A5062221935- Chronic Lymphocytic Leukemia Research
- Lymphoma Diagnosis and Treatment
- Immunodeficiency and Autoimmune Disorders
- Chronic Myeloid Leukemia Treatments
- Galectins and Cancer Biology
- Viral-associated cancers and disorders
- Gastrointestinal Tumor Research and Treatment
- Multiple Myeloma Research and Treatments
- Calcium signaling and nucleotide metabolism
- Immune Cell Function and Interaction
- Protein Degradation and Inhibitors
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- SARS-CoV-2 and COVID-19 Research
- Phagocytosis and Immune Regulation
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cutaneous lymphoproliferative disorders research
- Complement system in diseases
- Cancer Mechanisms and Therapy
- CNS Lymphoma Diagnosis and Treatment
- Immunotherapy and Immune Responses
- Eosinophilic Disorders and Syndromes
- Diabetes Treatment and Management
- Acute Lymphoblastic Leukemia research
- PI3K/AKT/mTOR signaling in cancer
Dana-Farber Cancer Institute
2017-2025
Harvard University
2017-2024
Clinica Universidad de Navarra
2023
Centro de Investigación Biomédica en Red de Cáncer
2023
Brigham and Women's Hospital
2020
Dana-Farber Brigham Cancer Center
2020
Istituti di Ricovero e Cura a Carattere Scientifico
2011-2018
Policlinico San Matteo Fondazione
2018
University of Pavia
2011-2015
Summary MYD 88 mutations are present in 95% of Waldenstrom Macroglobulinaemia ( WM ) patients, and support diagnostic discrimination from other IgM‐secreting B‐cell malignancies. Diagnostic can be difficult among suspected wild‐type WT cases. We systematically reviewed the clinical, pathological laboratory studies for 64 patients. World Health Organization consensus guidelines were used to establish clinicopathological diagnosis. Up 30% cases had an alternative diagnosis, including IgM...
Summary Ibrutinib is associated with response rate of 90% and median progression‐free survival (PFS) in excess 5 years Waldenström macroglobulinaemia (WM) patients. CXCR4 mutations are detected 30–40% patients WM associate lower rates shorter PFS to ibrutinib therapy. Both frameshift ( FS ) nonsense NS have been described. The impact these on outcomes not evaluated We studied consecutive a diagnosis WM, therapy, for the presence differences between groups. Of 180 patients, 68 (38%) had...
BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells Waldenström macroglobulinemia (WM). Venetoclax a potent antagonist triggers vitro apoptosis of WM cells. The activity venetoclax remains to be clarified.We performed multicenter, prospective phase II study patients with previously treated (NCT02677324). was dose-escalated from 200 mg maximum dose 800 daily for up 2 years.Thirty-two were evaluable, including 16 exposed Bruton tyrosine kinase...
Abstract Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The is registered ClinicalTrials.Gov (NCT02604511). With median follow-up 50 months, overall, major, and VGPR response rates were 100%, 87%, 30%. rate was numerically but not significantly lower than without CXCR4 mutations (14% vs. 44%; p = 0.09). time to minor 0.9 major 1.9 though longer...
Background Cytokine release triggered by a hyperactive immune response is thought to contribute severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2)–related failure. Bruton tyrosine kinase (BTK) involved in innate immunity, and BTK inhibitors block cytokine release. We assessed the next-generation inhibitor zanubrutinib SARS-CoV-2–infected patients with distress. Method Cohort 1 had prospective, randomized, double-blind, placebo-controlled design; cohort 2 single-arm design....
Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas and diffuse large lymphoma. Deregulation of signaling pathways involved in normal development (NOTCH pathway, NF-κB, BCR signaling) demonstrated splenic We studied mutations NOTCH pathway 46 patients hepatitis virus-positive lymphoma 64 unrelated HCV. NOTCH2 were detected 9 (20%) patients, NOTCH1 2 (4%). By contrast, only one HCV-negative had a or mutation. The frequency the...
Abstract Proteasome inhibition is a standard of care for the primary treatment patients with Waldenström macroglobulinemia (WM). We present long-term follow-up prospective, phase II clinical trial that evaluated combination ixazomib, dexamethasone, and rituximab (IDR) in 26 treatment-naive WM. IDR was administered as 6 monthly induction cycles followed by every-2-month maintenance cycles. The MYD88 L265P mutation detected all patients, CXCR4 mutations were 15 (58%). median time to response...
Summary Little is known about TP 53 mutations in Waldenström Macroglobulinaemia ( WM ). We evaluated 265 patients for by next‐generation sequencing, and validated the findings Sanger sequencing. were identified 6 (2·6%) that impacted DNA ‐binding domain. All six MYD 88‐ CXCR 4 ‐mutated. Ibrutinib showed activity carrying all three mutations. With a median follow‐up of 18 months, 2 (33%) with biallelic inactivation died progressive disease. are rare , associate 88 show response to ibrutinib.
Abstract Activating MYD88 mutations promote pro-survival signaling through BTK and HCK, both targets of ibrutinib. Despite high response rates, complete responses to ibrutinib are lacking, other triggered pathways may contribute primary drug resistance. B-cell receptor (BCR) has been observed in lymphomas driven by mutated MYD88, even without activating the BCR pathway mutations. We identified activated SYK (p-SYK), a component complex with -mutated WM ABC DLBCL lymphoma cells. Confocal...
Key Points CXCR4 S338X clonality ≥25% is associated with lower very good partial response and shorter progression-free survival to ibrutinib. assessment represents a novel biomarker predict outcomes ibrutinib in Waldenström macroglobulinemia patients.
Abstract Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib venetoclax symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received 420 mg once daily (cycle 1), followed by a ramp-up to 400 2). The combination was then administered for 22 additional 4-week cycles. attainment very good partial response (VGPR) the primary end point. Forty-five were...
Mutations in MYD88 (MYD88MUT) are present approximately 93%–97% of patients with Waldenström macroglobulinemia (WM), nearly all which correspond to the c.978T>C transversion resulting a p.Leu265Pro (L265P) substitution at protein level.1,2 MYD88MUT helps support diagnosis WM and differentiate from other IgM-secreting B-cell malignancies, such as marginal zone lymphoma IgM myeloma, where it is absent or rarely expressed.2 The presence also associated better prognosis, lower risk histological...
Summary CXCR4 mutations impact disease presentation and treatment outcomes in Waldenström macroglobulinaemia (WM). Non‐uniform testing for may account discordant findings WM clinical trials. We compared two approaches used these trials detection of the most common (S338X) variant: targeted next‐generation sequencing (NGS) using unselected bone marrow (BM) samples, combined allele‐specific polymerase chain reaction (AS‐PCR) Sanger with CD19‐selected BM samples. Our showed that NGS frequently...
MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of frequent poor-prognosis subtypes diffuse large B-cell lymphoma (DLBCL). Although inhibition mutated pathway has an adverse impact on LPL/WM DLBCL cell survival, its role initiation remains to be clarified. We show that mice, human MYD88L265P promotes development a non-clonal, low-grade lymphoproliferative disorder with several clinicopathologic features resemble LPL/WM,...
Hematopoietic cell kinase (HCK) is an SRC family member that aberrantly upregulated in B-cell neoplasms dependent on MYD88-activating mutations and supports their growth survival. We showed herein activation of Toll-like receptor (TLR) signaling MYD88 wild-type B cells also triggered HCK expression, denoting path regulatory function for by MYD88. To clarify the cascades responsible aberrant expression MYD88-mutated lymphomas, we performed promoter-binding transcription factor (TF) profiling,...