MYD88 Mutations Research Articles

A rare case of splenic marginal zone lymphoma with MYD88 mutation transformed into diffuse large B-cell lymphoma: case report and literature review.

In indolent lymphomas, histological transformation (HT) often results in a poor prognosis and presents a significant challenge in the management of these lymphomas. Previous studies have indicated that MYD88 mutations are associated with transformation in certain haematologic malignancies. We report a rare case of splenic marginal zone lymphoma (SMZL) harbouring an MYD88 mutation, which was transformed into diffuse large B-cell lymphoma (DLBCL) and accompanied by newly emerging genetic abnormalities. The role of the MYD88 gene in SMZL is currently unclear. Through this case, we reviewed relevant studies, which indicated that MYD88 mutations, along with other genetic anomalies, may play a significant role in this process. In the future, it is essential to collect more of these rare cases for further research.

High Prevalence of MYD88 and CD79B Mutations in Primary Sinonasal Diffuse Large B-Cell Lymphoma: Identification of an MCD-like Subtype.

Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare aggressive lymphoma. Recently, genetic classification using Next Generation Sequencing (NGS) demonstrated that PSDLBCL largely consists of the MCD genotype, which has a poor prognosis mainly driven by MYD88 L265P and CD79B gene abnormalities. This study investigated the prevalence and clinicopathological significance of MYD88 L265P and CD79B Y196 mutations using droplet digital PCR in 55 patients with PSDLBCL, as well as the translocation of BCL2/BCL6/c-Myc with FISH. We found mutations in MYD88 L265P (29/55, 52.7%) and CD79B Y196 (20/55, 36.4%). The MCD-like subtype, defined by the mutation of MYD88 and/or CD79B, was found in 32 out of 55 cases (58.2%). This subtype largely consists of non-GCB type (31/32, 96.9%; P<0.01) and double-expressor cases (20/32, 62.5%; P=0.01) compared with the MYD88/CD79B co-wild type, with BCL6 translocation in a small subset (2/32, 6.3%) and no translocations of BCL2 (0/32) or c-Myc (0/32). The MCD-like subtype tended to relapse in specific sites such as the central nervous system, testis, and/or skin compared with the co-wild type (P=0.03), showing poorer outcomes in overall survival (P=0.02) and progression-free survival (P=0.01). In conclusion, our study highlights a high prevalence of MYD88 and CD79B mutations in PSDLBCL, identifying an aggressive MCD-like subtype with a distinct relapse pattern. This molecular subclassification can be helpful for both prognostic prediction and therapeutic strategy in patients with PSDLBCL.

A Diagnostic Challenge in the Biopsy of a Mammographic Abnormality

Abstract Introduction/Objective Primary breast marginal zone lymphoma (MZL) is an uncommon subtype of extranodal lymphoma, and its diagnosis presents challenges, particularly in distinguishing it from lymphoplasmacytic lymphoma (LPL). MYD88 L265P mutation has been identified in a subset of marginal zone lymphomas, comprising 6-9% of cases. This genetic alteration further complicates the differentiation between MZL and LPL in breast tumors. We present a case highlighting the diagnostic complexities associated with primary breast MZL. Methods/Case Report A 71-year-old female patient underwent mammographic screening, which revealed a suspicious lesion in her left breast. Subsequent PET scan showed a hypermetabolic area consistent with a primary breast lesion. Biopsy histology exhibited a diffuse atypical lymphoid infiltration with varying proportions of neoplastic lymphocytes. Immunohistochemical analysis revealed positivity for CD20, PAX5, BCL2, CD138, MUM1, and negativity for CD3, CD5, Cyclin D1, CD10, CD23, CD34, BCL6, TDT, CD30, GATA3, and CK AE1/3. Additionally, there was lambda light chain restriction, and the Ki67 proliferation rate index was approximately 50%. Fish analysis indicated abnormal BCL6 gene rearrangement. Molecular genetic testing confirmed the presence of MYD88 mutation with c.794T&amp;gt;C p.L265P. Notably, bone marrow biopsy showed no abnormalities, with normal hematopoiesis. Serum electrophoresis and immunofixation detected an IgM monoclonal protein with lambda light chain specificity. Results (if a Case Study enter NA) NA Conclusion The diagnosis of primary breast MZL was favored over LPL due to the absence of common LPL- associated symptoms such as bone marrow involvement. However, the distinction between these entities remains challenging, underscoring the importance of comprehensive diagnostic approaches integrating histopathology, immunohistochemistry, and molecular genetics. Further research is warranted to enhance diagnostic certainty in such cases, particularly as the management of MZL and LPL becomes increasingly specific with the advent of novel therapeutic agents and ongoing clinical trials.

Determination of MYD88 and CXCR4 mutation for clinical detection and their significance in Waldenström macroglobulinemia.

This study aims to explore the incidence and clinical features of MYD88 and CXCR4 mutations in patients with Waldenström macroglobulinemia (WM) and determine the optimal method for routine clinical practice. Additionally, we seek to evaluate the prognostic significance of these features across various therapeutic backgrounds [cytotoxic group, the Rituximab/Bortezomib-based group, and the Bruton's tyrosine kinase inhibitor (BTKi) group]. 385 symptomatic WM patients were analyzed for MYD88 and CXCR4 mutations using Sanger sequencing, next-generation sequencing (NGS), allele-specific quantitative polymerase chain reaction (AS-PCR), and/or droplet digital PCR (ddPCR). The overall MYD88 mutation rate was 87.8%, relatively lower than that in Western cohort. Both AS-PCR and ddPCR demonstrated high sensitivity in unsorted samples, detecting 98.5% and 97.7% of mutations, respectively, including those with low tumor burdens. The total CXCR4 mutation rate was 30.9%, with NGS exhibiting the highest sensitivity of 78.0%. CXCR4 mutation was significantly linked to shorter OS only within the BTKi treatment group. The multivariate analysis indicated that MYD88 and CXCR4 mutations were not independent prognostic factors in the non-BTKi group when considering IPSSWM clinical staging. However, in the BTKi treatment group, these mutations emerged as independent adverse prognostic factors, overshadowing the prognostic significance of IPSSWM classification (MYD88: HR=0.229, P=0.030; CXCR4: HR=3.349, P=0.012). Testing for MYD88 mutations using AS-PCR or ddPCR in unsorted samples is viable for routine clinical practice. Under BTKi treatment, MYD88 and CXCR4 mutations hold greater prognostic importance than IPSSWM staging in WM.

Next-Generation Integrated Sequencing Identifies Poor Prognostic Factors in Patients with MYD88-Mutated Chronic Lymphocytic Leukemia in Taiwan

Introduction: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western countries and is very rare in Asia. Methods: Peripheral blood or bone marrow mononuclear cells obtained at initial diagnosis from 215 patients with CLL were analyzed by using next-generation sequencing to investigate the ethnic differences in genetic abnormalities. Results: Whole-genome sequencing and whole-exome sequencing analyses on 30 cases showed that 9 genes, including IGLL5, MYD88, TCHH, DSCAM, AXDND1, BICRA, KMT2D, MYT1L, and RBM43, were more frequently mutated in our Taiwanese cohort compared with those of the Western cohorts. IGLL5, MYD88, and KMT2D genes were further analyzed by targeted sequencing in another 185 CLL patients, unraveling frequencies of 29.3%, 20.9%, and 15.0%, respectively. The most frequent positional mutation of MYD88 was V217F (26/45, 57.8%), followed by L265P (9/45, 20.0%). MYD88 mutations were significantly associated with IGLL5 mutations (p = 0.0004), mutated IGHV (p < 0.0001) and 13q deletion (p = 0.0164). CLL patients with co-occurrence of MYD88 mutations with KMT2D or/and IGLL5 mutations were associated with a significantly inferior survival compared to those with MYD88 mutation alone (not reached vs. 131.8 months, p = 0.007). In multivariate analysis, MYD88 mutation without KMT2D or IGLL5 mutations was an independently favorable predictor. Conclusions: IGLL5, MYD88, and KMT2D mutations were enriched in Taiwanese CLL, and co-occurrence of MYD88 mutations with KMT2D or/and IGLL5 mutations was associated with a poorer prognosis.

Analysis of Therapeutic Efficacy and Adverse Prognostic Factors of Secondary Central Nervous System Lymphoma

To explore the therapeutic efficacy and prognostic factors of induction therapy for secondary central nervous system lymphoma (SCNSL). Clinical data of patients diagnosed with SCNSL from 2010 to 2021 at Guangdong Provincial People's Hospital were retrospectively collected. A retrospective cohort study was performed on all and grouped patients to analyze the efficacy and survival. Multivariate logistic regression analysis was used to explore the adverse prognostic factors. Thirty-seven diffuse large B-cell lymphoma patients with secondary central involvement were included in the research. Their 2-year overall survival (OS) rate was 46.01% and median survival time was 18.1 months. The 2-year OS rates of HD-MTX group and TMZ group were 34.3% and 61%, median survival time were 8.7 and 38.3 months, and median progression-free survival time were 8.1 and 47 months, respectively. Multivariate logistic regression analysis showed that age, sex, IPI, Ann Arbor stage were correlated with patient survival time. The median survival time of patients with CD79B, KMT2D, CXCR4, ERBB2, TBL1XR1, BTG2, MYC, MYD88, and PIM1 mutations was 8.2 months, which was lower than the overall level. HD-MTX combined with TMZ as the first-line strategy may improve patient prognosis, and early application of gene sequencing is beneficial for evaluating prognosis.

Intraparenchymal low-grade B-cell lymphomas of the central nervous system: Clinicopathologic and molecular analysis of three cases and a review of the literature

Primary central nervous system (CNS) lymphomas represent 1 % of all non-Hodgkin lymphomas, with diffuse large B-cell lymphomas as the prevailing subtype. Low-grade B-cell lymphomas are exceptional with only 24 marginal zone B-cell lymphomas (EMZL) and 1 follicular lymphoma (FL) previously reported so far. While their molecular profiles are studied elsewhere, data on primary intraparenchymal CNS cases remain limited. The objective of the present study is to contribute new cases of primary intraprenchymal low-grade B-cell lymphomas in the CNS and characterize their mutational profile. We conducted a comprehensive review of cases and a literature review to identify similar instances. Clinical, imaging, histological, immunohistochemical, and molecular characteristics were analyzed. Diagnoses were established according to established criteria. We present three novel cases of intraparenchymal CNS low-grade B-cell lymphomas. One case of intraparenchymal EMZL exhibited plasmacytic differentiation, while another lacked a plasma cell component. The third case was diagnosed as FL. The L265P mutation of MYD88 was absent in all cases. Next generation sequencing revealed pathogenic mutations in SPEN (Glu1970ValfsTer64) and ARID1A (Pro1355LeufsTer118) genes in one EMZL case. In conclusion, intraparenchymal CNS low-grade B-cell lymphomas are rare, with few reported cases. Our findings expand knowledge on their clinical and molecular features. We present the first molecular profile of primary CNS intraparenchymal EMZL, underscoring the need for further research to understand their biology and optimize treatment strategies.

Deep sequencing as a diagnostic tool in patients with suspected primary vitreoretinal lymphoma

PurposeTo compare the diagnostic utility of metagenomic deep sequencing (MDS) to cytology, flow cytometry and gene rearrangement by PCR in ocular samples of patients with suspected vitreoretinal lymphoma (VRL).MethodsPatients with...

Primary diffuse large B-cell lymphoma of the central nervous system identified with CSF biomarkers

BackgroundDiagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy.Case presentations.The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3.ConclusionsTaken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment.

Cytoplasmic Lipid Droplets Predict Worse Prognosis in Diffuse Large B-Cell Lymphoma: Next-Generation Sequencing Deciphering Lipogenic Genes.

Burkitt lymphoma is characterized by high cell turnover and numerous cytoplasmic vacuoles that are demonstrated to be lipid droplets (LDs) decorated by adipophilin. By contrast, cytoplasmic vacuoles are variably observed in diffuse large B-cell lymphoma (DLBCL) and less well characterized. In this study, we first validated in DLBCL that cytoplasmic vacuoles are indeed LDs by Oil-red-O stain, Bodipy fluorescent stain, and electron microscopy. Second, in a cohort of DLBCL patients (n=52) we showed that LDs in effusional lymphoma cells were associated with a poorer prognosis (P=0.029, log-rank test) and higher International Prognostic Index (IPI) score (94% vs. 66%, P=0.026) than those without. Moreover, using adipophilin as a surrogate marker for LDs, we found in another cohort of biopsy specimen (n=85) that expression of adipophilin by lymphoma cells predicted a poorer prognosis (P=0.007, log-rank test) and higher IPI score (63% vs. 30%, P=0.005). In addition, whole exome sequencing of effusional DLBCL cells showed LD-positive DLBCL shared genetic features with the MCD (MYD88 and CD79B mutations) subtype and highlighted OSBPL10 and CUBN as the most frequently mutated genes involved in lipogenesis. Whole transcriptome analysis by comparing effusional DLBCL cells with versus without LDs showed upregulation of EHHADH, SLC1A1, CD96, INPP4B, and RNF183 relevant for lymphoma lipogenesis and upregulation of epithelial-mesenchymal transition and KRAS signaling pathways. Higher expression of EHHADH and CD96 were validated in LD-positive clinical samples and LD-rich cell lines than LD-poor cells along with the known lipogenic gene, FASN. Our findings highlight the roles of LDs and adipophilin expression in DLBCL, suggest that these markers may predict prognosis and show that lipogenic genes may be potential therapeutic targets.

Comparative Study on the Clinicopathologic and Molecular Characteristics of Primary and Secondary Diffuse Large B-cell Lymphoma in the Central Nervous System.

Diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive B-cell lymphoma with clinical and molecular heterogeneity. Primary CNS-DLBCL (PCNSL) affects the brain, eyes, leptomeninges, or spinal cord without systemic involvement. Secondary CNS-DLBCL (SCNSL) manifests concurrently with systemic lymphoma or as an isolated CNS relapse with poor prognosis. Next-generation sequencing (NGS) was used to identify genomic alterations in 32 PCNSL and 9 SCNSL cases. Single nucleotide variants and copy number variations in addition to the clinicopathologic data and proposed risk predictive values were compared to aid in diagnostic differentiation between the two types of lymphomas. The MCD genotype, characterized by mutations in MYD88 and CD79B, is the most common alteration in PCNSL and is associated with lower survival rates. The frequency of MYD88 mutation was significantly higher in PCNSL compared to SCNSL (75.0% vs. 33.3%; p=0.042). Recurrent copy number loss of 6p21 occurred in 56.1% of cases, more often in PCNSL (65.6%) than in SCNSL (22.2%) (p=0.028). Diagnostic positive predictive values (PPV) of MYD88 mutation and 6p21 loss for PCNSL were 89% and 91%, respectively. PPV of both alterations was 93% for the diagnosis of PCNSL. MYD88 mutation and 6p21 loss were significantly higher in PCNSL than in SCNSL, and novel risk prediction models based on these distinct genomic profiles can aid in the clinical differentiation of PCNSL and SCNSL.

Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma.

Developing therapies for the activated B-cell like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) remains an area of unmet medical need. A subset of ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation of interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling is driven by its catalytic and scaffolding functions, necessitating complete removal of this protein and its escape mechanisms for complete therapeutic suppression. Herein, we describe the identification and characterization of a dual-functioning molecule, KT-413 and show it efficiently degrades IRAK4 and the transcription factors Ikaros and Aiolos. KT-413 achieves concurrent degradation of these proteins by functioning as both a heterobifunctional degrader and a molecular glue. Based on the demonstrated activity and safety of KT-413 in preclinical studies, a phase 1 clinical trial in B-cell lymphomas, including MYD88 mutant ABC DLBCL, is currently underway.

Abstract B008: Utilizing pathway incompatibility for synthetic lethality: A therapeutic strategy for B-cell lymphoma

Abstract Previous pan-cancer analyses revealed co-occurring mutations exploitable for combination therapies and mutually exclusive mutations assumed to reflect functional redundancy (Mina M et al. 2017; Sanchez-Vega F et al. 2018). However, we recently highlighted an alternative scenario when mutual exclusivity reflects the incapability of two pathways to function together, a phenomenon we term “pathway incompatibility” (Chan LN et al. 2020). We found that STAT5-and ERK-activating genetic lesions were not only mutually exclusive in B-ALL cases, but also reciprocally inhibited each other at the signal transduction level, inducing cell death instead of promoting leukemogenesis. Notably, we demonstrated, for the first time, that pharmacological activation of STAT5 in ERK-driven B-ALL cells and ERK in STAT5-driven B-ALL cells represents a tractable synthetic lethality (Chan LN et al. 2020). We now take the important next step of identifying potential candidates for synthetic lethal genetic interactions resulting from pathway incompatibility in B-cell malignancies more broadly. Diffuse large B-cell lymphoma (DLBCL) is a rapidly growing blood cancer affecting older adults and constituting about 25% of all lymphoma cases in the US. Around 40% of patients develop relapsed or refractory DLBCL (Pfreundschuh M et al. 2006; Ngu H et al. 2022). Thus, there is an unmet need to develop new therapeutic strategies to improve clinical outcomes. Studying 1684 DLBCL cases from published datasets, we found that about 30% of DLBCL cases carry loss-of-function (LOF) CBP or gain-of-function (GOF) MYD88 genetic lesions. CBP encodes a histone acetyltransferase and, together with p300, functions as a transcriptional coactivator and tumor suppressor. Conversely, GOF MYD88 mutations drive lymphomagenesis by regulating kinases and transcription factors. Our analysis revealed that LOF CBP and GOF MYD88 genetic lesions co-occurred less frequently than expected by chance (odds ratio: 0.57, P=0.0), indicating their mutual exclusivity. Experiments with human DLBCL cell lines expressing wild-type MYD88 and CBP showed that CBP/p300 inhibitors did not impact cell viability. However, cells expressing a GOF MYD88 mutant or stimulated with a toll-like receptor (TLR) agonist to activate MYD88 became sensitized to CBP/p300 inhibitors, resulting in cell death. This suggests that LOF CBP and GOF MYD88 are incompatible for cell survival, with their co-occurrence resulting in synthetic lethality. We then tested a synthetic lethality-based therapeutic concept based on CBP-MYD88 incompatibility in DLBCL. We found that MYD88-mutated DLBCL cell lines were more sensitive to pharmacological inhibition of CBP/p300, while CBP-deficient DLBCL cell lines showed increased sensitivity to TLR agonist treatment. In summary, we identified mutual exclusivity between LOF CBP and GOF MYD88 lesions in DLBCL, where their co-occurrence induces cell death. Moreover, we demonstrated the therapeutic potential of synthetic lethality resulting from co-introduction of LOF CBP and GOF MYD88 in DLBCL. Citation Format: Mia Knupke, Lai Chan. Utilizing pathway incompatibility for synthetic lethality: A therapeutic strategy for B-cell lymphoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B008.

Gender disparities in Waldenstrom macroglobulinemia: Insights from a comprehensive analysis.

e19064 Background: Waldenstrom Macroglobulinemia (WM) is a rare, complex hematological malignancy with paucity of research about the landscape of gender disparities regarding clinical phenotype, genotype and outcomes. The aim of our abstract to identify those gender-based variations in WM. Methods: This is a retrospective study using a large WM database at Moffitt Cancer Center (MCC). We reviewed the baseline characteristics and molecular information of patients evaluated at MCC from years 1995 to 2020 and outcomes based on gender. Chi-square tests were used for comparing categorical variables and t-test for continuous variables. Kaplan-Meier method was used to compare survival. Results: Total of 265 patients with WM were identified, 63% (167) were males and 37% (98) were females. Mean age at diagnosis was 76 years for both groups, most of the patients were white non-Hispanics (94% in men vs 96% in women) (P=0.09) and had performance status (PS) 0 at diagnosis, 63% in men, 70% in women. The table summarizes baseline characteristics based on gender, men had slightly lower hemoglobin mean 11.1 vs11.5 in women (P =0.013), lower platelet count mean 209 vs 264 in women (P=&lt;0.001) and slightly lower albumin mean 3.8 vs 3.92 in women (P=0.0445). Hyperviscosity and plasmapheresis were more in women 10% vs 2% in men (P=&lt;0.001), Cryoglobulinemia was more in men 11% vs 1% (P=&lt;0.001). There were no statically significant gender differences based on the presence of mutations in MYD88, CXCR4, tp53, or del6q. The median overall survival (mOS) was slightly longer in lower-risk WM female pts, but not in high-risk (based on International Prognostic Scoring System for WM). The overall mOS was 98 months (mo) for females compared to 95 for males, P=0.004. The mOS for low-risk WM was 137 vs 132 mo, for intermediate risk 89 vs 87 mo, and for high-risk 37 vs 39 mo respectively for females and males (P=&lt;0.001). The rate of Diffuse Large B Cell Lymphoma transformation was not different (7% and 4%, respectively for women and men, (P=0.11) Women were more likely to respond to Bendamustine + Rituximab (BR)/BR + steroids than men (43%vs 25%, p=0.04)There were no differences in response to Cytoxan+ Rituximab+ Prednisone, Bruton’s tyrosine kinase inhibitors, or Venetoclax treatment. Conclusions: This retrospective review of a large database of WM patients highlights important gender differences in clinical WM disease features. Women had better overall survival, mainly in lower risk WM and higher responses to immunosuppressive therapy. Although disparities in WM may be multifactorial, disparities based on gender needs more studies to be explored for better understanding of the disease biology and outcomes. [Table: see text]

Deciphering the Prognostic Significance of MYD88 and CD79B Mutations in Diffuse Large B-Cell Lymphoma: Insights into Treatment Outcomes.

The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different MYD88 and CD79B mutation status merit further investigation. This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among MYD88-CD79Bco-mut, MYD88/CD79Bsingle-mut, and MYD88-CD79Bco-wt DLBCL patients. Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing MYD88-CD79Bco-mut, MYD88/CD79Bsingle-mut, and MYD88-CD79Bco-wt treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology. In the MCD subtype, patients with MYD88-CD79Bco-mut showed comparable progression-free survival (PFS) and overall survival (OS) compared to MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt. However, in the non-MCD subtype, patients with MYD88-CD79Bco-mut exhibited significantly inferior OS than MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt, while there was no significant OS difference between MYD88/CD79Bsingle-mut and MYD88-CD79Bco-wt (median OS: 68.8 [95% CI 22-NA] vs NA [95% CI 112-NA] vs 177.7 [95% CI 159-NA]months; MYD88-CD79Bco-mut vs MYD88/CD79Bsingle-mut: p=0.02; MYD88-CD79Bco-mut vs MYD88-CD79Bco-wt: p=0.03; MYD88/CD79Bsingle-mut vs MYD88-CD79Bco-wt: p=0.33). Regarding patients with MYD88-CD79Bco-mut, there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the MYD88-CD79Bco-mut group, patients with PIM1mut had better PFS than PIM1wt (median PFS: 8.34 [95% CI 5.56-NA] vs 43.8 [95% CI 26.4-NA] months; p=0.02). Possible mechanisms contributing to the superior PFS of PIM1mut patients may include activated lymphocyte-mediated immunity and interferon response, a higher proportion of natural killer T cells and plasmacytoid dendritic cells, as well as suppressed angiogenesis and epithelial-mesenchymal transition, along with lower fibroblast and stromal score. In the MCD subtype, patients with MYD88-CD79Bco-mut showed comparable PFS and OS compared to MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt, while in the non-MCD subtype, they exhibited significantly inferior OS. There was no significant disparity in PFS and OS of MYD88-CD79Bco-mut between the MCD and non-MCD subtypes. The presence of PIM1mut within the MYD88-CD79Bco-mut group correlated with better PFS, which may result from an intricate interplay of immune processes and tumor microenvironment alterations.

New classifications of malignant lymphomas - What changes are relevant for practice?

An internationally uniform lymphoma classification is of fundamental importance for the comparability of clinical studies. There are currently 2 parallel classifications: the "International Consensus Classification" and the WHO-classification. Follicular lymphoma 3B is classified separately as follicular large cell lymphoma in WHO-HAEM5. The diagnostic criteria of lymphoplasmocytic lymphoma (LPL) have been adjusted, both classifications recommend molecular testing for MYD88 and CXCR4 mutations. There are no significant diagnostic changes in aggressive B-cell lymphomas. The ICC classify NLPBL and THRLBCL into the group of large B-cell lymphomas (LBCL). NLPHL/NLPBL-specific therapy must be considered, which differs greatly from the therapy of DLBCL, especially in the early stages. Peripheral T-cell lymphomas are a group of nodal T-cell lymphomas with a TFH phenotype and frequent mutations; peripheral T-cell lymphoma (NOS) is therefore a diagnosis of exclusion. Indolent T-cell lymphomas/lymphoproliferations of the GI tract are rare but must be differentiated from aggressive T-cell lymphomas. The WHO-HAEM5 also includes reactive/non-neoplastic lymph node lesions classified according to B or T cell predominance.

The Molecular Landscape of Primary CNS Lymphomas (PCNSLs) in Children and Young Adults.

Pediatric brain tumors are often noted to be different from their adult counterparts in terms of molecular features. Primary CNS lymphomas (PCNSLs) are mostly found in elderly adults and are uncommon in children and teenagers. There has only been scanty information about the molecular features of PCNSLs at a young age. We examined PCNSLs in 34 young patients aged between 7 and 39 years for gene rearrangements of BCl2, BCL6, CCND1, IRF4, IGH, IGL, IGK, and MYC, homozygous deletions (HD) of CDKN2A, and HLA by FISH. Sequencing was performed using WES, panel target sequencing, or Sanger sequencing due to the small amount of available tissues. The median OS was 97.5 months and longer than that for older patients with PCNSLs. Overall, only 14 instances of gene rearrangement were found (5%), and patients with any gene rearrangement were significantly older (p = 0.029). CDKN2A HD was associated with a shorter OS (p < 0.001). Only 10/31 (32%) showed MYD88 mutations, which were not prognostically significant, and only three of them were L265P mutations. CARD11 mutations were found in 8/24 (33%) cases only. Immunophenotypically, the cases were predominantly GCB, in contrast to older adults (61%). In summary, we showed that molecular findings identified in the PCNSLs of the older patients were only sparingly present in pediatric and young adult patients.

Combination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial

Potential synergism between Bruton’s tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142)

A Case of Lymphoplasmacytic Cell Lymphoma Characterized by Marked Nuclear Fission and Brain Gyrus Nuclei of Lymphocytes

A 67-year-old male was admitted to the hospital due to fatigue and thrombocytopenia. Peripheral blood cells analysis showed the white blood cells count of 2.99 × 109 /L, red blood cell (RBC) count of 2.08 × 1012/L, platelet count of 15 × 109 /L. β2- microglobulin of serum was 5.50 mg/L. Whole-body positron emission tomography-computed tomography suggested altered reactivity in the lymph nodes of the bilateral neck. Morphological examination of bone marrow (BM) indicated the presence of abnormal smaller lymphocytes, accounting for 12.5% of the total nucleated cells. Strikingly, nuclear fission or brain gyrus nuclei were prominently observed in all abnormal lymphocytes (Figure 1, original magnification 1000×; Wright–Giemsa stain). The proportion of plasma cells was 0.5%, and no morphological abnormalities were observed. Additionally, some RBCs were exhibited a rouleaux arrangement. Flow cytometry analysis of BM identified 16.12% of κ-restricted B lymphocytes expressing CD5- , CD10- , CD19+ , CD20+ . A minimal proportion of 0.03% plasma cells with κ/λ ratio of 1.07. Consistent results were confirmed by immunohistochemistry in the BM biopsy. Immunofixation electrophoresis revealed abnormal monoclonal bands in the IgM and κ lanes. Furthermore, mutations of MYD88 (L265P), CXCR4 (T318fs), and TP53 (R306X) were identified through next-generation sequencing analysis. A diagnosis of lymphoplasmic cell lymphoma/waldenström macroglobulinemia (LPL/WM) was established.

Diagnosis and treatment understanding of Waldenström macroglobulinemia in China: a cross-sectional study

Objective: To conduct a nationwide physician survey to better understand clinicians' disease awareness, treatment patterns, and experience of Waldenström macroglobulinemia (WM) in China. Methods: This cross-sectional study was conducted from February 2022 to July 2022 by recruiting clinicians with WM treatment experience from hematology, hematology-oncology, and oncology departments throughout China. Quantitative surveys were designed based on the qualitative interviews. Results: The study included 415 clinicians from 219 hospitals spread across thirty-three cities and twenty-two provinces. As for diagnosis, the laboratory tests prescribed by physicians for suspected WM patients were relatively consistent (92% -99% recommendation for laboratory, 79% -95% recommendation for pathology, 96% recommendation for gene testing, and 63% -83% recommendation for imaging examination). However, from a physician's perspective, there was 22% misdiagnosis occurred in clinical practice. The rate of misdiagnosis was higher in lower-level hospitals than in tertiary grade A hospitals (29% vs 21%, P<0.001). The main reasons for misdiagnosis were that WM was easily confused with other diseases, and physicians lacked the necessary knowledge to make an accurate diagnosis. In terms of gene testing in clinical practice, 96% of participating physicians believed that WM patients would require gene testing for MYD88 and CXCR4 mutations because the results of gene testing would aid in confirming diagnosis and treatment options. In terms of treatment, 55% of physicians thought that the most important goal was to achieve remission, while 54% and 51% of physicians wanted to improve laboratory and/or examination results and extend overall survival time, respectively. Among patients with treatment indications, physicians estimated that approximately 21% of them refused to receive treatment, mainly owing to a lack of affordable care and disease awareness. When selecting the most appropriate treatment regimens, physicians would consider patient affordability (63% ), comorbidity (61% ), and risk level (54% ). Regimens containing Bruton tyrosine kinase inhibitor (BTKi) were most widely recommended for both treatment-naïve and relapsed/refractory patients (94% for all patients, 95% for treatment-naïve patients, and 75% for relapsed/refractory patients), and most physicians recommended Ibrutinib (84% ). For those patients who received treatment, physicians reported that approximately 23% of patients did not comply with the treatment regimen due to a lack of affordability and disease awareness. Furthermore, 66% of physicians believe that in the future, increasing disease awareness and improving diagnosis rates is critical. Conclusions: This study is the first national physician survey of WM conducted in China. It systematically describes the issues that exist in WM diagnosis and treatment in China, such as a high rate of misdiagnosis, limited access to gene testing and new drugs, and poor patient adherence to treatment. Chinese doctors believe that improving doctors' and patients' understanding of WM is one of the most urgent issues that must be addressed right now.