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Liu T, Fillbrunn M, Zhang S, Chen J, Li W, Platt J, Niehoff N, Sajeev G, Signorovitch J. Treatment patterns and healthcare resource utilization in ruxolitinib-treated patients with myelofibrosis with and without anemia: a real-world analysis. Ann Hematol 2025; 104:1605-1616. [PMID: 40069437 DOI: 10.1007/s00277-025-06279-0] [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: 12/04/2024] [Accepted: 02/18/2025] [Indexed: 04/26/2025]
Abstract
Anemia affects many patients with myelofibrosis and is associated with poor prognosis. The Janus kinase inhibitor ruxolitinib is often used in myelofibrosis but may cause or worsen anemia. Using healthcare claims data from the IQVIA PharMetrics Plus database, this retrospective analysis evaluated healthcare resource utilization (HCRU), healthcare costs, and treatment patterns in ruxolitinib-treated patients with myelofibrosis stratified by anemia diagnosis prior to ruxolitinib initiation. Of 11,499 patients diagnosed with myelofibrosis between January 2011 and December 2022, 481 had ≥ 1 ruxolitinib claim on or after the myelofibrosis diagnosis date and were included in this analysis. Mean follow-up was 2.0 years. At baseline, anemic patients (n = 257) were older (mean age, 60.2 vs. 56.8 years; P < 0.001) and had a higher mean Charlson Comorbidity Index (1.0 vs. 0.5; P < 0.001) than nonanemic patients (n = 224). During follow-up, anemic patients exhibited higher median annual all-cause HCRU (inpatient admissions, 0.3 vs. 0.0 [P < 0.001]; outpatient visits, 40.0 vs. 20.0 [P < 0.001]; emergency department visits, 0.4 vs. 0.0 [P < 0.010]) and also had numerically higher median annual all-cause total healthcare costs ($198,491 vs. $170,419; P = 0.549) and medical costs ($44,830 vs. $12,017; P = 0.638) but significantly lower median annual total pharmacy costs ($129,381 vs. $136,686; P < 0.050), compared with nonanemic patients. Ruxolitinib discontinuation rates were higher and median time to discontinuation was approximately 1 year earlier in anemic patients (14.1 vs. 23.8 months; P < 0.010). In conclusion, patients with myelofibrosis and baseline anemia who are treated with ruxolitinib may be an HCRU-intensive population, suggesting a potential need for alternative treatments that reduce their medical resource burden.
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Affiliation(s)
- Tom Liu
- GSK plc, Philadelphia, PA, USA.
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A ElKourashy S, Soliman D, El Omri A, Y Taha R, Elsabah H, Alashi H, Chandra P, El Omri H. A comparative retrospective study of pre-fibrotic primary myelofibrosis versus overtly fibrotic stage in Qatar: clinicopathological, genetic landscape, risk stratification and survival data (2008-2021) - a single center experience. Hematology 2024; 29:2392467. [PMID: 39665684 DOI: 10.1080/16078454.2024.2392467] [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: 10/25/2023] [Accepted: 08/10/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND In MENA region, there is a lack of evidence on Primary Myelofibrosis (PMF), leading to its underrepresentation in medical literature. This study marks the first comprehensive report on PMF data in Qatar, presenting findings from a single-center study spanning 13 years (2008-2021). METHODS Clinicopathological data, genetic features, and disease progression parameters of pre-PMF and overt PMF subgroups were collected. Overall survival (OS), progression-free survival (PFS), DIPSS plus four categories and merged low and high-risk DIPSS scoring groups were assessed. RESULTS Pre-PMF patients showed higher hemoglobin (P < 0.001), and platelet counts (P < 0.05) but lower blast counts, LDH levels, constitutional symptoms (P < 0.0001), and splenomegaly (P < 0.010) than overt PMF patients. JAK2 V617F mutation was more common in pre-PMF (P = 0.059), while unfavorable karyotypes were exclusive to overt PMF (P = 0.028). Median overall survival was significantly longer at 276.9 months (IQR: 315.9, 276.9 months) to what was previously reported. Overt PMF patients predominantly fell into the higher DIPSS risk category (P < 0.001) and showed greater disease progression than pre-PMF (P < 0.0001). Complications including refractory anaemia (P < 0.001) and leukemic transformation (P = 0.043), increased notably in the high-risk group. Furthermore, 86.2% of high-risk patients required treatment versus 59.4% of the lower-risk group (P = 0.020). CONCLUSIONS To the best of our knowledge our research represents the first and largest published dataset on PMF in MENA region to be published. Merged DIPSS plus scoring came to be a pragmatic tool for defining high-risk patients who significantly differ in mortality, progression, need for treatment and leukemic transformation.
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Affiliation(s)
- Sarah A ElKourashy
- Department of Haematology and Bone Marrow Transplant, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar
- Weill Cornell Medicine - Qatar (WCM-Q), Doha, Qatar
| | - Dina Soliman
- Weill Cornell Medicine - Qatar (WCM-Q), Doha, Qatar
- Department of Laboratory Medicine and Pathology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar
- Department of Clinical Pathology, National Cancer Institute, Cairo, Egypt
| | - Abdelfatteh El Omri
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation, Doha, Qatar
- Vice President for Medical and Health Sciences Office, QU-Health, Qatar University, Doha, Qatar
| | - Ruba Y Taha
- Department of Haematology and Bone Marrow Transplant, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar
| | - Hesham Elsabah
- Department of Haematology and Bone Marrow Transplant, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar
| | - Hind Alashi
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation, Doha, Qatar
- Department of Public Health, College of Health Sciences, QU-Health, Qatar University, Doha, Qatar
| | - Prem Chandra
- Medical Research Center, Hamad Medical Corporation, Doha, Qatar
| | - Halima El Omri
- Department of Haematology and Bone Marrow Transplant, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar
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Liu X, Wang B, Liu Y, Yu Y, Wan Y, Wu J, Wang Y. JAK2 inhibitors for the treatment of Philadelphia-negative myeloproliferative neoplasms: current status and future directions. Mol Divers 2024; 28:3445-3456. [PMID: 38006563 DOI: 10.1007/s11030-023-10742-3] [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: 07/23/2023] [Accepted: 10/05/2023] [Indexed: 11/27/2023]
Abstract
The overactivation of Janus kinases 2 (JAK2) by gain-of-function mutations in the JAK2, Myeloproliferative leukemia virus oncogene, or Calreticulin genes are the most important factor in the development of Philadelphia-negative myeloproliferative neoplasms (MPNs). The discovery of the JAK2V617F mutation is a significant breakthrough in understanding the pathogenesis of MPNs, and inhibition of JAK2 abnormal activation has become one of the most effective strategies against MPNs. Currently, three JAK2 inhibitors for treating MPNs have been approved, and several are being evaluated in clinical trials. However, persistent challenges in terms of drug resistance and off-target effects remain unresolved. In this review, we introduce and classify the available JAK2 inhibitors in terms of their mechanisms and clinical considerations. Additionally, through an analysis of target points, binding modes, and structure-activity inhibitor relationships, we propose strategies such as combination therapy and allosteric inhibitors to overcome specific challenges. This review offers valuable insights into current trends and future directions for optimal management of MPNs using JAK2 inhibitors.
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Affiliation(s)
- Xiaofeng Liu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Binyou Wang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
- Zigong Mental Health Center, Zigong Affiliated Hospital of Southwest Medical University, Zigong, 643000, China
| | - Yuan Liu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Yang Yu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
- Zigong Mental Health Center, Zigong Affiliated Hospital of Southwest Medical University, Zigong, 643000, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
| | - Ying Wan
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Jianming Wu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China.
- Zigong Mental Health Center, Zigong Affiliated Hospital of Southwest Medical University, Zigong, 643000, China.
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China.
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
| | - Yiwei Wang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China.
- Zigong Mental Health Center, Zigong Affiliated Hospital of Southwest Medical University, Zigong, 643000, China.
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China.
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Kappenstein M, von Bubnoff N. Real-World Electronic Medical Records Data Identify Risk Factors for Myelofibrosis and Can Be Used to Validate Established Prognostic Scores. Cancers (Basel) 2024; 16:1416. [PMID: 38611094 PMCID: PMC11011132 DOI: 10.3390/cancers16071416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasia arising de novo as primary myelofibrosis (PMF) or secondary to polycythemia vera or essential thrombocythemia. Patients experience a high symptom burden and a marked reduction in life expectancy. Despite progress in molecular understanding and treatment, the clinical and prognostic heterogeneity of MF complicates treatment decisions. The International Prognostic Scoring System (IPSS) integrates clinical factors for risk stratification in MF. This study leverages the TriNetX database with more than 64,000 MF patients to assess the impact of accessible parameters on survival and complicating events, including AML transformation, cachexia, increased systemic inflammation, thrombosis and hemorrhage. Age over 65 years correlated with increased risks of death, AML transformation, thrombosis and hemorrhage. Anemia (Hb < 10 g/dL), leukocytosis (>25 × 103/µL) and thrombocytopenia (<150 × 103/µL) reduced survival and increased risks across all assessed events. Monocytosis is associated with decreased survival, whereas eosinophilia and basophilia were linked to improved survival. Further, as proof of concept for the applicability of TriNetX for clinical scores, we devised a simplified IPSS, and confirmed its value in predicting outcomes. This comprehensive study underscores the importance of age, anemia, leukocytosis and thrombocytopenia in predicting disease trajectory and contributes to refining prognostic models, addressing the challenges posed by the disease's heterogeneity.
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Affiliation(s)
| | - Nikolas von Bubnoff
- Medical Center, Department of Hematology and Oncology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
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Amé S, Barraco F, Ianotto J, Jourdan E, Rey J, Viallard J, Wémeau M, Kiladjian J. Advances in management of primary myelofibrosis and polycythaemia vera: Implications in clinical practice. EJHAEM 2023; 4:779-791. [PMID: 37601853 PMCID: PMC10435696 DOI: 10.1002/jha2.734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 05/31/2023] [Indexed: 08/22/2023]
Abstract
Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare BCR-ABL1-negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic complications and progression to fibrosis or leukaemia or fibrosis for PV. Both diseases are characterised by biological and clinical heterogeneity, leading to great variability in their management in routine clinical practice. In this review, we present an updated overview of the diagnosis, prognosis and treatment of PMF and PV, and we discuss how our multidisciplinary expert group based across France translates this evidence-based knowledge into routine clinical practice.
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Affiliation(s)
- Shanti Amé
- Department of HaematologyInstitut de Cancérologie Strasbourg Europe (ICANS)StrasbourgFrance
| | - Fiorenza Barraco
- Department of HaematologyLyon Sud Hospital CentrePierre‐BéniteFrance
| | | | - Eric Jourdan
- Department of Clinical HaematologyUniversity Hospital of NimesNimesFrance
| | - Jérôme Rey
- Department of HaematologyInstitute Paoli‐CalmettesMarseilleFrance
| | | | - Mathieu Wémeau
- Department of HaematologyHospital Centre of RoubaixRoubaixFrance
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The Manifestation of a Patient With Myelofibrosis in 68Ga-DOTA-FAPI-04 PET/CT Mimicking "Super Bone Imaging". Clin Nucl Med 2022; 47:1056-1058. [PMID: 36342793 DOI: 10.1097/rlu.0000000000004427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
ABSTRACT Primary myelofibrosis is a chronic inflammatory disease of the bone marrow. It progresses from an early robust inflammatory state to a more advanced fibrotic response, representing the advanced stage of the disease. We report a 50-year-old woman who was diagnosed with primary myelofibrosis. 18F-FDG PET/CT showed mild uptake in diffuse sclerotic lesions in the bone matrix, whereas 68Ga-DOTA-FAPI-04 showed intense uptake at the whole skeleton.
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Tiwari N, Singh A, Singh B, Verma SP, Tripathi AK. Ruxolitinib and tuberculosis: A case report with brief review. Indian J Tuberc 2022; 69:354-358. [PMID: 35760486 DOI: 10.1016/j.ijtb.2021.06.003] [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: 11/18/2020] [Revised: 04/08/2021] [Accepted: 06/08/2021] [Indexed: 06/15/2023]
Abstract
JAK 2 inhibitors are widely used for the treatment of primary myelofibrosis. Ruxolitinib is the most commonly used JAK inhibitor in clinical practice. We report two cases of Primary Myelofibrosis who developed tuberculosis on active treatment with ruxolitinib. Our first case was a 48 year male who developed disseminated tuberculosis during fourth month of treatment and second case was a 50 year male developing tubercular lymphadenitis during second month of treatment respectively. These case reports indicate reactivation of underling tubercular infection as a very dreaded complication of this treatment. The prevalence of tuberculosis is much higher in India compared to the west. A thorough pretreatment evaluation should ideally be done using Mantoux test or interferon gamma release assay (IGRA) to rule out latent tuberculosis. Furthermore, the patients should be counselled regarding the possibility of reactivation of infections including tuberculosis. Also, proper follow up is the need of hour in all patients on any kind of immunomodulators.
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Affiliation(s)
- Neema Tiwari
- Department of Clinical Hematology, King George's Medical University, Lucknow, India
| | - Aparajita Singh
- Department of Clinical Hematology, King George's Medical University, Lucknow, India
| | - Bhupendra Singh
- Department of Clinical Hematology, King George's Medical University, Lucknow, India
| | | | - Anil Kumar Tripathi
- Department of Clinical Hematology, King George's Medical University, Lucknow, India
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Talpaz M, Prchal J, Afrin L, Arcasoy M, Hamburg S, Clark J, Kornacki D, Colucci P, Verstovsek S. Safety and Efficacy of Ruxolitinib in Patients with Myelofibrosis and Low Platelet Counts (50 - 100 × 10 9/L): Final Analysis of an Open-Label Phase 2 Study. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:336-346. [PMID: 34911667 DOI: 10.1016/j.clml.2021.10.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/27/2021] [Accepted: 10/27/2021] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Treatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50 - 100 × 109/L) are reported. PATIENTS AND METHODS Patients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 109/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety. RESULTS Of 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were -20.5% (-55.8% to 38.5%, n=51) and -39.8% (-98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3). CONCLUSION A starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.
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Affiliation(s)
- Moshe Talpaz
- Department of Internal Medicine, Division of Hematology and Oncology, Michigan Medicine - The University of Michigan, Ann Arbor, MI.
| | - Josef Prchal
- Hematology, University of Utah, HCI and VAH Medical Center, Salt Lake City, UT
| | - Lawrence Afrin
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC. Present address: AIM Center for Personalized Medicine, Purchase, NY
| | - Murat Arcasoy
- Division of Hematology, Duke Cancer Institute, Durham, NC
| | - Solomon Hamburg
- Tower Cancer Research Foundation, Beverly Hills, CA. Present address: Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Westwood, CA
| | - Jason Clark
- Incyte Corporation, Wilmington, DE. Present address: AstraZeneca, West Chester, PA
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Liso A, Venuto S, Coda ARD, Giallongo C, Palumbo GA, Tibullo D. IGFBP-6: At the Crossroads of Immunity, Tissue Repair and Fibrosis. Int J Mol Sci 2022; 23:ijms23084358. [PMID: 35457175 PMCID: PMC9030159 DOI: 10.3390/ijms23084358] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/04/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022] Open
Abstract
Insulin-like growth factors binding protein-6 (IGFBP-6) is involved in a relevant number of cellular activities and represents an important factor in the immune response, particularly in human dendritic cells (DCs). Over the past several years, significant insights into the IGF-independent effects of IGFBP-6 were discovered, such as the induction of chemotaxis, capacity to increase oxidative burst and neutrophils degranulation, ability to induce metabolic changes in DCs, and, more recently, the regulation of the Sonic Hedgehog (SHH) signaling pathway during fibrosis. IGFBP-6 has been implicated in different human diseases, and it plays a rather controversial role in the biology of tumors. Notably, well established relationships between immunity, stroma activity, and fibrosis are prognostic and predictive of response to cancer immunotherapy. This review aims at describing the current understanding of mechanisms that link IGFBP-6 and fibrosis development and at highlighting the multiple roles of IGFBP-6 to provide an insight into evolutionarily conserved mechanisms that can be relevant for inflammation, tumor immunity, and immunological diseases.
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Affiliation(s)
- Arcangelo Liso
- Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy; (S.V.); (A.R.D.C.)
- Correspondence:
| | - Santina Venuto
- Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy; (S.V.); (A.R.D.C.)
| | - Anna Rita Daniela Coda
- Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy; (S.V.); (A.R.D.C.)
| | - Cesarina Giallongo
- Department of Medical Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy; (C.G.); (G.A.P.)
| | - Giuseppe Alberto Palumbo
- Department of Medical Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy; (C.G.); (G.A.P.)
| | - Daniele Tibullo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy;
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Saleh J, Regmi A, Speiser JJ, Mudaliar KM, Omman R, Velankar M, Mirza KM. A Case of Primary Myelofibrosis With Transformation to Leukemia Cutis. Am J Dermatopathol 2022; 44:58-61. [PMID: 34132659 DOI: 10.1097/dad.0000000000001999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT We report an extraordinary case of primary myelofibrosis with transformation to leukemia cutis. A 64-year-old Caucasian man with a history of JAK2-positive primary myelofibrosis presented with erythematous papulonodules on his right lower extremity. A punch biopsy revealed a normal epidermis with an underlying diffuse dermal infiltrate composed of medium-to-large-sized myeloid cells and leukocytes. Neoplastic cells were immunoreactive for LCA, CD34, CD61, CD117, and CD68 and negative for lysozyme, CD20, CD3, myeloperoxidase, and TdT. These findings were consistent with a diagnosis of leukemia cutis. A concurrent bone marrow biopsy demonstrated a markedly fibrotic, hypercellular marrow without a significant increase in blasts. With no morphologic evidence of bone marrow involvement by acute myeloid leukemia, our case suggests that the patient's primary myelofibrosis transformed to leukemia cutis. Our patient died 2 months after the onset of his skin nodules. Our case demonstrates that leukemia cutis should be included in the differential diagnosis for cutaneous nodular lesions in patients with a history of an advanced-stage hematological malignancy.
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Affiliation(s)
- Jasmine Saleh
- Department of Pathology and Laboratory Medicine, Loyola University Medical Center, Maywood, IL; and
| | - Aayushma Regmi
- Department of Pathology and Laboratory Medicine, Loyola University Medical Center, Maywood, IL; and
| | - Jodi J Speiser
- Department of Pathology and Laboratory Medicine, Loyola University Medical Center, Maywood, IL; and
| | - Kumaran M Mudaliar
- Department of Pathology and Laboratory Medicine, Loyola University Medical Center, Maywood, IL; and
| | - Reeba Omman
- Department of Pathology, University of Florida, Jacksonville, FL
| | - Milind Velankar
- Department of Pathology and Laboratory Medicine, Loyola University Medical Center, Maywood, IL; and
| | - Kamran M Mirza
- Department of Pathology and Laboratory Medicine, Loyola University Medical Center, Maywood, IL; and
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11
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Longhitano L, Tibullo D, Vicario N, Giallongo C, La Spina E, Romano A, Lombardo S, Moretti M, Masia F, Coda ARD, Venuto S, Fontana P, Parenti R, Li Volti G, Di Rosa M, Palumbo GA, Liso A. IGFBP-6/sonic hedgehog/TLR4 signalling axis drives bone marrow fibrotic transformation in primary myelofibrosis. Aging (Albany NY) 2021; 13:25055-25071. [PMID: 34905501 PMCID: PMC8714138 DOI: 10.18632/aging.203779] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 12/03/2021] [Indexed: 12/16/2022]
Abstract
Primary myelofibrosis is a Ph-negative chronic myeloproliferative neoplasm characterized by bone marrow fibrosis and associated with the involvement of several pathways, in addition to bone marrow microenvironment alterations, mostly driven by the activation of the cytokine receptor/JAK2 pathway. Identification of driver mutations has led to the development of targeted therapy for myelofibrosis, contributing to reducing inflammation, although this currently does not translate into bone marrow fibrosis remission. Therefore, understanding the clear molecular cut underlying this pathology is now necessary to improve the clinical outcome of patients. The present study aims to investigate the involvement of IGFBP-6/sonic hedgehog /Toll-like receptor 4 axis in the microenvironment alterations of primary myelofibrosis. We observed a significant increase in IGFBP-6 expression levels in primary myelofibrosis patients, coupled with a reduction to near-normal levels in primary myelofibrosis patients with JAK2V617F mutation. We also found that both IGFBP-6 and purmorphamine, a SHH activator, were able to induce mesenchymal stromal cells differentiation with an up-regulation of cancer-associated fibroblasts markers. Furthermore, TLR4 signaling was also activated after IGFBP-6 and purmorphamine exposure and reverted by cyclopamine exposure, an inhibitor of the SHH pathway, confirming that SHH is involved in TLR4 activation and microenvironment alterations. In conclusion, our results suggest that the IGFBP-6/SHH/TLR4 axis is implicated in alterations of the primary myelofibrosis microenvironment and that IGFBP-6 may play a central role in activating SHH pathway during the fibrotic process.
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Affiliation(s)
- Lucia Longhitano
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Daniele Tibullo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Nunzio Vicario
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Cesarina Giallongo
- Department of Scienze Mediche Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia", University of Catania, Catania 95123, Italy
| | - Enrico La Spina
- Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. "Policlinico-Vittorio Emanuele", University of Catania, Catania 95123, Italy
| | - Alessandra Romano
- Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. "Policlinico-Vittorio Emanuele", University of Catania, Catania 95123, Italy
| | - Sofia Lombardo
- Department of Medical Oncology, The Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Marina Moretti
- Department of Medicine, University of Perugia, Perugia 06129, Italy
| | - Francesco Masia
- Department of Medicine, University of Perugia, Perugia 06129, Italy
| | | | - Santina Venuto
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71100, Italy
| | - Paolo Fontana
- Department of Medical Oncology, The Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Rosalba Parenti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Michelino Di Rosa
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Giuseppe A Palumbo
- Department of Scienze Mediche Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia", University of Catania, Catania 95123, Italy
| | - Arcangelo Liso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71100, Italy
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Kim J, Byun JM, Hong J, Koh Y, Shin DY, Kim I, Yoon SS, Park H, Bang SM. Incidence, characteristics and risk factors of thromboembolic events in East Asian patients with BCR-ABL1 negative myeloproliferative neoplasms. Sci Rep 2021; 11:17819. [PMID: 34497309 PMCID: PMC8426379 DOI: 10.1038/s41598-021-97464-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 08/25/2021] [Indexed: 01/14/2023] Open
Abstract
The vascular complications have been a major cause of morbidity and mortality among all subtypes of BCR-ABL1 negative myeloproliferative neoplasms (MPN), but the ethnicity-specific data was limited. We therefore conducted a multi-center retrospective, longitudinal cohort study to evaluate the incidence, characteristics and risk factors of thromboembolic events of MPN patients. Of 256 patients, 27.3% experienced thromboembolic events, majority of which occurred before or within 12 months of MPN diagnosis. The multivariable Cox proportional analyses identified leukocytosis (HR 2.67, 95% CI 1.36-5.24, q = 0.004) and history of thrombosis (HR 9.68, 95% CI 2.00-46.88, q = 0.005) as the risk factors for thromboembolism. In subgroup analysis of polycythemia vera and hemoglobin concentration (HR 1.97, 95% CI 1.28-3.04, q = 0.002) appeared to be a significant risk factor of thrombosis, along with age and thrombosis history. In essential thrombocythemia, severity of the established IPSET score was closely correlated with the frequency of thromboembolic events. In primary myelofibrosis, history of thrombosis was associated with thrombosis events (HR 13.85, 95% CI 1.2-159.5, q = 0.035). Overall survival was worse in patients who experienced thromboembolic events. Our study highlighted the importance of recognizing high risk patients and implementing personalized intervention.
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Affiliation(s)
- Jinyong Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Ja Min Byun
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea. .,Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110744, Korea. .,Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, 110744, Korea.
| | - Junshik Hong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110744, Korea.,Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, 110744, Korea
| | - Youngil Koh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110744, Korea.,Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, 110744, Korea
| | - Dong-Yeop Shin
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110744, Korea.,Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, 110744, Korea
| | - Inho Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Sung-Soo Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110744, Korea.,Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, 110744, Korea
| | - Hyunkyung Park
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, 07061, Korea
| | - Soo-Mee Bang
- Department of Internal Medicine, Seoul Nationl University College of Medicine, Seoul National University Bundang Hospital, Seongnam, 463-707, Korea
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Retrospective Analysis of the Clinical Use and Benefit of Lenalidomide and Thalidomide in Myelofibrosis. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:e956-e960. [DOI: 10.1016/j.clml.2020.07.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/08/2020] [Accepted: 07/13/2020] [Indexed: 12/15/2022]
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Zhou FP, Wang CC, Du HP, Cao SB, Zhang J. Primary myelofibrosis with concurrent CALR and MPL mutations: A case report. World J Clin Cases 2020; 8:5618-5624. [PMID: 33344552 PMCID: PMC7716329 DOI: 10.12998/wjcc.v8.i22.5618] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 10/06/2020] [Accepted: 10/20/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by recurrent mutations in the JAK2, CALR, and MPL genes. The CALR and MPL co-mutation is very rare. To our knowledge, no more than five cases have been reported. Here, we report a case of PMF in which a CALR and MPL co-mutation was detected by next-generation sequencing (NGS) technology, and a literature review was performed.
CASE SUMMARY A 73-year-old woman was admitted to our hospital in 2018 due to abdominal distension. The patient had splenomegaly, lymphadenopathy, leukopenia, anemia, and immature granulocytes in peripheral blood. There were dacrocytes and atypical megakaryocytes in bone marrow, and megakaryocytic proliferation was very active, accompanied by reticulin fibrosis grade 2. By NGS analysis of the bone marrow sample, we detected mutations in CALR, MPL, and PIK3RI, while JAK2 V617F and BCR-ABL were negative. Therefore, the patient was diagnosed with PMF and received oral ruxolitinib. However, the spleen and hematologic responses were poor. We review the literature, analyze previous reports of the mutation sites in our patient and differences between our patient and other reported cases of co-mutated CALR and MPL genes, and discuss the reason why the CALR and MPL co-mutations are rare and possible mechanisms and their impact on the prognosis of patients.
CONCLUSION CALR and MPL mutations can be concurrent in MPN, but they are rare. The use of NGS may help to identify more patients with co-mutated CALR and MPL genes. This will help to further explore the mechanism and its impact on these patients to develop appropriate treatment strategies.
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Affiliation(s)
- Feng-Ping Zhou
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang Province, China
| | | | - Hua-Ping Du
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang Province, China
| | - Shan-Bo Cao
- Acornmed Biotechnology Co., Ltd., Beijing 100176, China
| | - Jin Zhang
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang Province, China
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15
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Risk of disease transformation and second primary solid tumors in patients with myeloproliferative neoplasms. Blood Adv 2020; 3:3700-3708. [PMID: 31765478 DOI: 10.1182/bloodadvances.2019000655] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/30/2019] [Indexed: 12/22/2022] Open
Abstract
This study aimed to elucidate patterns of disease transformation to secondary myelofibrosis (SMF) or secondary acute myeloid leukemia (SAML) and the development of second primary malignancies in South Korean patients with BCR-ABL1-negative myeloproliferative neoplasms (MPNs). By using nationwide public health care insurance claims data, we identified and analyzed 7454 patients with MPNs who were newly diagnosed with essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF) from 2008 to 2016 and used the data to appropriately trace the disease course. Transformation to SMF or SAML was rare in patients with ET and PV, but patients with PMF had an 8-year cumulative incidence of SAML of 21.4%. Patients with PV or ET had an 8-year cumulative incidence of second primary solid tumors of ∼14%. Patients with MPNs had a 2 times higher risk of developing second primary solid tumors than that of the general South Korean population. Compared with patients with PMF, patients with SMF had a similar overall survival with a lower risk of developing SAML. The use of ruxolitinib did not increase the risk of developing B-cell lymphoma over a median follow-up period of 16.2 months. Disease transformation to SMF or SAML was rare in patients with ET or PV, but SAML was common in patients with PMF. South Korean patients with MPNs had a significantly higher risk of developing second primary solid tumors than that of the general population, particularly for kidney, prostate, brain, liver, and lung cancers.
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Abstract
Myelofibrosis (MF) is characterized by a presence of an extra fibrous tissue in the bone marrow and additional hematopoiesis. The somatic mutation in the Janus kinase 2 (JAK2) gene (V617F) occurs gradually and is detected in about 50.0% of myelofibrosis or essential thrombo-cytopenia (ET) patients. Our aim was to determine the genotype status according to the carriers of the V617F mutation in patients with MF at the Hematology Ward of the University Hospital "Ivan Rilski" in Sofia, Bulgaria. DNA samples were isolated from venous blood of patients with various hematological disorders. DNA was amplified by polymerase chain reaction (PCR) and subsequent restriction analysis was performed using a BsaXI restriction enzyme. The genotype status was determined on 2.0% agarose gel. We analyzed 38 patients initially suspected of carrying MF or osteomyelofibrosis (OMF). After trepanobiopsy, 20 out of 38 patients were confirmed as myelofibrotic (52.6%), 5/38 (13.2%) were diagnosed as ET, 1/38 (2.6%) was diagnosed as myeloproliferative neoplasm (MPN), 6/38 (15.8%) had polycythemia vera (PV). In six patients, the presence of disease was rejected. Patients with MF were divided into three groups according to the JAK2 V617F genotype status: homozygous for the mutation (3/20 or 15.0%), heterozygous (9/20 or 45.0%) and homozygous for the wild type allele (8/20 or 40.0%). The triggering factor of MF is still unknown. It was considered that this factor could have a genetic nature. Mutations in three genes were mainly accepted as an actual predisposing events to this disease: point mutations leading to amino acid substitutions in JAK2 (V617F) and in MPL (W515L, W515K), as well as insertion or deletion in CALK We have proven that carriers of the V617F mutation prevailed in the group of patients with MF (altogether 12 patients or 60.0%). Previous studies also showed that JAK2 V617F is present in more than half of MF patients within their blood-forming cells. Therefore, the risk of evolution to MF could be associated with V617F-mutant allele burden in patients with MPN.
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Li J, Ma X, Liu C, Li H, Zhuang J, Gao C, Zhou C, Liu L, Wang K, Sun C. Exploring the Mechanism of Danshen against Myelofibrosis by Network Pharmacology and Molecular Docking. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:8363295. [PMID: 30622613 PMCID: PMC6304517 DOI: 10.1155/2018/8363295] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 10/19/2018] [Accepted: 11/12/2018] [Indexed: 02/06/2023]
Abstract
Danshen (Salvia miltiorrhiza Bunge), a natural powerful drug for various conditions treatment, has traditionally been used in Asian countries for centuries as anticancer agent, anti-inflammatory agent, and antioxidant. More recently, it is explored in combination with other herbs for skeletal diseases therapy; bone-targeting compounds with pharmacological activities have been isolated from various sources of traditional Chinese medicine (TCM), including Danshen. In this case, some evidence supports that Danshen may treat myelofibrosis (MF) by exerting its antitumor effect. To study the specific mechanism of Danshen in the treatment of MF, we used bioinformatics databases to determine its active ingredients. Then, identification of target proteins related to MF was made using a network pharmacology analysis platform. In our results, 20 key active compounds and 457 key targets of Danshen were identified. In-depth network analysis of the top diseases, functions, and pathways suggested that a common underlying mechanism linked Danshen involvement with MF. Finally, 5 potential targets were confirmed by the analysis; these 5 targets, as well as 20 previously identified compounds, were subjected to molecular docking experiments. The results indicated that cryptotanshinone of Danshen may affect MF by acting on the key genes in the JAK-STAT signalling pathway and the TGF-β signalling pathway.
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Affiliation(s)
- Jie Li
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China
| | - Xiaoran Ma
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China
| | - Cun Liu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China
| | - Huayao Li
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China
| | - Jing Zhuang
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang 261041, Shandong, China
| | - Chundi Gao
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China
| | - Chao Zhou
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang 261041, Shandong, China
| | - Lijuan Liu
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang 261041, Shandong, China
| | - Kejia Wang
- College of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao 266071, Shandong, China
| | - Changgang Sun
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang 261041, Shandong, China
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