|
1
|
Butler LA, Forsyth C, Harrison C, Perkins AC. Real World Management of Cytopenias and Infections in Patients With Myelofibrosis Treated With Ruxolitinib. EJHAEM 2025; 6:e70007. [PMID: 40123795 PMCID: PMC11927021 DOI: 10.1002/jha2.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 03/25/2025]
Abstract
Introduction Ruxolitinib was the first JAK2 inhibitor approved for the treatment of primary and secondary myelofibrosis. It is currently used worldwide as first-line therapy for advanced disease (intermediate-2 and high-risk) and is effective in polycythaemia vera (PV) and essential thrombocythaemia (ET), but not funded for this indication in many countries. Ruxolitinib has proven benefits with respect to symptom control, reduction in spleen size and prolongation of survival; however, it rarely induces a substantial reduction in allele burden and never provides a cure. Moreover, there are frequently encountered adverse effects and dosing issues that require careful management to optimise its therapeutic benefit. Methods and Results In this case-based review, we use seven informative common clinical scenarios to discuss appropriate investigation and management of cytopenias and infection issues. Conclusions We make recommendations based on 15 years of experience in using ruxolitinib and other JAK inhibitors for the treatment of myelofibrosis. We discuss when allogeneic haematopoietic stem cell transplantation (AHSCT) should be considered and some of the currently available alternative JAK inhibitors and trial options when AHSCT is not an option.
Collapse
Affiliation(s)
- Liesl A. Butler
- Monash UniversityMelbourneVictoriaAustralia
- Alfred HealthMelbourneVictoriaAustralia
| | - Cecily Forsyth
- Central Coast HaematologyNorth GosfordNew South WalesAustralia
| | | | - Andrew C. Perkins
- Monash UniversityMelbourneVictoriaAustralia
- Alfred HealthMelbourneVictoriaAustralia
| |
Collapse
|
|
2
|
Boldrini V, Vannucchi AM, Guglielmelli P. A safety evaluation of ruxolitinib for the treatment of polycythemia vera. Expert Opin Drug Saf 2024; 23:1-7. [PMID: 38156903 DOI: 10.1080/14740338.2023.2299391] [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: 04/26/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
INTRODUCTION Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm hallmarked by deregulated proliferation of hematopoietic stem cells leading to prevalent expansion of red cell mass, increased rate of vascular events, splenomegaly, disease-associated symptoms, and risk of evolution to secondary myelofibrosis and blast phase. PV is pathogenetically associated with autonomously persistent activation of JAK2, which causes overproduction of blood cells and an inflammatory condition responsible for the clinical manifestations of the disease. Extensively supported by preclinical studies, targeting JAK2-dependent signaling represents a rational therapeutic approach to PV, finally leading to the approval of ruxolitinib, a JAK1/2 inhibitor. AREAS COVERED (LITERATURE RESEARCH) We analyzed reports of phase 2 and phase 3 trials with ruxolitinib in PV and relevant literature dealing with efficacy and safety aspects, including most recent real-world reports. EXPERT OPINION Ruxolitinib is the only JAK2 inhibitor approved for the treatment of PV with well-known efficacy for splenomegaly, symptoms, and potentially reduction of vascular events. The treatment regimen is notably manageable and safe, with the most prevalent side effects primarily encompassing myelosuppression, hyperlipidemia, non-melanoma skin cancer and infections, mainly reactivation of Herpes Zoster. These effects necessitate ongoing surveillance and proactive preventive measures.
Collapse
Affiliation(s)
- Valentina Boldrini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alessandro M Vannucchi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- CRIMM, Center for Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Paola Guglielmelli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- CRIMM, Center for Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| |
Collapse
|
|
3
|
Adesola AA, Cozma MA, Chen YF, Srichawla BS, Găman MA. Risk of hepatitis B reactivation in patients with myeloproliferative neoplasms treated with ruxolitinib. World J Hepatol 2023; 15:1188-1195. [PMID: 38075009 PMCID: PMC10698348 DOI: 10.4254/wjh.v15.i11.1188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 10/23/2023] [Accepted: 11/09/2023] [Indexed: 11/24/2023] Open
Abstract
Classical Philadelphia-negative myeloproliferative neoplasms (MPNs), i.e., polycythemia vera, essential thrombocythemia, and primary/secondary myelofibrosis, are clonal disorders of the hematopoietic stem cell in which an uncontrolled proliferation of terminally differentiated myeloid cells occurs. MPNs are characterized by mutations in driver genes, the JAK2V617F point mutation being the most commonly detected genetic alteration in these hematological malignancies. Thus, JAK inhibition has emerged as a potential therapeutic strategy in MPNs, with ruxolitinib being the first JAK inhibitor developed, approved, and prescribed in the management of these blood cancers. However, the use of ruxolitinib has been associated with a potential risk of infection, including opportunistic infections and reactivation of hepatitis B. Here, we briefly describe the association between ruxolitinib treatment in MPNs and hepatitis B reactivation.
Collapse
Affiliation(s)
- Adeniyi Abraham Adesola
- Department of Medicine and Surgery, Faculty of Clinical Sciences, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Matei-Alexandru Cozma
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Gastroenterology, Colentina Clinical Hospital, Bucharest 020125, Romania
| | - Yong-Feng Chen
- Department of Basic Medical Sciences, Medical College of Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Bahadar Singh Srichawla
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, United States
| | - Mihnea-Alexandru Găman
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest 022328, Romania
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest 030304, Romania.
| |
Collapse
|
|
4
|
Kirito K. Recent progress of JAK inhibitors for hematological disorders. Immunol Med 2023; 46:131-142. [PMID: 36305377 DOI: 10.1080/25785826.2022.2139317] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 10/19/2022] [Indexed: 10/31/2022] Open
Abstract
JAK inhibitors are important therapeutic options for hematological disorders, especially myeloproliferative neoplasms. Ruxolitinib, the first JAK inhibitor approved for clinical use, improves splenomegaly and ameliorates constitutional symptoms in both myelofibrosis and polycythemia vera patients. Ruxolitinib is also useful for controlling hematocrit levels in polycythemia vera patients who were inadequately controlled by conventional therapies. Furthermore, pretransplantation use of ruxolitinib may improve the outcome of allo-hematopoietic stem cell transplantation in myelofibrosis. In contrast to these clinical merits, evidence of the disease-modifying action of ruxolitinib, i.e., reduction of malignant clones or improvement of bone marrow pathological findings, is limited, and many myelofibrosis patients discontinued ruxolitinib due to adverse events or disease progression. To overcome these limitations of ruxolitinib, several new types of JAK inhibitors have been developed. Among them, fedratinib was proven to provide clinical merits even in patients who were resistant or intolerant to ruxolitinib. Pacritinib and momelotinib have shown merits for myelofibrosis patients with thrombocytopenia or anemia, respectively. In addition to treatment for myeloproliferative neoplasms, recent studies have demonstrated that JAK inhibitors are novel and attractive therapeutic options for corticosteroid-refractory acute as well as chronic graft versus host disease.
Collapse
Affiliation(s)
- Keita Kirito
- Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan
| |
Collapse
|
|
5
|
Alamino VA, Onofrio LI, Acosta CDV, Ferrero PV, Zacca ER, Cadile II, Mussano ED, Onetti LB, Montes CL, Gruppi A, Acosta Rodriguez EV. Tofacitinib treatment of rheumatoid arthritis increases senescent T cell frequency in patients and limits T cell function in vitro. Eur J Immunol 2023; 53:e2250353. [PMID: 37179252 PMCID: PMC10524217 DOI: 10.1002/eji.202250353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 04/11/2023] [Accepted: 05/11/2023] [Indexed: 05/15/2023]
Abstract
Unraveling the immune signatures in rheumatoid arthritis (RA) patients receiving various treatment regimens can aid in comprehending the immune mechanisms' role in treatment efficacy and side effects. Given the critical role of cellular immunity in RA pathogenesis, we sought to identify T-cell profiles characterizing RA patients under specific treatments. We compared 75 immunophenotypic and biochemical variables in healthy donors (HD) and RA patients, including those receiving different treatments as well as treatment-free patients. Additionally, we conducted in vitro experiments to evaluate the direct effect of tofacitinib on purified naïve and memory CD4+ and CD8+ T cells. Multivariate analysis revealed that tofacitinib-treated patients segregated from HD at the expense of T-cell activation, differentiation, and effector function-related variables. Additionally, tofacitinib led to an accumulation of peripheral senescent memory CD4+ and CD8+ T cells. In vitro, tofacitinib impaired the activation, proliferation, and effector molecules expression and triggered senescence pathways in T-cell subsets upon TCR-engagement, with the most significant impact on memory CD8+ T cells. Our findings suggest that tofacitinib may activate immunosenescence pathways while simultaneously inhibiting effector functions in T cells, both effects likely contributing to the high clinical success and reported side effects of this JAK inhibitor in RA.
Collapse
Affiliation(s)
- Vanina A Alamino
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
- Laboratorio de Inmunología, Hospital Nacional de Clínicas, UNC, Córdoba, Argentina
| | - Luisina I Onofrio
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
- Laboratorio de Inmunología, Hospital Nacional de Clínicas, UNC, Córdoba, Argentina
| | | | - Paola V Ferrero
- Laboratorio de Inmunología, Hospital Nacional de Clínicas, UNC, Córdoba, Argentina
| | - Estefanía R Zacca
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
- Laboratorio de Inmunología, Hospital Nacional de Clínicas, UNC, Córdoba, Argentina
| | - Isaac I Cadile
- Servicio de Reumatología, Hospital Nacional de Clínicas, UNC, Córdoba, Argentina
| | - Eduardo D Mussano
- Servicio de Reumatología, Hospital Nacional de Clínicas, UNC, Córdoba, Argentina
| | - Laura B Onetti
- Servicio de Reumatología, Hospital Nacional de Clínicas, UNC, Córdoba, Argentina
| | - Carolina L Montes
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
| | - Adriana Gruppi
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
| | - Eva V Acosta Rodriguez
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
| |
Collapse
|
|
6
|
Pan C, Cao M, Yan C, Ou X, Zhang X, Xu W, Xu Y, Cui X. Hepatitis B virus reactivation associated with Janus kinase (JAK) inhibitors: a retrospective study of pharmacovigilance databases and review of the literature. Expert Opin Drug Saf 2023; 22:469-476. [PMID: 36794347 DOI: 10.1080/14740338.2023.2181339] [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] [Received: 10/07/2022] [Accepted: 01/06/2023] [Indexed: 02/17/2023]
Abstract
BACKGROUND Recently, there have been clinical reports of hepatitis B virus reactivation (HBVr) related with Janus kinase (JAK) inhibitors. However, there were no studies to investigate the association between HBVr and different JAK inhibitors. RESEARCH DESIGN AND METHODS This study was a retrospective review utilizing the FAERS pharmacovigilance database and a systematic literature search for all cases of HBVr reported with JAK inhibitors. Disproportionality analysis and Bayesian analysis were used in data detection to screen the suspected HBVr after the administration of different JAK inhibitors, based on the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database from Q4 2011 to Q1 2022. RESULTS There were a total number of 2097 (0.02%) reports of HBVr in FAERS, of which 41 (1.96%) were associated with JAK inhibitors. Baricitinib appeared to have the strongest signal among four JAK inhibitors, based on the highest reporting odds ratio (ROR = 4.45, 95% confidence interval [CI] 1.67-11.89). Ruxolitinib also showed signals, whereas no signals were detected among Tofacitinib and Upadacitinib. CONCLUSION While there may be an association between JAK inhibitors and HBVr, it appears to be a numerically uncommon occurrence. Further studies are needed to optimize the safety profiles of JAK inhibitors.
Collapse
Affiliation(s)
- Chen Pan
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Mingnan Cao
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Cilin Yan
- School of Automation Science and Electrical Engineering, Beihang University, Beijing, China
| | - Xiaojuan Ou
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xia Zhang
- Department of Rheumatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wanyi Xu
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ye Xu
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiangli Cui
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
7
|
Ge H, Wang C, Tian C, Diao Y, Wang W, Ma X, Zhang J, Li H, Zhao Z, Zhu L. Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms. Biomed Pharmacother 2022; 156:113884. [DOI: 10.1016/j.biopha.2022.113884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 11/02/2022] Open
|
|
8
|
Gerds AT, Gotlib J, Ali H, Bose P, Dunbar A, Elshoury A, George TI, Gundabolu K, Hexner E, Hobbs GS, Jain T, Jamieson C, Kaesberg PR, Kuykendall AT, Madanat Y, McMahon B, Mohan SR, Nadiminti KV, Oh S, Pardanani A, Podoltsev N, Rein L, Salit R, Stein BL, Talpaz M, Vachhani P, Wadleigh M, Wall S, Ward DC, Bergman MA, Hochstetler C. Myeloproliferative Neoplasms, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20:1033-1062. [PMID: 36075392 DOI: 10.6004/jnccn.2022.0046] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.
Collapse
Affiliation(s)
- Aaron T Gerds
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | - Haris Ali
- City of Hope National Medical Center
| | | | | | | | | | | | | | | | - Tania Jain
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | | | | | | | | | | | - Stephen Oh
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | | | - Rachel Salit
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | - Brady L Stein
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | - Sarah Wall
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Dawn C Ward
- UCLA Jonsson Comprehensive Cancer Center; and
| | | | | |
Collapse
|
|
9
|
Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations-10 Children and Review of the Literature. J Clin Immunol 2022; 42:1071-1082. [PMID: 35486339 PMCID: PMC9402491 DOI: 10.1007/s10875-022-01257-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/21/2022] [Indexed: 01/23/2023]
Abstract
INTRODUCTION Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. METHODS A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. RESULTS Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. CONCLUSIONS Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.
Collapse
|
|
10
|
Sjoblom M, Chtioui H, Fraga M, Stalder G, Grandoni F, Blum S. Hepatitis B reactivation during ruxolitinib treatment. Ann Hematol 2022; 101:2081-2086. [PMID: 35488090 DOI: 10.1007/s00277-022-04851-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/19/2022] [Indexed: 11/24/2022]
Affiliation(s)
- Marissa Sjoblom
- Emergency Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Haithem Chtioui
- Service of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Montserrat Fraga
- Division of Gastroenterology and Hepatology, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Gregoire Stalder
- Service and Central Laboratory of Hematology, Department of Oncology and Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Francesco Grandoni
- Service and Central Laboratory of Hematology, Department of Oncology and Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Sabine Blum
- Service and Central Laboratory of Hematology, Department of Oncology and Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Rue du Bugnon 46, CH-1011, Lausanne, Switzerland.
| |
Collapse
|
|
11
|
Loscocco GG, Vannucchi AM. Role of JAK inhibitors in myeloproliferative neoplasms: current point of view and perspectives. Int J Hematol 2022; 115:626-644. [PMID: 35352288 DOI: 10.1007/s12185-022-03335-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 03/06/2022] [Accepted: 03/15/2022] [Indexed: 12/29/2022]
Abstract
Classic Philadelphia-negative myeloproliferative neoplasms (MPN) include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), classified as primary (PMF), or secondary to PV or ET. All MPN, regardless of the underlying driver mutation in JAK2/CALR/MPL, are invariably associated with dysregulation of JAK/STAT pathway. The discovery of JAK2V617F point mutation prompted the development of small molecules inhibitors of JAK tyrosine kinases (JAK inhibitors-JAKi). To date, among JAKi, ruxolitinib (RUX) and fedratinib (FEDR) are approved for intermediate and high-risk MF, and RUX is also an option for high-risk PV patients inadequately controlled by or intolerant to hydroxyurea. While not yet registered, pacritinib (PAC) and momelotinib (MMB), proved to be effective particularly in thrombocytopenic and anemic MF patients, respectively. In most cases, JAKi are effective in reducing splenomegaly and alleviating disease-related symptoms. However, almost 50% lose response by three years and dose-dependent toxicities may lead to suboptimal dosing or treatment discontinuation. To date, although not being disease-modifying agents, JAKi represent the therapeutic backbone particularly in MF patient. To optimize therapeutic strategies, many trials with drug combinations of JAKi with novel molecules are ongoing. This review critically discusses the role of JAKi in the modern management of patients with MPN.
Collapse
Affiliation(s)
- Giuseppe G Loscocco
- Department of Experimental and Clinical Medicine, University of Florence, CRIMM, Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla, 3 pad 27B, 50134, Florence, Italy
- Doctorate School GenOMec, University of Siena, Siena, Italy
| | - Alessandro M Vannucchi
- Department of Experimental and Clinical Medicine, University of Florence, CRIMM, Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla, 3 pad 27B, 50134, Florence, Italy.
| |
Collapse
|
|
12
|
Strickland M, Quek L, Psaila B. The immune landscape in BCR-ABL negative myeloproliferative neoplasms: inflammation, infections and opportunities for immunotherapy. Br J Haematol 2022; 196:1149-1158. [PMID: 34618358 PMCID: PMC9135025 DOI: 10.1111/bjh.17850] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 09/05/2021] [Accepted: 09/11/2021] [Indexed: 01/06/2023]
Abstract
Breakpoint cluster region-Abelson (BCR-ABL) negative myeloproliferative neoplasms (MPNs) are chronic myeloid neoplasms initiated by the acquisition of gene mutation(s) in a haematopoietic stem cell, leading to clonal expansion and over-production of blood cells and their progenitors. MPNs encompass a spectrum of disorders with overlapping but distinct molecular, laboratory and clinical features. This includes polycythaemia vera, essential thrombocythaemia and myelofibrosis. Dysregulation of the immune system is key to the pathology of MPNs, supporting clonal evolution, mediating symptoms and resulting in varying degrees of immunocompromise. Targeting immune dysfunction is an important treatment strategy. In the present review, we focus on the immune landscape in patients with MPNs - the role of inflammation in disease pathogenesis, susceptibility to infection and emerging strategies for therapeutic immune modulation. Further detailed work is required to delineate immune perturbation more precisely in MPNs to determine how and why vulnerability to infection differs between clinical subtypes and to better understand how inflammation results in a competitive advantage for the MPN clone. These studies may help shed light on new designs for disease-modifying therapies.
Collapse
Affiliation(s)
- Marie Strickland
- MRC Molecular Haematology UnitMRC Weatherall Institute of Molecular Medicine, University of OxfordOxford
- National Institutes for Health Research Biomedical Research CentreUniversity of OxfordOxford
| | - Lynn Quek
- Department of Haematological MedicineKing's College Hospital NHS Foundation TrustLondon
- Department of Haematology, School of Cancer and Pharmaceutical SciencesKing's College LondonLondonUK
| | - Bethan Psaila
- MRC Molecular Haematology UnitMRC Weatherall Institute of Molecular Medicine, University of OxfordOxford
- National Institutes for Health Research Biomedical Research CentreUniversity of OxfordOxford
| |
Collapse
|
|
13
|
Cattaneo D, Iurlo A. Immune Dysregulation and Infectious Complications in MPN Patients Treated With JAK Inhibitors. Front Immunol 2021; 12:750346. [PMID: 34867980 PMCID: PMC8639501 DOI: 10.3389/fimmu.2021.750346] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
BCR-ABL1-negative myeloproliferative neoplasms are burdened by a reduced life expectancy mostly due to an increased risk of thrombo-hemorrhagic events, fibrotic progression/leukemic evolution, and infectious complications. In these clonal myeloid malignancies, JAK2V617F is the main driver mutation, leading to an aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Therefore, its inhibition represents an attractive therapeutic strategy for these disorders. Several JAK inhibitors have entered clinical trials, including ruxolitinib, the first JAK1/2 inhibitor to become commercially available for the treatment of myelofibrosis and polycythemia vera. Due to interference with the JAK-STAT pathway, JAK inhibitors affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells. Therefore, even though the clinical use of these drugs in MPN patients has led to a dramatic improvement of symptoms control, organ involvement, and quality of life, JAK inhibitors–related loss of function in JAK-STAT signaling pathway can be a cause of different adverse events, including those related to a condition of immune suppression or deficiency. This review article will provide a comprehensive overview of the current knowledge on JAK inhibitors’ effects on immune cells as well as their clinical consequences, particularly with regards to infectious complications.
Collapse
Affiliation(s)
- Daniele Cattaneo
- Hematology Division, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Alessandra Iurlo
- Hematology Division, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| |
Collapse
|
|
14
|
Handley G, Hand J. Adverse Effects of Immunosuppression: Infections. Handb Exp Pharmacol 2021; 272:287-314. [PMID: 34671868 DOI: 10.1007/164_2021_550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Immunosuppressive therapies are currently indicated for a wide range of diseases. As new agents emerge and indications evolve the landscape grows increasingly complex. Therapies can target pathologic immune system over-activation in rheumatologic or autoimmune disease, or conditioning and graft versus host disease (GVHD) prophylactic regimens may eliminate or inhibit host immune function to improve graft survival and risk of complication in solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). With immunosuppressive therapy, infections occur. Complex disease states, host factors, and concomitant therapies contribute to a "net state" of immunosuppression that must be considered and may confound perceived increased infection risks in patients receiving treatment.
Collapse
Affiliation(s)
- Guy Handley
- Division of Infectious Disease and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Jonathan Hand
- Department of Infectious Diseases, Ochsner Health, The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, USA.
| |
Collapse
|
|
15
|
Philadelphia-Negative Chronic Myeloproliferative Neoplasms during the COVID-19 Pandemic: Challenges and Future Scenarios. Cancers (Basel) 2021; 13:cancers13194750. [PMID: 34638236 PMCID: PMC8507529 DOI: 10.3390/cancers13194750] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/09/2021] [Accepted: 09/17/2021] [Indexed: 12/30/2022] Open
Abstract
An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) started in December 2019 in China and then become pandemic in February 2020. Several publications investigated the possible increased rate of COVID-19 infection in hematological malignancies. Based on the published data, strategies for the management of chronic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are provided. The risk of severe COVID-19 seems high in MPN, particularly in patients with essential thrombocythemia, but not negligible in myelofibrosis. MPN patients are at high risk of both thrombotic and hemorrhagic complications and this must be accounted in the case of COVID-19 deciding on a case-by-case basis. There are currently no data to suggest that hydroxyurea or interferon may influence the risk or severity of COVID-19 infection. Conversely, while the immunosuppressive activity of ruxolitinib might pose increased risk of infection, its abrupt discontinuation during COVID-19 syndrome is associated with worse outcome. All MPN patients should receive vaccine against COVID-19; reassuring data are available on efficacy of mRNA vaccines in MPNs.
Collapse
|
|
16
|
Duan MH, Cao XX, Chang L, Zhou DB. Risk of hepatitis B virus reactivation following ruxolitinib treatment in patients with myeloproliferative neoplasms. ACTA ACUST UNITED AC 2021; 26:460-464. [PMID: 34184610 DOI: 10.1080/16078454.2021.1945234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Objectives The aim of this retrospective analysis was to assess the incidence of hepatitis B virus (HBV) reactivation among patients with myeloproliferative neoplasms (MPN) during and after ruxolitinib treatment. Methods Between February 2013 and February 2020, 224 patients with MPN were treated using ruxolitinib at Peking Union Medical College Hospital. Of these, 6 had chronic, and 56 had resolved HBV infection, including 43 patients who received combination treatment with thalidomide, prednisone, and stanozolol (TSP) during ruxolitinib treatment. Results Two patients with chronic HBV infection who did not take any antiviral prophylaxis developed HBV reactivation and hepatitis flare. The other four patients with chronic HBV infection, who took antiviral prophylaxis before ruxolitinib treatment, did not develop HBV reactivation. Also, no patients with resolved HBV infection received antiviral prophylaxis and developed HBV reactivation. Conclusion This study demonstrated that HBV reactivation and hepatitis flare might commonly occur a few months after initiating ruxolitinib treatment in patients with chronic HBV infection who did not take antiviral prophylaxis, especially in combination with TSP. Still, it was extremely rare in patients with resolved HBV infection.
Collapse
Affiliation(s)
- Ming-Hui Duan
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Xin-Xin Cao
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Long Chang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Dao-Bin Zhou
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| |
Collapse
|
|
17
|
Cornberg M, Sandmann L, Protzer U, Niederau C, Tacke F, Berg T, Glebe D, Jilg W, Wedemeyer H, Wirth S, Höner Zu Siederdissen C, Lynen-Jansen P, van Leeuwen P, Petersen J. S3-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zur Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion – (AWMF-Register-Nr. 021-11). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:691-776. [PMID: 34255317 DOI: 10.1055/a-1498-2512] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Markus Cornberg
- Deutsches Zentrum für Infektionsforschung (DZIF), Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover; Centre for individualised infection Medicine (CiiM), Hannover.,Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Lisa Sandmann
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Ulrike Protzer
- Institut für Virologie, Technische Universität München/Helmholtz Zentrum München, München
| | | | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin
| | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig
| | - Dieter Glebe
- Institut für Medizinische Virologie, Nationales Referenzzentrum für Hepatitis-B-Viren und Hepatitis-D-Viren, Justus-Liebig-Universität Gießen, Gießen
| | - Wolfgang Jilg
- Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensberg, Regensburg
| | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Stefan Wirth
- Zentrum für Kinder- und Jugendmedizin, Helios Universitätsklinikum Wuppertal, Wuppertal
| | | | - Petra Lynen-Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Pia van Leeuwen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Jörg Petersen
- IFI Institut für Interdisziplinäre Medizin an der Asklepios Klinik St. Georg, Hamburg
| | | |
Collapse
|
|
18
|
Garcia-Horton A, Smith E, Maze D, McNamara C, Sibai H, Gupta V. Risk of hepatitis B virus reactivation in HBsAg-negative, anti-HBc-positive patients with myeloproliferative neoplasms treated with ruxolitinib. Leuk Lymphoma 2021; 62:495-497. [PMID: 33459565 DOI: 10.1080/10428194.2020.1832671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Alejandro Garcia-Horton
- Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada
| | - Elliot Smith
- Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada
| | - Dawn Maze
- Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada
| | - Caroline McNamara
- Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada
| | - Hassan Sibai
- Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada
| | - Vikas Gupta
- Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada
| |
Collapse
|
|
19
|
Wolff D, Fatobene G, Rocha V, Kröger N, Flowers ME. Steroid-refractory chronic graft-versus-host disease: treatment options and patient management. Bone Marrow Transplant 2021; 56:2079-2087. [PMID: 34218265 PMCID: PMC8410585 DOI: 10.1038/s41409-021-01389-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 06/14/2021] [Accepted: 06/22/2021] [Indexed: 02/05/2023]
Abstract
Chronic graft-versus-host disease (cGVHD) is one of the major causes of late mortality after allogenic hematopoietic stem cell transplantation. Moderate-to-severe cGVHD is associated with poor health-related quality of life and substantial disease burden. While corticosteroids with or without calcineurin inhibitors comprise the first-line treatment option, the prognosis for patients with steroid-refractory cGVHD (SR-cGVHD) remains poor. The mechanisms underlying steroid resistance are unclear, and there are no standard second-line treatment guidelines for patients with SR-cGVHD. In this review, we provide an overview on current treatment options of cGVHD and use a series of theoretical case studies to elucidate the rationale of choices of second- and third-line treatment options for patients with SR-cGVHD based on individual patient profiles.
Collapse
Affiliation(s)
- Daniel Wolff
- grid.411941.80000 0000 9194 7179Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - Giancarlo Fatobene
- grid.411074.70000 0001 2297 2036Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil ,Vila Nova Star Hospital and IDOR, Rede D’Or, São Paulo, Brazil
| | - Vanderson Rocha
- grid.411074.70000 0001 2297 2036Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil ,Vila Nova Star Hospital and IDOR, Rede D’Or, São Paulo, Brazil
| | - Nicolaus Kröger
- grid.13648.380000 0001 2180 3484Department of Stem Cell Transplantation, University Medical Center Hamburg, Hamburg, Germany
| | - Mary E. Flowers
- grid.34477.330000000122986657Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, Seattle, WA USA
| |
Collapse
|
|
20
|
Coltro G, Vannucchi AM. The safety of JAK kinase inhibitors for the treatment of myelofibrosis. Expert Opin Drug Saf 2020; 20:139-154. [PMID: 33327810 DOI: 10.1080/14740338.2021.1865912] [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] [Indexed: 12/15/2022]
Abstract
INTRODUCTION During the last decade, the development of small molecule inhibitors of Janus kinases (JAKi) contributed to revolutionize the therapeutic landscape of myelofibrosis (MF). JAKi proved to be effective in controlling disease-related symptoms and splenomegaly with remarkable inter-drug variability. However, in some cases the border between clinical efficacy of JAKi and dose-dependent toxicities is narrow leading to sub-optimal dose modifications and/or treatment discontinuation. AREAS COVERED In the current review, the authors aimed at providing a comprehensive review of the safety profile of JAKi that are currently approved or in advanced clinical development. Also, a short discussion of promising JAKi in early clinical evaluation and molecules 'lost' early in clinical development is provided. Finally, we discuss the possible strategies aimed at strengthening the safety of JAKi while improving the therapeutic efficacy. EXPERT OPINION Overall, JAKi display a satisfactory risk-benefit ratio, with main toxicities being gastrointestinal or related to the myelo/immunosuppressive effects, generally mild and easily manageable. However, JAKi may be associated with potentially life-threatening toxicities, such as neurological and infectious events. Thus, many efforts are needed in order to optimize JAKi-based therapeutic strategies without burdening patient safety. This could be attempted through drug combinations or the development of more selective molecules.
Collapse
Affiliation(s)
- Giacomo Coltro
- Department of Clinical and Experimental Medicine, University of Florence , Florence, Italy.,CRIMM, Center of Research and Innovation for Myeloproliferative Neoplasms, AOU Careggi , Florence, Italy
| | - Alessandro M Vannucchi
- Department of Clinical and Experimental Medicine, University of Florence , Florence, Italy.,CRIMM, Center of Research and Innovation for Myeloproliferative Neoplasms, AOU Careggi , Florence, Italy
| |
Collapse
|
|
21
|
Sadjadian P, Wille K, Griesshammer M. Ruxolitinib-Associated Infections in Polycythemia Vera: Review of the Literature, Clinical Significance, and Recommendations. Cancers (Basel) 2020; 12:cancers12113132. [PMID: 33114733 PMCID: PMC7693745 DOI: 10.3390/cancers12113132] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 10/21/2020] [Accepted: 10/21/2020] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Polycythemia vera (PV) is a chronic blood disease characterized by elevated red blood cells and splenomegaly. About 98% of all PV patients harbor the JAK2 mutation. Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, received approval as a second-line indication in PV patients who are resistant or intolerant to standard therapy hydroxyurea in both the United States (2014) and Europe (2015). In the studies relevant to approval, RUX achieved excellent PV control. Due to its mechanism of action, RUX also has immunosuppressive effects. As expected, an increased rate of infection was observed in clinical studies and in practical application. In this overview, we have compiled all previous literature references on RUX and infections in PV. However, apart from a few individual cases with special infections and an increased rate of zoster infections, there are no exceptional high infection problems. Recommendations are given on how infections in RUX treated PV patients can be avoided. Abstract Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, is approved for second-line therapy in patients with polycythemia vera (PV) who are resistant or intolerant to hydroxyurea. Due to the immunomodulatory and immunosuppressive effect of RUX, there is an increased susceptibility to infections. However, an increased risk of infection is inherent to even untreated myeloproliferative neoplasms (MPN). To obtain more information on the clinical significance of RUX-associated infections in PV, we reviewed the available literature. There is no evidence-based approach to managing infection risks. Most data on RUX-associated infections are available for MF. In all studies, the infection rates in the RUX and control groups were fairly similar, with the exception of infections with the varicella zoster virus (VZV). However, individual cases of bilateral toxoplasmosis retinitis, disseminated molluscum contagiosum, or a mycobacterium tuberculosis infection or a hepatitis B reactivation are reported. A careful assessment of the risk of infection for PV patients is required at the initial presentation and before the start of RUX. Screening for hepatitis B is recommended in all patients. The risk of RUX-associated infections is lower with PV than with MF, but compared to a normal population there is an increased risk of VZV infection. However, primary VZV prophylaxis for PV patients is not recommended, while secondary prophylaxis can be considered individually. As early treatment is most effective for VZV, patients should be properly informed and trained to seek medical advice immediately if cutaneous signs of VZV develop. Vaccination against influenza, herpes zoster, and pneumococci should be considered in all PV patients at risk of infection, especially if RUX treatment is planned. Current recommendations do not support adjusting or discontinuing JAK inhibition in MPN patients to reduce the risk of COVID-19.
Collapse
|
|
22
|
Ibrahim U, Petrone GEM, Mascarenhas J, Keyzner A. Peritransplantation Use of Ruxolitinib in Myelofibrosis. Biol Blood Marrow Transplant 2020; 26:2177-2180. [PMID: 32818555 DOI: 10.1016/j.bbmt.2020.08.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/11/2020] [Accepted: 08/11/2020] [Indexed: 11/25/2022]
Abstract
Ruxolitinib is an oral JAK1/2 inhibitor that is approved for use in patients with intermediate and high-risk myelofibrosis (MF) based on its proven spleen and symptom burden reduction. Its impact on hematopoietic stem cell transplantation (HSCT) outcomes is largely unknown, however. A significant number of patients proceeding to HSCT have been treated with ruxolitinib, and the specifics of its peritransplantation use vary widely in the published literature. Here we review the currently published data and experience to guide management of patients with MF on ruxolitinib proceeding to HSCT.
Collapse
Affiliation(s)
- Uroosa Ibrahim
- Tisch Cancer Institute, Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Giulia Eva Maria Petrone
- Tisch Cancer Institute, Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - John Mascarenhas
- Tisch Cancer Institute, Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alla Keyzner
- Tisch Cancer Institute, Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
| |
Collapse
|
|
23
|
Masarova L, Bose P, Verstovsek S. The Rationale for Immunotherapy in Myeloproliferative Neoplasms. Curr Hematol Malig Rep 2020; 14:310-327. [PMID: 31228096 DOI: 10.1007/s11899-019-00527-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW The classic, chronic Philadelphia chromosome negative myeloproliferative neoplasms (MPN)-essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)-are clonal malignancies of hematopoietic stem cells and are associated with myeloproliferation, organomegaly, and constitutional symptoms. Expanding knowledge that chronic inflammation and a dysregulated immune system are central to the pathogenesis and progression of MPNs serves as a driving force for the development of agents affecting the immune system as therapy for MPN. This review describes the rationale and potential impact of anti-inflammatory, immunomodulatory, and targeted agents in MPNs. RECENT FINDINGS The advances in molecular insights, especially the discovery of the Janus kinase 2 (JAK2) V617F mutation and its role in JAK-STAT pathway dysregulation, led to the development of the JAK inhibitor ruxolitinib, which currently represents the cornerstone of medical therapy in MF and hydroxyurea-resistant/intolerant PV. However, there remain significant unmet needs in the treatment of these patients, and many agents continue to be investigated. Novel, more selective JAK inhibitors might offer reduced myelosuppression or even improvement of blood counts. The recent approval of a novel, long-acting interferon for PV patients in Europe, might eventually lead to its broader clinical use in all MPNs. Targeted immunotherapy involving monoclonal antibodies, checkpoint inhibitors, or therapeutic vaccines against selected MPN epitopes could further enhance tumor-specific immune responses. Immunotherapeutic approaches are expanding and hopefully will extend the therapeutic armamentarium in patients with myeloproliferative neoplasms.
Collapse
Affiliation(s)
- Lucia Masarova
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0428, Houston, TX, 77030, USA.
| | - Prithviraj Bose
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0428, Houston, TX, 77030, USA
| | - Srdan Verstovsek
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0428, Houston, TX, 77030, USA
| |
Collapse
|
|
24
|
La Rosée F, Bremer HC, Gehrke I, Kehr A, Hochhaus A, Birndt S, Fellhauer M, Henkes M, Kumle B, Russo SG, La Rosée P. The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia 2020; 34:1805-1815. [PMID: 32518419 PMCID: PMC7282206 DOI: 10.1038/s41375-020-0891-0] [Citation(s) in RCA: 168] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/14/2020] [Accepted: 05/22/2020] [Indexed: 12/11/2022]
Abstract
A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).
Collapse
Affiliation(s)
- F La Rosée
- Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - H C Bremer
- Lungenzentrum Donaueschingen, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - I Gehrke
- Klinik für Innere Medizin IV, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - A Kehr
- Klinik für Innere Medizin IV, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - A Hochhaus
- Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
| | - S Birndt
- Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
| | - M Fellhauer
- Apotheke/Institut für Klinische Pharmazie, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - M Henkes
- Klinik für Innere Medizin II, Hämatologie, Onkologie, Immunologie, Infektiologie und Palliativmedizin, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - B Kumle
- Klinik für Akut- und Notfallmedizin, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - S G Russo
- Klinik für Anästhesiologie, Intensiv-, Notfall- und Schmerzmedizin, Villingen-Schwenningen, Germany
- Medizinische Fakultät, Universität Göttingen, Göttingen, and Fakultät für Gesundheit, Universität Witten/Herdecke, Witten, Germany
| | - P La Rosée
- Klinik für Innere Medizin II, Hämatologie, Onkologie, Immunologie, Infektiologie und Palliativmedizin, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany.
- Medizinische Fakultät der Friedrich-Schiller-Universität Jena, Universitätsklinikum Jena, Jena, Germany.
| |
Collapse
|
|
25
|
Abstract
Myeloproliferative diseases, including myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS), are driven by genetic abnormalities and increased inflammatory signaling and are at high risk to transform into acute myeloid leukemia (AML). Myeloid-derived suppressor cells were reported to enhance leukemia immune escape by suppressing an effective anti-tumor immune response. MPNs are a potentially immunogenic disease as shown by their response to interferon-α treatment and allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Novel immunotherapeutic approaches such as immune checkpoint inhibition, tumor vaccination, or cellular therapies using target-specific lymphocytes have so far not shown strong therapeutic efficacy. Potential reasons could be the pro-inflammatory and immunosuppressive microenvironment in the bone marrow of patients with MPN, driving tumor immune escape. In this review, we discuss the biology of MPNs with respect to the pro-inflammatory milieu in the bone marrow (BM) and potential immunotherapeutic approaches.
Collapse
|
|
26
|
Rumi E, Sant'Antonio E, Cavalloni C, Comolli G, Ferretti VV, Cassaniti I, Pietra D, Trotti C, Ciboddo M, Furione M, Vanni D, Casetti IC, Favaron C, Baldanti F, Arcaini L, Cazzola M. Impaired virus-specific T cell responses in patients with myeloproliferative neoplasms treated with ruxolitinib. Hematol Oncol 2020; 38:554-559. [PMID: 32583904 DOI: 10.1002/hon.2769] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/21/2020] [Accepted: 06/22/2020] [Indexed: 01/14/2023]
Abstract
Ruxolitinib is effective in myeloproliferative neoplasms (MPN) but can cause reactivation of silent infections. We aimed at evaluating viral load and T-cell responses to human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) in a cohort of 25 MPN patients treated with ruxolitinib. EBV-DNA and HCMV-DNA were quantified monthly using real-time polimerase chain reaction (PCR) on peripheral blood samples, and T-cell subsets were analyzed by flowcytometry. HCMV and EBV-directed T-cell responses were evaluated using the IFN-γ ELISPOT assay. Most patients had CD4+ and/or CD8+ T-cells below the normal range; these reductions were related to the duration of ruxolitinib treatment. In fact, reduced T-lymphocytes' subsets were found in 93% of patients treated for ≥5 years and in 45% of those treated for <5 years (P = .021). The former also had lower median numbers of CD4+ and CD8+ cells. Subclinical reactivation of EBV and HCMV occurred in 76% and 8% of patients. We observed a trend to an inverse relationship between EBV and CMV-specific CD4+ and CD8+ T-cell responses and viral load, and a trend to an inverse correlation with ruxolitinib dose. Therefore, our data suggest that the ruxolitinib treatment may interfere with immunosurveillance against EBV and HCMV.
Collapse
Affiliation(s)
- Elisa Rumi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Chiara Cavalloni
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Giuditta Comolli
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Experimental Research Laboratories, Biotechnology Area, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Irene Cassaniti
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Daniela Pietra
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Chiara Trotti
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Michele Ciboddo
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Milena Furione
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Daniele Vanni
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | | | - Cristina Favaron
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Fausto Baldanti
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Luca Arcaini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Mario Cazzola
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| |
Collapse
|
|
27
|
Abstract
Ruxolitinib is a Janus kinase (JAK) inhibitor that is FDA-approved for the treatment of myelofibrosis, polycythemia vera, and acute graft-versus-host disease. Its use in treating various dermatologic diseases has been a topic of growing interest due to its favorable safety profile and targeted inhibition of several cytokines that perpetuate inflammatory skin conditions. The PubMed/MEDLINE and ClinicalTrials.gov databases were searched for literature on off-label uses of ruxolitinib in dermatology and ongoing trials studying its safety and efficacy. There is randomized controlled trial (RCT) evidence for the successful use of ruxolitinib in treating alopecia, atopic dermatitis, and psoriasis, with ongoing RCTs for its use in vitiligo. Smaller studies have confirmed the success of ruxolitinib in treating conditions such as dermatomyositis and hypereosinophilic syndrome, among others. No serious adverse effects were reported with the use of ruxolitinib in dermatology, but further research is needed to determine its efficacy, delivery route, and optimal dosing for treating dermatologic conditions.
Collapse
Affiliation(s)
- Jessica Wu
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Jan Smogorzewski
- Division of Dermatology, Harbor-UCLA Medical Center, Torrance, CA, USA
| |
Collapse
|
|
28
|
Could ruxolitinib be effective in patients with COVID-19 infection at risk of acute respiratory distress syndrome (ARDS)? Ann Hematol 2020; 99:1675-1676. [PMID: 32405693 PMCID: PMC7220809 DOI: 10.1007/s00277-020-04067-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 04/27/2020] [Indexed: 01/27/2023]
|
|
29
|
Galimberti S, Baldini C, Baratè C, Ricci F, Balducci S, Grassi S, Ferro F, Buda G, Benedetti E, Fazzi R, Baglietto L, Lucenteforte E, Di Paolo A, Petrini M. The CoV-2 outbreak: how hematologists could help to fight Covid-19. Pharmacol Res 2020; 157:104866. [PMID: 32387301 PMCID: PMC7202852 DOI: 10.1016/j.phrs.2020.104866] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 04/24/2020] [Accepted: 04/26/2020] [Indexed: 02/08/2023]
Abstract
COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for COVID-19 is here proposed.
Collapse
Affiliation(s)
- Sara Galimberti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Chiara Baldini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Federica Ricci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Serena Balducci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Susanna Grassi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Ferro
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gabriele Buda
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | | | - Laura Baglietto
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Ersilia Lucenteforte
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Antonello Di Paolo
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Mario Petrini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| |
Collapse
|
|
30
|
Iurlo A, Cattaneo D, Bucelli C. Management of Myelofibrosis: from Diagnosis to New Target Therapies. Curr Treat Options Oncol 2020; 21:46. [DOI: 10.1007/s11864-020-00734-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
|
|
31
|
Sakiyama E, Chinen Y, Tsukamoto T, Takimoto-Shimomura T, Kuwahara-Ota S, Matsumura-Kimoto Y, Shimura Y, Kobayashi T, Horiike S, Kuroda J. Tuberculosis Peritonitis During Treatment of Polycythemia Vera with Ruxolitinib. Infect Drug Resist 2020; 13:1017-1021. [PMID: 32308443 PMCID: PMC7152536 DOI: 10.2147/idr.s249030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 03/31/2020] [Indexed: 01/11/2023] Open
Abstract
Ruxolitinib is a selective JAK1/2 inhibitor that is widely used for the treatment of myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera (PV). Despite its clinical efficacy for MPNs, ruxolitinib possesses immunosuppressive properties that potentially increase the risks for opportunistic infection, such as mycobacterium tuberculosis (MTB) infection, and reactivation of occult viral infection. Herein, we report the case of a 76-year-old male with PV who developed tuberculosis peritonitis under ruxolitinib therapy for 28 weeks. While previous studies and case reports have suggested an increased risk of MTB infection of various organs during ruxolitinib treatment of MPNs, this case is apparently the first of tuberculosis peritonitis in a patient with MPN treated with ruxolitinib. A review of previous case reports suggests the need for careful observation for MTB from the relatively early phase of ruxolitinib treatment, given that the median duration from the start of ruxolitinib treatment to the emergence of MTB was 20 weeks (range: 3-88 weeks). Clinicians should consider tuberculosis peritonitis as a differential diagnosis when patients with MPN treated with ruxolitinib develop infectious abdominal symptoms.
Collapse
Affiliation(s)
- Emiko Sakiyama
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshiaki Chinen
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Taku Tsukamoto
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoko Takimoto-Shimomura
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Saeko Kuwahara-Ota
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yayoi Matsumura-Kimoto
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuji Shimura
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tsutomu Kobayashi
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shigeo Horiike
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Junya Kuroda
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| |
Collapse
|
|
32
|
|
|
33
|
Khalid F, Damlaj M, AlZahrani M, Abuelgasim KA, Gmati GE. Reactivation of tuberculosis following ruxolitinib therapy for primary myelofibrosis: Case series and literature review. Hematol Oncol Stem Cell Ther 2020; 14:252-256. [PMID: 32201152 DOI: 10.1016/j.hemonc.2020.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 11/24/2019] [Accepted: 02/21/2020] [Indexed: 10/24/2022] Open
Abstract
Primary myelofibrosis (PMF) is a subtype of BCR-ABL1 negative myeloproliferative neoplasm. Its characteristic features include clonal myeloproliferation, dysregulation of kinase signaling pathway, abnormal release of cytokines leading to fibrosis in the bone marrow, osteosclerosis, and extramedullary hematopoiesis. Approximately 20% of deaths occur because of disease progression, but death may also result occur because of cardiovascular complications or as a consequence of either infection or bleeding. The only and curative option for PMF is allogeneic hematopoietic stem cell transplant (allo-HSCT); however, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is highly effective in reducing constitutional symptoms and spleen volume, and has been found to improve survival. Ruxolitinib decreases the activity of type I T-helper cells, leading to decreased release of cytokines including tumor necrosis factor-α, interleukin-1 (IL-1), IL-6, interferon-γ, and production of IL-12, which can be a risk factor for opportunistic infections. In this report, we describe three cases of tuberculosis reactivation shortly after initiation of ruxolitinib therapy followed by a literature review.
Collapse
Affiliation(s)
- Farhan Khalid
- Division of Hematology and HSCT, Department of Oncology, King Abdul Aziz Medical City, Riyadh, Saudi Arabia
| | - Moussab Damlaj
- Division of Hematology and HSCT, Department of Oncology, King Abdul Aziz Medical City, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Mohsen AlZahrani
- Division of Hematology and HSCT, Department of Oncology, King Abdul Aziz Medical City, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Khadega A Abuelgasim
- Division of Hematology and HSCT, Department of Oncology, King Abdul Aziz Medical City, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Giamal Edin Gmati
- Division of Hematology and HSCT, Department of Oncology, King Abdul Aziz Medical City, Riyadh, Saudi Arabia; King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
| |
Collapse
|
|
34
|
Prem S, Loach D, Lipton J, Kumar R, Gupta V. EBV reactivation mimicking a lymphoproliferative disorder associated with ruxolitinib therapy for myelofibrosis. Blood Res 2019; 54:282-284. [PMID: 31915655 PMCID: PMC6942146 DOI: 10.5045/br.2019.54.4.282] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 01/22/2019] [Accepted: 08/13/2019] [Indexed: 12/20/2022] Open
Affiliation(s)
- Shruti Prem
- Division of Allo-BMT, Princess Margaret Centre, Toronto, ON, Canada
| | - David Loach
- Division of Allo-BMT, Princess Margaret Centre, Toronto, ON, Canada
| | - Jeffrey Lipton
- Division of Allo-BMT, Princess Margaret Centre, Toronto, ON, Canada
| | - Rajat Kumar
- Division of Allo-BMT, Princess Margaret Centre, Toronto, ON, Canada
| | - Vikas Gupta
- Division of Leukemia, Princess Margaret Centre, Toronto, ON, Canada
| |
Collapse
|
|
35
|
Elli EM, Baratè C, Mendicino F, Palandri F, Palumbo GA. Mechanisms Underlying the Anti-inflammatory and Immunosuppressive Activity of Ruxolitinib. Front Oncol 2019; 9:1186. [PMID: 31788449 PMCID: PMC6854013 DOI: 10.3389/fonc.2019.01186] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 10/21/2019] [Indexed: 12/20/2022] Open
Abstract
The JAK-STAT signaling pathway plays a central role in signal transduction in hematopoietic cells, as well as in cells of the immune system. The occurrence in most patients affected by myeloproliferative neoplasms (MPNs) of driver mutations resulting in the constitutive activation of JAK2-dependent signaling identified the deregulated JAK-STAT signal transduction pathway as the major pathogenic mechanism of MPNs. It also prompted the development of targeted drugs for MPNs. Ruxolitinib is a potent and selective oral inhibitor of both JAK2 and JAK1 protein kinases. Its use in patients with myelofibrosis is associated with a substantial reduction in spleen volume, attenuation of symptoms and decreased mortality. With growing clinical experience, concerns about infectious complications, and increased risk of B-cell lymphoma, presumably caused by the effects of JAK1/2 inhibition on immune response and immunosurveillance, have been raised. Evidence shows that ruxolitinib exerts potent anti-inflammatory and immunosuppressive effects. Cellular targets of ruxolitinib include various components of both the innate and adaptive immune system, such as natural killer cells, dendritic cells, T helper, and regulatory T cells. On the other hand, immunomodulatory properties have proven beneficial in some instances, as highlighted by the successful use of ruxolitinib in corticosteroid-resistant graft vs. host disease. The objective of this article is to provide an overview of published evidence addressing the key question of the mechanisms underlying ruxolitinib-induced immunosuppression.
Collapse
Affiliation(s)
- Elena Maria Elli
- Hematology Division and Bone Marrow Transplant Unit, Ospedale San Gerardo, ASST Monza, Monza, Italy
| | - Claudia Baratè
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Francesco Mendicino
- Hematology Unit, Department of Hemato-Oncology, Ospedale Annunziata, Cosenza, Italy
| | - Francesca Palandri
- Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy
| | - Giuseppe Alberto Palumbo
- Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia", University of Catania, Catania, Italy
| |
Collapse
|
|
36
|
Sant'Antonio E, Bonifacio M, Breccia M, Rumi E. A journey through infectious risk associated with ruxolitinib. Br J Haematol 2019; 187:286-295. [PMID: 31468506 DOI: 10.1111/bjh.16174] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ruxolitinib has proved to be effective for the treatment of patients with myelofibrosis (either primary or secondary) and polycythaemia vera, and its approval led to a significant change in the current treatment algorithm. Despite its efficacy and beyond its well described haematological toxicity, a peculiar immunosuppressive effect emerged as our clinical experience grew, both within and outside of a clinical trial setting. Definite and negative interactions with multiple pathways of the immune system of patients have been reported so far, involving both adaptive and innate immune responses. These pathophysiological mechanisms may contribute to the increased risk of reactivation of silent infections (e.g., tuberculosis, hepatitis B virus and varicella zoster virus) that have been associated with the drug. Even though such infectious events may be fatal or may lead to significant impairment of organ function, compromising the eligibility of patients for an allotransplant procedure, there are no dedicated guidelines that may help us in assessing and managing the risk of developing serious infections. On this basis, our aim for the present work was to review the current knowledge on the pathophysiological mechanisms through which ruxolitinib may exert its immunosuppressive effect, and to illustrate our personal approach to the management of three peculiar clinical scenarios, for which a risk-based algorithm is suggested.
Collapse
Affiliation(s)
- Emanuela Sant'Antonio
- Department of Oncology, Division of Haematology, Azienda USL Toscana Nord Ovest, Lucca, Italy
| | | | - Massimo Breccia
- Division of Cellular Biotechnologies and Haematology, University Sapienza, Roma, Italy
| | - Elisa Rumi
- Department of Haematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| |
Collapse
|
|
37
|
Sasadeusz J, Grigg A, Hughes PD, Lee Lim S, Lucas M, McColl G, McLachlan SA, Peters MG, Shackel N, Slavin M, Sundararajan V, Thompson A, Doyle J, Rickard J, De Cruz P, Gish RG, Visvanathan K. Screening and Prophylaxis to Prevent Hepatitis B Reactivation: Other Populations and Newer Agents. Clin Liver Dis 2019; 23:521-534. [PMID: 31266625 DOI: 10.1016/j.cld.2019.04.012] [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: 02/07/2023]
Abstract
Because of the relatively high prevalence of both hepatitis B infection and various forms of autoimmune inflammatory diseases treated with aggressive immunotherapy, reactivation of hepatitis B occurs in a substantial number of patients. The risk of reactivation depends on the degree and duration of immunosuppression. A large number of drug treatments have resulted in reactivation of hepatitis B virus infection and, based on the mechanisms and extent of immunosuppression, recommendations for some of the newer classes of immunosuppressive drugs are provided.
Collapse
Affiliation(s)
- Joe Sasadeusz
- Peter Doherty Institute for Infection and Immunity, Elizabeth Street, Melbourne, Victoria 3000, Australia; University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia.
| | - Andrew Grigg
- Olivia Newton John Cancer Research Institute, Austin Hospital, 145 Studley Road, Heidelberg, Victoria 3084, Australia
| | - Peter D Hughes
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia
| | - Seng Lee Lim
- National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore
| | - Michaela Lucas
- University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia
| | - Geoff McColl
- University of Queensland Oral Health Centre, 288 Herston Road, Queensland 4006, Australia
| | - Sue Anne McLachlan
- St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia
| | - Marion G Peters
- University of California, San Francisco, S357 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Nicholas Shackel
- Ingham Institute, 1 Campbell Street, Liverpool, Sydney, North South Wales 2170, Australia
| | - Monica Slavin
- Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia; Victorian Comprehensive Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia
| | - Vijaya Sundararajan
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia; Department of Public Health, La Trobe University, Plenty Road, Bundoora, Victoria 3086, Australia
| | - Alexander Thompson
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia
| | - Joseph Doyle
- The Alfred and Monash University, 85 Commercial Road, Melbourne, Victoria 3004, Australia; Burnet Institute, 85 Commercial Road, Melbourne, Victoria 3004, Australia
| | - James Rickard
- Olivia Newton John Cancer Research Institute, Austin Hospital, 145 Studley Road, Heidelberg, Victoria 3084, Australia
| | - Peter De Cruz
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia
| | - Robert G Gish
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Kumar Visvanathan
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia
| |
Collapse
|
|
38
|
Zarakas MA, Desai JV, Chamilos G, Lionakis MS. Fungal Infections with Ibrutinib and Other Small-Molecule Kinase Inhibitors. CURRENT FUNGAL INFECTION REPORTS 2019; 13:86-98. [PMID: 31555394 DOI: 10.1007/s12281-019-00343-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Purpose of review Small molecule kinase inhibitors (SMKIs) have revolutionized the management of malignant and autoimmune disorders. Emerging clinical reports point toward an increased risk for invasive fungal infections (IFIs) in patients treated with certain SMKIs. In this mini-review, we highlight representative examples of SMKIs that have been associated with or are expected to give rise to IFIs. Recent findings The clinical use of the Bruton's tyrosine kinase inhibitor ibrutinib as well as other FDA-approved SMKIs has been associated with IFIs. The fungal infection susceptibility associated with the clinical use of certain SMKIs underscores their detrimental effects on innate and adaptive antifungal immune responses. Summary The unprecedented development and clinical use of SMKIs is expected to give rise to an expansion of iatrogenic immunosuppressive factors predisposing to IFIs (and other opportunistic infections). Beyond increased clinical surveillance, better understanding of the pathogenesis of SMKI-associated immune dysregulation should help devising improved risk stratification and prophylaxis strategies in vulnerable patients.
Collapse
Affiliation(s)
- Marissa A Zarakas
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jigar V Desai
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Georgios Chamilos
- Department of Clinical Microbiology and Microbial Pathogenesis, School of Medicine, University of Crete, Greece, and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300, Heraklion, Crete, Greece
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
39
|
Maschmeyer G, De Greef J, Mellinghoff SC, Nosari A, Thiebaut-Bertrand A, Bergeron A, Franquet T, Blijlevens NMA, Maertens JA. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia (ECIL). Leukemia 2019; 33:844-862. [PMID: 30700842 PMCID: PMC6484704 DOI: 10.1038/s41375-019-0388-x] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/31/2018] [Accepted: 01/11/2019] [Indexed: 02/08/2023]
Abstract
A multitude of new agents for the treatment of hematologic malignancies has been introduced over the past decade. Hematologists, infectious disease specialists, stem cell transplant experts, pulmonologists and radiologists have met within the framework of the European Conference on Infections in Leukemia (ECIL) to provide a critical state-of-the-art on infectious complications associated with immunotherapeutic and molecular targeted agents used in clinical routine. For brentuximab vedotin, blinatumomab, CTLA4- and PD-1/PD-L1-inhibitors as well as for ibrutinib, idelalisib, HDAC inhibitors, mTOR inhibitors, ruxolitinib, and venetoclax, a detailed review of data available until August 2018 has been conducted, and specific recommendations for prophylaxis, diagnostic and differential diagnostic procedures as well as for clinical management have been developed.
Collapse
Affiliation(s)
- Georg Maschmeyer
- Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Charlottenstrasse 72, 14467, Potsdam, Germany.
| | - Julien De Greef
- Department of Internal Medicine and Infectious Diseases, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
- Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Hematology, Henri Mondor Teaching Hospital, Créteil, France
| | - Sibylle C Mellinghoff
- Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Annamaria Nosari
- Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | | | - Anne Bergeron
- Department of Pneumology, Université Paris Diderot, APHP Saint-Louis Hospital, Paris, France
| | - Tomas Franquet
- Department of Radiology, Hospital de Sant Pau, Barcelona, Spain
| | | | - Johan A Maertens
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
- Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium
| |
Collapse
|
|
40
|
March-Rodriguez Á, Bellosillo B, Álvarez-Larrán A, Besses C, Pujol RM, Toll A. Rapidly Growing and Aggressive Cutaneous Squamous Cell Carcinomas in a Patient Treated with Ruxolitinib. Ann Dermatol 2019; 31:204-208. [PMID: 33911570 PMCID: PMC7992689 DOI: 10.5021/ad.2019.31.2.204] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 03/02/2018] [Accepted: 03/07/2018] [Indexed: 12/28/2022] Open
Abstract
Ruxolitinib is a Janus kinase (JAK)1 and JAK2 inhibitor approved for the treatment of myelofibrosis and for polycythemia patients who are resistant or intolerant to hydroxyurea. We report a 72 year-old man patient with polycythemia vera who developed multiple cutaneous squamous cell carcinomas (cSCCs) with keratoacanthoma-like histological features while on treatment with ruxolitinib. Similar lesions have been reported in an isolated patient who also received ruxolitinib. Our case confirms that ruxolitinib may induce eruptive cSCCs with characteristic clinical and histological features that differentiate them from conventional non-drug induced lesions. Moreover, we performed a mutational panel analysis of the tumors. The lack of specific mutations in these tumors suggests an impairment of immunosurveillance in the origin of the cutaneous lesions. Frequent and thorough dermatological examinations in patients receiving ruxolitinib with a history of photodamage, skin cancer and/or previous hydroxyurea intake is thus recommended.
Collapse
Affiliation(s)
| | - Beatriz Bellosillo
- Department of Pathology, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | | | - Carles Besses
- Department of Hematology, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Ramon M Pujol
- Department of Dermatology, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Agustí Toll
- Department of Dermatology, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| |
Collapse
|
|
41
|
Wang B, Mufti G, Agarwal K. Reactivation of hepatitis B virus infection in patients with hematologic disorders. Haematologica 2019; 104:435-443. [PMID: 30733266 PMCID: PMC6395346 DOI: 10.3324/haematol.2018.210252] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 01/18/2019] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B reactivation is the reappearance or rise of hepatitis B virus (HBV) DNA in patients with past or chronic HBV infection, usually occurring in the context of immunosuppression. HBV reactivation has been most commonly reported in patients with hematologic disorders, with potentially serious and life-threatening consequences. In this review, we discuss the basis and presentation of HBV reactivation, and risk factors in terms of the host, the virus and the immunosuppression regimen, including newer agents used to manage hematologic malignancies. We overview the management of HBV reactivation, highlighting an up-dated recommendation on the use of newer nucleoside and nucleotide analogs, such as tenofovir and entecavir, for antiviral prophylaxis.
Collapse
Affiliation(s)
| | - Ghulam Mufti
- Department of Hematology, King's College Hospital, London, UK
| | | |
Collapse
|
|
42
|
Zitti B, Bryceson YT. Natural killer cells in inflammation and autoimmunity. Cytokine Growth Factor Rev 2018; 42:37-46. [PMID: 30122459 DOI: 10.1016/j.cytogfr.2018.08.001] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/09/2018] [Indexed: 12/31/2022]
Abstract
First described 40 years ago, natural killer (NK) cells represent the founding members of the innate lymphoid cell (ILC) family. They were initially defined by their ability to kill cancer cells of hematopoietic origin. More recently, NK cells are recognized not only for their ability to kill infected or malignant cells, but also for mediating cytotoxicity against a range of normal immune cells. They thereby play an important physiological role in controlling immune responses and maintaining homeostasis. Besides cytotoxic activity, NK cells activation is accompanied by secretion of pro-inflammatory cytokines. Hence, NK cells have the potential to act both in driving inflammation and in restricting adaptive immune responses that may otherwise lead to excessive inflammation or even autoimmunity. Here, we highlight how NK cell activity is linked to inflammasome activation and review new molecular insights to the roles of NK cells in inflammation and autoimmunity. Furthermore, in light of new insights to NK cell differentiation and memory, we deliberate on how distinct NK cell subsets may impact immunoregulatory functions. Hypothetically, memory-like or adaptive NK cells could drive NK cell-mediated autoreactive diseases. Together, new findings underscore the complex yet important physiological roles of NK cells in both promoting inflammation and exerting immunoregulation and maintenance of immune homeostasis. Insights raise intriguing questions as to how NK cells themselves maintain self-tolerance.
Collapse
Affiliation(s)
- Beatrice Zitti
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Yenan T Bryceson
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
| |
Collapse
|
|
43
|
Krauth MT, Burgstaller S, Buxhofer-Ausch V, Gastl G, Geissler K, Keil F, Krippl P, Melchardt T, Petzer A, Rumpold H, Sliwa T, Wöhrer S, Wölfler A, Gisslinger H. Ruxolitinib therapy for myelofibrosis in Austria : Consensus on therapy management. Wien Klin Wochenschr 2018; 130:495-504. [PMID: 30043249 PMCID: PMC6132876 DOI: 10.1007/s00508-018-1365-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 07/04/2018] [Indexed: 12/19/2022]
Abstract
The oral Janus associated kinase (JAK1/2) inhibitor ruxolitinib has been available for treatment of patients with intermediate or high-risk myelofibrosis in Europe since 2012. Since its introduction, the expertise of prescribing doctors with respect to ruxolitinib function, efficacy and adverse effects has consistently been augmented, resulting in therapy modalities that are better tailored to individual patients as well as in increased safety of the treatment. The present consensus on ruxolitinib therapy management has been elaborated by Austrian experts in myeloproliferative neoplasms in line with international treatment guidelines. Our recommendations aim to contribute to an improved management of patients with myelofibrosis treated with ruxolitinib.
Collapse
Affiliation(s)
- Maria-Theresa Krauth
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University Vienna, Vienna, Austria.
| | - Sonja Burgstaller
- Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Veronika Buxhofer-Ausch
- Department of Internal Medicine I, Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz-Elisabethinen, Linz, Austria
| | - Günther Gastl
- Department of Internal Medicine V, Division Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria
| | - Klaus Geissler
- Fifth Medical Department, Hospital Hietzing, Vienna, Austria
| | - Felix Keil
- Third Medical Department, Hanusch Hospital, Vienna, Austria
| | - Peter Krippl
- Department of Internal Medicine, LKH Fürstenfeld, Krankenhausverbund Feldbach, Fürstenfeld, Austria
| | - Thomas Melchardt
- Third Medical Department, Division Hematology and Medical Oncology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Andreas Petzer
- Department of Internal Medicine I, Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz-Elisabethinen, Linz, Austria
| | - Holger Rumpold
- Internal Medicine II, Medical Oncology, Hematology, Gastroenterology and Rheumatology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
| | - Thamer Sliwa
- Third Medical Department, Hanusch Hospital, Vienna, Austria
| | - Stefan Wöhrer
- Permedio Center for Personalized Medicine and Sanatorium Hera Vienna, Vienna, Austria
| | - Albert Wölfler
- Division of Hematology, Medical University of Graz, Graz, Austria
| | - Heinz Gisslinger
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University Vienna, Vienna, Austria
| |
Collapse
|
|
44
|
Risk of viral reactivation in patients with occult hepatitis B virus infection during ruxolitinib treatment. Ann Hematol 2018; 98:215-218. [DOI: 10.1007/s00277-018-3405-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 06/20/2018] [Indexed: 01/30/2023]
|
|
45
|
Ruxolitinib for the Treatment of Essential Thrombocythemia. Hemasphere 2018; 2:e56. [PMID: 31723782 PMCID: PMC6746005 DOI: 10.1097/hs9.0000000000000056] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 05/13/2018] [Accepted: 05/14/2018] [Indexed: 12/21/2022] Open
Abstract
Deregulated Janus Kinase 2 (JAK2) activation is central to the pathogenesis of most myeloproliferative neoplasms (MPNs), of which essential thrombocythemia (ET) is the most common entity. Patients with ET are risk-stratified according to their risk of thrombo-hemorrhagic complications. High-risk patients are offered treatments to reduce their platelet count using cytoreductive therapy. The disease course is often long and therapy intolerance is not infrequent. Ruxolitinib, a Janus Kinase (JAK) 1/JAK2 inhibitor, has demonstrated efficacy in patients with both myelofibrosis (MF) and polycythemia vera and is well tolerated. Side effects include predictable cytopenias and an augmented risk of infections. Ruxolitinib has been investigated in a small group of ET patients who were refractory/intolerant to hydroxycarbamide (HC) and demonstrated improvements in both symptoms and splenomegaly. Of note, a proportion of treated patients (13.2%) also had a significant reduction in platelet counts. However, these results require further validation in comparison with conventional therapy. Recently, a randomized-controlled phase 2 study (MAJIC-ET) assessed the role of Ruxolitinib in patients refractory or intolerant to HC. This study revealed that Ruxolitinib demonstrated some clinical efficacy but was only superior in terms of symptom control. In clinical practice, some individuals with ET do exhaust all potential treatment options and there may well be a role for Ruxolitinib in such patients or those with a significant symptom burden. However, in the wider context the goal of therapy with the use of JAK inhibitor therapy in ET needs to be defined carefully and we explore this within this timely review article.
Collapse
|
|
46
|
How I treat myelofibrosis after failure of JAK inhibitors. Blood 2018; 132:492-500. [PMID: 29866811 DOI: 10.1182/blood-2018-02-785923] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/28/2018] [Indexed: 12/16/2022] Open
Abstract
The introduction of JAK inhibitors, leading to regulatory approval of ruxolitinib, represents a major therapeutic advance in myelofibrosis (MF). Most patients experience reduction in splenomegaly and improved quality of life from symptom improvement. It is a paradox, however, that, despite inhibition of signaling downstream of disease-related driver mutations, JAK inhibitor treatment is not associated with consistent molecular or pathologic responses in MF. Furthermore, there are important limitations to JAK inhibitor therapy including development of dose-limiting cytopenias and/or nonhematological toxicities such as neuropathy or opportunistic infections. Over half of the patients discontinue treatment within 3 years of starting treatment. Although data are sparse, clinical outcome after JAK inhibitor "failure" is likely poor; consequently, it is important to understand patterns of failure to select appropriate salvage treatment(s). An algorithmic approach, particularly one that incorporates cytogenetics/molecular data, is most helpful in selecting stem cell transplant candidates. Treatment of transplant-ineligible patients relies on a problem-based approach that includes use of investigational drugs, or consideration of splenectomy or radiotherapy. Data from early phase ruxolitinib combination studies, despite promising preclinical data, have not shown clear benefit over monotherapy thus far. Development of effective treatment strategies for MF patients failing JAK inhibitors remains a major unmet need.
Collapse
|
|
47
|
Tsukamoto Y, Kiyasu J, Tsuda M, Ikeda M, Shiratsuchi M, Ogawa Y, Yufu Y. Fatal Disseminated Tuberculosis during Treatment with Ruxolitinib Plus Prednisolone in a Patient with Primary Myelofibrosis: A Case Report and Review of the Literature. Intern Med 2018; 57:1297-1300. [PMID: 29279479 PMCID: PMC5980814 DOI: 10.2169/internalmedicine.9165-17] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
A 73-year-old man with primary myelofibrosis (PMF) was being treated with hydroxyurea, which was changed to ruxolitinib treatment because of worsening constitutional symptoms. Although ruxolitinib rapidly induced relief, he developed a high-grade fever. A comprehensive fever work-up found no apparent cause of the fever, except for PMF. Therefore, we increased the dose of ruxolitinib and added prednisolone, which was gradually withdrawn with resolution of the fever. However, the patient subsequently developed disseminated tuberculosis and died eight months after initiation of ruxolitinib. Our case highlights the importance of assessing and monitoring the immune status of patients receiving ruxolitinib.
Collapse
Affiliation(s)
- Yasuhiro Tsukamoto
- Department of Hematology, Iizuka Hospital, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Junichi Kiyasu
- Department of Hematology, Iizuka Hospital, Japan
- Department of Clinical Research Institute, National Kyushu Cancer Center, National Hospital Organization, Japan
| | - Mariko Tsuda
- Department of Hematology, Iizuka Hospital, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | | | - Motoaki Shiratsuchi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yuji Yufu
- Department of Hematology, Iizuka Hospital, Japan
| |
Collapse
|
|
48
|
Polverelli N, Palumbo GA, Binotto G, Abruzzese E, Benevolo G, Bergamaschi M, Tieghi A, Bonifacio M, Breccia M, Catani L, Tiribelli M, D'Adda M, Sgherza N, Isidori A, Cavazzini F, Martino B, Latagliata R, Crugnola M, Heidel F, Bosi C, Ibatici A, Soci F, Penna D, Scaffidi L, Aversa F, Lemoli RM, Vitolo U, Cuneo A, Russo D, Cavo M, Vianelli N, Palandri F. Epidemiology, outcome, and risk factors for infectious complications in myelofibrosis patients receiving ruxolitinib: A multicenter study on 446 patients. Hematol Oncol 2018; 36:561-569. [PMID: 29624703 DOI: 10.1002/hon.2509] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 03/04/2018] [Indexed: 12/16/2022]
Abstract
Infections represent one of the major concerns regarding the utilization of ruxolitinib (RUX) in patients with myelofibrosis. With the aim to investigate epidemiology, outcome and risk factors for infections in RUX-exposed patients, we collected clinical and laboratory data of 446 myelofibrosis patients treated with RUX between June 2011 and November 2016 in 23 European Hematology Centers. After a median RUX exposure of 23.5 months (range, 1-56), 123 patients (28%) experienced 161 infectious events (grades 3-4 32%, fatal 9%), for an incidence rate of 17 cases per 100 pts/y. The rate of infections tended to decrease over time: 14% of patients developed the first infection within 6 months, 5% between 6 and 12 months, 3.7% between 12 and 18 months, 3.4% between 18 and 24 months, and 7.9% thereafter (P < .0001). Respiratory tract infections were more frequently observed (81 events, 50%), and bacteria were the most frequent etiological agents (68.9%). However, also viral (14.9%) and fungal infections (2.5%) were observed. In multivariate analysis, previous infectious event (HR 2.54; 95% CI, 1.51-4.28; P = .0005) and high international prognostic score system category (IPSS) (HR 1.53; 95% CI, 1.07-2.20; P = .021) significantly correlated with higher infectious risk. On the contrary, spleen reduction ≥50% from baseline after 3 months of treatment (P = .02) was associated with better infection-free survival. Taken together, these findings reinforce the concept of disease severity as the most important risk factor for infections, and describe, for the first time, that a positive therapeutic effect in reducing splenomegaly may also reduce subsequent infectious complications.
Collapse
Affiliation(s)
- Nicola Polverelli
- Unit of Blood Diseases and Stem Cells Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Giuseppe A Palumbo
- Division of Hematology, AOU "Policlinico-V. Emanuele", University of Catania, Catania, Italy
| | - Gianni Binotto
- Unit of Hematology and Clinical Immunology, University of Padova, Padova, Italy
| | | | - Giulia Benevolo
- Division of Hematology, Città della Salute e della Scienza Hospital, Turin, Italy
| | - Micaela Bergamaschi
- Clinic of Hematology, Department of Internal Medicine (DiMI), IRCCS AOU San Martino-IST, Genoa, Italy
| | - Alessia Tieghi
- Division of Hematology, Azienda Ospedaliera-IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
| | | | - Massimo Breccia
- Division of Cellular Biotechnologies and Hematology, University Sapienza, Rome, Italy
| | - Lucia Catani
- Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy
| | - Mario Tiribelli
- Division of Hematology and BMT, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
| | - Mariella D'Adda
- Division of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Nicola Sgherza
- Division of Hematology, Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy
| | - Alessandro Isidori
- Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
| | | | - Bruno Martino
- Division of Hematology, Azienda Ospedaliera "Bianchi Melacrino Morelli", Reggio Calabria, Italy
| | - Roberto Latagliata
- Division of Cellular Biotechnologies and Hematology, University Sapienza, Rome, Italy
| | - Monica Crugnola
- Division of Hematology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Florian Heidel
- Internal Medicine II, Hematology and Oncology, Friedrich-Schiller-University Medical Center, Jena, Germany
| | - Costanza Bosi
- Division of Hematology, AUSL di Piacenza, Piacenza, Italy
| | - Adalberto Ibatici
- Division of Hematology and Bone Marrow Transplant, IRCCS San Martino-IST, Genoa, Italy
| | - Francesco Soci
- Division of Hematology, Azienda Ospedaliera-IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
| | - Domenico Penna
- Division of Hematology and BMT, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
| | - Luigi Scaffidi
- Department of Hematology, University of Verona, Verona, Italy
| | - Franco Aversa
- Division of Hematology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Roberto M Lemoli
- Clinic of Hematology, Department of Internal Medicine (DiMI), IRCCS AOU San Martino-IST, Genoa, Italy
| | - Umberto Vitolo
- Division of Hematology, Città della Salute e della Scienza Hospital, Turin, Italy
| | - Antonio Cuneo
- Division of Hematology, University of Ferrara, Ferrara, Italy
| | - Domenico Russo
- Unit of Blood Diseases and Stem Cells Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Michele Cavo
- Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy
| | - Nicola Vianelli
- Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy
| | - Francesca Palandri
- Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy
| |
Collapse
|
|
49
|
Caocci G, Ghiani S, Mocci C, La Nasa G. Combination Therapy with Ruxolitinib and Hydroxyurea for the Treatment of Myeloid-Predominant Leukocytosis in a Patient with Myelofibrosis. Acta Haematol 2018; 139:164-165. [PMID: 29597187 DOI: 10.1159/000487582] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/09/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Giovanni Caocci
- Hematology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Silvia Ghiani
- Hematology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Cristina Mocci
- Surgical Pathology Department, A. Businco Hospital, AOB Cagliari, Cagliari, Italy
| | - Giorgio La Nasa
- Hematology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| |
Collapse
|
|
50
|
Lussana F, Cattaneo M, Rambaldi A, Squizzato A. Ruxolitinib-associated infections: A systematic review and meta-analysis. Am J Hematol 2018; 93:339-347. [PMID: 29150886 DOI: 10.1002/ajh.24976] [Citation(s) in RCA: 166] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 11/13/2017] [Accepted: 11/14/2017] [Indexed: 12/14/2022]
Abstract
Ruxolitinib exerts immunosuppressive activity that may increase the risk of infectious complications. We performed a systematic review of the literature with the aim of estimating the risk of infections in patients treated with ruxolitinib. Studies were identified by electronic search of MEDLINE and EMBASE database. Differences in the incidence of infectious events between ruxolitinib and comparison groups were expressed as odds ratios (ORs) and 95% confidence intervals (95% CI). Five phase III randomized clinical trials (RCTs) (3 phase IIIa with their extended phase and 2 phase IIIb), 6 phase IV studies and 28 case reports were included in this systematic review. Ruxolitinib was associated with a statistically significant increased risk of herpes zoster infection compared to control group in 3 RCTs including patients with polycythemia vera (OR 7.39 [1.33, 41.07]) and in a pooled analysis of the extended phase IIIa RCTs (OR 5.20 [95%CI 1.27, 21.18]). In the larger phase IV post-marketing study, the incidence of the most frequent infections was 8% for herpes zoster, 6.1% for bronchitis and 6% for urinary tract infections. In the published case reports, the most frequent infections were tuberculosis (N = 10), hepatitis B reactivation (N = 5) and pneumocystis jeroveci infection (N = 2). Evidence is not solid enough to accurately estimate the risk of infection in ruxolitinib-treated patients. However, published data clearly suggest that the infection risk may be clinically relevant. Well-designed studies are warranted to evaluate the risk of ruxolitinib-associated infection, in order to identify the most appropriate antimicrobial prophylactic strategy.
Collapse
Affiliation(s)
- Federico Lussana
- Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XIII; Bergamo Italy
| | - Marco Cattaneo
- Medicina III, Ospedale San Paolo, ASST Santi Paolo e Carlo Dipartimento di Scienze della Salute; Università degli Studi di Milano; Milan Italy
| | - Alessandro Rambaldi
- Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XIII; Bergamo Italy
- Department of Oncology and Hematology; Università degli Studi di Milano; Milan Italy
| | - Alessandro Squizzato
- Research Center on Thromboembolic Disorders and Antithrombotic Therapies, Department of Clinical and Experimental Medicine; University of Insubria; Varese Italy
| |
Collapse
|