptosis. Moreover, combination therapy regulated expression of multiple transcriptomes in DLBCL cells, involving apoptosis, cell cycle, phosphorylation, and other biological processes, and significantly inhibited tumor growth in DLBCL-bearing xenograft mice. Taken together, these findings verify the in vivo therapeutic potential of chidamide and venetoclax combination therapy in DLBCL, warranting pre-clinical trials for patients with DLBCL.

PET/CT diagnostic value in suspicion of palatine tonsils’ lymphoma recurrence

&lt;b&gt;Introduction:&lt;/b&gt; Diffuse large B-cell lymphoma (DLBCL) is a non-homogenous group of neoplasms of the lymphatic system in terms of morphology, genetics, and clinical aspects. The follow-up of patients treated for lymphoma includes the following examinations: clinical, laboratory, and imaging. According to the recommendation of the National Comprehensive Cancer Network (NCCN) from 2020, the observation of patients with DLBCL is mostly based on the PET/CT examination with &lt;sup&gt;18&lt;/sup&gt;F-FDG, especially when suspecting the extranodal lymphoma recurrence. &lt;/br&gt;&lt;/br&gt; &lt;b&gt;Aim:&lt;/b&gt; The aim of the study was to define the predictive value of the PET/CT examination in the evaluation of the recurrence of DLBCL in the palatine tonsils. &lt;/br&gt;&lt;/br&gt; &lt;b&gt;Material and methods:&lt;/b&gt; The analysis of the medical documentation of patients treated in our Department was performed. Research material included patients with suspicion of local recurrence of DLBCL in the palatine tonsils. Thirty-three patients were included in the study: 22 women and 11 men. The age range was 23–73 years with a mean of 53 years. &lt;/br&gt;&lt;/br&gt; &lt;b&gt;Results:&lt;/b&gt; The confirmation of the local recurrence of DLBCL in the histological examination was obtained in 11 patients – 7 women and 4 men aged 58–73 years (μ= 65.4). SUV&lt;sub&gt;max&lt;/sub&gt; in the palatine tonsil in those patients ranged: for the right tonsil 3.6–9.5 (μ=6.0), and for the left tonsil 3.8–9.5 (μ = 6.1). The second group of the patients did not present any local recurrence of DLBCL in the palatine tonsils. The histological diagnosis was chronic tonsillitis. The age of those patients ranged from 23 up to 73 years (μ = 43.1 years). SUV&lt;sub&gt;max&lt;/sub&gt; ranged: for the right palatine tonsil 2.8-27.7 (μ = 8.62), for the left palatine tonsil 3.8–27.4 (μ = 8.60). The sensitivity of PET/CT in the recurrence assessment in our study was 100%, while the specificity was 33.3%. The additional predictive value was 0.33.

LINC00461 Regulates the Recurrence of Large B Cell Lymphoma through the miR-411-5p/BNIP3 Pathway.

Objective To analyze the mechanism of LINC00461 regulating the recurrence of diffuse large B cell lymphoma (DLBCL) through microRNA (miR)-411-5p/BCL2 interacting protein 3 (BNIP3) pathway. Methods DLBCL samples in TCGA and GSE12453 were used for differential analysis to find long noncoding RNA (lncRNA) related to DLBCL recurrence. The 4 DLBCL data with the highest and lowest expression levels of LINC00461 in the TCGA database were selected for GSEA enrichment analysis. The targeting relationships of miR-411-5p with LINC00461 and BNIP3 were verified by the dual luciferase report. Blood samples from DLBCL patients were used to analyze the correlation between miR-411-5p and LINC00461 or BNIP3. LINC00461, miR-411-5p, or BNIP3 was overexpressed or silenced by transfection, and a tumor-bearing nude mice model was constructed to detect their effects on proliferation and apoptosis. Results The level of LINC00461 in DLBCL was significantly higher than that in normal cases, and the level in recurrence DLBCL was significantly higher than that in nonrecurrence. The enrichment analysis results showed that the function of LINC00461 was closely related to apoptosis. The results shown that miR-411-5p bound to LINC00461 and BNIP3 and was negatively correlated with LINC00461 and BNIP3 mRNA in blood of DLBCL patients. Suppressing the level of LINC00461 inhibited cell proliferation and induced apoptosis. The inhibition of LINC00461 or overexpression of miR-411-5p reduced the expression of BNIP3 protein, thereby inducing apoptosis at the in vivo and in vitro levels. Conclusion LINC00461 may induce miR-411-5p to “sponge,” thereby increasing the expression of BNIP3 protein, and exerting the function of inhibiting apoptosis and promoting DLBCL recurrence.

Safety and efficacy of high-dose cytarabine MEAM therapy and other treatments for auto-peripheral blood stem cell transplantation: A retrospective comparative study.

The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara-C), and melphalan (MEL) is widely used before auto-peripheral blood stem cell transplantation (auto-PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200-400mg/m2 for 4 days, but we decided to increase the dosage of Ara-C from the standard to 2g/m2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high-dose Ara-C MEAM therapy. The high-dose Ara-C MEAM protocol consisted of MCNU 300mg/m2 on day -7, ETP 200mg/m2 on days -6, -5, -4, -3 and Ara-C 2g/m2 on day -4 -3, and MEL 140mg/m2 on day -2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020. All patients got engraftment and there were no cases of treatment-related mortality. In all cases, the 3-year overall survival (OS) and progression-free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty-one cases of diffuse large B-cell lymphoma recurrence, for which there is proven usefulness of auto-PBSCT, showed good results after transplantation, with the 3-year OS and PFS after transplantation being 100% and 74.3%, respectively. The safety and efficacy of high-dose Ara-C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.

Successful Use of Intravitreal Bevacizumab and Methotrexate in a Case of Neovascularization of the Iris and Pseudohypopyon Secondary to Recurrent Diffuse Large B-Cell Lymphoma

In this case report, we aim to describe a rare case of recurrent diffuse large B-cell lymphoma (DLBCL) reportedly in remission presenting with primary anterior segment findings and use of intravitreal bevacizumab and methotrexate to treat the sequelae. The patient presented with hypopyon and neovascularization of the iris (NVI). Anterior chamber studies including flow cytometry and imaging revealed DLBCL recurrence with central nervous system (CNS) involvement. Over one month, he was treated with one intravitreal injection of bevacizumab, repeat injections of methotrexate, and systemic therapies with the resolution of ocular symptoms but persistent systemic disease. This case highlights the utility of anterior chamber paracentesis in diagnosis and intravitreal bevacizumab and methotrexate in the treatment for anterior segment manifestations of intraocular lymphoma (IOL).

Поражение центральной нервной системы при диффузной В-клеточной крупноклеточной лимфоме

Introduction. Current approaches used to predict the recurrence of diffuse large B-cell lymphoma (DLBCL) with involvement of the central nervous system (CNS) need to be improved. Data from national studies on the incidence and clinical and laboratory characteristics of primary CNS DLBCL and secondary CNS involvement in systemic DLBCL are fragmentary and do not allow us to assess the overall picture. Aim. An assessment on the territory of the Siberian metropolis of data on the incidence and clinical and laboratory characteristics of DLBCL patients with primary CNS lymphoma (PCNSL) and secondary CNS involvement, as well as validation of the CNS-International Prognostic Index (CNS-IPI) on this sample. Materials and methods. The study group consisted of 47 patients with PCNSL and 35 with secondary CNS involvement in systemic DLBCL, the comparison group consisted of 202 patients with DLBCL without CNS involvement. Results. All patients with secondary CNS involvement in DLBCL belonged to the medium and high risk groups (p = 0.007) according to the CNS-IPI, which confirms its prognostic value. The risk factors for secondary CNS involvement in DLBCL were ECOG performance status ≥ 2, HIV infection, age over 60 years, a history of chronic kidney disease, ≥ 2 extranodal sites, and high expression of Ki-67 (&gt;75% positive tumor cells), non-GCB subtype of lymphoma, and presence of anemia. When assessing the characteristics of the clinical course of the disease, a number of peculiarities of the primary and secondary CNS involvement in DLBCL were identified. In particular, in terms of overall survival, the PCNSL group had a more favorable prognosis (p = 0.051). Conclusion. The results of the study confirm the importance of the CNS-IPI as a tool of a hematologist to determine the group of patients needing prevention of recurrence of DLBCL in the CNS. New data on a higher incidence of chronic kidney disease, arterial hypertension and thyroid disorders in the group of patients with PCNSL require further study.

Investigation of the Heterogeneity Evolution and Drug Resistance Mechanism of Diffuse Large B-Cell Lymphoma Under the Treatment of a Novel HDAC Inhibitor LAQ824

Aims:Diffuse large B-cell lymphoma (DLBCL), the most frequent malignant lymphoma subtype, is a group of highly invasive diseases with great heterogeneity in genomic alterations, clinical characteristics, morphological manifestations, treatment response and prognosis. Although most DLBCL patients can be cured by immunochemotherapy, nearly 40% of DLBCL patients still develop drug resistance and relapse. For relapsed/ refractory (R/R) DLBCL patients, there is still no optimal treatment. The heterogeneity and clonal evolution of tumor cells are the core driving forces for the occurrence and development of DLBCL, and the root causes for their refractory, recurrence and drug resistance. In this study, we screened out a novel small molecule compound effectively killing DLBCL cells, and analyzed its potential mechanism of anti-tumor. Meanwhile, by using single cell sequencing technology, we try to further investigate the heterogeneity and clona evolution and drug resistance mechanism of DLBCL under different drug pressure, explore core driver factors of drug resistance, evaluate and develop new treatment strategies.Methods:In this study, GEXSCOPE microfluidic platform was used for single-cell transcriptome sequencing. Seruat software was used for cell type recognition and clustering analysis. In order to further investigate the molecular mechanism of LAQ824 inducing the apoptosis of DLBCL cells and explore the target of LAQ824, antibody chip was performed to detect the phosphorylation of related signaling pathway. Gene expression was detected by real-time qPCR and Western blot. ChIP, RNA interfering (RNAi) and dual-luciferase activity assay were performed to validate the potential drug resistance targets for LAQ824. Moreover, WES of 21 DLBCL cell lines were performed to map mutations and analyze the correlation between related mutations and LAQ824 resistance. In this study, we established DLBCL animal models using NOD SCID mice transplanted with DLBCL cell lines, by which we could evaluate the tumor inhibition efficiency of LAQ824 alone and/or combination with other small molecular inhibitors.Results:Using GDSC database, we screened out Dacinostat (LAQ824), a novel HDAC inhibitor, was highly sensitive that could effectively induce the apoptosis of most DLBCL cells at low concentrations. Functional assay showed that LAQ824 could inhibit cell proliferation and promote apoptosis of tumor cells. LAQ824 treatment could significantly upregulate the acetylation level of histone H3 within a certain concentration range, and the DNA damage repair function of DLBCL cells was supressed by inhibiting Chk2 expression, thus significantly inducing cell apoptosis and effectively killing DLBCL cells. Meanwhile, through single-cell sequencing analysis, it was found that c-Fos could be activated under certain drug pressure of LAQ824. As a potential drug-resistant core driver gene, the expression level of c-Fos is highly correlated with IC50 of LAQ824 and the prognosis of patients with DLBCL, which can be used as a sensitivity indicator of LAQ824. Treatment with c-Fos inhibitor combined with LAQ824 can significantly improve the tumor inhibition rate, validated both in vitro and in vivo, which is expected to alleviate the recurrence and drug resistance of DLBCL patients.Conclusions:In general, we explores potential therapeutic drugs for DLBCL parients, adjusts and explores new clinical treatment strategies on this basis, and provides theoretical basis and data support for the realization of individualized precise treatment and the solution of DLBCL recurrence and drug resistance. DisclosuresNo relevant conflicts of interest to declare.

Diffuse Large B-Cell Lymphoma With a Background of Extensive Granulomatous Inflammation: A Potential Pitfall for Misdiagnosis

Granulomatous inflammation has been reported to be associated with Hodgkin and non-Hodgkin lymphomas. Here, we report a case of recurrent diffuse large B-cell lymphoma (DLBCL) with extensive granulomatous inflammation that was initially misdiagnosed as granulomatous lymphadenitis. In 2019, a 75-year-old Caucasian male presented to our hospital with an enlarged right supraclavicular lymph node. He had a medical history of prostate cancer (in 2004), DLBCL (initially diagnosed in 2009), and rectal adenocarcinoma (in 2017), all of which responded well to treatment. In 2018, the patient had experienced right axillary adenopathy, weight loss, and intermittent night sweats. An excisional biopsy of a right axillary lymph node, performed at another institution, was diagnosed as granulomatous lymphadenitis. In 2019, at our hospital, an excisional biopsy of a right supraclavicular lymph node showed DLBCL in a background of granulomatous inflammation. A review of the prior right axillary lymph node biopsy also showed DLBCL with a background of extensive granulomatous inflammation. Chemotherapy was initiated and the patient’s follow-up showed a good response. We report this case to raise awareness that granulomatous inflammation may obscure the diagnosis of some neoplasms, such as DLBCL, which are less commonly known to have granulomatous inflammation. This may result in delayed treatment and may ultimately affect outcomes.

Clonal evolution in diffuse large B-cell lymphoma with central nervous system recurrence

BackgroundThe prognosis of patients with secondary central nervous system lymphoma (SCNSL) is poor and despite massive advances in understanding the mutational landscape of primary diffuse large B-cell lymphoma (DLBCL), the genetic comparison to SCNSL is still lacking. We therefore collected paired samples from six patients with DLBCL with available biopsies from a lymph node (LN) at primary diagnosis and the central nervous system (CNS) at recurrence.Patients and methodsA targeted, massively parallel sequencing approach was used to analyze 216 genes recurrently mutated in DLBCL. Healthy tissue from each patient was also sequenced in order to exclude germline mutations. The results of the primary biopsies were compared with those of the CNS recurrences to depict the genetic background of SCNSL and evaluate clonal evolution.ResultsSequencing was successful in five patients, all of whom had at least one discordant mutation that was not detected in one of their samples. Four patients had mutations that were found in the CNS but not in the primary LN. Discordant mutations were found in genes known to be important in lymphoma biology such as MYC, CARD11, EP300 and CCND3. Two patients had a Jaccard similarity coefficient below 0.5 indicating substantial genetic differences between the primary LN and the CNS recurrence.ConclusionsThis analysis gives an insight into the genetic landscape of SCNSL and confirms the results of our previous study on patients with systemic recurrence of DLBCL with evidence of substantial clonal diversification at relapse in some patients, which might be one of the mechanisms of treatment resistance.

Recurrent diffuse large B-cell lymphomamimicking primary breast cancer

Breast lymphoma can represent 0.8%–2.2% of extranodal lymphomas and 0.1%–0.5% of primary breast neoplasms. Imaging findings are not specific, and its distinction from primary invasive breast carcinoma should be based on clinical data and histopathological analysis. We present the case of a 62-year-old woman who showed an unusual pattern of recurrent diffuse large B-cell lymphoma (DLBCL) mimicking primary breast cancer on imaging studies, including mammography, ultrasound, magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET-CT).

S2647 An Unfortunate Association: Diffuse Large B-Cell Lymphoma With Chronic Hepatitis C

INTRODUCTION: Hepatitis C virus (HCV) is among the most common chronic viral infections, with potential sequelae of cirrhosis and hepatocellular carcinoma. In addition to hepatic complications, there are well established links from multiple studies between HCV and B-cell malignancies. While direct-acting antiviral (DAA) therapy is effective inducing regression in low-grade B-cell malignancies, for high-grade diffuse large B-cell lymphoma (DLBCL) associated with HCV treatment includes chemotherapy in addition to DAA therapy. Here we present a case of a newly diagnosed DLBCL in the setting of chronic HCV. CASE DESCRIPTION/METHODS: A 44 y.o male with a PMH of chronic HCV, h/o renal transplant, and CKD 3 presented with complaints of R-sided posterior chest mass which grew suddenly over 3 weeks. Patient reported a renal transplant approximately 20 years ago for congenital vesicoureteral reflux from a living, non-related donor and was on immunosuppression with prednisone, azathioprine, and cyclosporine. CT chest showed a large, irregular soft tissue mass in the posterior right chest wall encasing the right 11th rib with several enlarged mediastinal and periportal lymph nodes. He underwent a core biopsy of the mass which showed a new diagnosis of DLBCL, double expressor subtype with double/triple hit negative by FISH. Outpatient HCV workup showed genotype 4 with RNA levels 4.4 million; U/S liver showed no signs of cirrhosis. Patient was followed by oncology outpatient with initial labs showing concern for spontaneous tumor lysis syndrome and advised to return to ER. On presentation to ER, patient’s labs were unremarkable except for mild AKI on CKD3 which eventually resolved and was started on dose-adjusted R-CHOP therapy. He was discharged with plans to start DAA therapy with Epclusa and close follow-up with GI to monitor for sustained virological response. DISCUSSION: It’s hypothesized HCV plays a role in sustained B-cell activation and prevention of apoptosis by chronic antigenic stimulus rather than direct oncogenic effect, thereby predisposing to B-cell lymphoid malignancies. Treatment with DAAs stops persistent activation of B-cell lymphocytes. In addition, the combination of DAAs with chemotherapy including rituximab is well-tolerated without pharmacological interactions or significant hepatotoxicity, especially in patients without abnormal LFTs at baseline. Finally, initiating DAAs after chemotherapy in these cases helps to prevent recurrence of DLBCL once SVR is achieved.Figure 1.: CT Scan of R-posterior Rib Mass 60 mm × 64 mm.Figure 2.: Rib Mass Biopsy DLBCL 100X H&E.Figure 3.: Rib Mass Biopsy DLBCL 200X Ki-67 IHC.