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Guijosa A, Sarosiek S, Castillo JJ. Current and emerging treatment perspectives for adults with Waldenström macroglobulinemia. Expert Rev Anticancer Ther 2025; 25:485-497. [PMID: 40176471 DOI: 10.1080/14737140.2025.2488312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 03/31/2025] [Indexed: 04/04/2025]
Abstract
INTRODUCTION Waldenström Macroglobulinemia (WM) is distinguished from other indolent lymphomas by its unique molecular landscape and clinical behavior. With the emergence of new therapeutic options and improved survival rates, it has become increasingly important to balance the goal of prolonging survival with minimizing treatment-related toxicities. AREAS COVERED This review focuses on the current therapeutic strategies for WM, emphasizing the clinical effectiveness of various agents and treatment groups and their associated toxicity profiles. Additionally, we discuss emerging therapies and combinations, which have shown encouraging preliminary results. EXPERT OPINION WM remains an incurable disease, yet its indolent nature and the growing array of therapeutic options have significantly improved outcomes in first- and subsequent-line settings. Chemoimmunotherapy and BTK inhibitors have demonstrated high efficacy and durable responses, with the latter offering a stem-cell-sparing approach. However, unlike in CLL or multiple myeloma, evidence supporting the superiority of targeted agents over chemoimmunotherapy is not available. Consequently, treatment decisions depend on patient characteristics and shared decision-making to carefully balance risks, select appropriate regimens, and encourage clinical trial participation to advance in understanding this rare disease.
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Affiliation(s)
- Alberto Guijosa
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Shayna Sarosiek
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jorge J Castillo
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Tzilas V, Nicholson AG, Gavriatopoulou M, Ntanasis-Stathopoulos I, Dimopoulos MA, Bouros D. A 74-Year-Old Man With Waldenström Macroglobulinemia and Progressive Dyspnea. Chest 2024; 165:e39-e43. [PMID: 38336442 DOI: 10.1016/j.chest.2023.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/26/2023] [Accepted: 08/03/2023] [Indexed: 02/12/2024] Open
Abstract
CASE PRESENTATION A 74-year-old man presented to our department with progressive dyspnea on exertion over the last year. The patient did not report any other symptoms. He had previously smoked with a 60 pack-year history. He worked in an office and did not report any environmental, occupational, or domestic exposures. His history included asymptomatic Waldenström's macroglobulinemia that was diagnosed 18 months before respiratory symptoms. He was not receiving any treatment and was monitored regularly by the hematology department.
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Affiliation(s)
- Vasilios Tzilas
- 5th Respiratory Department, Hospital for Diseases of the Chest, "Sotiria," Athens, Greece.
| | - Andrew G Nicholson
- Department of Histopathology, Royal Brompton and Harefield Hospitals, Guy's and St Thomas NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, England
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - Demosthenes Bouros
- Medical School, National and Kapodistrian University of Athens, Athens, Greece; Athens Medical Center, Athens, Greece
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Rao AK, Syed F, Garrido D, Holladay CS, Saylors J. A Case of Type 1 Cryoglobulinemia With Lymphoplasmacytic Lymphoma and Dry Gangrene. Cureus 2024; 16:e52659. [PMID: 38380210 PMCID: PMC10878008 DOI: 10.7759/cureus.52659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2024] [Indexed: 02/22/2024] Open
Abstract
Lymphoplasmacytic lymphoma (LPL) is an uncommon condition, accounting for only 2% of all non-Hodgkin's lymphoma cases. Individuals with LPL face the risk of vascular blockage when associated with type I cryoglobulinemia, leading to related symptoms. Until now, no instances of LPL with dry gangrene have been documented. However, we present a rare case involving LPL accompanied by dry gangrene in both the right upper extremity (RUE) and left lower extremity (LLE). The patient was effectively managed using a combination of chemotherapy, steroids, plasmapheresis, and salvage surgery.
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Affiliation(s)
- Abhinav K Rao
- Department of Internal Medicine, Trident Medical Center, North Charleston, USA
| | - Fahim Syed
- Department of Internal Medicine, Trident Medical Center, North Charleston, USA
| | - Diego Garrido
- Department of General Surgery, Trident Medical Center, North Charleston, USA
| | - Charles S Holladay
- Department of Hematology and Oncology, Trident Medical Center, North Charleston, USA
| | - Julia Saylors
- Department of Hematology and Oncology, Trident Medical Center, North Charleston, USA
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Hussain M, Yellapragada S, Al Hadidi S. Differential Diagnosis and Therapeutic Advances in Multiple Myeloma: A Review Article. Blood Lymphat Cancer 2023; 13:33-57. [PMID: 37731771 PMCID: PMC10508231 DOI: 10.2147/blctt.s272703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 09/07/2023] [Indexed: 09/22/2023]
Abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by the abnormal clonal proliferation of plasma cells that may result in focal bone lesions, renal failure, anemia, and/or hypercalcemia. Recently, the diagnosis and treatment of MM have evolved due to a better understanding of disease pathophysiology, improved risk stratification, and new treatments. The incorporation of new drugs, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies and high-dose chemotherapy followed by hematopoietic stem cell transplantation, has resulted in a significant improvement in patient outcomes and QoL. In this review, we summarize differential diagnoses and therapeutic advances in MM.
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Affiliation(s)
- Munawwar Hussain
- Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Sarvari Yellapragada
- Michael E. DeBakey VA Medical Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Samer Al Hadidi
- Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Nekooghadam SM, Bozorgmehr R, Safavi-Naini SAA. Acrocyanosis and Progressive Skin Necrosis as Manifestation of Waldenstrom Macroglobulinemia Associated With Type I Cryoglobulinemia: A Case Report. INT J LOW EXTR WOUND 2023; 22:605-609. [PMID: 34166124 DOI: 10.1177/15347346211026994] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Waldenstrom macroglobulinemia (WM), a rare malignant disorder, occurs as a result of abnormal proliferation of lymphocytes that produce immunoglobulin M. In rare cases, WM complicates by type I cryoglobulinemia. Type I cryoglobulinemia usually presents with cutaneous manifestations such as Raynaud's phenomenon, purpura, necrosis, and gangrene. Various medical conditions, including thrombotic events, rheumatologic disorders, and malignancies, may present with skin discoloration and necrosis. Patients suffering from malignant diseases who initially present with skin manifestations usually are misdiagnosed by physicians. Here, we describe a 72-year-old man presenting with a 6-month acrocyanosis and progressive skin necrosis who was misdiagnosed by physicians. Finally, he was diagnosed to have WM associated with type I cryoglobulinemia. Though uncommon, hematologic malignancies can present with cutaneous manifestations. In some cases, patients may manifest with skin disorders alone. Early and prompt treatment of these diseases may save the patient life, relieve patient symptoms, and increase life quality.
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Affiliation(s)
- Seyed M Nekooghadam
- Shohada-E-Tajrish Hospital, Shahid Beheshti Univesity of Medical Science, Tehran, Iran
| | - Rama Bozorgmehr
- Clinical Research Development Unit, Shohada-E-Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed A A Safavi-Naini
- National Research Institute of Tuberculosis and Lung Diseases, Massih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abstract
Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by the presence of lymphoplasmacytic lymphoma (LPL) in the bone marrow accompanied by a monoclonal immunoglobulin type M (IgM) in the serum. WM was first described only 80 years ago and became reportable in the US as a malignancy in 1988. Very little systematic research was conducted prior to 2000 to characterize incidence, clinical characteristics, risk factors or diagnostic and prognostic criteria, and there were essentially no WM-specific clinical interventional trials. Since the inaugural meeting of the International Workshop in Waldenström's Macroglobulinemia (IWWM) in 2000, WM has become the focus of a steadily increasing and productive body of research, engaging a growing number of investigators throughout the world. This introductory overview provides summary of the current understanding of the epidemiology of WM/LPL as a backdrop for a series of consensus panel recommendations arising from research presented at the 11th IWWM.
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Affiliation(s)
- Mary L McMaster
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Health and Human Services, Commissioned Corps of the United States Public Health Service, Washington, DC.
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Salem AE, Shah HR, Covington MF, Koppula BR, Fine GC, Wiggins RH, Hoffman JM, Morton KA. PET-CT in Clinical Adult Oncology: I. Hematologic Malignancies. Cancers (Basel) 2022; 14:cancers14235941. [PMID: 36497423 PMCID: PMC9738711 DOI: 10.3390/cancers14235941] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/28/2022] [Accepted: 11/24/2022] [Indexed: 12/03/2022] Open
Abstract
PET-CT is an advanced imaging modality with many oncologic applications, including staging, assessment of response to therapy, restaging and evaluation of suspected recurrence. The goal of this 6-part series of review articles is to provide practical information to providers and imaging professionals regarding the best use of PET-CT for the more common adult malignancies. In the first article of this series, hematologic malignancies are addressed. The classification of these malignancies will be outlined, with the disclaimer that the classification of lymphomas is constantly evolving. Critical applications, potential pitfalls, and nuances of PET-CT imaging in hematologic malignancies and imaging features of the major categories of these tumors are addressed. Issues of clinical importance that must be reported by the imaging professionals are outlined. The focus of this article is on [18F] fluorodeoxyglucose (FDG), rather that research tracers or those requiring a local cyclotron. This information will serve as a resource for the appropriate role and limitations of PET-CT in the clinical management of patients with hematological malignancy for health care professionals caring for adult patients with hematologic malignancies. It also serves as a practical guide for imaging providers, including radiologists, nuclear medicine physicians and their trainees.
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Affiliation(s)
- Ahmed Ebada Salem
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA
- Department of Radiodiagnosis and Intervention, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt
| | - Harsh R. Shah
- Department of Medicine, Division of Hematology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA
| | - Matthew F. Covington
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA
| | - Bhasker R. Koppula
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA
| | - Gabriel C. Fine
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA
| | - Richard H. Wiggins
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA
| | - John M. Hoffman
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA
| | - Kathryn A. Morton
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA
- Intermountain Healthcare Hospitals, Murray, UT 84123, USA
- Correspondence: ; Tel.: +1-1801-581-7553
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Should Patients with Waldenström Macroglobulinemia Receive a BTK Inhibitor as Frontline Therapy? HEMATO 2022. [DOI: 10.3390/hemato3040046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Waldenström Macroglobulinemia (WM) is a rare indolent lymphoma with heterogeneous clinical presentation. As there are no randomised trials suggesting the best treatment option in treatment-naive patients, guidelines suggest either rituximab-combining regimens or BTK-inhibitors (BTKi) as feasible alternatives. Several factors play in the decision-making process: patients’ age and fitness, disease characteristics and genotype. Chemoimmunotherapy (CIT) represents a fixed-duration, less expensive and effective option, able to achieve prolonged time-to-next treatment even in patients with unfavourable genotypes. Immunosuppression and treatment-related second cancers may represent serious concerns. Proteasome-inhibitor-based regimens are effective with rapid disease control, although bortezomib-related neuropathy discourages the choice of these agents and treatment schedules may not be easily manageable in the elderly. BTKi have demonstrated high rates of response and prolonged survival together with the convenience of an oral administration and limited cytopenias. However, outcomes are impacted by genotype and some concerns remain, in particular the continuous drug exposure that may result in extra-haematological complications and drug resistance. Although next-generation BTKi have improved treatment tolerance, the question whether BTKi should be offered as frontline therapy to every patient is still debated. Giving fixed-duration schedule, prolonged time-to-next treatment and outcomes independent of genotype, CIT is still our preferred choice in WM. However, BTKi remain a valuable option in frail patients unsuitable for CIT.
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Dammacco R, Lisch W, Kivelä TT, Terpos E, Kastritis E, Sisto D, Mavilio A, Ria R, Alessio G, Vacca A, Dammacco F. The Spectrum of Ocular Manifestations in Patients with Waldenström's Macroglobulinemia. Ocul Immunol Inflamm 2022; 30:1659-1668. [PMID: 34270382 DOI: 10.1080/09273948.2021.1933068] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE To investigate the ocular manifestations in 91 Waldenström's macroglobulinemia (WM) patients. METHODS Retrospective, cross-sectional, observational analysis. RESULTS Ocular impairments, detected in 19 patients, included flame-shaped hemorrhages, venous sausaging, papilledema, macular detachments, or central retinal vein occlusion in 16 patients; paraproteinemic keratopathy in 2; and a CANOMAD syndrome in 1. Best-corrected visual acuity was ≥0.5 logMAR units in 11 of 38 eyes. Intraocular pressure was increased in seven eyes. Genetic analysis in seven patients showed a mutation in the MYD88 gene in six patients and a nonsense mutation in the CXCR4 gene in five patients. Plasmapheresis followed by chemotherapy with or without the addition of rituximab resulted in improvement or normalization of the ophthalmological findings in 15 patients. CONCLUSION The ocular manifestations of WM are protean and potentially sight threatening. Recent advances in genomic profiling and chemotherapy have remarkably improved the hematological and ophthalmological outcomes of these patients.
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Affiliation(s)
- Rosanna Dammacco
- Department of Ophthalmology and Neuroscience, University of Bari "Aldo Moro", Medical School, Bari, Italy
| | - Walter Lisch
- Department of Ophthalmology, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Tero T Kivelä
- Department of Ophthalmology, University of Helsinki, Helsinki, Finland
| | - Evangelos Terpos
- Department of Clinical Therapeutics, National and Kapodistrian School of Medicine, University of Athens, Athens, Greece
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, National and Kapodistrian School of Medicine, University of Athens, Athens, Greece
| | - Dario Sisto
- Department of Ophthalmology and Neuroscience, University of Bari "Aldo Moro", Medical School, Bari, Italy
| | - Alberto Mavilio
- Social Health District, Glaucoma Center, Azienda Sanitaria Locale, Brindisi, Italy
| | - Roberto Ria
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Medical School, Bari, Italy
| | - Giovanni Alessio
- Department of Ophthalmology and Neuroscience, University of Bari "Aldo Moro", Medical School, Bari, Italy
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Medical School, Bari, Italy
| | - Franco Dammacco
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Medical School, Bari, Italy
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Lin JM, Yuan XJ, Zhang L, Li G, Gan XR, Xu WH. Does Waldenstrom's macroglobulinemia also cause bone destruction? A rare case report. J Int Med Res 2022; 50:3000605221096161. [PMID: 35485877 PMCID: PMC9067037 DOI: 10.1177/03000605221096161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 04/05/2022] [Indexed: 12/03/2022] Open
Abstract
Waldenstrom's macroglobulinemia (WM) is a rare type of malignant B-cell lymphoma. The main feature of WM is elevated serum monoclonal immunoglobulin M, similar to multiple myeloma (MM). Unlike in MM, the rarity of destructive bone lesions in WM has been repeatedly emphasized. We report a unique case of WM with a vertebral compression fracture as the first symptom. This case highlights that the presence or absence of bone destruction may not clearly distinguish between WM and MM. The possibility of WM should be considered in patients with vertebral fracture and destruction as the first presentation. Performing vertebral bone marrow aspiration biopsy during percutaneous vertebroplasty is a convenient and effective method to assist in the diagnosis of WM.
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Affiliation(s)
- Jun-Ming Lin
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
| | - Xiao-Jun Yuan
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
| | - Lu Zhang
- Department of Assisted Reproduction, Yichun Maternal and Child Health Hospital, Jiangxi Province, P.R. China
| | - Guang Li
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
| | - Xin-rong Gan
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
| | - Wen-Hua Xu
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
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Baksh M, Jiang L, Bhatia U, Alegria V, Sher T, Roy V, Chanan‐Khan A, Ailawadhi S, Parrondo RD. Management of lytic bone disease in lymphoplasmacytic lymphoma: A case report and review of the literature. Clin Case Rep 2021; 9:e05181. [PMID: 34934497 PMCID: PMC8650751 DOI: 10.1002/ccr3.5181] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 11/17/2021] [Accepted: 11/21/2021] [Indexed: 12/22/2022] Open
Abstract
Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is often differentiated from myeloma based on the presence of lytic bone lesions (LBL). However, WM/LPL can present with LBL, and management is poorly understood. We describe a case of an 81-year-old woman with LPL who presented with LBL and was successfully treated with chemoimmunotherapy.
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Affiliation(s)
- Mizba Baksh
- Division of Hematology‐OncologyMayo ClinicJacksonvilleFloridaUSA
| | - Liuyan Jiang
- Department of PathologyMayo ClinicJacksonvilleFloridaUSA
| | - Unnati Bhatia
- Division of Hematology‐OncologyMayo ClinicJacksonvilleFloridaUSA
| | - Victoria Alegria
- Division of Hematology‐OncologyMayo ClinicJacksonvilleFloridaUSA
| | - Taimur Sher
- Division of Hematology‐OncologyMayo ClinicJacksonvilleFloridaUSA
| | - Vivek Roy
- Division of Hematology‐OncologyMayo ClinicJacksonvilleFloridaUSA
| | - Asher Chanan‐Khan
- Division of Hematology‐OncologyMayo ClinicJacksonvilleFloridaUSA
- Department of Cancer BiologyMayo ClinicJacksonvilleFloridaUSA
- Hematology‐OncologySt. Vincent's RiversideJacksonvilleFloridaUSA
| | - Sikander Ailawadhi
- Division of Hematology‐OncologyMayo ClinicJacksonvilleFloridaUSA
- Department of Cancer BiologyMayo ClinicJacksonvilleFloridaUSA
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Sandhu S, Sandhu PK, Sroussi HY. The peculiar palatal mass. J Am Dent Assoc 2021; 153:1184-1188. [PMID: 34836619 DOI: 10.1016/j.adaj.2021.07.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/08/2021] [Accepted: 07/26/2021] [Indexed: 11/25/2022]
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Salem AE, Zaki YH, El-Hussieny G, ElNoueam KI, Shaaban AM, Koppula BR, Bustoros M, Salama M, Elsayes KM, Morton K, Covington MF. An Overview of Selected Rare B-Cell Lymphoproliferative Disorders: Imaging, Histopathologic, and Clinical Features. Cancers (Basel) 2021; 13:cancers13225853. [PMID: 34831006 PMCID: PMC8616256 DOI: 10.3390/cancers13225853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/18/2021] [Accepted: 11/18/2021] [Indexed: 11/16/2022] Open
Abstract
Lymphoproliferative disorders (LPD) are conditions characterized by the uncontrolled proliferation of B or T-cell lines. They encompass a wide spectrum of abnormalities, which may be broadly classified as reactive processes or malignant diseases, such as lymphoma, based on their cellular clonality and clinical behavior. While some of these disorders are rare, they may be encountered sporadically in clinical practice, causing diagnostic dilemmas owing to overlap in their clinical and imaging features with more common disorders. The updated 4th edition WHO classification of lymphoid neoplasms was released in 2016 to incorporate the rapid clinical, pathological, molecular biology and cytogenetic advances of some of these disorders. Despite these updates, very little information is presented in the literature from the radiology perspective. The aim of this article is to familiarize radiologists and other physicians with certain rare variants of B-cell lymphoproliferative disorders with a focus on imaging features of these disorders, as well as to provide an overview of some important updates contained within the new WHO classification of lymphoid neoplasms.
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Affiliation(s)
- Ahmed Ebada Salem
- Department of Radiology and Imaging Sciences, Utah University School of Medicine, Salt Lake City, UT 84123, USA; (A.E.S.); (A.M.S.); (B.R.K.); (K.M.); (M.F.C.)
- Department of Radiodiagnosis and Intervention, Faculty of Medicine, Alexandria University, Alexandria 21566, Egypt; (Y.H.Z.); (K.I.E.)
| | - Yehia H. Zaki
- Department of Radiodiagnosis and Intervention, Faculty of Medicine, Alexandria University, Alexandria 21566, Egypt; (Y.H.Z.); (K.I.E.)
| | - Gamal El-Hussieny
- Department of Medical Oncology and Nuclear Medicine, Faculty of Medicine, Alexandria University, Alexandria 21566, Egypt;
| | - Khaled I. ElNoueam
- Department of Radiodiagnosis and Intervention, Faculty of Medicine, Alexandria University, Alexandria 21566, Egypt; (Y.H.Z.); (K.I.E.)
| | - Akram M. Shaaban
- Department of Radiology and Imaging Sciences, Utah University School of Medicine, Salt Lake City, UT 84123, USA; (A.E.S.); (A.M.S.); (B.R.K.); (K.M.); (M.F.C.)
| | - Bhasker Rao Koppula
- Department of Radiology and Imaging Sciences, Utah University School of Medicine, Salt Lake City, UT 84123, USA; (A.E.S.); (A.M.S.); (B.R.K.); (K.M.); (M.F.C.)
| | - Mark Bustoros
- Division of Hematology and Medical Oncology, Weil Cornell Medicine, Cornell University, New York, NY 10021, USA;
| | - Mohamed Salama
- Department of Pathology, Mayo Clinic, Rochester, MN 55901, USA;
| | - Khaled M. Elsayes
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: ; Tel.: +1-713-745-3025
| | - Kathryn Morton
- Department of Radiology and Imaging Sciences, Utah University School of Medicine, Salt Lake City, UT 84123, USA; (A.E.S.); (A.M.S.); (B.R.K.); (K.M.); (M.F.C.)
| | - Matthew F. Covington
- Department of Radiology and Imaging Sciences, Utah University School of Medicine, Salt Lake City, UT 84123, USA; (A.E.S.); (A.M.S.); (B.R.K.); (K.M.); (M.F.C.)
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Trotman J, Buske C, Tedeschi A, Matous JV, MacDonald D, Tam CS, Tournilhac O, Ma S, Treon SP, Oriol A, Ping J, Briso EM, Arango-Hisijara I, Dimopoulos MA. Single-Agent Ibrutinib for Rituximab-Refractory Waldenström Macroglobulinemia: Final Analysis of the Substudy of the Phase III Innovate TM Trial. Clin Cancer Res 2021; 27:5793-5800. [PMID: 34380643 PMCID: PMC9401517 DOI: 10.1158/1078-0432.ccr-21-1497] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/09/2021] [Accepted: 08/05/2021] [Indexed: 01/07/2023]
Abstract
PURPOSE The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia. Results from the final analysis are now reported. PATIENTS AND METHODS Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed. RESULTS After a median follow-up of 58 months (range: 9-61), median PFS was 39 months [95% confidence interval (CI): 25-not evaluable]; 60-month PFS rate was 40%. In MYD88L265P/CXCR4WHIM and MYD88L265P/CXCR4WT subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (≥ partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin ≤11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of -37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation. CONCLUSIONS In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia.
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Affiliation(s)
- Judith Trotman
- Concord Hospital, University of Sydney, Concord, New South Wales, Australia.
| | - Christian Buske
- Comprehensive Cancer Center Ulm and Institute of Experimental Cancer Research, University Hospital of Ulm, Ulm, Germany
| | | | | | - David MacDonald
- The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
| | - Constantine S Tam
- St. Vincent's Hospital, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
| | - Olivier Tournilhac
- Hématologie Clinique Adulte et Thérapie Cellulaire, CHU Hotel Dieu Hématologie, Clermont-Ferrand, France
| | - Shuo Ma
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | | | - Albert Oriol
- Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
| | - Jerry Ping
- Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California
| | - Eva M Briso
- Pharmacyclics Switzerland GmbH, an AbbVie Company, Schaffhausen, Switzerland
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15
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Li J, Zhang R, Gu F, Liu ZL, Sun P. Optical coherence tomography angiography characteristics in Waldenström macroglobulinemia retinopathy: A case report. World J Clin Cases 2020; 8:6071-6079. [PMID: 33344607 PMCID: PMC7723702 DOI: 10.12998/wjcc.v8.i23.6071] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/11/2020] [Accepted: 10/26/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Waldenström macroglobulinemia (WM) is a distinct clinicopathologic entity characterized by the infiltration of the bone marrow by clonal lymphoplasmacytic cells that produce monoclonal immunoglobulin M (IgM) in the blood, and patients may present with symptoms related to the infiltration of the hematopoietic tissues or the effects of monoclonal IgM in the blood. Funduscopic abnormalities were noted in some of the patients due to hyperviscosity or other retinal lesions. Optical coherence tomography angiography (OCTA) as a non-invasive imaging tool can give qualitative and quantitative information about the status of retinal and choroidal vessels, which might be useful for diagnosing patients with WM-associated retinopathy.
CASE SUMMARY The patient was a 67-year-old man who presented with sudden visual disturbance in both eyes. Ophthalmic tests showed that best corrected visual acuity (BCVA) for this patient was 20/100 in the right eye and 20/1000 in the left eye. Fundus examination, optical coherence tomography (OCT), and OCTA revealed substantial bilateral optic disc edema, dilated and tortuous retinal veins, and diffuse intraretinal blot hemorrhages and edema which were consistent with bilateral central retinal vein occlusion (CRVO). Meanwhile, remarkable bilateral serous macular detachments (SMD) were noticed on OCT. Systemic examinations showed that the patient had anemia and extremely high level of monoclonal IgM and infiltration of clonal lymphoplasmacytic cells in bone marrow. The diagnosis of WM with hyperviscosity and retinopathy was made based on the clinical manifestation and laboratory findings. He was subsequently treated with intravitreal ranibizumab injection, plasmapheresis, and bortezomib plus rituximab with dexamethasone. Six months after treatments, the central macular volume decreased by 16.1% in the right eye and 28.6% in the left eye on OCT, and the patient’s BCVA was improved to 20/60 in the right eye and 20/400 in the left eye. Very good partial response was obtained after systemic treatment.
CONCLUSION WM may affect visual function and present as bilateral CRVO. OCTA can show characteristic changes in both retina and choroid vasculatures, which might be of great value for diagnosing or following patients with WM retinopathy. Intravitreal anti-vascular endothelial growth factor treatment combined with systemic therapy might be beneficial for WM patients with retinopathy (SMD and CRVO).
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Affiliation(s)
- Jun Li
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Rui Zhang
- Department of Hematology, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Feng Gu
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Zhe-Li Liu
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Peng Sun
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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16
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Li J, Zhang R, Gu F, Liu ZL, Sun P. Optical coherence tomography angiography characteristics in Waldenström macroglobulinemia retinopathy: A case report. World J Clin Cases 2020. [DOI: 10.12998/wjcc.v8.i23.6065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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17
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Schmidt K, Sack U, Graf R, Winkler W, Popp O, Mertins P, Sommermann T, Kocks C, Rajewsky K. B-Cell-Specific Myd88 L252P Expression Causes a Premalignant Gammopathy Resembling IgM MGUS. Front Immunol 2020; 11:602868. [PMID: 33343574 PMCID: PMC7747680 DOI: 10.3389/fimmu.2020.602868] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 10/19/2020] [Indexed: 12/20/2022] Open
Abstract
A highly recurrent somatic L265P mutation in the TIR domain of the signaling adapter MYD88 constitutively activates NF-κB. It occurs in nearly all human patients with Waldenström’s macroglobulinemia (WM), a B cell malignancy caused by IgM-expressing cells. Here, we introduced an inducible leucine to proline point mutation into the mouse Myd88 locus, at the orthologous position L252P. When the mutation was introduced early during B cell development, B cells developed normally. However, IgM-expressing plasma cells accumulated with age in spleen and bone, leading to more than 20-fold elevated serum IgM titers. When introduced into germinal center B cells in the context of an immunization, the Myd88L252P mutation caused prolonged persistence of antigen-specific serum IgM and elevated numbers of antigen-specific IgM plasma cells. Myd88L252P-expressing B cells switched normally, but plasma cells expressing other immunoglobulin isotypes did not increase in numbers, implying that IgM expression may be required for the observed cellular expansion. In order to test whether the Myd88L252P mutation can cause clonal expansions, we introduced it into a small fraction of CD19-positive B cells. In this scenario, five out of five mice developed monoclonal IgM serum paraproteins accompanied by an expansion of clonally related plasma cells that expressed mostly hypermutated VDJ regions. Taken together, our data suggest that the Myd88L252P mutation is sufficient to promote aberrant survival and expansion of IgM-expressing plasma cells which in turn can cause IgM monoclonal gammopathy of undetermined significance (MGUS), the premalignant condition that precedes WM.
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Affiliation(s)
- Kristin Schmidt
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Ulrike Sack
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Robin Graf
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Wiebke Winkler
- Biology of Malignant Lymphomas, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Oliver Popp
- Proteomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Philipp Mertins
- Proteomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Thomas Sommermann
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Christine Kocks
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Transgenics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Klaus Rajewsky
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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18
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Grimont CN, Castillo Almeida NE, Gertz MA. Current and Emerging Treatments for Waldenström Macroglobulinemia. Acta Haematol 2020; 144:146-157. [PMID: 32810857 DOI: 10.1159/000509286] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/09/2020] [Indexed: 12/30/2022]
Abstract
Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma. The primary goal of therapy is to reduce symptoms related to direct infiltration of the bone marrow and decrease monoclonal IgM-associated complications. Active agents in the management of WM can be broadly classified as rituximab-alkylator combination therapy, proteasome inhibitor-based therapy, and Bruton's tyrosine kinase inhibitor-based therapy. MYD88L265P and CXCR4 genetic status are pivotal for tailoring treatment options. Ibrutinib is a suitable treatment option for both treatment-naïve and relapsing WM patients. Recent advances in the intracellular B cell and cytokine signaling pathways have contributed to the development of novel therapeutic strategies. Current clinical trials are promising and may further advance WM-directed therapy.
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Affiliation(s)
- Christopher N Grimont
- Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Natalia E Castillo Almeida
- Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Morie A Gertz
- Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA,
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19
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Diagnosis of a difficult to differentiate case of early-onset hyperviscosity syndrome caused by IgM type multiple myeloma: a case report. Int J Hematol 2020; 112:741-745. [PMID: 32572827 DOI: 10.1007/s12185-020-02917-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 05/18/2020] [Accepted: 06/04/2020] [Indexed: 10/24/2022]
Abstract
Hyperviscosity syndrome (HVS) can cause multiple organ damage if not treated immediately. IgM multiple myeloma (IgM MM) is a very rare form of myeloma with clinical features such as elevated serum IgM, and anemia, that resemble Waldenström macroglobulinemia (WM). Distinguishing between these two diseases is important, but can be a challenging problem. It is well known that MyD88 mutations and t(11;14) translocations are useful for differential diagnosis. We diagnosed HVS in a 29-year-old male with IgM MM. He was treated with triplet therapy, autologous hematopoietic stem cell transplantation, and carfilzomib consolidation therapy. His clinical course was monitored by serum IgM levels, and bone marrow myeloma cell counts by multiparameter flow cytometry analysis. After this series of treatments, his HSV disappeared and he reached stringent complete response. In cases of early onset of HVS, IgM MM should be considered in addition to WM.
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20
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Madamsetty VS, Paulus A, Akhtar S, Manna A, Rachamalla HR, Banerjee R, Mukhopadhyay D, Chanan-Khan A. Novel tumor-targeted liposomes comprised of an MDM2 antagonist plus proteasome inhibitor display anti-tumor activity in a xenograft model of bortezomib-resistant Waldenstrom macroglobulinemia. Leuk Lymphoma 2020; 61:2399-2408. [PMID: 32558607 DOI: 10.1080/10428194.2020.1775204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Targeted drug delivery remains an active area of investigation in hematologic cancers. We have previously reported on a novel nanoparticle formulation (D1X) that can encapsulate drugs within a liposome whose lipid bilayer contains dexamethasone, which serves as a targeting ligand for drug delivery to tumor cells that express glucocorticoid receptors. We tested the activity of D1X-encapsulated bortezomib (D1XB) in combination with D1X-encapsulated nutlin (D1XN) in B-lymphoma/Waldenstrom macroglobulinemia (WM) cells. WM cells treated with D1XB + D1XN experienced cell cycle arrest, ER stress and apoptosis. In mice xenografted with bortezomib-resistant WM cells, D1XB + D1XN treatment resulted in significantly lower tumor burden compared to vehicle or nonliposomal parent drugs. In vivo biodistribution studies showed minimal uptake of D1X-based drugs in normal mice tissues. Our studies demonstrate that highly targeted delivery of both bortezomib and nutlin encapsulated in D1X nanoparticles are cytotoxic to and delay in vivo growth of bortezomib-resistant WM cells.
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Affiliation(s)
- Vijay Sagar Madamsetty
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, USA
| | - Aneel Paulus
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Sharoon Akhtar
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Alak Manna
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Harikrishna Reddy Rachamalla
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.,Academy of Scientific and Innovative Research (AcSIR, CSIR - Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, India
| | - RajKumar Banerjee
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.,Academy of Scientific and Innovative Research (AcSIR, CSIR - Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, India
| | - Debabrata Mukhopadhyay
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, USA
| | - Asher Chanan-Khan
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, USA.,Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.,Mayo Clinic Cancer Center at St. Vincent's Medical Center Riverside, Jacksonville, FL, USA
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21
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Dalal NH, Dores GM, Curtis RE, Linet MS, Morton LM. Cause-specific mortality in individuals with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia, 2000-2016. Br J Haematol 2020; 189:1107-1118. [PMID: 32090327 DOI: 10.1111/bjh.16492] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 12/24/2019] [Indexed: 02/07/2023]
Abstract
Data on cause-specific mortality after lymphoplasmacytic lymphoma (LPL) and Waldenström macroglobulinaemia (WM) are lacking. We identified causes of death amongst 7289 adults diagnosed with incident first primary LPL (n = 3108) or WM (n = 4181) during 2000-2016 in 17 USA population-based cancer registries. Based on 3132 deaths, 16-year cumulative mortality was 23·2% for lymphomas, 8·4% for non-lymphoma cancers and 14·7% for non-cancer causes for patients aged <65 years at diagnosis of LPL/WM, versus 33·4%, 11·2% and 48·7%, respectively, for those aged ≥75 years. Compared with the general population, patients with LPL/WM had a 20% higher risk of death due to non-cancer causes (n = 1341 deaths, standardised mortality ratio [SMR] 1·2, 95% confidence interval [CI] 1·1-1·2), most commonly from infectious (n = 188; SMR 1·8, 95% CI 1·6-2·1), respiratory (n = 143; SMR 1·2, 95% CI 1·0-1·4), and digestive (n = 80; SMR 1·8, 95% CI 1·4-2·2) diseases, but no excess mortality from cardiovascular diseases (n = 477, SMR 1·1, 95% CI 1·0-1·1). Risks were highest for non-cancer causes within 1 year of diagnosis (n = 239; SMR<1year 1·3, 95% CI 1·2-1·5), declining thereafter (n = 522; SMR≥5years 1·1, 95% CI 1·1-1·2). Myelodysplastic syndrome/acute myeloid leukaemia deaths were notably increased (n = 46; SMR 4·4, 95% CI 3·2-5·9), whereas solid neoplasm deaths were only elevated among ≥5-year survivors (n = 145; SMR≥5years 1·3, 95% CI 1·1-1·5). This work identifies new areas for optimising care and reducing mortality for patients with LPL/WM.
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Affiliation(s)
- Nicole H Dalal
- Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA.,Duke University School of Medicine, Durham, NC, USA
| | - Graça M Dores
- Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA.,United States Food and Drug Administration, Center for Biologics Evaluation and Research, Silver Spring, MD, USA
| | - Rochelle E Curtis
- Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA
| | - Martha S Linet
- Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA
| | - Lindsay M Morton
- Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA
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22
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Maqbool MG, Tam CS, Morison IM, Simpson D, Mollee P, Schneider H, Chan H, Juneja S, Harvey Y, Nath L, Hissaria P, Prince HM, Wordsworth H, Opat S, Talaulikar D. A practical guide to laboratory investigations at diagnosis and follow up in Waldenström macroglobulinaemia: recommendations from the Medical and Scientific Advisory Group, Myeloma Australia, the Pathology Sub-committee of the Lymphoma and Related Diseases Registry and the Australasian Association of Clinical Biochemists Monoclonal Gammopathy Working Group. Pathology 2020; 52:167-178. [PMID: 31902622 DOI: 10.1016/j.pathol.2019.11.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 11/07/2019] [Accepted: 11/10/2019] [Indexed: 01/30/2023]
Abstract
Waldenström macroglobulinaemia (WM) is an indolent non-Hodgkin lymphoma which usually presents with symptoms related to infiltration of bone marrow or other tissues like lymph nodes, liver or spleen and has certain unusual clinical manifestations, e.g., renal and central nervous system (CNS) involvement. It also has an array of laboratory features including hypersecretion of IgM, cryoglobulinaemia, increased plasma viscosity and identification of mutated MYD88L265P in more than 90% of cases. In this review, we aim to provide a guide to the laboratory investigations recommended for WM at initial diagnosis and at follow-up. A discussion on the nuances of diagnosis and differential diagnoses is followed by bone marrow (BM) assessment, measurement of paraprotein and other ancillary investigations. Recommendations are provided on laboratory work-up at diagnosis, in the asymptomatic follow-up phase, and during and post-treatment. Finally, we briefly discuss the implications of laboratory diagnosis in regard to recruitment and monitoring on clinical trials.
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Affiliation(s)
- M Gohar Maqbool
- Department of Haematology, ACT Pathology, Canberra Hospital, ACT, Australia; ANU Medical School, College of Medicine and Health, Australian National University, Canberra, ACT, Australia
| | - Constantine S Tam
- Peter MacCallum Cancer Center, St Vincent's Hospital and University of Melbourne, Melbourne, Vic, Australia
| | - Ian M Morison
- Southern Community Laboratories, Dunedin, New Zealand; Australasian Association of Clinical Biochemists (AACB) Monoclonal Gammopathy Working Group (MGWG), Australia
| | - David Simpson
- Department of Haematology, Waitemata District Health Board, Auckland, New Zealand; Medical and Scientific Advisory Group, Myeloma Australia
| | - Peter Mollee
- Australasian Association of Clinical Biochemists (AACB) Monoclonal Gammopathy Working Group (MGWG), Australia; Medical and Scientific Advisory Group, Myeloma Australia; Department of Haematology, Princess Alexandra Hospital and University of Queensland Medical School, Brisbane, Qld, Australia
| | - Hans Schneider
- Australasian Association of Clinical Biochemists (AACB) Monoclonal Gammopathy Working Group (MGWG), Australia; Alfred Pathology Service and Monash University, Melbourne, Vic, Australia
| | - Henry Chan
- Department of Haematology, Waitemata District Health Board, Auckland, New Zealand; Medical and Scientific Advisory Group, Myeloma Australia
| | - Surender Juneja
- Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, Vic, Australia; Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia
| | - Yasmin Harvey
- Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia; Sullivan Nicolaides Pathology, Brisbane, Qld, Australia
| | - Lakshmi Nath
- Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia; Department of Haematology and Transfusion Medicine, Clinpath Pathology, Adelaide, SA, Australia
| | - Pravin Hissaria
- Australasian Association of Clinical Biochemists (AACB) Monoclonal Gammopathy Working Group (MGWG), Australia; Royal Adelaide Hospital, University of Adelaide and SA Pathology, Adelaide, SA, Australia
| | - H Miles Prince
- Medical and Scientific Advisory Group, Myeloma Australia; Epworth Healthcare, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Vic, Australia
| | - Helen Wordsworth
- Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia; Sullivan Nicolaides Pathology, Brisbane, Qld, Australia
| | - Stephen Opat
- Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia; Department of Haematology, Monash Health, Melbourne, Vic, Australia
| | - Dipti Talaulikar
- Department of Haematology, ACT Pathology, Canberra Hospital, ACT, Australia; ANU Medical School, College of Medicine and Health, Australian National University, Canberra, ACT, Australia; Medical and Scientific Advisory Group, Myeloma Australia; Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia.
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23
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Advani P, Paulus A, Ailawadhi S. Updates in prognostication and treatment of Waldenström’s macroglobulinemia. Hematol Oncol Stem Cell Ther 2019; 12:179-188. [DOI: 10.1016/j.hemonc.2019.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 04/22/2019] [Accepted: 05/05/2019] [Indexed: 11/30/2022] Open
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24
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Imaging of Waldenström Macroglobulinemia: A Comprehensive Review for the Radiologist in the Era of Personalized Medicine. AJR Am J Roentgenol 2019; 213:W248-W256. [PMID: 31287727 DOI: 10.2214/ajr.19.21493] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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25
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Beech C, Kumar D, Hendrickson J, Perincheri S, Tormey C, Bahar B. Cryoglobulinemia as a Possible Primer for TRALI: Report of a Case. Lab Med 2019; 50:313-319. [PMID: 30657960 DOI: 10.1093/labmed/lmy073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Waldenström macroglobulinemia (WM) is a form of lymphoplasmacytic lymphoma that can cause hyperviscosity syndrome due to unchecked monoclonal antibody production. Some patients are also found to have associated cryoglobulinemia, which can cause systemic complications including vasculitis, renal disease, and pulmonary complications. Cryoglobulins can also serve as a source of interference with various laboratory assays. Therapeutic plasma exchange (TPE) is one of the recommended treatment modalities to manage hyperviscosity. Herein, we present the case of an 84-year-old female patient with Waldenström macroglobulinemia who presented with hyperviscosity syndrome and discrepant laboratory findings, and who then developed transfusion-related acute lung injury (TRALI) during TPE. This case is one of many in the emerging possible linkages observed between cryoglobulinemia and TRALI.
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Affiliation(s)
- Cameron Beech
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT.,Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Deepika Kumar
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT.,Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Jeanne Hendrickson
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT.,Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Sudhir Perincheri
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT
| | - Christopher Tormey
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT.,Department of Pathology and Laboratory Medicine Service, VA Connecticut Healthcare System, West Haven, CT
| | - Burak Bahar
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT
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26
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WITHDRAWN: Updates in Prognostication and Treatment of Waldenström’s Macroglobulinemia. Hematol Oncol Stem Cell Ther 2019. [DOI: 10.1016/j.hemonc.2019.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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27
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Burstedt D, Tippett JC. Severe Hypertriglyceridemia During Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth 2019; 33:3418-3422. [PMID: 31076303 DOI: 10.1053/j.jvca.2019.04.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 04/02/2019] [Accepted: 04/05/2019] [Indexed: 01/04/2023]
Affiliation(s)
- David Burstedt
- Baylor Scott & White Healthcare/Texas A&M University Health Science Center College of Medicine, Temple, TX
| | - J Clint Tippett
- Baylor Scott & White Healthcare/Texas A&M University Health Science Center College of Medicine, Temple, TX.
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28
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Hao M, Barlogie B, Tricot G, Liu L, Qiu L, Shaughnessy JD, Zhan F. Gene Expression Profiling Reveals Aberrant T-cell Marker Expression on Tumor Cells of Waldenström's Macroglobulinemia. Clin Cancer Res 2018; 25:201-209. [PMID: 30279229 DOI: 10.1158/1078-0432.ccr-18-1435] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 08/01/2018] [Accepted: 09/27/2018] [Indexed: 12/26/2022]
Abstract
PURPOSE That the malignant clone of Waldenström's macroglobulinemia (WM) demonstrates significant intraclonal heterogeneity with respect to plasmacytoid differentiation indicates the mechanistic complexity of tumorigenesis and progression. Identification of WM genes by comparing different stages of B cells may provide novel druggable targets. EXPERIMENTAL DESIGN The gene expression signatures of CD19+ B cells (BC) and CD138+ plasma cells (PC) from 19 patients with WM were compared with those of BCs from peripheral blood and tonsil and to those of PCs from the marrow of healthy (N-PC) and multiple myeloma donors (MM-PC), as well as tonsil (T-PC). Flow cytometry and immunofluorescence were used to examine T-cell marker expression on WM tumor cells. RESULTS Consistent with defective differentiation, both BCs and PCs from WM cases expressed abnormal differentiation markers. Sets of 55 and 46 genes were differentially expressed in WM-BC and WM-PC, respectively; and 40 genes uniquely dysregulated in WM samples were identified. Dysregulated genes included cytokines, growth factor receptors, and oncogenes not previously implicated in WM or other plasma cell dyscrasias. Interestingly, strong upregulation of both IL6 and IL6R was confirmed. Supervised cluster analysis of PC revealed that marrow-derived WM-PC was either MM-PC-like or T-PC-like, but not N-PC-like. The aberrant expression of T-cell markers was confirmed at the protein level in WM-BC. CONCLUSIONS We showed that comparative microarray profiles allowed gaining more comprehensive insights into the biology of WM. The data presented here have implications for the development of novel therapies, such as targeting aberrant T-cell markers in WM.
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Affiliation(s)
- Mu Hao
- Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.,Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa
| | - Bart Barlogie
- Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Guido Tricot
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa
| | - Lanting Liu
- Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China
| | - Lugui Qiu
- Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China
| | - John D Shaughnessy
- Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Fenghuang Zhan
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa.
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An update on the diagnosis and management of the polyneuropathy of POEMS syndrome. J Neurol 2018; 266:258-267. [PMID: 30264176 PMCID: PMC6343023 DOI: 10.1007/s00415-018-9068-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 09/10/2018] [Accepted: 09/17/2018] [Indexed: 01/05/2023]
Abstract
POEMS syndrome is a rare, chronic, disabling paraneoplastic disorder characterized by peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cells disorder and skin changes. Diagnosis relies on the fulfillment of a set of clinical criteria of which polyneuropathy and a monoclonal plasma cell dyscrasia are early and essential features. Treatment may be either local or systemic and is aimed at the monoclonal plasma cell disorder. Our knowledge of the pathogenesis underlying the POEMS syndrome has advanced greatly over the past years, favoring an important progression in the recognition and management of this disorder. Here, we discuss the recent literature that has advanced our knowledge of the pathogenesis and clinical management of the polyneuropathy in POEMS syndrome.
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30
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Atrash S, Zhang Q, Papanikolaou X, Stein C, Abdallah AO, Barlogie B. Clinical Presentation and Gene Expression Profiling of Immunoglobulin M Multiple Myeloma Compared With Other Myeloma Subtypes and Waldenström Macroglobulinemia. J Glob Oncol 2018; 4:1-8. [PMID: 30241189 PMCID: PMC6180798 DOI: 10.1200/jgo.2016.008003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Multiple myeloma (MM) is a clonal bone marrow disease characterized by the neoplastic transformation of differentiated postgerminal B cells. It is a heterogeneous disease both at the genetic level and in terms of clinical outcome. Immunoglobulin M (IgM) MM is a rare subtype of myeloma. Similar to Waldenström macroglobulinemia (WM), patients with MM experience IgM monoclonal gammopathy; however, both diseases are distinct in terms of treatment and clinical behavior. MATERIALS AND METHODS To shed light on the presentation of IgM MM, its prognosis, and its gene expression profiling, we identified and characterized 21 patients with IgM MM from our database. RESULTS One of these patients presented with a rare IgM monoclonal gammopathy of undetermined significance that progressed to smoldering myeloma. The median survival of the 21 patients was 4.9 years, which was comparable to a matched group of patients with non-IgM MM with similar myeloma prognostic factors (age, gender, albumin, creatinine, anemia, lactate dehydrogenase, β2-microglobulin, cytogenetics abnormalities), but much less than the median survival reported for patients with WM (9 years). We identified a cluster of genes that differ in their expression profile between MM and WM and found that the patients with IgM MM displayed a gene expression profile most similar to patients with non-IgM MM, confirming that IgM MM is a subtype of MM that should be differentiated from WM. CONCLUSION Because the prognosis of IgM MM and WM differ significantly, an accurate diagnosis is essential. Our gene expression model can assist with the differential diagnosis in controversial cases.
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Affiliation(s)
- Shebli Atrash
- Shebli Atrash, Qing Zhang, Xenofon Papanikolaou, Caleb Stein, Al-Ola Abdallah, and Bart Barlogie, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Qing Zhang, Levine Cancer Institute, Charlotte, NC
| | - Qing Zhang
- Shebli Atrash, Qing Zhang, Xenofon Papanikolaou, Caleb Stein, Al-Ola Abdallah, and Bart Barlogie, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Qing Zhang, Levine Cancer Institute, Charlotte, NC
| | - Xenofon Papanikolaou
- Shebli Atrash, Qing Zhang, Xenofon Papanikolaou, Caleb Stein, Al-Ola Abdallah, and Bart Barlogie, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Qing Zhang, Levine Cancer Institute, Charlotte, NC
| | - Caleb Stein
- Shebli Atrash, Qing Zhang, Xenofon Papanikolaou, Caleb Stein, Al-Ola Abdallah, and Bart Barlogie, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Qing Zhang, Levine Cancer Institute, Charlotte, NC
| | - Al-Ola Abdallah
- Shebli Atrash, Qing Zhang, Xenofon Papanikolaou, Caleb Stein, Al-Ola Abdallah, and Bart Barlogie, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Qing Zhang, Levine Cancer Institute, Charlotte, NC
| | - Bart Barlogie
- Shebli Atrash, Qing Zhang, Xenofon Papanikolaou, Caleb Stein, Al-Ola Abdallah, and Bart Barlogie, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Qing Zhang, Levine Cancer Institute, Charlotte, NC
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31
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Kastritis E, Dimopoulos MA. Proteasome Inhibitors in Waldenström Macroglobulinemia. Hematol Oncol Clin North Am 2018; 32:829-840. [PMID: 30190021 DOI: 10.1016/j.hoc.2018.05.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Waldenström macroglobulinemia (WM) remains an incurable B-cell lymphoproliferative disorder, yet therapy is only considered for patients with symptomatic disease. Primary therapy options for WM include combinations based on anti-CD20 monoclonal antibodies, mainly rituximab. However, proteasome inhibitors have become an important part of WM therapy both as primary therapy and as salvage option. Bortezomib is the proteasome inhibitor most studied and with extensive clinical experience, but new proteasome inhibitors (carfilzomib, ixazomib, oprozomib), with different toxicity profiles, routes of administration, and probably with preserved or improved activity, have become available and may also find their way into WM therapy.
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Affiliation(s)
- Efstathios Kastritis
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, 80 Vassilisis Sofias Avenue, Athens 11528, Greece.
| | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, 80 Vassilisis Sofias Avenue, Athens 11528, Greece
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32
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Mazzucchelli M, Frustaci AM, Deodato M, Cairoli R, Tedeschi A. Waldenstrom's Macroglobulinemia: An Update. Mediterr J Hematol Infect Dis 2018; 10:e2018004. [PMID: 29326801 PMCID: PMC5760071 DOI: 10.4084/mjhid.2018.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 11/13/2017] [Indexed: 12/19/2022] Open
Abstract
Waldenstrom Macroglobulinemia is a rare lymphoproliferative disorder with distinctive clinical features. Diagnostic and prognostic characterisation in WM significantly changed with the discovery of two molecular markers: MYD88 and CXCR4. Mutational status of these latter influences both clinical presentation and prognosis and demonstrated therapeutic implications. Treatment choice in Waldenstrom disease is strictly guided by patients age and characteristics, specific goals of therapy, the necessity for rapid disease control, the risk of treatment-related neuropathy, disease features, the risk of immunosuppression or secondary malignancies and potential for future autologous stem cell transplantation. The therapeutic landscape has expanded during the last years and the approval of ibrutinib, the first drug approved for Waldenstrom Macroglobulinemia, represents a significant step forward for a better management of the disease.
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Affiliation(s)
- Maddalena Mazzucchelli
- Department of Haematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano
| | - Anna Maria Frustaci
- Department of Haematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano
| | - Marina Deodato
- Department of Haematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano
| | - Roberto Cairoli
- Department of Haematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano
| | - Alessandra Tedeschi
- Department of Haematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano
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Abstract
Waldenstrom Macroglobulinemia is a rare lymphoproliferative disorder with distinctive clinical features. Diagnostic and prognostic characterisation in WM significantly changed with the discovery of two molecular markers: MYD88 and CXCR4. Mutational status of these latter influences both clinical presentation and prognosis and demonstrated therapeutic implications. Treatment choice in Waldenstrom disease is strictly guided by patients age and characteristics, specific goals of therapy, the necessity for rapid disease control, the risk of treatment-related neuropathy, disease features, the risk of immunosuppression or secondary malignancies and potential for future autologous stem cell transplantation. The therapeutic landscape has expanded during the last years and the approval of ibrutinib, the first drug approved for Waldenstrom Macroglobulinemia, represents a significant step forward for a better management of the disease.
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34
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Aiello A, D’Ausilio A, Lo Muto R, Randon F, Laurenti L. Cost-effectiveness analysis of ibrutinib in patients with Waldenström macroglobulinemia in Italy. JOURNAL OF MARKET ACCESS & HEALTH POLICY 2017; 5:1393308. [PMID: 29201288 PMCID: PMC5700492 DOI: 10.1080/20016689.2017.1393308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 10/10/2017] [Indexed: 06/07/2023]
Abstract
Background and Objective: Ibrutinib has recently been approved in Europe for Waldenström Macroglobulinemia (WM) in symptomatic patients who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy. The aim of the study is to estimate the incremental cost-effectiveness ratio (ICER) of ibrutinib in relapse/refractory WM, compared with the Italian current therapeutic pathways (CTP). Methods: A Markov model was adapted for Italy considering the National Health System perspective. Input data from literature as well as global trials were used. The percentage use of therapies, and healthcare resources consumption were estimated according to expert panel advice. Drugs ex-factory prices and national tariffs were used for estimating costs. The model had a 15-year time horizon, with a 3.0% discount rate for both clinical and economic data. Deterministic and probabilistic sensitivity analyses were performed to test the results strength. Results: Ibrutinib resulted in increased Life Years Gained (LYGs) and increased costs compared to CTP, with an ICER of €52,698/LYG. Sensitivity analyses confirmed the results of the BaseCase. Specifically, in the probabilistic analysis, at a willingness to pay threshold of €60,000/LYG ibrutinib was cost-effective in 84% of simulations. Conclusions: Ibrutinib has demonstrated a positive cost-effectiveness profile in Italy.
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Affiliation(s)
- Andrea Aiello
- Price and Market Access Department, Creativ – Ceutical, Milan, Italy
| | - Anna D’Ausilio
- Price and Market Access Department, Creativ – Ceutical, Milan, Italy
| | - Roberta Lo Muto
- Health Economics Market Access Reimbursement Department, Janssen-Cilag, Cologno Monzese, Italy
| | - Francesca Randon
- Health Economics Market Access Reimbursement Department, Janssen-Cilag, Cologno Monzese, Italy
| | - Luca Laurenti
- Department of Hematology, Catholic University of Rome, “A. Gemelli” Hospital, Rome, Italy
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35
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Growková K, Kryukova E, Kufová Z, Filipová J, Ševčíková T, Říhová L, Kaščák M, Kryukov F, Hájek R. Waldenström's macroglobulinemia: Two malignant clones in a monoclonal disease? Molecular background and clinical reflection. Eur J Haematol 2017; 99:469-478. [PMID: 28886236 DOI: 10.1111/ejh.12959] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2017] [Indexed: 12/12/2022]
Abstract
Waldenström's macroglobulinemia (WM) is a complex disease characterized by apparent morphological heterogeneity within the malignant clonal cells representing a continuum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. At the molecular level, the neoplastic B cell-derived clone has undergone somatic hypermutation, but not isotype switching, and retains the capability of plasmacytic differentiation. Although by classical definition, WM is formed by monoclonal expansion, long-lived clonal B lymphocytes are of heterogeneous origin. Even more, according to current opinion, plasma cells also conform certain population with pathogenic and clinical significance. In this article, we review the recent advances in the WM clonal architecture, briefly describe B-cell development during which the molecular changes lead to the malignant transformation and mainly focus on differences between two principal B-lineage clones, including analysis of their genome and transcriptome profiles, as well as immunophenotype features. We assume that the correct identification of a number of specific immunophenotypic molecular and expression alterations leading to proper aberrant clone detection can help to guide patient monitoring throughout treatment and successfully implement therapy strategies directed against both B- and plasma cell tumor WM clones.
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Affiliation(s)
- Kateřina Growková
- Department of Biology and Ecology, Faculty of Science, University of Ostrava, Ostrava, Czech Republic.,Department of Clinical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Elena Kryukova
- Department of Clinical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Haemato-Oncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Zuzana Kufová
- Department of Clinical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Jana Filipová
- Department of Biology and Ecology, Faculty of Science, University of Ostrava, Ostrava, Czech Republic.,Department of Clinical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Tereza Ševčíková
- Department of Biology and Ecology, Faculty of Science, University of Ostrava, Ostrava, Czech Republic.,Department of Clinical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Lucie Říhová
- Department of Clinical Haematology, University Hospital Brno, Brno, Czech Republic
| | - Michal Kaščák
- Department of Haemato-Oncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Fedor Kryukov
- Department of Clinical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Haemato-Oncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Roman Hájek
- Department of Clinical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Haemato-Oncology, University Hospital Ostrava, Ostrava, Czech Republic
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36
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Castillo JJ, Jurczyszyn A, Brozova L, Crusoe E, Czepiel J, Davila J, Dispenzieri A, Eveillard M, Fiala MA, Ghobrial IM, Gozzetti A, Gustine JN, Hajek R, Hungria V, Jarkovsky J, Jayabalan D, Laubach JP, Lewicka B, Maisnar V, Manasanch EE, Moreau P, Morgan EA, Nahi H, Niesvizky R, Paba-Prada C, Pika T, Pour L, Reagan JL, Richardson PG, Shah J, Spicka I, Vij R, Waszczuk-Gajda A, Gertz MA. IgM myeloma: A multicenter retrospective study of 134 patients. Am J Hematol 2017; 92:746-751. [PMID: 28383205 DOI: 10.1002/ajh.24753] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 03/30/2017] [Accepted: 04/03/2017] [Indexed: 12/22/2022]
Abstract
IgM myeloma is a rare hematologic malignancy for which the clinicopathological features and patient outcomes have not been extensively studied. We carried out a multicenter retrospective study in patients with diagnosis of IgM myeloma defined by >10% marrow involvement by monoclonal plasma cells, presence of an IgM monoclonal paraproteinemia of any size, and anemia, renal dysfunction, hypercalcemia, lytic lesions and/or t(11;14) identified by FISH. A total of 134 patients from 20 centers were included in this analysis. The median age at diagnosis was 65.5 years with a male predominance (68%). Anemia, renal dysfunction, elevated calcium and skeletal lytic lesions were found in 37, 43, 19, and 70%, respectively. The median serum IgM level was 2,895 mg dL-1 with 19% of patients presenting with levels >6,000 mg dL-1 . International Staging System (ISS) stages 1, 2, and 3 were seen in 40 (33%), 54 (44%), and 29 (24%) of patients, respectively. The malignant cells expressed CD20 (58%) and cyclin D1 (67%), and t(11;14) was the most common cytogenetic finding (39%). The median overall survival (OS) was 61 months. Higher ISS score was associated with worse survival (P = 0.02). Patients with IgM myeloma present with similar characteristics and outcomes as patients with more common myeloma subtypes.
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Affiliation(s)
- Jorge J. Castillo
- Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School; Boston Massachusetts USA
| | | | | | - Edvan Crusoe
- Professor Edgar Santos University Hospital; Salvador Brazil
| | - Jacek Czepiel
- Jagiellonian University Medical College; Krakow Poland
| | - Julio Davila
- University Hospital of Salamanca; Salamanca Spain
| | | | | | - Mark A. Fiala
- Washington University School of Medicine; Saint Louis Missouri USA
| | - Irene M. Ghobrial
- Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School; Boston Massachusetts USA
| | | | - Joshua N. Gustine
- Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School; Boston Massachusetts USA
| | - Roman Hajek
- University of Ostrava and Faculty Hospital Ostrava; Ostrava Czech Republic
| | - Vania Hungria
- Santa Casa de Misericordia Hospital; Sao Paulo Brazil
| | | | | | - Jacob P. Laubach
- Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School; Boston Massachusetts USA
| | | | | | | | | | - Elizabeth A. Morgan
- Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School; Boston Massachusetts USA
| | - Hareth Nahi
- Karolinska University Hospital; Stockholm Sweden
| | | | - Claudia Paba-Prada
- Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School; Boston Massachusetts USA
| | - Tomas Pika
- Palacky University Hospital; Olomouc Czech Republic
| | - Ludek Pour
- University Hospital Brno; Brno Czech Republic
| | - John L. Reagan
- Rhode Island Hospital, Alpert Medical School of Brown University; Providence Rhode Island USA
| | - Paul G. Richardson
- Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School; Boston Massachusetts USA
| | - Jatin Shah
- The University of Texas MD Anderson Cancer Center; Houston Texas USA
| | - Ivan Spicka
- Charles University Hospital; Prague Czech Republic
| | - Ravi Vij
- Washington University School of Medicine; Saint Louis Missouri USA
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37
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Cao XX, Meng Q, Cai H, Mao YY, Duan MH, Zhu TN, Zhang W, Han B, Zhuang JL, Cai HC, Chen M, Feng J, Han X, Zhang Y, Yang C, Zhang L, Zhou DB, Li J. [Evaluation of clinical characteristics, MYD88(L265P) mutation, CXCR4(WHIM) mutation and prognosis in Waldenström macroglobulinemia: A single center retrospective study of 93 patients]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2017; 38:494-498. [PMID: 28655092 PMCID: PMC7342974 DOI: 10.3760/cma.j.issn.0253-2727.2017.06.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Indexed: 11/05/2022]
Abstract
Objective: To evaluate the clinical characteristics, MYD88(L265P) mutation, CXCR4(W)HIM mutation and prognosis in patients with Waldenström macroglobulinemia (WM). Methods: The clinical characteristics, International Prognostic Scoring System for symptomatic WM (WPSS) , and overall survival (OS) were retrospectively assayed in 93 patients with newly diagnosed WM at Peking Union Medical College Hospital during January 2000 to August 2016. The MYD88(L265P) mutation and CXCR4(W)HIM mutation were tested among 34 patients. Results: The median age of the 93 patients was 64 years (range, 33-85 years) with a male-to-female ratio of 2.44. According to WPSS, we included 16 (17.2%) low-risk, 44 (47.3%) intermediate-risk and 33 (35.5%) high-risk patients. Eight patients had secondary amyloidosis. With a median follow-up of 44 (1-201) months, the median OS was 84 months. Cox regression multifactor analysis showed WPSS risk group (HR=2.342, 95% CI 1.111-4.950, P=0.025) , whether patients had secondary amyloidosis (HR=5.538, 95% CI 1.958-15.662, P=0.001) and whether patients received new drugs (HR=3.392, 95% CI 1.531-7.513, P=0.003) were independent factors associated with OS. We have investigated the presence of the MYD88(L265P) and CXCR4(WHIM) mutation in 34 patients and found that MYD88(L265P) mutation was occurred in 32 patients (94.1%) and CXCR4(WHIM) mutation was occurred in 8 patients (23.5%). Seven of 8 patients who harbored CXCR4(WHIM)-mutated also exhibited the MYD88(L)265P mutation. Patients with MYD88(L265P)CXCR4(WHIM) vs MYD88(L265P)CXCR4(WT) presented with more severe anemia, lower platelet level, higher M protein level and more hyper-viscosity syndrome. Conclusion: WPSS risk group, whether patients had secondary amyloidosis or received new drugs are independent factors for OS in WM. MYD88(L265P) and CXCR4(WHIM) mutation, the most common somatic variants in WM, often occur together and impact the clinical presentation.
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Affiliation(s)
- X X Cao
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
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38
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Gustine JN, Meid K, Dubeau T, Hunter ZR, Xu L, Yang G, Ghobrial IM, Treon SP, Castillo JJ. Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenström macroglobulinaemia. Br J Haematol 2017; 177:717-725. [PMID: 28485115 DOI: 10.1111/bjh.14743] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 03/06/2017] [Indexed: 12/29/2022]
Abstract
Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenström macroglobulinaemia (WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. We carried out a large retrospective study in 825 newly diagnosed WM patients, of who 113 (14%) developed symptomatic hyperviscosity. The median serum IgM level at the time of symptomatic hyperviscosity was 61·8 g/l (range 31-124 g/l). Forty-four patients (36%) had symptomatic hyperviscosity at the time of WM diagnosis. A serum IgM level >60 g/l at diagnosis was associated with a median time to symptomatic hyperviscosity of 3 months, whereas the median time for patients with serum IgM level of 50·01-60 g/l was approximately 3 years. Adjusting for other clinical factors, the odds of developing symptomatic hyperviscosity were 370-fold higher with serum IgM levels >60 g/l, and showed an association with CXCR4 mutational status. Symptomatic hyperviscosity did not impact overall survival (P = 0·12). The findings support the use of serum IgM level >60 g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient.
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Affiliation(s)
- Joshua N Gustine
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Kirsten Meid
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Toni Dubeau
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Zachary R Hunter
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Lian Xu
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Guang Yang
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Irene M Ghobrial
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Steven P Treon
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jorge J Castillo
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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39
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Yun S, Johnson AC, Okolo ON, Arnold SJ, McBride A, Zhang L, Baz RC, Anwer F. Waldenström Macroglobulinemia: Review of Pathogenesis and Management. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2017; 17:252-262. [PMID: 28366781 PMCID: PMC5413391 DOI: 10.1016/j.clml.2017.02.028] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 02/26/2017] [Accepted: 02/28/2017] [Indexed: 11/20/2022]
Abstract
Waldenström macroglobulinemia (WM) is a low-grade B-cell clonal disorder characterized by lymphoplasmacytic bone marrow involvement associated with monoclonal immunoglobulin M. Although WM remains to be an incurable disease with a heterogeneous clinical course, the recent discovery of mutations in the MYD88 and CXCR4 genes further enhanced our understanding of its pathogenesis. Development of new therapies including monoclonal antibodies, proteasome inhibitors, and Bruton tyrosine kinase inhibitors have made the management of WM increasingly complex. Treatment should be tailored to the individual patient while considering many clinical factors. The clinical outcomes are expected to continue to improve, given the emergence of novel therapeutics and better understanding of the underlying pathogenesis.
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Affiliation(s)
- Seongseok Yun
- Department of Medicine, University of Arizona, Tucson, AZ; Department of Hematology and Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
| | | | | | - Stacy J Arnold
- Division of Pathology, Department of Medicine, University of Arizona, Tucson, AZ
| | - Ali McBride
- College of Pharmacy, University of Arizona, Tucson, AZ
| | - Ling Zhang
- Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center, Tampa, FL
| | - Rachid C Baz
- Department of Hematology and Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
| | - Faiz Anwer
- Division of Hematology, Oncology, Blood, and Marrow Transplantation, Department of Medicine, University of Arizona, Tucson, AZ.
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40
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Franzini A, Gribaudi G, Pirola E, Pluderi M, Goldaniga MC, Marfia G, Rampini PM. Waldenstrom macroglobulinemia presenting as a bilateral subdural chronic hematoma. J Clin Neurosci 2017; 40:89-91. [PMID: 28262409 DOI: 10.1016/j.jocn.2017.02.032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 02/10/2017] [Indexed: 10/20/2022]
Affiliation(s)
- Andrea Franzini
- Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
| | - Giulia Gribaudi
- Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
| | - Elena Pirola
- Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
| | - Mauro Pluderi
- Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
| | | | - Giovanni Marfia
- Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
| | - Paolo Maria Rampini
- Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
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Olszewski AJ, Treon SP, Castillo JJ. Evolution of Management and Outcomes in Waldenström Macroglobulinemia: A Population-Based Analysis. Oncologist 2016; 21:1377-1386. [PMID: 27473042 PMCID: PMC5189618 DOI: 10.1634/theoncologist.2016-0126] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 06/20/2016] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM) is a rare lymphoma affecting older patients. Its management largely relies on small phase II trials and it is unclear how their results translate into clinical practice in the community. METHOD We evaluated changes in the presentation, management, and survival among 2,666 Medicare beneficiaries diagnosed with WM between 1994 and 2011, using Medicare claims linked to Surveillance, Epidemiology and End Results data. RESULTS Prevalence of transfusions, anemia, thrombocytopenia, and neuropathy at diagnosis significantly increased over time, whereas the use of plasmapheresis was low (2.5%) and stable. The proportion of patients starting chemotherapy within 1 year of WM diagnosis increased from 39% in 1994 to 62% in 2011 (p < .0001). Treatments based on classic alkylators and purine analogs predominated in the 1990s, but were quickly replaced by rituximab-containing regimens after 2000. Rituximab monotherapy has been prescribed for >50% of patients since 2004, and combination chemoimmunotherapy for a further 30%. Most patients initiating multiagent regimens in 2012-2013 received rituximab with bortezomib or bendamustine. These changes were accompanied by significant improvements in overall and WM-related survival, but also by a significant increase in cost of chemotherapy. Mean Medicare payments for chemotherapy drugs accrued in the first year of treatment rose from $9,464 in 1994-2000 to $29,490 after 2008. CONCLUSION Hematologists have rapidly adopted innovative, expensive therapies for WM before completion of randomized trials. This underscores the need to assess the comparative value of such therapies in rare malignancies through a combination of clinical and observational data. IMPLICATIONS FOR PRACTICE Most older patients with Waldenström macroglobulinemia currently treated in the U.S. receive rituximab as monotherapy or in combination with bortezomib or bendamustine. Newly designed trials should consider control arms aligned with this prevalent real-life standard. Compared with the 1990s, patients diagnosed according to current criteria are more likely to have anemia or neuropathy, or to receive early chemotherapy, but only 2.5% require plasmapheresis at diagnosis. The incremental clinical value of newly introduced agents needs to be assessed through a combination of clinical and health services research, taking into consideration their associated survival benefits, toxicities, and associated costs of care.
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Affiliation(s)
- Adam J Olszewski
- Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, USA
- Division of Hematology-Oncology, Rhode Island Hospital, Providence, Rhode Island, USA
| | - Steven P Treon
- Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Jorge J Castillo
- Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
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Bartáková H, Novák J, Jakša R, Beneš J, Votruba J. Endobronchial involvement as an extremely rare manifestation of the Waldenström's disease. CLINICAL RESPIRATORY JOURNAL 2016; 12:816-819. [DOI: 10.1111/crj.12567] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 08/30/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Hana Bartáková
- Department of Tuberculosis and Respiratory Diseases; First Faculty of Medicine, Charles University and General University Hospital in Prague; Prague Czech Republic
| | - Jan Novák
- Department of Internal Medicine and Haematology, Third Faculty of Medicine; Charles University in Prague and Faculty Hospital Královské Vinohrady; Prague Czech Republic
| | - Radek Jakša
- Institute of Pathology, General University Hospital, First Faculty of Medicine; Charles University in Prague; Prague Czech Republic
| | - Jiří Beneš
- Department of Radiology, General University Hospital, First Faculty of Medicine; Charles University in Prague; Prague Czech Republic
| | - Jiří Votruba
- Department of Tuberculosis and Respiratory Diseases; First Faculty of Medicine, Charles University and General University Hospital in Prague; Prague Czech Republic
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43
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Cornell RF, Bachanova V, D'Souza A, Woo-Ahn K, Martens M, Huang J, Al-Homsi AS, Chhabra S, Copelan E, Diaz MA, Freytes CO, Gale RP, Ganguly S, Hamadani M, Hildebrandt G, Kamble RT, Kharfan-Dabaja M, Kindwall-Keller T, Lazarus HM, Marks DI, Nishihori T, Olsson RF, Saad A, Usmani S, Vesole DH, Yared J, Mark T, Nieto Y, Hari P. Allogeneic Transplantation for Relapsed Waldenström Macroglobulinemia and Lymphoplasmacytic Lymphoma. Biol Blood Marrow Transplant 2016; 23:60-66. [PMID: 27789362 DOI: 10.1016/j.bbmt.2016.10.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 10/13/2016] [Indexed: 12/22/2022]
Abstract
Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and IgM production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients who received adult alloHCT for WM/LPL. Data were obtained from the Center for International Blood and Marrow Transplant Research database (2001 to 2013). Patients received myeloablative(n = 67) or reduced-intensity conditioning (RIC; n = 67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n = 18) failed prior autologous HCT. About half (n = 82, 57%) had chemosensitive disease at the time of transplantation, whereas 22% had progressive disease. Rates of progression-free survival, overall survival, relapse, and nonrelapse mortality at 5 years were 46%, 52%, 24%, and 30%, respectively. Patients with chemosensitive disease and better pretransplant disease status experienced significantly superior overall survival. There were no significant differences in progression-free survival based on conditioning (myeloablative, 50%, versus RIC, 41%) or graft source. Conditioning intensity did not impact treatment-related mortality or relapse. The most common causes of death were primary disease and graft-versus-host disease (GVHD). AlloHCT yielded durable survival in select patients with WM/LPL. Strategies to reduce mortality from GVHD and post-transplant relapse are necessary to improve this approach.
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Affiliation(s)
- Robert F Cornell
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Veronika Bachanova
- Bone and Marrow Transplant Program, University of Minnesota Medical Center, Minneapolis, Minnesota
| | - Anita D'Souza
- Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
| | - Kwang Woo-Ahn
- Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Michael Martens
- Department of Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jiaxing Huang
- Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - A Samer Al-Homsi
- Blood and Marrow Transplant, Spectrum Health, Grand Rapids, Michigan
| | - Saurabh Chhabra
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Edward Copelan
- Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina
| | - Miguel-Angel Diaz
- Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain
| | | | - Robert Peter Gale
- Hematology Research Center, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom
| | - Siddhartha Ganguly
- Blood and Marrow Transplantation, Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas
| | - Mehdi Hamadani
- Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Gerhard Hildebrandt
- Division of Hematology and Blood & Marrow Transplantation, University of Kentucky Markey Cancer Center, Lexington, Kentucky
| | - Rammurti T Kamble
- Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
| | - Mohamed Kharfan-Dabaja
- Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer and Research Institute, Tampa, Florida
| | - Tamila Kindwall-Keller
- Division of Hematology/Oncology, University of Virginia Health System, Charlottesville, Virginia
| | - Hillard M Lazarus
- Seidman Cancer Center, University Hospital Case Medical Center, Cleveland, Ohio
| | - David I Marks
- Adult Bone Marrow Transplant, University Hospitals Bristol NHS Trust, Bristol, United Kingdom
| | - Taiga Nishihori
- Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer and Research Institute, Tampa, Florida
| | - Richard F Olsson
- Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Clinical Research Sormland, Uppsala University, Uppsala, Sweden
| | - Ayman Saad
- Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Saad Usmani
- Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina
| | - David H Vesole
- John Theurer Cancer Center at Hackensack UMC, Hackensack, New Jersey
| | - Jean Yared
- Blood & Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine, University of Maryland Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland
| | - Tomer Mark
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Yago Nieto
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Parameswaran Hari
- Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
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Gavriatopoulou M, Kastritis E, Kyrtsonis MC, Vassilakopoulos TP, Roussou M, Fotiou D, Migkou M, Mpakiri M, Tasidou A, Terpos E, Dimopoulos MA. Phase 2 study of ofatumumab, fludarabine and cyclophosphamide in relapsed/refractory Waldenström’s macroglobulinemia. Leuk Lymphoma 2016; 58:1506-1508. [DOI: 10.1080/10428194.2016.1233541] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Maria Gavriatopoulou
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Maria Roussou
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Despoina Fotiou
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Magdalini Migkou
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Evangelos Terpos
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
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45
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Greuter T, Browne M, Dommann-Scherrer C, Binder D, Renner C, Kapp U. IgM multiple myeloma with an extremely rare non-aggressive presentation: A case report. Oncol Lett 2016; 12:2801-2803. [PMID: 27698861 DOI: 10.3892/ol.2016.5034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 06/16/2016] [Indexed: 01/23/2023] Open
Abstract
In the present study, the case of a 41-year-old man with immunoglobulin (Ig)M multiple myeloma (MM) that presented with an unusually non-aggressive clinical course who has survived for >9 years to date, is presented. Initial diagnosis of symptomatic MM was established according to the International Myeloma Working Group consensus statement and guidelines. Due to the mild symptoms, no therapy was administered and the patient was closely followed up. Eight years after initial diagnosis, clinical, morphological and genetic progression occurred with the development of hypercalcemia, progressively deteriorating polyneuropathy, clonal expansion of plasma cells up to 50% of hematopoietic cells and demonstration of the typical t(11;14) translocation (Ig heavy chain locus rearrangement). Subsequently, 4 cycles of induction chemotherapy with velcade, cyclophosphamide and dexamethasone, were administered. At the time of writing, the patient remained alive in generally good health. To the best of our knowledge, with a survival time of >9 years, this case reports the longest survival time of an IgM MM patient to date, which contradicts previous evidence that suggests IgM MM exhibits an aggressive clinical course.
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Affiliation(s)
- Thomas Greuter
- Department of Medicine, GZO-Zurich Regional Health Center, 8620 Wetzikon, Zurich, Switzerland
| | - Martin Browne
- North Coast Cancer Institute, Coffs Harbour Health Campus, Coffs Harbour, New South Wales 2450, Australia
| | | | - Daniel Binder
- Division of Hematology, Cantonal Hospital Winterthur, 8401 Winterthur, Zurich, Switzerland
| | | | - Ursula Kapp
- Department of Medicine, GZO-Zurich Regional Health Center, 8620 Wetzikon, Zurich, Switzerland
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46
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Santos T, Machado S, Sousa V, Campos M. Cast nephropathy: an extremely rare renal presentation of Waldenström's macroglobulinaemia. BMJ Case Rep 2015; 2015:bcr-2015-211210. [PMID: 26446315 DOI: 10.1136/bcr-2015-211210] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Renal involvement in Waldenström's macroglobulinaemia (WM) is very unusual when compared to multiple myeloma. We report a case of a patient who developed anuric acute kidney injury secondary to cast nephropathy, dependent on high-flux haemodialysis. Complementary study revealed the presence of blood IgM monoclonal gammopathy and a massive bone marrow lymphoplasmacytic infiltration. There were no osteolytic lesions and no clinical signs/symptoms of hyperviscosity syndrome. The diagnosis of WM was established and a dexamethasone plus cyclophosphamide regime was started, in addition to plasmapheresis. The patient partially recovered renal function allowing haemodialysis and plasmapheresis withdrawal. He remained asymptomatic with a good response to chemotherapy and 12 months after his renal function remained stable. This is a rare clinical case in which WM presented as an IgM cast nephropathy, which in turn is an extremely rare renal presentation of this equally rare haematological disorder.
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Affiliation(s)
- Tânia Santos
- Department of Nephrology, Coimbra's Hospital and University Center, Coimbra, Portugal
| | - Susana Machado
- Department of Nephrology, Coimbra's Hospital and University Center, Coimbra, Portugal
| | - Vítor Sousa
- Department of Pathology, Coimbra's Hospital and University Center, Coimbra, Portugal Coimbra's Medical College, Coimbra, Portugal
| | - Mário Campos
- Department of Nephrology, Coimbra's Hospital and University Center, Coimbra, Portugal
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47
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Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia. Leukemia 2015; 29:2338-46. [DOI: 10.1038/leu.2015.164] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/07/2015] [Accepted: 05/15/2015] [Indexed: 12/17/2022]
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48
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49
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Banwait R, Aljawai Y, Cappuccio J, McDiarmid S, Morgan EA, Leblebjian H, Roccaro AM, Laubach J, Castillo JJ, Paba-Prada C, Treon S, Redd R, Weller E, Ghobrial IM. Extramedullary Waldenström macroglobulinemia. Am J Hematol 2015; 90:100-4. [PMID: 25349134 DOI: 10.1002/ajh.23880] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 10/23/2014] [Accepted: 10/25/2014] [Indexed: 01/09/2023]
Abstract
Disease assessment in Waldenstrom Macroglobulinemia (WM) is dependent on the percent involvement of B-cell neoplasm in the bone marrow and IgM paraprotein in the serum. A subset of patients also demonstrates extramedullary involvement, which is infrequently examined. The role of extramedullary involvement in the diagnosis and prognosis of WM is poorly understood. The purpose of this study is to report the characteristics of WM patients with extramedullary disease (EMD). Nine hundred and eight-five patients with WM were evaluated at one academic center and the presence of EMD was assessed in these patients. Forty-three (4.4%) patients were identified to have EMD. Nine (21%) patients presented with involvement at WM diagnosis, while 34 (79%) developed EMD post-therapy for WM. Most frequent EMD sites involved were pulmonary (30%), soft tissue (21%), cerebrospinal fluid (23%), renal (8%), and bone (9%). The median overall survival at 10 years was 79% (95% CI: 57-90%). This is the first study to describe the clinical characteristics, response and overall survival in patients with extramedullary WM. Further studies to define the molecular characteristics of this entity and mechanisms of its development are warranted.
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Affiliation(s)
- Ranjit Banwait
- Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts
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50
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Coimbra S, Neves R, Lima M, Belo L, Santos-Silva A. Waldenström's macroglobulinemia - a review. Rev Assoc Med Bras (1992) 2014. [DOI: 10.1590/1806-9282.60.05.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Waldenström's macroglobulinemia (WM) is a lymphoproliferative disease of B lymphocytes, characterized by a lymphoplasmocytic lymphoma in the bone marrow and by IgM monoclonal hypergammaglobulinemia. It was first described in 1944 by Jan Gösta Waldenström, reporting two patients with oronasal bleeding, lymphadenopathy, anemia, thrombocytopenia, high erythrocyte sedimentation rate and serum viscosity, normal radiography and bone marrow infiltrated by lymphoid cells. The WM is a rare disease with a typically indolent clinical course, affecting mainly individuals aged between 63 and 68 years. Most patients have clinical signs and symptoms related to hyperviscosity resulting from IgM monoclonal gammopathy, and/or cytopenias resulting from bone marrow infiltration by lymphoma. The differential diagnosis with other lymphomas is essential for the assessment of prognosis and therapeutic approach. Treatment of patients with asymptomatic WM does not improve the quality of life of patients, or increase their survival, being recommended, therefore, their follow-up. For the treatment of symptomatic patients, alkylating agents, purine analogs and anti-CD20 monoclonal antibodies are used. However, the disease is incurable and the response to therapy is not always favorable. Recent studies have shown promising results with bortezomib, an inhibitor of proteasomes, and some patients respond to thalidomide. In patients with relapse or refractory to therapy, autologous transplantation may be indicated. The aim of this paper is to describe in detail the current knowledge on the pathophysiology of WM, main clinical manifestations, diagnosis, prognosis and treatment.
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Affiliation(s)
| | | | | | - Luís Belo
- University of Porto, Portugal; University of Porto, Portugal
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