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1
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Lafont T, Booth S, Wakefield H. Ixazomib-induced thrombotic microangiopathy resolving without complement pathway inhibition: a case report. Leuk Lymphoma 2025; 66:569-571. [PMID: 39565042 DOI: 10.1080/10428194.2024.2428360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/05/2024] [Accepted: 11/06/2024] [Indexed: 11/21/2024]
Affiliation(s)
- Tanguy Lafont
- Faculty of Life Sciences & Medicine, King's College London, London, UK
- Royal BerkshireNHS Foundation Trust, Reading, UK
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Stephen Booth
- Department of Clinical Haematology, Royal Berkshire NHS Foundation Trust, Reading, UK
| | - Harry Wakefield
- University Department of Renal Medicine, Reading, UK Royal Berkshire NHS Foundation Trust
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2
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Deng Z, Wang S, Wang C. Proteasome inhibitor-associated thrombotic microangiopathy: a real-world retrospective and pharmacovigilance database analysis. Support Care Cancer 2025; 33:184. [PMID: 39939437 DOI: 10.1007/s00520-025-09219-w] [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: 05/22/2024] [Accepted: 01/28/2025] [Indexed: 02/14/2025]
Abstract
OBJECTIVES Thrombotic microangiopathy (TMA) is associated with carfilzomib, but the potential association between bortezomib or ixazomib exposure and TMA is still unknown. Besides, the knowledge of carfilzomib-induced TMA is based mainly on case reports. We aim to quantify the risk and better characterize the clinical features of proteasome inhibitor (PI)-induced TMA. METHODS Data from 2004 to 2023 on TMA events induced by PIs were retrieved from the FDA Adverse Event Reporting System (FAERS) database and conducted disproportionality analyse. Case reports/series from 2004 to 2023 on PI-induced TMA were extracted and analyzed retrospectively. RESULTS FAERS pharmacovigilance data identified 225 TMA cases across 213 individuals related to PIs therapy. PIs were significantly associated with TMA (n = 213, ROR 1.71 [1.49-1.96]; EBGM 1.70 [1.52]), and carfilzomib had the greatest proportion (58.7%) and highest positive signal values (n = 125, ROR 17.97 [15.04-21.47]; EBGM 17.49 [15.07]) of TMA. Sixty cases (median age: 63 years) from 35 studies showed evidence of TMA, with 37 (61.7%) were male. The typical initial symptoms were gastrointestinal symptoms (45.3%), fever (24.5%), fatigue/asthenia (20.8%), neurological signs (18.9%), and dyspnea (17.0%). The median time to TMA onset was 8 days. Most patients presented with hemolytic anemia (98.1%), thrombocytopenia (96.6%), and acute kidney injury (96.7%). Cessation of PIs and treatment with plasma exchange therapy (25.0%), hemodialysis (31.7%), and eculizumab (26.7%) were associated with improved hematologic outcomes (96.3%) and renal outcomes (93.3%). CONCLUSION This study identified PIs agents with significant reporting associations with TMA. A prompt diagnosis of TMA and supportive treatments are necessary for patients receiving PIs concurrent with anemia, thrombocytopenia, and acute kidney injury.
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Affiliation(s)
- Zhenzhen Deng
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Tongzipo Street, Yuelu District, Changsha, 410013, Hunan, China
| | - Shengfeng Wang
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Tongzipo Street, Yuelu District, Changsha, 410013, Hunan, China
| | - Chunjiang Wang
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Tongzipo Street, Yuelu District, Changsha, 410013, Hunan, China.
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3
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Akhdar G, Akpan I. Navigating the Nexus: Lenalidomide-Associated Thrombotic Thrombocytopenic Purpura. Cureus 2024; 16:e62975. [PMID: 39050339 PMCID: PMC11265961 DOI: 10.7759/cureus.62975] [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: 06/23/2024] [Indexed: 07/27/2024] Open
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) marked by thrombocytopenia, microangiopathic hemolytic anemia, and microvascular thrombosis leading to end-organ damage. While TTP commonly results from hereditary or acquired ADAMTS13 deficiency, its association with lenalidomide is notably rare. The link between lenalidomide and TMA is unclear and requires more studies, given the high mortality risk associated with TTP. The underlying mechanism may involve immunomodulatory effects leading to ADAMTS13 inhibitory antibody formation. Herein, we present a case of a 56-year-old male with a history of multiple myeloma status post autologous stem cell transplant, on lenalidomide maintenance therapy for over five years, who presented with progressive weakness, jaundice, palpitations, and paraesthesia in his extremities. On arrival, the patient was afebrile and was neurologically intact except for the subjective paraesthesia. He was found to have critically low ADAMTS13 activity at <0.03 IU/mL and detectable ADAMTS13 inhibitors, with other findings of TTP, requiring discontinuation of lenalidomide, in addition to receiving treatment for this life-threatening TMA.
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Affiliation(s)
- Ghida Akhdar
- Internal Medicine, Piedmont Athens Regional Medical Center, Athens, USA
| | - Inemesit Akpan
- Internal Medicine, Piedmont Athens Regional Medical Center, Athens, USA
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4
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Comerford C, Glavey S, Quinn J, O’Sullivan JM. The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies. J Thromb Haemost 2022; 20:1766-1777. [PMID: 35644028 PMCID: PMC9546473 DOI: 10.1111/jth.15773] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/11/2022] [Accepted: 05/25/2022] [Indexed: 11/30/2022]
Abstract
Cancer associated thrombosis (CAT) is associated with significant morbidity and mortality, highlighting an unmet clinical need to improve understanding of the pathophysiology of CAT. Multiple myeloma (MM) is associated with one of the highest rates of thrombosis despite widespread use of thromboprophylactic agents. The pathophysiology of thrombosis in MM is multifactorial and patients with MM appear to display a hypercoagulable phenotype with potential contributory factors including raised von Willebrand factor (VWF) levels, activated protein C resistance, impaired fibrinolysis, and abnormal thrombin generation. In addition, the toxic effect of anti-myeloma therapies on the endothelium and contribution to thrombosis has been widely described. Elevated VWF/factor VIII (FVIII) plasma levels have been reported in heterogeneous cohorts of patients with MM and other hematological malignancies. In specific studies, high plasma VWF levels have been shown to associate with VTE risk and reduced overall survival. While the mechanisms underpinning this remain unclear, dysregulation of the VWF and A Disintegrin And Metalloprotease Thrombospondin type 1, motif 13 (ADAMTS-13) axis is evident in certain solid organ malignancies and correlates with advanced disease and thrombosis. Furthermore, thrombotic microangiopathic conditions arising from deficiencies in ADAMTS-13 and thus an accumulation of prothrombotic VWF multimers have been reported in patients with MM, particularly in association with specific myeloma therapies. This review will discuss current evidence on the pathophysiological mechanisms underpinning thrombosis in MM and in particular summarize the role of VWF/FVIII in hematological malignancies with a focus on thrombotic risk and emerging evidence for contribution to disease progression.
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Affiliation(s)
- Claire Comerford
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular SciencesRoyal College of Surgeons in IrelandDublinIreland
- Department of HaematologyBeaumont HospitalDublinIreland
| | - Siobhan Glavey
- Department of HaematologyBeaumont HospitalDublinIreland
- School of PathologyRoyal College of Surgeons in IrelandDublinIreland
| | - John Quinn
- Department of HaematologyBeaumont HospitalDublinIreland
- School of MedicineRoyal College of Surgeons in IrelandDublinIreland
| | - Jamie M. O’Sullivan
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular SciencesRoyal College of Surgeons in IrelandDublinIreland
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5
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Filippone EJ, Newman ED, Li L, Gulati R, Farber JL. Thrombotic Microangiopathy, an Unusual Form of Monoclonal Gammopathy of Renal Significance: Report of 3 Cases and Literature Review. Front Immunol 2021; 12:780107. [PMID: 34858436 PMCID: PMC8631422 DOI: 10.3389/fimmu.2021.780107] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 10/22/2021] [Indexed: 12/25/2022] Open
Abstract
Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.
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Affiliation(s)
- Edward J Filippone
- Divsion of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Eric D Newman
- Divsion of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Li Li
- Department of Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Rakesh Gulati
- Divsion of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - John L Farber
- Department of Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
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6
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Freyer CW, Bange EM, Skuli S, Hsu M, Lin J, Cuker A, Cohen AD, Garfall A. Carfilzomib-Induced Atypical Hemolytic Uremic Syndrome in a Patient With Heterozygous CFHR3/CFHR1 Deletion Treated With Eculizumab. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:e845-e849. [PMID: 34366267 DOI: 10.1016/j.clml.2021.06.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 11/19/2022]
Affiliation(s)
- Craig W Freyer
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Erin M Bange
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Sarah Skuli
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Miles Hsu
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - John Lin
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Adam Cuker
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Adam D Cohen
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Alfred Garfall
- Hospital of the University of Pennsylvania, Philadelphia, PA
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7
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Valério P, Barreto JP, Ferreira H, Chuva T, Paiva A, Costa JM. Thrombotic microangiopathy in oncology - a review. Transl Oncol 2021; 14:101081. [PMID: 33862523 PMCID: PMC8065296 DOI: 10.1016/j.tranon.2021.101081] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 12/31/2022] Open
Abstract
Thrombotic microangiopathy is a syndrome triggered by a wide spectrum of situations, some of which are specific to the Oncology setting. It is characterized by a Coombs-negative microangiopathic haemolytic anemia, thrombocytopenia and organ injury, with characteristic pathological features, resulting from platelet microvascular occlusion. TMA is rare and its cancer-related subset even more so. TMA triggered by drugs is the most common within this group, including classic chemotherapy and the latest targeted therapies. The neoplastic disease itself and hematopoietic stem-cell transplantation could also be potential triggers. Evidence-based medical guidance in the management of cancer-related TMA is scarce and the previous knowledge about primary TMA is valuable to understand the disease mechanisms and the potential treatments. Given the wide spectrum of potential causes for TMA in cancer patients, the aim of this review is to gather the vast information available. For each entity, pathophysiology, clinical features, therapeutic approaches and prognosis will be covered.
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Affiliation(s)
- Patrícia Valério
- Nephrology Department, Setúbal Hospital Center, Portugal Rua Camilo Castelo Branco 175, 2910-549 Setúbal, Portugal.
| | - João Pedro Barreto
- Laboratory Diagnosis Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Hugo Ferreira
- Nephrology Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Teresa Chuva
- Nephrology Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Ana Paiva
- Nephrology Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - José Maximino Costa
- Nephrology Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
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8
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Bridoux F, Cockwell P, Glezerman I, Gutgarts V, Hogan JJ, Jhaveri KD, Joly F, Nasr SH, Sawinski D, Leung N. Kidney injury and disease in patients with haematological malignancies. Nat Rev Nephrol 2021; 17:386-401. [PMID: 33785910 DOI: 10.1038/s41581-021-00405-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Acute kidney injury (AKI) is common in patients with cancer, especially in those with haematological malignancies. Kidney injury might be a direct consequence of the underlying haematological condition. For example, in the case of lymphoma infiltration or extramedullary haematopoiesis, it might be caused by a tumour product; in the case of cast nephropathy it might be due to the presence of monoclonal immunoglobulin; or it might result from tumour complications, such as hypercalcaemia. Kidney injury might also be caused by cancer treatment, as many chemotherapeutic agents are nephrotoxic. High-intensity treatments, such as high-dose chemotherapy followed by haematopoietic stem cell transplantation, not only increase the risk of infection but can also cause AKI through various mechanisms, including viral nephropathies, engraftment syndrome and sinusoidal obstruction syndrome. Some conditions, such as thrombotic microangiopathy, might also result directly from the haematological condition or the treatment. Novel immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cell therapy, can also be nephrotoxic. As new therapies for haematological malignancies with increased anti-tumour efficacy and reduced toxicity are developed, the number of patients receiving these treatments will increase. Clinicians must gain a good understanding of the different mechanisms of kidney injury associated with cancer to better care for these patients.
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Affiliation(s)
- Frank Bridoux
- Department of Nephrology, and Centre d'Investigation Clinique (CIC INSERM 1402), Centre Hospitalier Universitaire et Université de Poitiers, Poitiers, France.,CNRS, UMR7276, Limoges, France.,Centre de référence Amylose AL et autres maladies par dépôt d'immunoglobulines monoclonales, Poitiers, France
| | - Paul Cockwell
- Department of Nephrology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.,Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Ilya Glezerman
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell Medical College, New York, NY, USA
| | - Victoria Gutgarts
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell Medical College, New York, NY, USA
| | - Jonathan J Hogan
- Renal, Electrolyte and Hypertension Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Kenar D Jhaveri
- Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Great Neck, NY, USA
| | - Florent Joly
- Department of Nephrology, and Centre d'Investigation Clinique (CIC INSERM 1402), Centre Hospitalier Universitaire et Université de Poitiers, Poitiers, France
| | - Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Deirdre Sawinski
- Renal, Electrolyte and Hypertension Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Nelson Leung
- Division of Nephrology and Hypertension, Division of Hematology, Mayo Clinic, Rochester, MN, USA.
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9
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Darwin A, Malpica L, Dhanoa J, Hashmi H. Carfilzomib-induced atypical haemolytic uraemic syndrome: a diagnostic challenge and therapeutic success. BMJ Case Rep 2021; 14:14/2/e239091. [PMID: 33637496 PMCID: PMC7919563 DOI: 10.1136/bcr-2020-239091] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) that presents with renal insufficiency, thrombocytopaenia and microangiopathic haemolytic anaemia. Typical HUS is associated with Shiga toxin while atypical HUS (aHUS) is due to overactivation of the alternative complement pathway. aHUS has numerous causes, including drugs, with rare reports of carfilzomib, a proteasome inhibitor used in multiple myeloma, as causative agent. Cases vary in presentation, presenting a diagnostic challenge. Historically, TMAs were treated with plasma exchange. aHUS, however, is considered refractory to plasma exchange and best treated with eculizumab, a monoclonal antibody targeting C5, a terminal complement protein. We report a patient with history of multiple myeloma who presented with headaches, elevated blood pressure, petechiae, ecchymosis and haemolytic anaemia. His condition was determined to be carfilzomib-induced aHUS and he was successfully treated with eculizumab. Early detection and treatment of drug-induced aHUS is vital in reducing morbidity and mortality related to the condition.
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Affiliation(s)
- Alicia Darwin
- Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Leonger Malpica
- Department of Blood & Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, USA
| | - Jugraj Dhanoa
- Internal Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Hamza Hashmi
- Department of Blood & Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, USA .,Department of Hematology Oncology, Medical University of South Carolina, Charleston, South Carolina, USA
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10
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Bridoux F, Leung N, Belmouaz M, Royal V, Ronco P, Nasr SH, Fermand JP. Management of acute kidney injury in symptomatic multiple myeloma. Kidney Int 2021; 99:570-580. [PMID: 33440212 DOI: 10.1016/j.kint.2020.11.010] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/23/2020] [Accepted: 11/03/2020] [Indexed: 01/15/2023]
Abstract
Symptomatic multiple myeloma is commonly complicated by acute kidney injury through various mechanisms. The most frequent is the precipitation of monoclonal free light chains with uromodulin in the distal tubules, defining light chain cast nephropathy. Early diagnosis and identification of the cause of acute kidney injury are required for optimizing management and avoiding chronic kidney injury that strongly affects quality of life and patient survival. In light chain cast nephropathy, often manifesting with severe acute kidney injury, renal recovery requires urgent intervention based on vigorous rehydration, correction of precipitating factors, and efficient anti-plasma cell chemotherapy to rapidly reduce the secretion of nephrotoxic free light chains. Currently, the association of the proteasome inhibitor bortezomib with high-dose dexamethasone is the standard regimen in newly diagnosed patients. The addition of another drug such as cyclophosphamide or an immunodulatory agent may improve free light chain response but raises tolerance concerns in frail patients. Further studies are warranted to confirm the role of anti-CD38 monoclonal antibodies, whose efficacy and tolerance have been documented in patients without renal impairment. Despite controversial results from randomized studies, recent data suggest that in patients with light chain cast nephropathy and acute kidney injury requiring dialysis, the combination of chemotherapy with free light chain removal through high-cutoff hemodialysis may increase renal response recovery rates. Kidney biopsy may be helpful in guiding management and assessing renal prognosis that appears to depend on the extent of cast formation and interstitial fibrosis/tubular atrophy. Because of continuous improvement in life expectancy of patients with multiple myeloma, renal transplantation is likely to be increasingly considered in selected candidates.
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Affiliation(s)
- Frank Bridoux
- Department of Nephrology, Dialysis, and Renal Transplantation, CIC INSERM 1402, CHU Poitiers, Poitiers, France; Centre national de référence Amylose AL & autres maladies par dépôts d'immunoglobulines monoclonales, CHU Poitiers, Poitiers, France; Centre National de la Recherche Scientifique UMR CNRS 7276/INSERM U1262, Université de Limoges, Limoges, France.
| | - Nelson Leung
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Mohamed Belmouaz
- Department of Nephrology, Dialysis, and Renal Transplantation, CIC INSERM 1402, CHU Poitiers, Poitiers, France; Centre national de référence Amylose AL & autres maladies par dépôts d'immunoglobulines monoclonales, CHU Poitiers, Poitiers, France
| | - Virginie Royal
- Division of Pathology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Canada
| | - Pierre Ronco
- Nephrology Department, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France; Sorbonne Université and Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche S 1135, Paris, France
| | - Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jean Paul Fermand
- Department of Hematology and Immunology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, INSERM UMR 1126, Paris, France; Intergroupe Francophone du Myélome (IFM), Paris, France
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11
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Monteith BE, Venner CP, Reece DE, Kew AK, Lalancette M, Garland JS, Shepherd LE, Pater JL, Hay AE. Drug-induced Thrombotic Microangiopathy with Concurrent Proteasome Inhibitor Use in the Treatment of Multiple Myeloma: A Case Series and Review of the Literature. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:e791-e800. [DOI: 10.1016/j.clml.2020.04.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/17/2020] [Accepted: 04/22/2020] [Indexed: 01/29/2023]
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12
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Chatzikonstantinou T, Gavriilaki M, Anagnostopoulos A, Gavriilaki E. An Update in Drug-Induced Thrombotic Microangiopathy. Front Med (Lausanne) 2020; 7:212. [PMID: 32528969 PMCID: PMC7256484 DOI: 10.3389/fmed.2020.00212] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 04/29/2020] [Indexed: 12/18/2022] Open
Affiliation(s)
| | - Maria Gavriilaki
- Laboratory of Clinical Neurophysiology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Eleni Gavriilaki
- BMT Unit, Hematology Department, G Papanicolaou Hospital, Thessaloniki, Greece
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13
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Santos MLC, Brito BBD, da Silva FAF, Botelho ACDS, Melo FFD. Nephrotoxicity in cancer treatment: An overview. World J Clin Oncol 2020; 11:190-204. [PMID: 32355641 PMCID: PMC7186234 DOI: 10.5306/wjco.v11.i4.190] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 01/24/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023] Open
Abstract
Anticancer drug nephrotoxicity is an important and increasing adverse drug event that limits the efficacy of cancer treatment. The kidney is an important elimination pathway for many antineoplastic drugs and their metabolites, which occurs by glomerular filtration and tubular secretion. Chemotherapeutic agents, both conventional cytotoxic agents and molecularly targeted agents, can affect any segment of the nephron including its microvasculature, leading to many clinical manifestations such as proteinuria, hypertension, electrolyte disturbances, glomerulopathy, acute and chronic interstitial nephritis, acute kidney injury and at times chronic kidney disease. The clinician should be alert to recognize several factors that may maximize renal dysfunction and contribute to the increased incidence of nephrotoxicity associated with these drugs, such as intravascular volume depletion, the associated use of nonchemotherapeutic nephrotoxic drugs (analgesics, antibiotics, proton pump inhibitors, and bone-targeted therapies), radiographic ionic contrast media or radiation therapy, urinary tract obstruction, and intrinsic renal disease. Identification of patients at higher risk for nephrotoxicity may allow the prevention or at least reduction in the development and severity of this adverse effect. Therefore, the aim of this brief review is to provide currently available evidences on oncologic drug-related nephrotoxicity.
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Affiliation(s)
- Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Bahia, Brazil
| | | | | | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Bahia, Brazil
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14
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Higuero Saavedra V, González-Calle V, Sobejano E, Sebastiá J, Cabrero M, Bastida JM, Puig N, Ocio EM, Mateos MV. Drug-induced Thrombotic Microangiopathy During Maintenance Treatment in a Patient With Multiple Myeloma. Hemasphere 2019; 3:e192. [PMID: 31723829 PMCID: PMC6746023 DOI: 10.1097/hs9.0000000000000192] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 02/18/2019] [Accepted: 02/20/2019] [Indexed: 01/14/2023] Open
Affiliation(s)
- Víctor Higuero Saavedra
- Hematology Department, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Verónica González-Calle
- Hematology Department, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Eduardo Sobejano
- Hematology Department, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Josefa Sebastiá
- Nephrology Department, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
| | - Mónica Cabrero
- Hematology Department, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Jose María Bastida
- Hematology Department, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
| | - Noemi Puig
- Hematology Department, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Enrique M. Ocio
- Hematology Department, Hospital Universitario Marqués de Valdecilla
| | - María-Victoria Mateos
- Hematology Department, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
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Late Presentation of Carfilzomib Associated Thrombotic Microangiopathy. AMERICAN JOURNAL OF MEDICAL CASE REPORTS 2019; 7:240-243. [PMID: 31457071 PMCID: PMC6711615 DOI: 10.12691/ajmcr-7-10-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Multiple Myeloma (MM) is a plasma cell disorder characterized by abnormal proliferation of plasma cells resulting in overproduction of paraprotein. Proteasome inhibitors (PI) have been a corner stone for the treatment of MM. Thrombotic Microangiopathy (TMA) is a recent hematological adverse event that has newly been recognized in multiple PI. TMA leads to end-organ damage and infarction by microthromobi. TMA pathophysiology is not well understood and has multiple etiologies. We present a case of PI-induced TMA, along with literature review of cases diagnosed from 2008-2018. Unique to our case is the onset of presentation, more than 24 months after initiating carfilzomib. Our case highlights the need for vigilant monitoring and the importance of clinical suspicion in patients at risk for TMA.
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16
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Saleem R, Reese JA, George JN. Drug-induced thrombotic microangiopathy: An updated systematic review, 2014-2018. Am J Hematol 2018; 93:E241-E243. [PMID: 29985540 DOI: 10.1002/ajh.25208] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 06/18/2018] [Indexed: 11/06/2022]
Affiliation(s)
- Rabia Saleem
- Department of Internal Medicine; College of Medicine, University of Oklahoma Health Sciences Center; Oklahoma City Oklahoma
| | - Jessica A. Reese
- Department of Biostatistics & Epidemiology; College of Public Health, University of Oklahoma Health Sciences Center; Oklahoma City Oklahoma
| | - James N. George
- Department of Internal Medicine; College of Medicine, University of Oklahoma Health Sciences Center; Oklahoma City Oklahoma
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17
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Drug-Induced Thrombotic Microangiopathy due to Cumulative Toxicity of Ixazomib. Case Rep Hematol 2018; 2018:7063145. [PMID: 30057831 PMCID: PMC6051099 DOI: 10.1155/2018/7063145] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 06/05/2018] [Indexed: 01/09/2023] Open
Abstract
Drug-induced thrombotic microangiopathies (DTMAs) are increasingly being recognized as an important category of thrombotic microangiopathies (TMAs). Cancer therapeutic agents including proteasome inhibitors (PIs) are among the most common medications reported to cause DTMA. PIs could cause DTMA either by an immune mechanism or dose-dependent/cumulative toxicity. Eleven cases of DTMA have been reported with bortezomib and carfilzomib. To the best of our knowledge, only one case of DTMA has been reported with ixazomib due to an immune-mediated mechanism. Here, we report the first case of ixazomib-induced DTMA due to cumulative toxicity rather than immune-mediated mechanism. In this article, we discuss the precipitating factors for cumulative toxicity of ixazomib, resulting in DTMA, diagnostic workup, and management of DTMA. We also discuss clinical reasoning based analysis of DTMA versus cancer-associated TMA as well as DTMA versus cyclic thrombocytopenia seen in PI use.
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18
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Abstract
INTRODUCTION Despite a major positive impact of proteasome inhibitors (PI), such as bortezomib and carfilzomib, on the survival of patients with multiple myeloma (MM) over the last few years, their use in clinical practice is limited by the development of drug resistance, significant side-effects or constraining administration schedules. Ixazomib is the first, and for now the only, oral PI, which was approved by the US Food and Drug Administration in 2015 and by the European Medicines Agency in 2016. Areas covered: In this review, we provide an overview of the preclinical and early-phase studies of ixazomib used as single-agent and in combination. Furthermore, we discuss the results of a recently published pivotal trial, which evaluated the safety profile and clinical benefit of the combination of ixazomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in 722 patients with relapsed/refractory MM. Expert opinion: Ixazomib combines the comfort of oral administration, substantial clinical efficacy and a good safety profile with manageable side-effects, which mainly comprise low-grade hematological, digestive or cutaneous events, and the agent will therefore play an active part in long-term treatment strategies, both as single agent and as part of combination regimens. Ongoing phase III trials are currently defining its place in first-line, maintenance and relapse settings.
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Affiliation(s)
- Antoine Bonnet
- a Department of Hematology , University Hospital Hôtel-Dieu , Nantes , France
| | - Philippe Moreau
- a Department of Hematology , University Hospital Hôtel-Dieu , Nantes , France
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19
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Abstract
Targeted therapies that act via unique molecular pathways and interfere with cancer cell growth and tumor progression have dramatically changed the cancer treatment paradigm. However, although, ideally, these therapies intend to target only cancer cells, they do often affect nonmalignant tissue. Numerous renal side effects have been reported to date. This article will review clinical presentation, presumed pathophysiology, and treatment of kidney side effects of targeted therapies. Feasibility of the continuation of cancer therapy despite renal toxicity will also be addressed.
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