Diffuse Large B-cell Lymphoma Research Articles

Прогностическое значение цитотоксических CD8-позитивных Т-лимфоцитов реактивного микроокружения опухоли при диффузной В-крупноклеточной лимфоме

AIM. To assess the prognostic value of cytotoxic CD8-positive Т-lymphocytes of the reactive tumor microenvironment in diffuse large B-cell lymphoma (DLBCL). MATERIALS & METHODS. The study enrolled 124 patients with newly diagnosed DLBCL. All patients received the standard R-CHOP first-line immunochemotherapy. Immunochemistry and morphometry were used to assess the relative count of CD8-positive Т-lymphocytes in the biopsy samples of lymph nodes or other tumor tissues. In each biopsy sample, 20 fields of view were analyzed to assess the mean relative count of CD8-positive Т-lymphocytes in the reactive tumor microenvironment. Т-cells were counted by double-blind technique. Patients were aged 23–80 years (median 59 years); there were 62 women and 62 men. RESULTS. Obtained by ROC-analysis, the threshold value of the CD8-positive Т-lymphocyte count in the reactive tumor microenvironment was 13 %. The subthreshold relative count of cytotoxic CD8-positive Т-lymphocytes (≤ 13 %) was associated with extranodal lesions in DLBCL patients as well as with the lack of complete response to the R-CHOP first-line therapy and worse progression-free (PFS) and overall survival (OS) rates. In the group with the above-threshold (> 13 %) count of CD8-positive Т-lymphocyte, the 5-year PFS was 60 % (median not reached), in the group with the subthreshold count it was 45.3 % (median 39 months; p = 0.036); the 5-year OS was 78.3 % (median not reached) and 45.3 % (median 40 months) in the groups with the above- and subthreshold CD8+ T-cell counts, respectively (p = 0.001). CONCLUSION. The results of the present study clearly indicate the need to assess the count of cytotoxic CD8-positive Т-lymphocytes of the reactive tumor microenvironment in DLBCL patients as early as on diagnosis verification. It is likely that this approach will allow clinicians to more accurately predict the course of DLBCL.

Real life clinical outcomes of relapsed/refractory diffuse large B cell lymphoma in the rituximab era: The STRIDER study.

Relapse and refractory (R/R) rates after first-line R-CHOP in diffuse large B cell lymphomas (DLBCL) are ~40% and ~15% respectively. We conducted a retrospective real-world analysis aimed at evaluating clinical outcomes of R/R DLBCL patients. Overall, 403 consecutive DLBCL patients treated in two large hematological centers in Torino, Italy were reviewed. At a median follow up of 50 months, 5-year overall survival from diagnosis (OS-1) was 66.5%, and 2-year progression free survival (PFS-1) was 68%. 134 (34.4%) patients relapsed (n = 46, 11.8%) or were refractory (n = 88, 22.6%) to R-CHOP. Most employed salvage treatments included platinum salt-based regimens in 38/134 (28.4%), lenalidomide in 14 (10.4%). Median OS and PFS after disease relapse or progression (OS-2 and PFS-2) were 6.7 and 5.1 months respectively. No significant difference in overall response rate, OS-2 or PFS-2 in patients treated with platinum-based regimens versus other regimens was observed. By multivariate analysis, age between 60 and 80 years, germinal center B cell type cell of origin and extranodal involvement of <2 sites were associated with better OS-2. Our findings confirm very poor outcomes of R/R DLBCL in the rituximab era. Widespread approval by national Medicine Agencies of novel treatments such as CAR-T cells and bispecific antibodies as second-line is eagerly awaited to improve these outcomes.

Prognosis Prediction of Diffuse Large B-Cell Lymphoma in 18F-FDG PET Images Based on Multi-Deep-Learning Models.

Diffuse large B-cell lymphoma (DLBCL), a cancer of B cells, has been one of the most challenging and complicated diseases because of its considerable variation in clinical behavior, response to therapy, and prognosis. Radiomic features from medical images, such as PET images, have become one of the most valuable features for disease classification or prognosis prediction using learning-based methods. In this paper, a new flexible ensemble deep learning model is proposed for the prognosis prediction of the DLBCL in 18F-FDG PET images. This study proposes the multi-R-signature construction through selected pre-trained deep learning models for predicting progression-free survival (PFS) and overall survival (OS). The proposed method is trained and validated on two datasets from different imaging centers. Through analyzing and comparing the results, the prediction models, including Age, Ann abor stage, Bulky disease, SUVmax, TMTV, and multi-R-signature, achieve the almost best PFS prediction performance (C-index: 0.770, 95% CI: 0.705-0.834, with feature adding fusion method and C-index: 0.764, 95% CI: 0.695-0.832, with feature concatenate fusion method) and OS prediction (C-index: 0.770 (0.692-0.848) and 0.771 (0.694-0.849)) on the validation dataset. The developed multiparametric model could achieve accurate survival risk stratification of DLBCL patients. The outcomes of this study will be helpful for the early identification of high-risk DLBCL patients with refractory relapses and for guiding individualized treatment strategies.

Metabolic pathway-based subtyping reveals distinct microenvironmental states associated with diffuse large B-cell lymphoma outcomes.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. Assigning patients to different risk categories and cytogenetic abnormality and genetic mutation groups has been widely applied for prognostic stratification of DLBCL. Increasing evidence has demonstrated that dysregulated metabolic processes contribute to the initiation and progression of DLBCL. Metabolic competition within the tumor microenvironment is also known to influence immune cell metabolism. However, metabolism- and immune-related stratification has not been established. Here, 1660 genes involved in 84 metabolic pathways were selected and tested to establish metabolic clusters (MECs) of DLBCL. MECs established based on independent lymphoma datasets distinguished different survival outcomes. The CIBERSORT algorithm and EcoTyper were applied to quantify the relative abundance of immune cell types and identify variation in cell states for 13 lineages comprising the tumor micro environment among different MECs, respectively. Functional characterization showed that MECs were an indicator of the immune microenvironment and correlated with distinctive mutational characteristics and oncogenic signaling pathways. The novel immune-related MECs exhibited promising clinical prognostic value and potential for informing DLBCL treatment decisions.

Diffuse large B-cell lymphoma with heart involvement: the relevance of the multidisciplinary and multiparameter approach

Lymphoma patients are at high risk of cardiovascular events due to anthracycline cardiotoxicity and, in rare cases, related to heart infiltration. The presence of cardiac masses adds further complexity to the management of lymphoma patients beyond myocardial chemotherapy-related toxicity, given possible unpredictable acute complications such as arrhythmias, atrioventricular block, myocardial ischemia, pericardial effusion and cardiac tamponade. Here we describe the clinical presentation and successful multidisciplinary management of diffuse large B-cell lymphoma with multifocal cardiac involvement identified by total body 18FDG positron emission tomography performed at disease staging.

Palliating hematologic oncologic emergencies with radiation in the age of targeted systemic therapies: three illustrative cases.

Hematologic oncologic emergencies with an urgent indication for radiation are a relatively routine occurrence for the radiation oncologist. As patients are living longer and have multiple treatment options for their relapsed or refractory diseases, it is important that palliative treatments avoid precluding patients from or delaying next-line potentially curative treatments wherever possible. We highlight the following experiences from our clinical practice: newly diagnosed plasma cell disease causing cord compression; life threatening cutaneous lymphoma with tumors covering the majority of the body surface area; and relapsed/refractory diffuse large B-cell lymphoma (DLBCL) requiring bridging radiation to a mass impinging on the brachial plexus combined with chimeric antigen receptor (CAR)-T cell therapy. In each case, urgent palliative radiation was utilized, but the approaches were nuanced, with careful consideration of subsequent potential therapies and how the current course of radiation should be tailored for the best interplay with the overall treatment course and trajectory of the disease. With the rapid development of new therapies, it can be difficult to stay up to date on the most recent practice guidelines. Drawing on hematologic-specific guidelines, such as those provided by the International Lymphoma Radiation Oncology Group, and disease site experts can aid in ensuring patients are appropriately palliated and eligible for future therapies.

Plasma circulating tumour DNA is a better source for diagnosis and mutational analysis of IVLBCL than tissue DNA.

Diagnosis of intravascular large B-cell lymphoma (IVLBCL) is a challenge due to its heterogeneous clinical presentation and lack of specific markers. This retrospective study investigated the utility of circulating tumour DNA (ctDNA) sequencing for diagnosing IVLBCL and analysing its mutation landscape. A cohort of 34 IVLBCL patients enrolled and underwent plasma ctDNA targeted sequencing. The median plasma ctDNA concentration was 135.0 ng/mL, significantly higher than that in diffuse large B-cell lymphoma (DLBCL) controls. Correlations were found between ctDNA concentration and disease severity indicators, LDH and SF. Mutation analysis revealed frequent mutations in B-cell receptor and NF-κB signalling pathways, including MYD88 (56%), CD79B (44%), TNFAIP3 (38%) and IRF4 (29%). CNS involvement was significantly related with BCL6 and CD58 mutation. Patients with complicated hemophagocytic lymphohistiocytosis had significantly higher mutation rates in B2M. Comparison with DLBCL subtypes showed distinctive mutation profiles in IVLBCL. Moreover, plasma ctDNA detected more mutations with higher variant allele fraction than tissue DNA, suggesting its superiority in sensitivity and accessibility. Dynamic monitoring of ctDNA during treatment correlated with therapeutic responses. This study revealed the role of ctDNA in IVLBCL diagnosis, mutation analysis, and treatment monitoring, offering a promising avenue for improving patient diagnosis in this rare lymphoma subtype.

Chimeric antigen receptor T-cell therapy for aggressive B-cell lymphomas.

Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary approach in the treatment of lymphoma. This review article provides an overview of the four FDA-approved CAR T-cell products for aggressive B-cell lymphoma, including diffuse large B-cell lymphoma and mantle cell lymphoma, highlighting their efficacy and toxicity as well as discussing future directions.

De novo hepatitis B in a patient with negative hepatitis B core antibody and high normal range hepatitis B surface antibody treated with R-CHOP therapy for Diffuse large B-cell lymphoma

De novo hepatitis B in a patient with negative hepatitis B core antibody and high normal range hepatitis B surface antibody treated with R-CHOP therapy for Diffuse large B-cell lymphoma

Large cell lymphoma through a liquid lens.

Liquid biopsy to provide a mutational snapshot of diffuse large B-cell lymphoma is an emerging technology of exciting potential utility. The report by Alcoceba etal. assesses the tractability of the EuroClonality-NDC assay to profile lymphoma using cell-free DNA and highlights the prognostic implication of attaining a major molecular response to therapy. Commentary on: Alcoceba etal. Liquid biopsy for molecular characterization of diffuse large B-cell lymphoma and early assessment of minimal residual disease. Br J Haematol 2024;205:109-121.

Disseminated Multiple Organ Lymphoma Presented as Vulvar Lesion Diagnosed by [18F]FDG PET/CT

We would like to present a 49-year-old female patient who was presented with a vulva lesion and palpable inguinal lymph nodes who were diagnosed with disseminated multiorgan involvement of high grade diffuse large B-cell lymphoma. The 18F-fluorodeoxyglucose positron emission tomography computerized tomography imaging showed multiple cervical, axillary, and abdominal lymph nodes, pulmonary nodules as well as gross hypermetabolic vulvar lesion.

Immunohistochemical study of non-Hodgkin lymphoma patients in Basrah (Single center experience)

Background. Non-Hodgkin lymphoma (NHL) represents a diverse group of lymphoid tissue cancers, predominantly arising from B-cells, T-cells, or natural killer cells. The accurate diagnosis of NHL subtypes is crucial, given their varying clinical behavior and treatment responses. This study focuses on the application of immunohistochemistry (IHC) in diagnosing and classifying NHL, comparing its efficacy to traditional hematoxylin and eosin (H&amp;E) staining methods. Methods. Conducted at Al-Sadr Teaching Hospital, Basrah, this cross-sectional study involved 48 newly diagnosed NHL cases in 2015. Patients were initially examined using H&amp;E-stained sections from lymph nodes and extranodal tissue biopsies. IHC staining, employing a range of primary antibodies, was then used to confirm diagnoses and subtype NHL cases. Results. The study revealed a predominance of diffuse large B-cell lymphoma (DLBCL) at 50%. Other subtypes that were identified included mantle cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, MALToma, peripheral T-cell lymphoma, and follicular lymphoma. The IHC method proved critical in identifying specific NHL subtypes, which were not detectable by H&amp;E staining alone, such as mantle cell lymphomas and peripheral T-cell lymphomas. The study highlighted discrepancies with regional studies, emphasizing variations due to sample size and regional factors. Conclusion. Immunohistochemical staining is an indispensable tool for accurately diagnosing and classifying NHL, complementing H&amp;E staining. This study underscores the need for a comprehensive diagnostic approach, including a panel of antibodies, to optimize the diagnostic process and ensure accurate treatment planning.

Evaluating the cancer aging and research group model in predicting immunochemotherapy toxicity among elderly patients with diffuse large B-cell lymphoma

BackgroundThe management of diffuse large B-cell lymphoma (DLBCL) in elderly patients is complicated by an increased risk of treatment-related toxicity associated with aging. This study aimed to validate the effectiveness of the Cancer Aging and Research Group (CARG) model in elderly patients with DLBCL receiving rituximab-based chemotherapy. MethodsIn this prospective study, elderly DLBCL patients (aged 65 years or older) receiving rituximab-based chemotherapy were consecutively assessed between August 2016 and December 2021 at one medical center in Taiwan using the CARG model to predict treatment-related toxicity. Patients were categorized into low-, medium-, and high-risk groups based on their CARG scores. Comparisons were made regarding toxicities and survival rates among these groups. ResultsNinety-one patients, with a median age of 70 years (range 65–96), were included. A substantial 81 % (74 patients) experienced grade 3–5 toxicity. The overall 2-year survival rate was 63.8 % after a median follow-up of 28 months (range, 2–46). The risk of grade 3–5 toxicity was 83 %, 78 %, and 87 %, respectively, among the low-, medium-, and high-risk groups (p = 0.60). The receiver operating characteristic (ROC) curve for CARG was 0.521 (95 % CI, 0.376–0.666), which was significantly lower than that for the Eastern Cancer Oncology Group score (ROC = 0.701, 95 % CI, 0.571–0.831). Similarly, compared with those of low-risk patients, hazard ratios for overall survival were 9.22 (95 % CI, 1.23–69.1; p = 0.031) and 14.6 (95 % CI, 1.90–112; p = 0.010) for medium- and high-risk patients, respectively. ConclusionWhile CARG exhibited limitations in predicting treatment-related toxicity in elderly DLBCL patients, it demonstrated potential efficacy in predicting survival outcomes.

Disulfidptosis: A Novel Prognostic Criterion and Potential Treatment Strategy for Diffuse Large B-Cell Lymphoma (DLBCL).

Diffuse Large B-cell Lymphoma (DLBCL), with its intrinsic genetic and epigenetic heterogeneity, exhibits significantly variable clinical outcomes among patients treated with the current standard regimen. Disulfidptosis, a novel form of regulatory cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to intracellular accumulation of disulfides. We investigated the expression variations of disulfidptosis-related genes (DRGs) in DLBCL using two publicly available gene expression datasets. The initial analysis of DRGs in DLBCL (GSE12453) revealed differences in gene expression patterns between various normal B cells and DLBCL. Subsequent analysis (GSE31312) identified DRGs strongly associated with prognostic outcomes, revealing eight characteristic DRGs (CAPZB, DSTN, GYS1, IQGAP1, MYH9, NDUFA11, NDUFS1, OXSM). Based on these DRGs, DLBCL patients were stratified into three groups, indicating that (1) DRGs can predict prognosis, and (2) DRGs can help identify novel therapeutic candidates. This study underscores the significant role of DRGs in various biological processes within DLBCL. Assessing the risk scores of individual DRGs allows for more precise stratification of prognosis and treatment strategies for DLBCL patients, thereby enhancing the effectiveness of clinical practice.

PROGNOSTIC SIGNIFICANCE OF CERTAIN GROWTH FACTORS AND THEIR RECEPTORS IN BLOOD SERUM OF PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA

The heterogeneity of diffuse large B-cell lymphoma (DLBCL) is the reason for an unfavorable response to therapy in 40 % of patients. Thus, the search for prognostic markers is relevant. Цель. Изучить содержание в сыворотке крови больных ДВКЛ некоторых факторов роста и их рецепторов для выявления прогностической значимости в течении заболевания. The aim of the study is to examine the content of some growth factors and their receptors in the blood serum of patients with DLBCL and to identify prognostic significance during the disease progression. Materials and methods. The ELISA method was used to determine the level of growth factors VEGF-A, VEGF-C, EGF, TGFβ1, IGF-I, IGF-II and their soluble receptors sVEGFR3, sEGFR, sTGFβR2 in the blood serum of patients with DLBCL after 4 courses of polychemotherapy, R-CHOP regimen. Thirty-two men and thirty-one women were enrolled in the study, average age 55.6 years. The parameters of healthy donors were considered the norm. STATISTICA 10.0 was used for data processing. Results. Before treatment, VEGF-A, IGF-I, IGF-II and TGFβ1 levels in the blood serum of all patients exceeded the norm by 2.1–4.3 times; the content of soluble receptors sEGFR and sTGFβR2 was lower by 1.4 and 3 times, respectively; EGF/ sEGFR and TGFβ1/ sTGFβR2 increased by 1.8 and 6.1 times, respectively. After 4 cycles of R-CHOP VEGF-A and sEGFR levels normalized in patients with subsequent remission; IGF-I, IGF-II, EGF/sEGFR and TGFβ1/sTGFβR2 decreased by 1.6, 1.8, 1.6 and 2.7 times, respectively, compared with the parameters before treatment; sTGFβR2 increased by 2.4 times. Normalization of indicators was not observed in patients with an unfavorable outcome. Conclusion. Minimally invasive and effective method for determining the content of certain growth factors and their receptors, in particular TGFβ1, sTGFβR2, VEGF-A, EGF, and sEGFR, in patients with DLBCL can be effective for predicting the disease progression.

Characteristics and Clinical Value of MYC , BCL2, and BCL6 Rearrangement Detected by Next-generation Sequencing in DLBCL.

MYC , BCL2, and BCL6 rearrangements are clinically important events of diffuse large B-cell lymphoma (DLBCL). The ability and clinical value of targeted next-generation sequencing (NGS) in the detection of these rearrangements in DLBCL have not been fully determined. We performed targeted NGS (481-gene-panel) and break-apart FISH of MYC , BCL2, and BCL6 gene regions in 233 DLBCL cases. We identified 88 rearrangements (16 MYC ; 20 BCL2 ; 52 BCL6 ) using NGS and 96 rearrangements (28 MYC ; 20 BCL2 ; 65 BCL6 ) using FISH. The consistency rates between FISH and targeted NGS for the detection of MYC , BCL2, and BCL6 rearrangements were 93%, 97%, and 89%, respectively. FISH-cryptic rearrangements (NGS+/FISH-) were detected in 7 cases (1 MYC ; 3 BCL2 ; 2 BCL6 ; 1 MYC::BCL6 ), mainly caused by small chromosomal insertions and inversions. NGS-/FISH+ were detected in 38 cases (14 MYC ; 4 BCL2 ; 20 BCL6 ).To clarify the cause of the inconsistencies, we selected 17 from the NGS-/FISH+ rearrangements for further whole genome sequencing (WGS), and all 17 rearrangements were detected with break points by WGS. These break points were all located outside the region covered by the probe of targeted NGS, and most (16/17) were located in the intergenic region. These results indicated that targeted NGS is a powerful clinical diagnostics tool for comprehensive MYC , BCL2, and BCL6 rearrangement detection. Compared to FISH, it has advantages in describing the break point distribution, identifying uncharacterized partners, and detecting FISH-cryptic rearrangements. However, the lack of high-sensitivity caused by insufficient probe coverage is the main limitation of the current technology.

Chromogenic LMO2 mRNA ISH Expression Correlates with LMO2 Protein and Gene Expression and Captures Their Survival Impact in Diffuse Large B-Cell Lymphoma, NOS.

LMO2 is a relevant gene involved in B-cell ontogeny and a survival predictor of aggressive large B-cell lymphomas (aLBCL). Most studies assessing LMO2 mRNA expression have relied on microarray platforms or qRT-PCR methods, overlooking tissue morphology. In this study, we evaluate LMO2 RNA expression by chromogenic in situ hybridization (CISH) in normal tissue and in a series of 82 aLBCL. LMO2 CISH was performed in formalin-fixed paraffin-embedded tissues, scored by three different methods, and correlated with a transcriptome panel. We obtained statistically significant results correlating the methods of evaluation with LMO2 protein expression and gene expression results. Normal tonsil tissue showed high levels of LMO2, particularly within the light zone of the germinal center. Conversely, in aLBCL, a notable reduction in LMO2 expression was noted, remarkably in cases carrying MYC rearrangements. Furthermore, significant results were obtained through overall survival and Cox regression survival analysis, incorporating International Prognostic Index data alongside LMO2 expression levels. We show a reliable method to identify LMO2 mRNA expression by CISH, effectively capturing many of the reported biologic features of LMO2.

Outcomes of Rituximab-abbs versus Rituximab in Patients with Diffuse Large B-Cell Lymphoma in a Noninferiority Study.

Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is one of the first line treatments for diffuse large B-cell lymphoma (DLBCL). Rituximab comprises most of the treatment cost for this regimen; therefore, biosimilars, such as rituximab-abbs are crucial to provide affordable care. Although rituximab-abbs was studied primarily in follicular lymphoma, the Food and Drug Administration (FDA) approved this drug for all indications of the reference product on the basis of extrapolation. Effectiveness and safety data surrounding the use of rituximab-abbs in DLBCL is lacking. To evaluate the effectiveness and safety of rituximab-abbs and reference product rituximab as R-CHOP treatment for patients with DLBCL. This noninferiority (NI) study compared the 2-year overall survival (OS), overall response rate (ORR), and incidence of adverse events (AEs) between rituximab-abbs and its reference product (RP) in R-CHOP among adult patients with newly diagnosed DLBCL. The study inclusion period was from 1 January 2019 to 31 December 2020. Analyses were performed on the basis of a noninferiority lower limit of 10% for OS and ORR, and an upper limit of 10% for serious AEs. There were 240 patients who received RP rituximab, while 295 patients received rituximab-abbs. The cohort had a mean age of 63.7±12.2 years and 43% were female. The 2-year OS was 81.0% and 79.6% (NI p < 0.01) while the ORR was 80.0% and 69.6% (NI p < 0.01), among the rituximab-abbs and rituximab groups, respectively. The incidence of infusion reaction AEs (NI p < 0.01) and noninfusion reaction AEs (NI p < 0.01) also met noninferiority. We demonstrated that rituximab-abbs was noninferior to rituximab in both effectiveness and safety among patients receiving R-CHOP for DLBCL in this study. Long-term follow-up would be needed to confirm these results.

Blockade of the CD47/SIRPα checkpoint axis potentiates the macrophage-mediated anti-tumor efficacy of tafasitamab.

Macrophages are one of the key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD19 antibody tafasitamab, approved in combination with lenalidomide for the treatment of relapsed or refractory (r/r) diffuse large B cell lymphoma (DLBCL). However, antibody-dependent cellular phagocytosis (ADCP) in the tumor microenvironment can be counteracted by increased expression of the inhibitory receptor SIRPα on macrophages and its ligand, the immune checkpoint molecule CD47 on tumor cells. The aim of this study was to investigate the impact of the CD47-SIRPα axis on tafasitamabmediated phagocytosis and explore the potential of anti-CD47 blockade to enhance its antitumor activity. Elevated expression of both SIRPα and CD47 was observed in DLBCL patient-derived lymph node biopsies compared to healthy controls. CRISPR-mediated CD47 overexpression impacted tafasitamab-mediated ADCP in vitro and increased expression of SIRPα on macrophages correlated with decreased ADCP activity of tafasitamab against DLBCL cell lines. Combination of tafasitamab and an anti-CD47 blocking antibody enhanced ADCP activity of in vitro generated macrophages. Importantly, tafasitamab-mediated phagocytosis was elevated in combination with CD47 blockade using primary DLBCL cells and patient-derived lymphoma-associated macrophages (LAMs) in an autologous setting. Furthermore, lymphoma cells with low CD19 expression were efficiently eliminated by the combination treatment. Finally, combined treatment of tafasitamab and an anti-CD47 antibody resulted in enhanced tumor volume reduction and survival benefit in lymphoma xenograft mouse models. These findings provide evidence that CD47 blockade can enhance the phagocytic potential of tumor targeting immunotherapies such as tafasitamab and suggest there is value in exploring the combination in the clinic.

Molecular Determinants of Sensitivity to Polatuzumab Vedotin in Diffuse Large B-Cell Lymphoma.

Polatuzumab vedotin (Pola-V) is an antibody-drug conjugate directed to the CD79B subunit of the B-cell receptor (BCR). When combined with conventional immunochemotherapy, Pola-V improves outcomes in diffuse large B-cell lymphoma (DLBCL). To identify determinants of Pola-V sensitivity, we used CRISPR-Cas9 screening for genes that modulated Pola-V toxicity for lymphomas or the surface expression of its target, CD79B. Our results reveal the striking impact of CD79B glycosylation on Pola-V epitope availability on the lymphoma cell surface and on Pola-V toxicity. Genetic, pharmacological, and enzymatic approaches that remove sialic acid from N-linked glycans enhanced lymphoma killing by Pola-V. Pola-V toxicity was also modulated by KLHL6, an E3 ubiquitin ligase that is recurrently inactivated in germinal center derived lymphomas. We reveal how KLHL6 targets CD79B for degradation in normal and malignant germinal center B cells, thereby determining expression of the surface BCR complex. Our findings suggest precision medicine strategies to optimize Pola-V as a lymphoma therapeutic. Significance: These findings unravel the molecular basis of response heterogeneity to Pola-V and identify approaches that might be deployed therapeutically to enhance the efficacy of CD79B-specific tumor killing. In addition, they reveal a novel post-translational mechanism used by normal and malignant germinal center B cells to regulate expression of the BCR. See related commentary by Leveille, p. 1577 See related article by Meriranta et al.