Publications by authors named "Joost S P Vermaat"

13 Publications

  • Page 1 of 1

Health-related quality of life and utility outcomes with selinexor in relapsed/refractory diffuse large B-cell lymphoma.

Future Oncol 2021 Apr 2;17(11):1295-1310. Epub 2021 Feb 2.

Servicio de Hematología, Hospital Universitario La Paz, Madrid, 28046, Spain.

Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Functional Assessment of Cancer Therapy (FACT) - Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Treatment responders maintained higher FACT - Lymphoma (p ≤ 0.05), FACT - General (p < 0.05) and EuroQoL five-dimensions five-levels index scores (p < 0.001) beginning in cycle 3. The estimated difference in health state utilities for treatment response and progressive disease was both statistically significant and clinically meaningful (mean difference: 0.07; p = 0.001). In patients with relapsed/refractory diffuse large B-cell lymphoma, objective response to selinexor was associated with HRQoL maintenance, reduction in disease-related HRQoL decrements and higher health utilities.
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http://dx.doi.org/10.2217/fon-2020-0946DOI Listing
April 2021

Treatment of patients with MYC rearrangement positive large B-cell lymphoma with R-CHOP plus lenalidomide: results of a multicenter HOVON phase II trial.

Haematologica 2020 12 1;105(12):2805-2812. Epub 2020 Dec 1.

Dept of Hematology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, the Netherlands.

Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).
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http://dx.doi.org/10.3324/haematol.2019.238162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716355PMC
December 2020

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial.

Lancet Haematol 2020 Jul;7(7):e511-e522

Hospital Universitario La Paz, Madrid, Spain.

Background: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit.

Methods: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling).

Findings: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor.

Interpretation: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting.

Funding: Karyopharm Therapeutics Inc.
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http://dx.doi.org/10.1016/S2352-3026(20)30120-4DOI Listing
July 2020

Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing.

Leukemia 2021 01 3;35(1):47-61. Epub 2020 Mar 3.

Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands.

Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, and flexible platform for AML diagnostics. We developed HAMLET (Human AML Expedited Transcriptomics) as bioinformatics pipeline for simultaneous detection of fusion genes, small variants, tandem duplications, and gene expression with all information assembled in an annotated, user-friendly output file. Whole transcriptome RNA sequencing was performed on 100 AML cases and HAMLET results were validated by reference assays and targeted resequencing. The data showed that HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and tandem duplications in FLT3 and KMT2A were detected by a novel algorithm based on soft-clipped reads with 100% sensitivity and 97.1% specificity. In conclusion, HAMLET has the potential to provide accurate comprehensive diagnostic information relevant for AML classification, risk assessment and targeted therapy on a single technology platform.
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http://dx.doi.org/10.1038/s41375-020-0762-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787979PMC
January 2021

is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling.

Proc Natl Acad Sci U S A 2020 02 11;117(8):4320-4327. Epub 2020 Feb 11.

Institute of Immunology, Ulm University, 89081 Ulm, Germany;

The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21-derived heavy chains (HCs) with IGLV3-21-derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21), we show that IGLV3-21-expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only facilitates effective homotypic BCR-BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms -expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21-expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors.
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http://dx.doi.org/10.1073/pnas.1913810117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049113PMC
February 2020

MYD88 in the driver's seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications.

Haematologica 2019 12 7;104(12):2337-2348. Epub 2019 Nov 7.

Department of Hematology, Leiden University Medical Center, Leiden

More than 50 subtypes of B-cell non-Hodgkin lymphoma (B-NHL) are recognized in the most recent World Health Organization classification of 2016. The current treatment paradigm, however, is largely based on 'one-size-fits-all' immune-chemotherapy. Unfortunately, this therapeutic strategy is inadequate for a significant number of patients. As such, there is an indisputable need for novel, preferably targeted, therapies based on a biologically driven classification and risk stratification. Sequencing studies identified mutations in the gene as an important oncogenic driver in B-cell lymphomas. mutations constitutively activate NF-κB and its associated signaling pathways, thereby promoting B-cell proliferation and survival. High frequencies of the hotspot (L265P) mutation are observed in extranodal diffuse large B-cell lymphoma and Waldenström macroglobulinemia, thereby demonstrating this mutation's potential as a disease marker. In addition, the presence of mutant predicts survival outcome in B-NHL subtypes and it provides a therapeutic target. Early clinical trials targeting have shown encouraging results in relapsed/refractory B-NHL. Patients with these disorders can benefit from analysis for the hotspot mutation in liquid biopsies, as a minimally invasive method to demonstrate treatment response or resistance. Given these clear clinical implications and the crucial role of in lymphomagenesis, we expect that analysis of this gene will increasingly be used in routine clinical practice, not only as a diagnostic classifier, but also as a prognostic and therapeutic biomarker directing precision medicine. This review focuses on the pivotal mechanistic role of mutated and its clinical implications in B-NHL.
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http://dx.doi.org/10.3324/haematol.2019.227272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959184PMC
December 2019

High frequency of inactivating tetraspanin mutations in diffuse large B-cell lymphoma at immune-privileged sites.

Blood 2019 09 31;134(12):946-950. Epub 2019 Jul 31.

Department of Tumor Immunology and.

Tetraspanin CD37 is predominantly expressed on the cell surface of mature B lymphocytes and is currently being studied as novel therapeutic target for B-cell lymphoma. Recently, we demonstrated that loss of CD37 induces spontaneous B-cell lymphoma in -knockout mice and correlates with inferior survival in patients with diffuse large B-cell lymphoma (DLBCL). Here, mutation analysis was performed in a cohort of 137 primary DLBCL samples, including 44 primary immune-privileged site-associated DLBCL (IP-DLBCL) samples originating in the testis or central nervous system. mutations were exclusively identified in IP-DLBCL cases (10/44, 23%) but absent in non-IP-DLBCL cases. The aberrations included 10 missense mutations, 1 deletion, and 3 splice-site mutations. Modeling and functional analysis of missense mutations revealed loss of function by impaired CD37 protein expression at the plasma membrane of human lymphoma B cells. This study provides novel insight into the molecular pathogenesis of IP-DLBCL and indicates that anti-CD37 therapies will be more beneficial for DLBCL patients without mutations.
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http://dx.doi.org/10.1182/blood.2019001185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789512PMC
September 2019

Generalized Molluscum Contagiosum Successfully Treated with Interferon-Alpha in a Patient with Folliculotropic Mycosis Fungoides.

Case Rep Dermatol 2019 Jan-Apr;11(1):52-56. Epub 2019 Feb 26.

Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.

We present the case of a 50-year-old patient with folliculotropic mycosis fungoides (FMF) unresponsive to retinoids and the chemotherapeutic regimens CHOP, gemcitabine, and brentuximab-vedotin. During immunosuppressive therapy, the patient developed extensive progressive molluscum contagiosum. The mollusca did not respond to topical imiquimod but showed a swift complete response to interferon-alpha 2a (IFNa). Recently, the patient started with alemtuzumab as induction therapy for an allogenic stem cell transplantation and simultaneously continued IFNa therapy.
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http://dx.doi.org/10.1159/000497349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477461PMC
February 2019

High Incidence and Clinical Significance of MYC Rearrangements in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.

Am J Surg Pathol 2018 11;42(11):1488-1494

Dermatology.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) and primary cutaneous follicle center lymphoma (PCFCL) are cutaneous B-cell lymphomas (CBCL) with different clinical characteristics and behavior. PCDLBCL-LT is the most aggressive CBCL with a relatively poor prognosis. In nodal diffuse large B-cell lymphoma (DLBCL), rearrangements of the MYC gene, especially in combination with a second hit in BCL2 and/or BCL6, and double protein expression of MYC and BCL2 (DE) are adverse prognostic factors. As the clinical significance of these factors in CBCL is largely unknown, we studied the frequency and prognostic value of MYC rearrangements and DE in a cohort of 44 patients with PCDLBCL-LT and 17 patients with PCFCL. Compared with nodal DLBCL (9% to 14%), the PCDLBCL-LT patients had a high incidence of MYC rearrangements (32%), but only 2 patients (4%) had a second hit, both with BCL6. PCDLBCL-LT patients with a MYC rearrangement showed an inferior disease-specific survival (Log-rank, P=0.036) and disease-free survival (Log-rank, P=0.028), but no significant adverse effect on overall survival (Log-rank, P=0.157) at 5 years compared with patients without a MYC rearrangement. DE, present in 65% of the PCDLBCL-LT patients, was not associated with reduced survival. In the PCFCL group, MYC rearrangements and DE were not detected. In conclusion, this study identifies a high incidence of MYC rearrangements in PCDLBCL-LT compared to nodal DLBCL and further shows that a MYC rearrangement is an inferior prognostic marker in these patients. Therefore, our data suggest that it is useful to perform MYC-FISH in all newly diagnosed PCDLBCL-LT patients.
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http://dx.doi.org/10.1097/PAS.0000000000001132DOI Listing
November 2018

Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids.

Cancer Cell 2011 Sep;20(3):370-83

Department of Medical Oncology, University Medical Center Utrecht, The Netherlands.

The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. Here, we demonstrate that endogenous mesenchymal stem cells (MSCs) become activated during treatment with platinum analogs and secrete factors that protect tumor cells against a range of chemotherapeutics. Through a metabolomics approach, we identified two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), that in minute quantities induce resistance to a broad spectrum of chemotherapeutic agents. Interestingly, blocking central enzymes involved in the production of these PIFAs (cyclooxygenase-1 and thromboxane synthase) prevents MSC-induced resistance. Our findings show that MSCs are potent mediators of resistance to chemotherapy and reveal targets to enhance chemotherapy efficacy in patients.
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http://dx.doi.org/10.1016/j.ccr.2011.08.010DOI Listing
September 2011

Liver surgery induces an immediate mobilization of progenitor cells in liver cancer patients: A potential role for G-CSF.

Cancer Biol Ther 2010 May 18;9(9):743-8. Epub 2010 May 18.

Department of Medical Oncology, UMC Utrecht, The Netherlands.

Background: In preclinical models recruitment of bone-marrow derived (endothelial) progenitor cells (BD(E)PCs) contributes to tumor growth and metastasis formation. Here we investigated whether these (E)PCs and mobilizing cytokines are released after partial hepatectomy or radiofrequency ablation (RFA) for liver tumors. In addition, we tested whether G-CSF could play a role in EPC mobilization in mice and in human volunteers.

Results: Patients undergoing partial hepatectomy or RFA showed an instantaneous release of EPCs following laparotomy and mobilization of the liver. Elevated EPC levels were maintained during the entire procedure, but dropped to near-baseline levels 4 h after completion of the procedure. Plasma G-CSF levels showed a 5-10-fold increase after the procedure and low-dose G-CSF administration to mice or healthy volunteers was sufficient to induce an immediate release of EPCs. Surgery also caused an increase in the plasma levels of VEGF, but not SDF-1alpha.

Methods: Before, during and after liver surgery plasma and mononuclear cells were collected from 12 patients undergoing partial hepatectomy or RFA. To explore the role of G-CSF C57Bl/6 mice and 20 human volunteers received G-CSF (0.3, 3 or 300microg). In all individuals, (E)PC numbers were determined by flow cytometry at predefined timepoints shortly after therapy. Plasma levels of G-CSF, VEGF and SDF-1alpha were measured by ELISA.

Conclusion: Compliant with previous published data concerning VDA and chemotherapy treatment, liver surgery induces an instantaneous release of EPCs, conceivably in response to elevated G-CSF levels. This suggests the value of exploring therapeutic avenues to prevent this process.
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http://dx.doi.org/10.4161/cbt.9.9.11551DOI Listing
May 2010