Intratumoral T-cell composition predicts epcoritamab-based treatment efficacy in B-cell non-Hodgkin lymphomas.

Leveraging endogenous tumor-resident T-cells for immunotherapy using bispecific antibodies (BsAb) targeting CD20 and CD3 has emerged as a promising therapeutic strategy for patients with B-cell non-Hodgkin lymphomas. However, features associated with treatment response or resistance are unknown. To this end, we analyzed data from patients treated with epcoritamab-containing regimens in the EPCORE NHL-2 trial ( NCT04663347 ). We observed downregulation of CD20 expression on B-cells following treatment initiation both in progressing patients and in patients achieving durable complete responses (CR), suggesting that CD20 downregulation does not universally predict resistance to BsAb-based therapy. Single-cell immune profiling of tumor biopsies obtained following one cycle of therapy revealed substantial clonal expansion of cytotoxic CD4+ and CD8+ T-cells in patients achieving CR, and an expansion of follicular helper and regulatory CD4+ T-cells in patients whose disease progressed. These results identify distinct tumor-resident T-cell profiles associated with response or resistance to BsAb therapy.

Multiplexed spatial profiling of Hodgkin Reed-Sternberg cell neighborhoods in classic Hodgkin lymphoma.

PURPOSE: Classic Hodgkin lymphoma (cHL) is a B cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of non-malignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown. EXPERIMENTAL DESIGN: We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV) positive and EBV-negative cHL tumors. RESULTS: We show that MHC-I expression on HRS cells is associated with immune inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD-1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T cell excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T cells high neighborhoods harboring HRS cells with augmented proliferative capacity. CONCLUSIONS: Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.

A practical approach to the modern diagnosis and classification of T-and NK-cell lymphomas.

T- and NK-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but show marked biologic and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow or other organs. More than 30 T/NK-cell derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (5th edition), both published in 2022, which integrate most recent knowledge in hematology, immunology, pathology and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype and genetic features into biologically and clinically relevant clinico-pathologic entities. Cell derivation from innate immune cells, or specific functional subsets of CD4+ T cells like follicular helper T cells, are major determinants delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histologic presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge.

The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.

Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IGH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing (WGS) data from 1173 MM samples. Integrating molecular time and structural variants (SV) within early chromosomal duplications, we indeed identified pre-gain deletions in 9.4% of HY patients without IGH translocations, challenging HY as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSG) and/or oncogenes in 2.4% of HY patients without IGH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to post-gain deletions as novel driver mechanisms in MM. Using multi-omics approaches to investigate their biological impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both oncogene and TSG activity, despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in patients with T- and/or NK-cell lymphoma.

ABSTRACT: Although significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in patients with lymphoma (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or natural killer-cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harboring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.

Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy.

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

Universal germline genetic testing in patients with hematologic malignancies using DNA isolated from nail clippings.

Not available.

Effects of Novel Insulin Resistance Indices on Early Renal Functions in Donors.

OBJECTIVE: To investigate the relationship between quickly calculable new insulin resistance (IR) indices used to evaluate IR in early kidney functions after donor nephrectomy. STUDY DESIGN: Descriptive design. Place and Duration of the Study: Department of Urology, Ufuk University Faculty of Medicine, Ankara, Turkiye, between January 2016 and August 2021. METHODOLOGY: The preoperative biochemical analyses of patients undergoing open donor nephrectomies and estimated glomerular filtration rates (eGFR) were recorded in the preoperative and first postoperative month. The IR indices (triglyceride glucose [TyG] index, TyG-body mass index [TyG-BMI], triglyceride/HDL cholesterol ratio [TG/HDL-C], and metabolic score for IR [METS-IR]) were computed. Additionally, the patients were separated into two categories. Group 1 had a less than 30% decrease in eGFR values in the postoperative first-month period, and group 2 had a more than 30% decrease. The relationship between variables was analysed using the Spearman correlation, and comparisons between groups were analysed using the independent t-test or Mann-Whitney U-test. RESULTS: A total of 107 patients were included in the study. The mean eGFR reduction rate was 31.81 ± 8.87 %. In the correlation analyses, an increase in the rate of decrease in postoperative GFR was associated with higher IR indices, specifically TyG (r = 0.19, p = 0.04), TG/HDL-C (r = 0.21, p = 0.02), and METS-IR (r = 0.21, p = 0.02). No statistically significant difference was found between the groups regarding all the calculated IR indices (p < 0.05). CONCLUSION: The results suggest a possible link between increased IR and postoperative renal function decline. KEY WORDS: Insulin resistance, Glomerular filtration rate, Donor nephrectomy, Triglyceride-Glucose index, METS-IR.

Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies.

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.

Role of flow cytometric immunophenotyping in the diagnosis of breast implant-associated anaplastic large cell lymphoma: A 6-year, single-institution experience.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon mature T-cell neoplasm occurring in patients with textured breast implants, typically after 7-10 years of exposure. Although cytopathologic or histopathologic assessment is considered the gold standard diagnostic method for BIA-ALCL, flow cytometry (FC)-based immunophenotyping is recommended as an adjunct test. However, the diagnostic efficacy of FC is not well reported. We reviewed 290 FC tests from breast implant pericapsular fluid and capsule tissue from 182 patients, including 16 patients with BIA-ALCL over a 6-year period, calculating diagnostic rates and test efficacy. FC showed an overall sensitivity of 75.9%, specificity of 100%, and negative and positive predictive values of 95.4% and 100%, respectively. Blinded expert review of false-negative cases identified diagnostic pitfalls, improving sensitivity to 96.6%. Fluid samples had better rates of adequate samples for FC testing compared with tissue samples. Paired with FC testing of operating room (OR)-acquired fluid samples, capsulectomy FC specimens added no diagnostic value in patients with concurrent fluid samples; no cases had positive capsule FC with negative fluid FC. Fluid samples are adequate for FC testing more often than tissue. Capsule tissue FC specimens do not improve FC efficacy when paired with OR-acquired fluid FC samples and are often inadequate samples. FC is 100% specific for BIA-ALCL and can serve as a confirmatory test but should not be the sole diagnostic method. Awareness of sample-specific diagnostic pitfalls greatly improves the sensitivity of BIA-ALCL testing by FC.

Radiographic Impact on the Clinical Decision Making of Achilles Tenotomy in Clubfoot: In Search of an Objective Cut-Off Value.

BACKGROUND: We tried to determine whether the indication of Achilles tenotomy (AT) in clubfoot patients based on clinical evaluation could be confirmed radiographically, and to find an objective radiographic cut-off value for its indication. METHODS: Eighty-six clubfeet from 60 patients, (26 bilateral and 34 unilateral) were included. A standard Ponseti treatment regimen was applied. Group 1 comprised patients who underwent AT immediately after serial plaster casting (26 feet). Group 2 comprised patients who underwent AT during the follow-up period (48 feet). Group 3 comprised patients who were assumed to have a corrected foot and did not undergo AT (12 feet). Group 4 comprised the healthy sides of the unilateral cases (34 feet). RESULTS: Both Group 1 and Group 2 showed significant improvement after tenotomy (p = 0.002). In order to differentiate between the normal and AT groups according to the pre-tenotomy angle, we obtained an optimal cut-off value of >85° according to the Youden index, a sensitivity of 96%, a specificity of 91.2%, a positive predictive value of 95.9%, a negative predictive value of 91.2%, and an accuracy rate of 94.4% (AUC: 0.983; p < 0.001). CONCLUSIONS: Feet with a lateral tibio-calcaneal angle > 85° can be considered pathologic and accepted as candidates for AT.

Immunochemotherapy plus lenalidomide for high-risk mantle cell lymphoma with measurable residual disease evaluation.

Chemoimmunotherapy followed by consolidative high-dose therapy with autologous stem cell rescue was a standard upfront treatment for fit patients with mantle cell lymphoma (MCL) in first remission; however, treatment paradigms are evolving in the era of novel therapies. Lenalidomide is an immunomodulatory agent with known efficacy in treating MCL. We conducted a single-center, investigator-initiated, phase II study of immunochemotherapy incorporating lenalidomide, without autologous stem cell transplant consolidation, enriching for patients with high-risk MCL (clinicaltrials gov. Identifier: NCT02633137). Patients received four cycles of lenalidomide-R-CHOP, two cycles of R-HiDAC, and six cycles of R-lenalidomide. The primary endpoint was rate of 3-year progression-free survival. We measured measurable residual disease (MRD) using a next-generation sequencing-based assay after each phase of treatment and at 6 months following end-oftreatment. We enrolled 49 patients of which 47 were response evaluable. By intent-to-treat, rates of overall and complete response were equivalent at 88% (43/49), one patient with stable disease, and two patients had disease progression during study; 3-year progression-free survival was 63% (primary endpoint not met) and differed by TP53 status (78% wild-type vs. 38% ALT; P=0.043). MRD status was prognostic and predicted long-term outcomes following R-HiDAC and at 6 months following end-of-treatment. In a high-dose therapy-sparing, intensive approach, we achieved favorable outcomes in TP53- wild-type MCL, including high-risk cases. We confirmed that sequential MRD assessment is a powerful prognostic tool in patients with MCL.

Mycetoma case series in Somalia.

Mycetoma is a suppurative chronic bacterial or fungal disease inoculated into the body by minor trauma which may penetrate from subcutaneous tissue to bone. Although the lower extremities are most commonly affected, rare forms can also be seen from time to time. The diagnostic triad of swelling in the affected area, multiple sinus formation, and purulent discharge with grains are typical. Definitive diagnosis is made by isolation of the causative pathogen, radiologic imaging, and histopathologic examination. Antifungal and antibacterial options are applied together with surgery. Our aim in this case series is to report and analyze 10 rare cases of mycetoma.

Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer.

There is a continuing debate about the proportion of cancer patients that benefit from precision oncology, attributable in part to conflicting views as to which molecular alterations are clinically actionable. To quantify the expansion of clinical actionability since 2017, we annotated 47,271 solid tumors sequenced with the MSK-IMPACT clinical assay using two temporally distinct versions of the OncoKB knowledge base deployed 5 years apart. Between 2017 and 2022, we observed an increase from 8.9% to 31.6% in the fraction of tumors harboring a standard care (level 1 or 2) predictive biomarker of therapy response and an almost halving of tumors carrying nonactionable drivers (44.2% to 22.8%). In tumors with limited or no clinical actionability, TP53 (43.2%), KRAS (19.2%), and CDKN2A (12.2%) were the most frequently altered genes. SIGNIFICANCE: Although clear progress has been made in expanding the availability of precision oncology-based treatment paradigms, our results suggest a continued unmet need for innovative therapeutic strategies, particularly for cancers with currently undruggable oncogenic drivers. See related commentary by Horak and Fröhling, p. 18. This article is featured in Selected Articles from This Issue, p. 5.

Novel identification of t(14;18)(q32;q21)/IGH::MALT1 in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a clonal B-cell malignancy and remains a chronic disease despite improvements in clinical outcomes since the use of targeted therapies. Both clinical and biological parameters are important for determining prognosis. Unlike other mature B-cell lymphomas, translocations involving the immunoglobulin heavy chain (IGH) locus are uncommon in CLL. There have been few case reports of CLL harbouring t(14;18)/IGH::BCL2 and t(14;19)/IGH::BCL3. Here we describe the first two cases of patients with CLL with documented t(14;18)(q32;q21)/IGH::MALT1. Both cases in this report were associated with lower-risk biological parameters. Thus, FISH testing for MALT1 in cases with unknown IGH translocation partners in the setting of CLL should be implemented in clinical practice to better define such cases.

Quantification of Measurable Residual Disease Detection by Next-Generation Sequencing-Based Clonality Testing in B-Cell and Plasma Cell Neoplasms.

Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in post-treatment settings can be crucial for relapse risk stratification in patients with B-cell and plasma cell neoplasms. Prior studies have focused on validation of various technical aspects of the MRD assays, but more studies are warranted to establish the performance characteristics and enable standardization and broad utilization in routine clinical practice. Here, the authors describe an NGS-based IGH MRD quantification assay, incorporating a spike-in calibrator for monitoring B-cell and plasma cell neoplasms based on their unique IGH rearrangement status. Comparison of MRD status (positive or undetectable) by NGS and flow cytometry (FC) assays showed high concordance (91%, 471/519 cases) and overall good linear correlation in MRD quantitation, particularly for chronic lymphocytic leukemia and B-lymphoblastic leukemia/lymphoma (R = 0.85). Quantitative correlation was lower for plasma cell neoplasms, where underestimation by FC is a known limitation. No significant effects on sequencing efficiency by the spike-in calibrator were observed, with excellent inter- and intra-assay reproducibility within the authors' laboratory, and in comparison to an external laboratory, using the same assay and protocols. Assays performed both at internal and external laboratories showed highly concordant MRD detection (100%) and quantitation (R = 0.97). Overall, this NGS-based MRD assay showed highly reproducible results with quantitation that correlated well with FC MRD assessment, particularly for B-cell neoplasms.