ABSTRACT
Waldenström macroglobulinemia (WM) is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M (IgM) protein (Owen et al., 2003). Common signs and symptoms include fatigue due to anemia, lymph node enlargement, hepatosplenomegaly, thrombocytopenia, symptoms related to high viscosity, and peripheral neuropathy, among others. Despite significant advances in WM treatment, this type of indolent lymphoma remains incurable, with a wide array of patient outcomes (Ruan et al., 2020). In recent years, chimeric antigen receptor T (CAR-T) cell therapy targeting cluster of differentiation 19 (CD19) has shown unprecedented response rates and durability in the treatment of B-cell malignancies. In this report, we describe a challenging case of WM that involved multiple extramedullary sites, relapsed, and was refractory to chemotherapy, immunotherapy, and targeted therapy. After anti-CD19 CAR-T cell therapy, the tumor burden significantly decreased and the patient's condition remained stable at the writing of this report.
Subject(s)
Antigens, CD19 , Immunotherapy, Adoptive , Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/therapy , Immunotherapy, Adoptive/methods , Male , Middle Aged , Receptors, Chimeric AntigenABSTRACT
Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.
Subject(s)
Cancer Vaccines , Waldenstrom Macroglobulinemia , Humans , Male , Cancer Vaccines/immunology , Cancer Vaccines/therapeutic use , Cancer Vaccines/administration & dosage , Middle Aged , Female , Waldenstrom Macroglobulinemia/immunology , Waldenstrom Macroglobulinemia/therapy , Waldenstrom Macroglobulinemia/genetics , Aged , Tumor Microenvironment/immunology , Precision Medicine/methods , Vaccines, DNA/immunology , Vaccines, DNA/therapeutic use , Antigens, Neoplasm/immunology , B-Lymphocytes/immunologyABSTRACT
PURPOSE OF REVIEW: Waldenström macroglobulinemia is a rare non-Hodgkin lymphoma (NHL) characterized by lymphoplasmacytic bone marrow infiltration associated with an immunoglobulin M (IgM) monoclonal gammopathy. Over the past two decades, a number of important novel therapies have emerged for the treatment of relapsed and refractory (R/R) WM. The purpose of this review is to discuss these novel agents. RECENT FINDINGS: Chemoimmunotherapy which formed the basis treatment for R/R WM is slowly being replaced by novel targeted agents. These therapies, including Bruton's tyrosine kinase inhibitors, proteasome inhibitors, and B-cell lymphoma 2 inhibitors, have widened the landscape of management. Emerging therapies currently under investigation, such as bispecific T-cell engagers, chimeric antigen T-cell receptor therapy, and novel small molecule inhibitors, have additionally shown the potential to improve response and survival. The treatment of R/R WM has greatly evolved, in large part due to a greater understanding of the biology of WM, and the evaluation of novel targeted agents in the basket trials of NHL, showing early activity in the small WM cohorts. Combination regimens with these established and emerging novel therapies have the potential to further improve disease control and induce higher rates of deep responses. Strategies aimed at altering the disease trajectory would require randomized controlled trials to provide relevant data on optimal integration and sequencing of more effective and tolerable regimens earlier in the disease course.
Subject(s)
Waldenstrom Macroglobulinemia , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/therapy , Humans , Disease Management , Recurrence , Molecular Targeted Therapy/methods , Drug Resistance, Neoplasm , Protein Kinase Inhibitors/therapeutic use , Immunotherapy/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
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.
Subject(s)
Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/therapy , Waldenstrom Macroglobulinemia/drug therapy , Cross-Sectional Studies , Protein Kinase Inhibitors/therapeutic use , Signal Transduction , Surveys and Questionnaires , Myeloid Differentiation Factor 88/geneticsABSTRACT
ABSTRACT: Histologic transformation of Waldenström macroglobulinemia (HT-WM) carries a poor prognosis with standard treatments. Here, we report the first series of HT-WM treated with chimeric antigen receptor T cells showing a high efficacy and no unexpected toxicity.
Subject(s)
Antigens, CD19 , Immunotherapy, Adoptive , Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/therapy , Waldenstrom Macroglobulinemia/immunology , Waldenstrom Macroglobulinemia/pathology , Male , Aged , Immunotherapy, Adoptive/methods , Female , Antigens, CD19/immunology , Middle Aged , Receptors, Chimeric Antigen/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Treatment OutcomeABSTRACT
The simultaneous occurrence of Waldenström macroglobulinemia and multiple myeloma in the same patient has been published as case reports. Patients with Waldenström macroglobulinemia often have a small clone of plasma cells. However, the concurrent occurrence of symptomatic myeloma with lytic bone lesions is rare. The diagnosis of this 'hybrid' entity is challenging, and there are no standard therapies. We present six patients from five centers (three in Israel and two in the United States). We describe these patients' unique clinical course and treatment approaches.
Subject(s)
Multiple Myeloma , Waldenstrom Macroglobulinemia , Humans , Multiple Myeloma/complications , Multiple Myeloma/diagnosis , Multiple Myeloma/therapy , Waldenstrom Macroglobulinemia/complications , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/therapy , Male , Aged , Middle Aged , Female , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aged, 80 and overABSTRACT
The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.
Subject(s)
Lymphoma, B-Cell , Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/therapy , Waldenstrom Macroglobulinemia/drug therapyABSTRACT
A macroglobulinemia de Waldenstrom é uma patologia rara dos linfócitos B caracterizada pela produção monoclonal de IgM, e que pode manifestar-se clinicamente com fadiga, astenia, perda de peso, sangramento de mucosas e do trato gastrointestinal, linfonodomegalias e alterações neurológicas. A doença é mais comum em pacientes idosos , do sexo masculino, com história familiar da doença...(AU)
Subject(s)
Waldenstrom Macroglobulinemia/pathology , Waldenstrom Macroglobulinemia/therapy , Paraproteinemias/diagnosisABSTRACT
La macroglobulinemia de Waldenström (MW) es una discrasia sanguínea caracterizada por la proliferación monoclonal de células linfoplasmocitarias en la médula ósea, ganglios linfáticos y bazo. Estos pacientes tienen niveles elevados en suero y depósito en tejidos de la inmunoglobulina (Ig) M, de tipo monoclonal, producida por estas células aberrantes. Presentamos el caso de un paciente afecto de MW, con lesiones cutáneas debidas al depósito de cadenas ligeras Kappa de IgM y con manifestaciones clínicas secundarias a la crioglobulinemia tipo I que el paciente tenía asociada. Discutimos los distintos proceso patológicos cutáneos provocados por la IgM en la MW (AU)
Waldenström macroglobulinemia is a blood dyscrasia characterized by monoclonal proliferation of Bcells in the bone marrow, lymph nodes, and spleen. Patients with this disease show elevated serum levels and tissue deposition of monoclonal immunoglobulin (Ig) M produced by these aberrant cells. We present the case of a patient with Waldenström macroglobulinemia who suffered cutaneous lesions resulting from deposition of k light chains of IgM and clinical manifestations secondary to associated type I cryoglobulinemia. We discuss the different pathological cutaneous processes caused by IgM in Waldenström macroglobulinemia (AU)
Subject(s)
Humans , Male , Middle Aged , Waldenstrom Macroglobulinemia/complications , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/therapy , Cryoglobulinemia/diagnosis , Cryoglobulinemia/therapy , Immunoglobulin M/administration & dosage , Hyperkeratosis, Epidermolytic/complications , Hyperkeratosis, Epidermolytic/diagnosis , Immunohistochemistry/methods , Immunoenzyme Techniques/methods , Waldenstrom Macroglobulinemia/physiopathology , Paraproteinemias/complications , Amylases , Immunohistochemistry/trends , Keratinocytes/cytology , Keratinocytes/ultrastructure , Plasmapheresis/methodsABSTRACT
Objetivo: Conocer la evolución clínica de los pacientes del Área Sanitaria de Guadalajara en los que fue diagnosticada una paraproteína sérica. Material y métodos: Estudio prospectivo de 186 pacientes en los que durante los años 1999 y 2000 se detectó de novo una banda monoclonal sérica. Resultados: La probabilidad acumulada de progresión a enfermedad maligna fue del 4,99% a los 43 meses en los pacientes cuya paraproteína fue clínicamente soslayada y 2% a los 23 meses en pacientes diagnosticados de gammapatía monoclonal de significado incierto. La probabilidad acumulada de supervivencia en los pacientes con mieloma múltiple fue 66,7% a los 21 meses. La tasa condicionada de mortalidad (paciente/mes) a los 4 años debido a enfermedad hematológica fue de 4,48.10-4 en pacientes clínicamente soslayados, 0 en los diagnosticados de gammapatía monoclonal de significado incierto y 1,388.10-2 en los diagnosticados de mieloma múltiple. Discusión: El seguimiento de pacientes con banda monoclonal benigna es fundamental, al menos durante los cuatro primeros años, ya que con ello podría conseguirse una mayor supervivencia en relación con su transformación en maligna
Objective: To study the clinical course of patients with a serum monoclonal protein at Guadalajara Health Area. Material and methods: Prospective study of 186 patients with a newly diagnosed monoclonal component. They have been collected during the years 1999 and 2000. Results: The cumulative transformation probability at 43 months was 4.99% for those patients whose monoclonal gammopathy was overlooked, and 2% at 23 months for patients with monoclonal gammopathy of undetermined significance. The cumulative probability of survival for patients with multiple myeloma was 66.7% at 21 months. The conditional mortality rate (patients/months) at 4 years due to haematological disease was 4.48x10-4 for overlooked patients, 0 for diagnosed of monoclonal gammopathy of undetermined significance and 1.388x10-2 for multiple myeloma diagnosed. Discussion: A non malignant M component must be followed up due to it could increase patients survival rate in relation with transformation in malignant disease
Subject(s)
Male , Female , Middle Aged , Humans , Cohort Studies , Paraproteinemias/diagnosis , Paraproteinemias/pathology , Paraproteinemias/therapy , Blood Protein Electrophoresis/methods , Multiple Myeloma/complications , Multiple Myeloma/diagnosis , Waldenstrom Macroglobulinemia/complications , Waldenstrom Macroglobulinemia/diagnosis , Prospective Studies , Waldenstrom Macroglobulinemia/pathology , Waldenstrom Macroglobulinemia/therapyABSTRACT
La plasmaféresis, palabra acuñada por John Jacob Abel en 1914, se refiere a retirar o remover el plasma sanguíneo con devolución del resto de los componentes sanguíneos hacia el donante o paciente. Aunque en el pasado se utilizaron métodos manuales, solo con la introducción de bolsas de sangre estériles, equipos desechables y el desarrollo de máquinas separadoras de células han permitido hoy realizar los procedimientos de plasmaféresis de manera segura y eficaz. El objetivo principal de los procedimientos de plasmaféresis es la remoción del plasma y con ello el retiro del elemento responsable del daño patológico. Actualmente las máquinas de plasmaféresis poseen una moderna tecnología computacional (microprocesadores) que permiten programar el procedimiento completo. Utilizan sensores ópticos para detectar la interfase deseada y proceder a recolectar el hemocomponente. El gran incremento en las indicaciones clínicas de la plasmaféresis en los últimos 20 años es reflejo del desarrollo de esta nueva tecnología y también se debe a un mejor conocimiento de la fisiopatología de las enfermedades. En este artículo se resumen las indicaciones actuales de la plasmaféresis terapéutica