Wolfram Klapper

Kiel University | CAU · Department of Pathology, Hematopathology Section

Importance The current standard-of-care salvage therapy in relapsed/refractory classic Hodgkin lymphoma (cHL) includes consolidation high-dose chemotherapy (HDCT)/autologous stem cell transplant (aSCT). Objective To investigate whether presalvage risk factors and fludeoxyglucose-18 (FDG) positron emission tomography (PET) response to reinduction c...

Next Generation Sequencing-based subtyping and interim- and end of treatment positron emission tomography (i/eot-PET) monitoring have high potential for upfront and on-treatment risk assessment of diffuse large B-cell lymphoma patients. We performed Dana Farber Cancer Institute (DFCI) and LymphGen genetic subtyping for the HOVON84 (n = 208, EudraCT...

The Tumor Microenvironment (TME) in classical Hodgkin Lymphoma (HL) contains abundant immune cells and only few neoplastic Hodgkin and Reed-Sternberg cells (HRSC). We analyzed the T-cell receptor (TCR) repertoire to detect T-cell expansion in the TME and blood. In contrast to solid cancer tissue, T-cells in the TME of HL are highly polyclonal at fi...

The complex and heterogeneous genomic landscape of multiple myeloma (MM) and many of its clinical and prognostic implications remains to be understood. In other cancers, such as breast cancer, using whole-exome sequencing (WES) and molecular signatures in clinical practice has revolutionized classification, prognostic prediction, and patient manage...

The success of targeted immunotherapies for hematological malignancies has heralded their potential as salvage therapies as well as in earlier treatment lines (Cappell & Kochenderfer, 2023). While conventional chemotherapy-based treatments can achieve long-term survival in up to 90 % of treated patients with classic Hodgkin lymphoma (cHL), these th...

Introduction CAR-T cell therapy has been established in relapse treatment of aggressive B-cell lymphomas and demonstrated superior outcome in patients with early and late relapsed/refractory B-cell lymphoma. However, only 50% of patients are cured, making biomarkers to predict response and to guide therapeutic intervention very important. Circulati...

On behalf of the European MCL Network, ML and EH contributed equally Introduction: In younger patients with mantle cell lymphoma (MCL), the addition of ibrutinib during induction immuno-chemotherapy and as 2-years maintenance with and without autologous stem cell transplantation (ASCT) has shown high efficacy in the 3-arm randomized TRIANGLE trial...

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma derived from transformed dark zone germinal center B cells. Intensive polychemotherapy in combination with the CD20-directed monoclonal antibody (mAb) rituximab is used as first-line therapy with high cure rates. The prognosis of patients significantly decreases in elderly and unfit patients or...

Introduction The TRIANGLE trial (Dreyling et al. 2024) has set a novel standard in first-line treatment of mantle cell lymphoma (MCL) patients aged 18-65 years, highlighting the role of ibrutinib in the management of these patients. During the planning stage of TRIANGLE, results of the LYSA-LYMA trial showed a progression-free survival (PFS) benefi...

Objectives Primary nodal marginal B-cell lymphoma (NMZL) is rare and histologically very variable. Its large-cell presentation is difficult to distinguish from nodal diffuse large B-cell lymphoma (nDLBCL) due to the absence of specific markers for nodal marginal zone lymphomas in general. Methods Using a comprehensive cohort of NMZLs and a control...

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOSSMARCB1-, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOSSMARCB1- show similar DNA methylation profiles, wi...

Tenosynovial giant cell tumor (TGCT) is a rare type of tumor that originates from the synovium of joints and tendon sheaths. It is characterized by recurring genetic abnormalities, often involving the CSF1 gene. Common symptoms include pain and swelling, which are not specific to TGCT, so MRI and a pathological biopsy are needed for an accurate dia...

Recent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from the European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC...

Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 34 patients with HA20, we show that heterozygous TNFAIP3 loss skews immune repertoires toward lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas. This s...

Progression or relapse in the central nervous system (CNS) remains a rare but mostly fatal event for patients with diffuse large B-cell lymphoma (DLBCL). In a retrospective analysis of 5189 patients treated within 19 prospective German and French phase 2/3 trials, we identified 159 patients experiencing a CNS event (relapse: 62%, progression: 38%)....

The Tumor Microenvironment (TME) in classical Hodgkin lymphoma (HL) contains abundant immune cells and only few neoplastic Hodgkin and Reed-Sternberg cells (HRSC). We analyzed the T-cell receptor (TCR) repertoire to detect T-cell expansion in the TME and blood. In contrast to solid cancer tissue, T-cells in the TME of HL are highly polyclonal at fi...

LBA7000 Background: We hypothesized that therapy with the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) guided by positron emission tomography after two cycles (PET2) could improve the treatment of advanced-stage classical Hodgkin lymphoma (AS-cHL). The HD21 trial aimed at demonstr...

Hodgkin–Reed–Sternberg cells (HRSCs) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leukocyte antigen class I (HLA‐I), considered to hamper activation of cytotoxic T cells in the tumor microenvironment (TME). Here, we demonstrate HLA‐I expression on HRSCs to be a strong determinant of TME composition whereas expression of HLA‐...

Recent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet, comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC)-N...

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligibl...

SRY-related HMG-box gene 11 (SOX11) is a transcription factor overexpressed in mantle cell lymphoma (MCL), a subset of Burkitt lymphomas (BL) and precursor lymphoid cell neoplasms but is absent in normal B-cells and other B-cell lymphomas. SOX11 has an oncogenic role in MCL but its contribution to BL pathogenesis remains uncertain. Here, we observe...

High-grade B-cell lymphoma with 11q aberrations (HGBL-11q) is a type of aggressive B-cell lymphoma that shares morphological, immunophenotypic and gene expression features with Burkitt lymphoma (BL). HGBL-11q and BL differ in terms of the MYC translocation and typical landscapes of structural and small nucleotide variants. HGBL-11q harbours the nam...

Frequency, distribution and prognostic meaning of ALK‐partner genes other than NPM1 in ALK‐positive anaplastic large‐cell lymphoma (ALCL) are unknown. Forty‐nine of 316 ALCL diagnosed in the NHL‐BFM study group showed no nuclear ALK expression suggestive of a variant ALK‐partner; 41 were analysed by genomic capture high‐throughput sequencing or spe...

Pediatric B-cell precursor (BCP) lymphoblastic malignancies are neoplasms with manifestation either in bone marrow/blood (BCP acute lymphoblastic leukemia, BCP-ALL) or less common in extramedullary tissue (BCP lymphoblastic lymphoma, BCP-LBL). Although both presentations are similar in morphology and immunophenotype molecular studies are virtually...

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD+B) versus without (R-HAD) in r/r MCL ineligible...

PURPOSE Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk stratification are lacking. PATIENTS AND METHODS To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untr...

Introduction: Depending on clinical and molecular risk factors, CNS relapse occurs in 1-15% of DLBCL patients (pts) and is associated with dismal outcomes. Despite its important role in further improving DLBCL therapy, a comprehensive and large-scale characterization of secondary CNS relapse remains challenging. Methods: We conducteda retrospective...

INTRODUCTION The GHSG-HD21 trial for newly diagnosed adult patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) compares the BrECADD regimen (Brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)...

Introduction The Tumor Microenvironment (TME) in classical Hodgkin Lymphoma (HL) contains abundant CD4+ and CD8+ T-cells and only few Hodgkin-Reed-Sternberg cells (HRSC). Despite their low abundance, HRSC comprise the neoplastic cell population that intensively interacts with cells of the TME. Understanding these interactions is crucial to the furt...

CAR-T-cell therapy (CARTCT) expands the range of therapeutic options for patients with hematologic malignancies. While complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are well known, pseudoprogression (PP) is until now mainly described after checkpoint inhibition. Some reports...

Primary cutaneous CD4+ small or medium T‐cell lymphoproliferative disorder (PCSM‐LPD) is a clonal T‐cell proliferation disease confined to the skin. PCSM‐LPD shares expression of T follicular helper (Tfh) cell markers with various mature T‐cell lymphomas. However, the benign presentation of PCSM‐LPD contrasts the clinical behavior of other Tfh‐lymp...

Next-generation sequencing (NGS)-based genetic subtyping and interim- and end-of-treatment ¹⁸ fluorodeoxyglucose-positron emission tomography (i/eot-PET) have high potential for upfront and on-treatment risk assessment to guide personalized treatment of diffuse large B-cell lymphoma (DLBCL-NOS). We performed NGS genetic subtyping according to the D...

Recent exome-wide studies discovered frequent somatic mutations in the epigenetic modifier ZNF217 in primary mediastinal B cell lymphoma (PMBCL) and related disorders. As functional consequences of ZNF217 alterations remain unknown, we comprehensively evaluated their impact in PMBCL. Targeted sequencing identified genetic lesions affecting ZNF217 i...

Background Lymphomas in children and adolescents differ from adulthood in relative frequency and variety of entities. In addition, young patients are cared for according to the specific standards of pediatric lymphoma study groups.Objective To present lymphomas of diagnostic and clinical relevance in the pediatric and adolescent group.Material and...

In diffuse large B-cell lymphoma (DLBCL), a positive interim positron emission tomography (PET) scan predicts treatment failure, but the proportion of high-risk patients thus identified is small. To improve prediction, we combined the interim PET result with the presence or absence of an associated IgM gammopathy. Of 108 DLBCL patients participatin...

Knowledge on the pathogenesis of FL is mainly based on data derived from advanced/systemic stages of FL (sFL) and only small cohorts of localized FL (lFL) have been characterized intensively so far. Comprehensive analysis with profiling of somatic copy number alterations (SCNA) and whole exome sequencing (WES) was performed in 147 lFL and 122 sFL....

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting. We report long-term outcomes of a pooled trials analysis comparing Cyclophos...

Session 4 of the 2021 European Association of Haematopathology/Society for Hematopathology Workshop focused on nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). First, the spectrum of immunophenotypic variations in NLPHL and the defining criteria for classic Hodgkin Lymphoma (CHL) were discussed. The added value of further immunophenotypic c...

Currently, treatment allocation of patients with Mantle Cell Lymphoma (MCL) is mainly based on age and medical fitness. The combined MCL International Prognostic Index (MIPI-c) allows to predict prognosis using clinical factors (MIPI) and the Ki-67 index. However, high p53 expression as surrogate for TP53 alterations has demonstrated to be an indep...

Hodgkin Reed Sternberg cells (HRSC) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leucocyte antigen class I (HLA-I), hampering activation of cytotoxic T-cells in the tumor microenvironment (TME). We identify the HLA-I expression status of HRSC, found in a minority of HL, as a strong determinant of TME composition. Combined wh...

Knowledge on the pathogenesis of FL is mainly based on data derived from advanced/systemic stages of FL (sFL) and only small cohorts of localized FL (lFL) have been characterized intensively so far. Comprehensive analysis with profiling of somatic copy number alterations (SCNA) and whole exome sequencing (WES) was performed in 147 lFL and 122 sFL....

Introduction Inborn errors of immunity (IEI) are characterized by a dysfunction of the immune system leading to increased susceptibility to infections, impaired immune regulation and cancer. We present a unique consanguineous family with a history of Hodgkin lymphoma, impaired EBV control and a late onset hemophagocytic lymphohistiocytosis (HLH)....

Recently, two new classifications were released: the International Consensus Classification (ICC) drafted by the Clinical Advisory Committee and the short version of the 5th Edition of the WHO classification of hematolymphoid tumors. In light of new clinical, morphological, and molecular data, both classifications also revised the classification of...

Background Long‐term clinical and molecular remissions in patients with mantle cell lymphoma (MCL) after autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Design and Methods Sixty‐five patients with MCL received ASCT (54 first‐line ASCT, 10 second‐line ASCT, and 1 third‐line ASCT). In the case of long‐term remi...

Currently, treatment allocation of patients with Mantle Cell Lymphoma (MCL) is mainly based on age and medical fitness. The combined MCL International Prognostic Index (MIPI-c) allows to predict prognosis using clinical factors (MIPI) and the Ki-67 index. However, high p53 expression as surrogate for TP53 alterations has demonstrated to be an indep...

Background: Diffuse large B-cell lymphoma (DLBCL) is classified into two molecular subtypes according to its cell of origin: germinal center B-cell (GCB) subtype and activated B-cell/non-GCB subtype. This latter subtype shows a poorer prognosis in adults. However, in pediatric DLBCL, the prognostic impact of the subtype is yet to be clarified. Ob...

Aims: Subclassification of large B-cell lymphoma (LBCL) is challenging due to the overlap in histopathologic, immunophenotypic, and genetic data. In particular, the criteria to separate diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) are difficult to apply in practice. The Lunenburg Lymphoma Biomarker Consortium previou...

Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-TCLPD) is a rare subtype of cutaneous T-cell lymphomas of unknown origin. We report for the first time, to the best of our knowledge, on an association of PCSM-TCLPD with pregnancy and briefly discuss the possible pathogenetic link.

Epstein-Barr virus (EBV) associated diffuse large B-cell lymphoma (DLBCL) represents a rare aggressive B-cell lymphoma subtype characterized by an adverse clinical outcome. EBV infection of lymphoma cells has been associated with different lymphoma subtypes while the precise role of EBV in lymphomagenesis and specific molecular characteristics of t...

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO...

The incidence of aggressive B-cell lymphomas increases with age, but for elderly or frail patients not eligible for doxorubicin-containing treatment standard therapy remains to be defined. In this prospective, multicenter, phase-2 B-R-ENDA trial, we investigated the feasibility, toxicity, and efficacy of 8 cycles rituximab combined with 6 cycles be...

Aims: To gain insight into the biology of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-LPD). Methods: We describe the histopathological and clinical characteristics of 177 PCSM-LPD diagnosed at our consultation center. We performed immunohistochemical multi-staining in a subset of cases (n=46) including PD1, Cycl...

We investigated whether outcome prediction of aggressive B-cell lymphoma patients can be improved by combining clinical, molecular genotype and radiomics features. MYC, BCL2 and BCL6 rearrangements were assessed using fluorescence in situ hybridization. Seventeen radiomics features were extracted from the baseline PET/CT of 323 patients: maximum st...