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Garcia-Manero G, Santini V, Zeidan AM, Komrokji RS, Pozharskaya V, Rose S, Keeperman K, Lai Y, Kalsekar S, Aggarwal B, Miteva D, Valcárcel D, Fenaux P, Shortt J, Della Porta MG, Platzbecker U. Long-Term Transfusion Independence with Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Lower-Risk Myelodysplastic Syndromes in the COMMANDS Trial. Adv Ther 2025:10.1007/s12325-025-03208-5. [PMID: 40377899 DOI: 10.1007/s12325-025-03208-5] [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: 03/07/2025] [Accepted: 04/10/2025] [Indexed: 05/18/2025]
Abstract
INTRODUCTION The efficacy of erythropoiesis-stimulating agents (ESAs) for transfusion-dependent (TD) anemia in lower-risk myelodysplastic syndromes (LR-MDS) is limited. Luspatercept achieved significantly greater rates of red blood cell (RBC) transfusion independence (TI) versus epoetin alfa (an ESA) in the phase 3 COMMANDS trial. This analysis assessed long-term RBC-TI, cumulative response, and safety with luspatercept in COMMANDS. METHODS Eligible patients aged ≥ 18 years, with ESA-naive, RBC TD LR-MDS were randomized 1:1 to receive luspatercept (1.0 mg/kg, titration to 1.75 mg/kg permitted) or epoetin alfa (450 IU/kg, titration to 1050 IU/kg). Disease assessment was carried out at week 24 (day 169) and every 24 weeks thereafter. Treatment continued until disease progression, lack of clinical benefit, unacceptable toxicity, or consent withdrawal. RESULTS At data cutoff (September 22, 2023; median follow-up: luspatercept 21.4 months, epoetin alfa 20.3 months), a greater proportion of patients treated with luspatercept (n = 182) versus epoetin alfa (n = 181) achieved a longest single RBC-TI period ≥ 1 year (44.5% vs. 27.6%; P = 0.0003) and ≥ 1.5 years (30.2% vs. 13.8%; P < 0.0001). Higher rates of RBC-TI ≥ 1.5 years with luspatercept over epoetin alfa were consistent across all prespecified subgroups, including patients with ring sideroblast-negative status and low baseline serum erythropoietin. Longer cumulative RBC-TI response [sum of all durations of RBC-TI for ≥ 12 weeks; week 1 to end of treatment (95% CI)] was observed with luspatercept [154.7 weeks (118.4-NR)] versus epoetin alfa [91.1 weeks (73.1-123.9)]. Rates of treatment-emergent adverse events, including asthenia and hypertension, generally decreased over time in both arms. Progression rates to high-risk MDS and acute myeloid leukemia were similarly low (< 5%) in both treatment arms. CONCLUSIONS These data demonstrated sustained, durable clinical benefit across subgroups and support luspatercept as the treatment of choice for anemia in patients with LR-MDS who are TD and ESA-naive. TRIAL REGISTRATION NUMBER NCT03682536.
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Affiliation(s)
| | - Valeria Santini
- MDS Unit, DMSC, University of Florence, AOUC, Florence, Italy
| | | | | | | | | | | | - Yinzhi Lai
- Bristol Myers Squibb, Princeton, NJ, USA
| | | | | | | | - David Valcárcel
- Vall d'Hebron, Institute of Oncology (VHIO), Vall d'Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Jake Shortt
- Monash Health and Monash University, Clayton, VIC, Australia
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Prakash S, Orazi A. Diagnostic Approach to Myeloproliferative Neoplasms and Myelodysplastic/Myeloproliferative Neoplasms. Adv Anat Pathol 2025:00125480-990000000-00147. [PMID: 40243206 DOI: 10.1097/pap.0000000000000493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
The International Consensus Classification (ICC) updated in 2022 the World Health Organization (WHO) classification of hematopoietic tumors (2016 revision of the 4th edition WHO classification). Although the major categories of myeloid neoplasms remained unchanged from the prior WHO classification, many disease entities including those in the myeloproliferative neoplasm (MPN) and myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) categories underwent updates. For all these disease subtypes, a careful integration of clinicopathologic findings and molecular data led to improved diagnostic definitions. Although the classification of MPNs received only minor changes, these included a simpler definition of accelerated phase of chronic myeloid leukemia. For the MDS/MPN group, in addition to the presence of one or more increased peripheral blood cell counts as evidence of myeloproliferative features, concomitant cytopenia as evidence of ineffective hematopoiesis is now an explicit diagnostic requirement for all the entities included in this category. The presence of specific mutations in the appropriate clinicopathologic context is now included in the diagnostic criteria for some of the MPN and MDS/MPN entities. This review aims to briefly discuss the diagnostic approach to MPNs and MDS/MPNs according to the ICC.
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Affiliation(s)
- Sonam Prakash
- Department of Laboratory Medicine, University of California, San Francisco, CA
| | - Attilio Orazi
- Department of Pathology, Texas Tech University Health Sciences Center, El Paso, TX
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Maberry MD, Nunnelee JS, Gonsalves WI. 68-Year-Old Man With "Thick Blood" and Fatigue. Mayo Clin Proc 2025:S0025-6196(24)00153-8. [PMID: 39903147 DOI: 10.1016/j.mayocp.2024.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 02/06/2025]
Affiliation(s)
- Mackenzie D Maberry
- Resident in Internal Medicine, Mayo Clinic School of Graduate Medical Education, Rochester, MN
| | - Jordan S Nunnelee
- Resident in Internal Medicine, Mayo Clinic School of Graduate Medical Education, Rochester, MN
| | - Wilson I Gonsalves
- Advisor to residents and Consultant in Hematology, Mayo Clinic, Rochester, MN
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Danielson DT, Muir JM. Educational Case: Essential thrombocythemia. Acad Pathol 2025; 12:100167. [PMID: 40104156 PMCID: PMC11919432 DOI: 10.1016/j.acpath.2025.100167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 10/01/2024] [Accepted: 01/04/2025] [Indexed: 03/20/2025] Open
Affiliation(s)
- David T Danielson
- Department of Pathology, Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Jeannie M Muir
- Department of Pathology, Walter Reed National Military Medical Center, Bethesda, MD, USA
- Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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Hoermann G, Khoury JD. Can molecular patterns help to classify overlapping entities in myeloid neoplasms? Histopathology 2025; 86:146-157. [PMID: 39428913 PMCID: PMC11648353 DOI: 10.1111/his.15339] [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] [Indexed: 10/22/2024]
Abstract
Myeloid neoplasms include myeloproliferative and myelodysplastic neoplasms and acute myeloid leukaemia. Historically, these diseases have been diagnosed based on clinicopathological features with sometimes arbitrary thresholds that have persisted even as molecular features were gradually incorporated into their classification. As such, although current diagnostic approaches can classify the majority of myeloid neoplasms accurately using a combination of molecular and clinicopathological features, some areas of overlap persist and occasionally pose diagnostic challenges. These include overlap across BCR::ABL1-negative myeloproliferative neoplasms; between clonal cytopenia of undetermined significance and myelodysplastic neoplasms; myelodysplastic/myeloproliferative neoplasms; and, detection of KIT mutations in myeloid neoplasms other than mastocytosis, raising the prospect of systemic mastocytosis. Molecular testing has become state of the art in the diagnostic work-up of myeloid neoplasms, and molecular patterns can inherently help to classify overlapping entities if considered within a framework of haematological presentations. For future development, molecular testing will likely include whole genome and transcriptome sequencing, and primarily molecular classifications of myeloid neoplasms have already been suggested. As such, genetically defined groups should still constitute the basis for our understanding of disease development from early onset to progression, while clinicopathological features could then be used to describe the stage of the disease rather than the specific type of myeloid neoplasm.
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Affiliation(s)
| | - Joseph D Khoury
- Department of Pathology, Microbiology, and ImmunologyUniversity of Nebraska Medical CenterOmahaUSA
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Heyrman B, Meers S, Sid S, Put N, Theunissen K, Van Eygen K, De Beule N, Clauwaert M, Maes H, Salembier A, Lemmens J, Velde AVD, Selleslag D, Bouziotis J, De Becker A, Anguille S. Real-life data of luspatercept in lower-risk myelodysplastic syndromes advocate new research objectives. EJHAEM 2024; 5:1096-1099. [PMID: 39415916 PMCID: PMC11474394 DOI: 10.1002/jha2.1027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/15/2024] [Accepted: 09/16/2024] [Indexed: 10/19/2024]
Affiliation(s)
- Bert Heyrman
- Department of HaematologyZiekenhuis Netwerk AntwerpenAntwerpBelgium
| | - Stef Meers
- Department of HaematologyAlgemeen Ziekenhuis KlinaBrasschaatBelgium
| | - Sélim Sid
- Department of HaematologyCentre Hospitalier Régional VerviersVerviersBelgium
| | - Natalie Put
- Department of HaematologyZiekenhuis Oost‐LimburgGenkBelgium
| | | | - Koen Van Eygen
- Department of HaematologyAlgemeen Ziekenhuis GroeningeKortrijkBelgium
| | - Nathan De Beule
- Department of HaematologyUniversitair Ziekenhuis BrusselJetteBelgium
| | - Maxime Clauwaert
- Department of HaematologyAlgemeen Ziekenhuis Sint‐LucasGentBelgium
| | - Helena Maes
- Department of HaematologyImelda ZiekenhuisBonheidenBelgium
| | | | - Jan Lemmens
- Department of HaematologyGasthuiszusters AntwerpenAntwerpBelgium
| | - Ann Van De Velde
- Department of HaematologyUniversitair Ziekenhuis AntwerpenEdegemBelgium
| | | | - Jason Bouziotis
- Clinical Trial CenterUniversitair Ziekenhuis AntwerpenEdegemBelgium
| | - Ann De Becker
- Department of HaematologyUniversitair Ziekenhuis BrusselJetteBelgium
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Della Porta MG, Garcia-Manero G, Santini V, Zeidan AM, Komrokji RS, Shortt J, Valcárcel D, Jonasova A, Dimicoli-Salazar S, Tiong IS, Lin CC, Li J, Zhang J, Pilot R, Kreitz S, Pozharskaya V, Keeperman KL, Rose S, Prebet T, Lai Y, Degulys A, Paolini S, Cluzeau T, Fenaux P, Platzbecker U. Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial. Lancet Haematol 2024; 11:e646-e658. [PMID: 39038479 DOI: 10.1016/s2352-3026(24)00203-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 07/24/2024]
Abstract
BACKGROUND The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial. METHODS COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting). FINDINGS Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis. INTERPRETATION Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups. FUNDING Celgene and Acceleron Pharma.
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Affiliation(s)
- Matteo Giovanni Della Porta
- Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Milan, Italy.
| | | | - Valeria Santini
- MDS Unit, Hematology, University of Florence, DMSC, AOUC, Florence, Italy
| | - Amer M Zeidan
- Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, Yale University, New Haven, CT, USA
| | | | - Jake Shortt
- Monash University and Monash Health, Melbourne, VIC, Australia
| | - David Valcárcel
- Vall Hebron Institute of Oncology (VHIO), Hematology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Anna Jonasova
- Medical Department, Hematology, Charles University General Hospital, Prague, Czech Republic
| | | | - Ing Soo Tiong
- Malignant Haematology & Stem Cell Transplantation, The Alfred, Melbourne, VIC, Australia; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Chien-Chin Lin
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jiahui Li
- Bristol Myers Squibb, Princeton, NJ, USA
| | | | | | - Sandra Kreitz
- Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland
| | | | | | | | | | - Yinzhi Lai
- Bristol Myers Squibb, Princeton, NJ, USA
| | - Andrius Degulys
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania; Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Stefania Paolini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Thomas Cluzeau
- Département d'Hématologie Clinique, Université Cote d'Azur, CHU Nice, Nice, France
| | - Pierre Fenaux
- Service d'Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France
| | - Uwe Platzbecker
- Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany
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Ogunbileje JO, Harris N, Wynn T, Kashif R, Stover B, Osa-Andrews B. ATP-Binding Cassette Transporter of Clinical Significance: Sideroblastic Anemia. J Pers Med 2024; 14:636. [PMID: 38929857 PMCID: PMC11204910 DOI: 10.3390/jpm14060636] [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: 04/15/2024] [Revised: 05/16/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
The ATP-binding cassette (ABC) transporters are a vast group of 48 membrane proteins, some of which are of notable physiological and clinical importance. Some ABC transporters are involved in functions such as the transport of chloride ions, bilirubin, reproductive hormones, cholesterol, and iron. Consequently, genetic or physiological disruption in these functions is manifested in various disease processes like cystic fibrosis, Tangier disease, and sideroblastic anemia. Among other etiologies, primary sideroblastic anemia results from a genetic mutation in the ATP-binding cassette-7 (ABCB7), a member of the ABC transporter family. There are not many articles specifically tackling the disease processes caused by ABC transporters in detail. Some testing methodologies previously reported in the available literature for investigating sideroblastic anemia need updating. Here, we expound on the relevance of ABCB7 as a clinically important ABC transporter and a rare participant in the disease process of Sideroblastic anemia. The other genetic and secondary etiologies of sideroblastic anemia, which do not involve mutations in the ABCB7 protein, are also described. We review the pathophysiology, clinical course, symptoms, diagnosis, and treatment of sideroblastic anemia with a focus on modern technologies for laboratory testing.
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Affiliation(s)
| | - Neil Harris
- College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Tung Wynn
- College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Reema Kashif
- College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Brian Stover
- College of Medicine, University of Florida, Gainesville, FL 32611, USA
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Li F, Qin T, Li B, Qu S, Pan L, Zhang P, Sun Q, Cai W, Gao Q, Jiao M, Li J, Ai X, Ma J, Gale RP, Xu Z, Xiao Z. Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis. Leukemia 2024; 38:1334-1341. [PMID: 38714876 PMCID: PMC11147759 DOI: 10.1038/s41375-024-02262-2] [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: 02/06/2024] [Revised: 04/19/2024] [Accepted: 04/23/2024] [Indexed: 06/05/2024]
Abstract
We investigated data from 180 consecutive patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) who were diagnosed according to the 2022 World Health Organization (WHO) classification of myeloid neoplasms to identify covariates associated with survival. At a median follow-up of 48 months (95% confidence interval [CI] 35-61 months), the median survival was 69 months (95% CI 59-79 months). Patients with bone marrow ring sideroblasts (RS) < 15% had shorter median overall survival (OS) than did those with bone marrow RS ≥ 15% (41 months [95% CI 32-50 months] versus 76 months [95% CI 59-93 months]; P < 0.001). According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.
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Affiliation(s)
- Fuhui Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Tiejun Qin
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Bing Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Shiqiang Qu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Lijuan Pan
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Peihong Zhang
- Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Qi Sun
- Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Wenyu Cai
- Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Qingyan Gao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Meng Jiao
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Junjie Li
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Xiaofei Ai
- Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jiao Ma
- Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Robert Peter Gale
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK
| | - Zefeng Xu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
| | - Zhijian Xiao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
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Wen D, Xiao H, Gao Y, Zeng H, Deng J. N6-methyladenosine-modified SENP1, identified by IGF2BP3, is a novel molecular marker in acute myeloid leukemia and aggravates progression by activating AKT signal via de-SUMOylating HDAC2. Mol Cancer 2024; 23:116. [PMID: 38822351 PMCID: PMC11141000 DOI: 10.1186/s12943-024-02013-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 04/30/2024] [Indexed: 06/02/2024] Open
Abstract
BACKGROUND Elevated evidence suggests that the SENPs family plays an important role in tumor progression. However, the role of SENPs in AML remains unclear. METHODS We evaluated the expression pattern of SENP1 based on RNA sequencing data obtained from OHSU, TCGA, TARGET, and MILE datasets. Clinical samples were used to verify the expression of SENP1 in the AML cells. Lentiviral vectors shRNA and sgRNA were used to intervene in SENP1 expression in AML cells, and the effects of SENP1 on AML proliferation and anti-apoptosis were detected using in vitro and in vivo models. Chip-qPCR, MERIP-qPCR, CO-IP, RNA pulldown, and dual-luciferase reporter gene assays were used to explore the regulatory mechanisms of SNEP1 in AML. RESULTS SENP1 was significantly upregulated in high-risk AML patients and closely related to poor prognosis. The AKT/mTOR signaling pathway is a key downstream pathway that mediates SENP1's regulation of AML proliferation and anti-apoptosis. Mechanistically, the CO-IP assay revealed binding between SENP1 and HDAC2. SUMO and Chip-qPCR assays suggested that SENP1 can desumoylate HDAC2, which enhances EGFR transcription and activates the AKT pathway. In addition, we found that IGF2BP3 expression was upregulated in high-risk AML patients and was positively correlated with SENP1 expression. MERIP-qPCR and RIP-qPCR showed that IGF2BP3 binds SENP1 3-UTR in an m6A manner, enhances SENP1 expression, and promotes AKT pathway conduction. CONCLUSIONS Our findings reveal a distinct mechanism of SENP1-mediated HDAC2-AKT activation and establish the critical role of the IGF2BP3/SENP1signaling axis in AML development.
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MESH Headings
- Animals
- Female
- Humans
- Male
- Mice
- Adenosine/analogs & derivatives
- Adenosine/metabolism
- Apoptosis
- Biomarkers, Tumor/metabolism
- Biomarkers, Tumor/genetics
- Cell Line, Tumor
- Cell Proliferation
- Cysteine Endopeptidases/metabolism
- Cysteine Endopeptidases/genetics
- Disease Progression
- Gene Expression Regulation, Leukemic
- Histone Deacetylase 2/metabolism
- Histone Deacetylase 2/genetics
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Prognosis
- Proto-Oncogene Proteins c-akt/metabolism
- RNA-Binding Proteins/metabolism
- RNA-Binding Proteins/genetics
- Signal Transduction
- Sumoylation
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Diguang Wen
- Department of Hematology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Hang Xiao
- Department of Hematology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Yueyi Gao
- Department of Hematology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Hanqing Zeng
- Department of Hematology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
| | - Jianchuan Deng
- Department of Hematology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
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11
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Gajzer DC, Yeung CCS. Significance of SF3B1 Mutations in Myeloid Neoplasms. Clin Lab Med 2023; 43:597-606. [PMID: 37865505 DOI: 10.1016/j.cll.2023.07.005] [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] [Indexed: 10/23/2023]
Abstract
Myelodysplastic neoplasm with low blasts and SF3B1 mutation (MDS-LB-SF3B1) has undergone significant classification changes in the past year with the publication of the 5th edition of the World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues and the International Consensus Classification. This article reviews the basic biology of SF3B1, iron metabolism, and dysfunction that leads to the formation of ring sideroblasts. It highlights neoplastic and non-neoplastic considerations to the differential diagnoses. Finally, a review on the evolution of the prognostic scoring system and treatment regimens that are available to patients with a diagnosis of MDS is presented.
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Affiliation(s)
| | - Cecilia C S Yeung
- University of Washington, Seattle, WA, USA; Fred Hutch Cancer Center, Seattle, WA, USA.
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12
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Tefferi A, Loscocco GG, Farrukh F, Szuber N, Mannelli F, Pardanani A, Hanson CA, Ketterling RP, De Stefano V, Carobbio A, Barbui T, Guglielmelli P, Gangat N, Vannucchi AM. A globally applicable "triple A" risk model for essential thrombocythemia based on Age, Absolute neutrophil count, and Absolute lymphocyte count. Am J Hematol 2023; 98:1829-1837. [PMID: 37665758 DOI: 10.1002/ajh.27079] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 08/15/2023] [Indexed: 09/06/2023]
Abstract
We examined the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), and monocyte (AMC) counts, on overall (OS), leukemia-free (LFS), and myelofibrosis-free (MFFS) survival in essential thrombocythemia (ET). Informative cases (N = 598; median age 59 years; females 62%) were retrospectively accrued from a Mayo Clinic database: JAK2 59%, CALR 27%, triple-negative 11%, and MPL 3%; international prognostic scoring system for ET (IPSET) risk high 21%, intermediate 42%, and low 37%; 7% (37/515) had abnormal karyotype and 10% (21/205) adverse mutations (SF3B1/SRSF2/U2AF1/TP53). At median 8.4 years, 163 (27%) deaths, 71 (12%) fibrotic, and 20 (3%) leukemic transformations were recorded. Multivariable analysis resulted in HR (95% CI) of 16.5 (9.9-27.4) for age > 70 years, 3.7 (2.3-6.0) for age 50-70 years, 2.4 (1.7-3.3) for ANC ≥8 × 109 /L, and 1.9 (1.4-2.6) for ALC <1.7 × 109 /L. The corresponding HR-based scores were 4, 2, 1, and 1, resulting in an new 4-tiered AgeAncAlc (AAA; triple A) risk model: high (5-6 points; median survival 8 years; HR 30.1, 95% CI 17.6-54), intermediate-2 (4 points; median 13.5 years; HR 12.7, 95% CI 7.1-23.0), intermediate-1 (2-3 points; median 20.7 years; HR 3.8, 95% CI 2.3-6.4) and low (0-1 points; median 47 years). The AAA model (Akaike Information Criterion [AIC] 621) performed better than IPSET (AIC 647) and was subsequently validated by an external University of Florence ET cohort (N = 485). None of the AAA variables predicted LFS while ALC <1.7 × 109 /L was associated with inferior MFFS (p = .01). Adverse mutations (p < .01) and karyotype (p < .01) displayed additional prognostic value without disqualifying the prognostic integrity of the AAA model. This study proposes a simple and globally applicable survival model for ET, which can be used as a platform for further molecular refinement. This study also suggests a potential role for immune-related biomarkers, as a prognostic tool in myeloproliferative neoplasms.
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Affiliation(s)
- Ayalew Tefferi
- Divisions of Hematology and Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Giuseppe G Loscocco
- Department of Experimental and Clinical Medicine, CRIMM, Center Research, and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy
| | - Faiqa Farrukh
- Divisions of Hematology and Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Natasha Szuber
- Department of Hematology, Université de Montréal, Quebec, Canada
| | - Francesco Mannelli
- Department of Experimental and Clinical Medicine, CRIMM, Center Research, and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy
| | - Animesh Pardanani
- Divisions of Hematology and Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Curtis A Hanson
- Divisions of Hematology and Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Rhett P Ketterling
- Divisions of Hematology and Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Valerio De Stefano
- Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Rome, Italy
| | | | - Tiziano Barbui
- FROM esearch Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Paola Guglielmelli
- Department of Experimental and Clinical Medicine, CRIMM, Center Research, and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy
| | - Naseema Gangat
- Divisions of Hematology and Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Alessandro M Vannucchi
- Department of Experimental and Clinical Medicine, CRIMM, Center Research, and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy
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13
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Islam A. An unusual response to 5-azacitidine by a patient with chronic myelomonocytic leukemia. Clin Case Rep 2023; 11:e7748. [PMID: 37546162 PMCID: PMC10397479 DOI: 10.1002/ccr3.7748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/10/2023] [Accepted: 07/19/2023] [Indexed: 08/08/2023] Open
Abstract
Key Clinical Message Hypomethylating agents may be useful in some but not all cases of myelodysplastic syndromes. In some versions of these conditions, this treatment may yield deleterious results. Abstract Chronic myelomonocytic leukemia (CMML) is considered to be a heterogeneous group of hematopoietic neoplasms. Usually it shares the features of myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) and is known as MDS/MPN. It occurs mostly in the elderly and has an inherent tendency to transform to acute myeloid leukemia. FDA has approved hypomethylating agents (HMAs) such as 5-azacitidine (AZA) and decitabine (DEC) for the treatment of this disorder. The extent of response rate to AZA varies considerably among patients. Our report describes a patient with CMML who not only did not respond to a conventional dose of intravenous (IV) therapy with AZA, but showed marked progression of the disease with the leucocyte count rising exponentially while undergoing the aforesaid treatment. We believe this is the first such case reported in the currently extant literature.
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Affiliation(s)
- Anwarul Islam
- Division of Hematology/Oncology, Department of MedicineBuffalo General HospitalBuffalo General Medical CenterBuffaloNew YorkUSA
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14
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Kawanishi M, Nishimura Y, Kinoshita T, Hashizaki T, Umemoto Y, Nishiyama K, Tajima F. Effects of continuous bicycle ergometer and step exercises from admission to discharge in a patient with myelodysplastic syndrome undergoing myeloablative conditioning and hematopoietic stem cell transplantation: A case report. Medicine (Baltimore) 2023; 102:e34001. [PMID: 37327278 PMCID: PMC10270509 DOI: 10.1097/md.0000000000034001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 05/24/2023] [Indexed: 06/18/2023] Open
Abstract
BACKGROUND In myelodysplastic syndromes (MDS), in addition to disease-related symptoms, many adverse events are associated with anticancer agents, myeloablative conditioning (MAC), and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Isolation and bed rest in a clean room severely limit physical activity, resulting in cardiopulmonary and muscle weakness. In addition, post-transplant patients may experience general fatigue, gastrointestinal symptoms, and infections associated with a weakened immune system, as well as graft-versus-host disease, which causes further decline in physical function and activities of daily living (ADL). Most reports on the rehabilitation of patients with hematopoietic tumors involve interventions before and after chemotherapy or transplantation. However, an important issue is to establish effective and feasible exercise programs in a clean room setting, where activity is severely limited and physical function is most likely to decline. CASE REPORT This case report describes the treatment progress of a 60-year-old man with MDS and thrombocytopenia scheduled to receive MAC and allo-HSCT, who continued bicycle ergometer and step exercises from admission to discharge. The patient was admitted for allo-HSCT, and on day 4, he started bicycle ergometer and step exercise in a clean room and continued until discharge. As a result, exercise tolerance and lower-extremity muscle strength were maintained at the time of hospital discharge. Furthermore, the patient was able to continue rehabilitation in a restricted environment without adverse events. CONCLUSIONS The rehabilitation and treatment course of this case may provide valuable information for patients with MDS and thrombocytopenia.
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Affiliation(s)
- Makoto Kawanishi
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
- Division of Rehabilitation, Wakayama Medical University Hospital, Wakayama, Japan
| | - Yukihide Nishimura
- Department of Rehabilitation Medicine, Iwate Medical University, Shiwa-gun, Japan
| | - Tokio Kinoshita
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
- Division of Rehabilitation, Wakayama Medical University Hospital, Wakayama, Japan
| | - Takamasa Hashizaki
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
- Division of Rehabilitation, Wakayama Medical University Hospital, Wakayama, Japan
| | - Yasunori Umemoto
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kazunari Nishiyama
- Department of Rehabilitation Medicine, Iwate Medical University, Shiwa-gun, Japan
| | - Fumihiro Tajima
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
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15
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Cherniawsky H, Razavi HM. A case of MDS/MPN overlap syndrome with ring sideroblasts and thrombocytosis: Tackling the quandary of thrombosis versus hemorrhage. Clin Case Rep 2023; 11:e7409. [PMID: 37260615 PMCID: PMC10227201 DOI: 10.1002/ccr3.7409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 11/25/2022] [Accepted: 05/05/2023] [Indexed: 06/02/2023] Open
Abstract
Key Clinical Message No formal treatment guidelines for MDS/MPN-RS-T exist. With salient features such as anemia and thrombocytosis, management is individualized and aims to address anemia, thrombosis, and in some cases acquired von Willebrand's disease. Abstract Myelodysplastic/myeloproliferative overlap syndrome with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare myeloid neoplasm showing myelodysplastic and myeloproliferative features. With extremely raised platelets, possibility of acquired von Willebrand and risk of hemorrhage is increased. With this quandary in mind, a descriptive case and a brief discussion of available treatments ensues.
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Affiliation(s)
- Hannah Cherniawsky
- Division of Haematology, Department of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Habib Moshref Razavi
- Division of Hematopathology and Transfusion Medicine, Fraser Health AuthorityUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
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16
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Jiang M, Chen M, Liu Q, Jin Z, Yang X, Zhang W. SF3B1 mutations in myelodysplastic syndromes: A potential therapeutic target for modulating the entire disease process. Front Oncol 2023; 13:1116438. [PMID: 37007111 PMCID: PMC10063959 DOI: 10.3389/fonc.2023.1116438] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/06/2023] [Indexed: 03/19/2023] Open
Abstract
Myelodysplastic syndromes (MDS) are clonal hematologic malignancies characterized by ineffective hematopoiesis and dysplasia of the myeloid cell lineage and are characterized by peripheral blood cytopenia and an increased risk of transformation to acute myeloid leukemia (AML). Approximately half of the patients with MDS have somatic mutations in the spliceosome gene. Splicing Factor 3B Subunit 1A (SF3B1), the most frequently occurring splicing factor mutation in MDS is significantly associated with the MDS-RS subtype. SF3B1 mutations are intimately involved in the MDS regulation of various pathophysiological processes, including impaired erythropoiesis, dysregulated iron metabolism homeostasis, hyperinflammatory features, and R-loop accumulation. In the fifth edition of the World Health Organization (WHO) classification criteria for MDS, MDS with SF3B1 mutations has been classified as an independent subtype, which plays a crucial role in identifying the disease phenotype, promoting tumor development, determining clinical features, and influencing tumor prognosis. Given that SF3B1 has demonstrated therapeutic vulnerability both in early MDS drivers and downstream events, therapy based on spliceosome-associated mutations is considered a novel strategy worth exploring in the future.
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17
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Scaramellini N, Fischer D, Agarvas AR, Motta I, Muckenthaler MU, Mertens C. Interpreting Iron Homeostasis in Congenital and Acquired Disorders. Pharmaceuticals (Basel) 2023; 16:ph16030329. [PMID: 36986429 PMCID: PMC10054723 DOI: 10.3390/ph16030329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/13/2023] [Accepted: 02/17/2023] [Indexed: 02/25/2023] Open
Abstract
Mammalian cells require iron to satisfy their metabolic needs and to accomplish specialized functions, such as hematopoiesis, mitochondrial biogenesis, energy metabolism, or oxygen transport. Iron homeostasis is balanced by the interplay of proteins responsible for iron import, storage, and export. A misbalance of iron homeostasis may cause either iron deficiencies or iron overload diseases. The clinical work-up of iron dysregulation is highly important, as severe symptoms and pathologies may arise. Treating iron overload or iron deficiency is important to avoid cellular damage and severe symptoms and improve patient outcomes. The impressive progress made in the past years in understanding mechanisms that maintain iron homeostasis has already changed clinical practice for treating iron-related diseases and is expected to improve patient management even further in the future.
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Affiliation(s)
- Natalia Scaramellini
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milano, Italy
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Dania Fischer
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Anand R. Agarvas
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
| | - Irene Motta
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milano, Italy
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Martina U. Muckenthaler
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Side, 69120 Heidelberg, Germany
| | - Christina Mertens
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
- Correspondence: ; Tel.: +49-6221564582; Fax: +49-6221564580
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18
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Prakash S, Arber DA, Bueso-Ramos C, Hasserjian RP, Orazi A. Advances in myelodysplastic/myeloproliferative neoplasms. Virchows Arch 2023; 482:69-83. [PMID: 36469102 DOI: 10.1007/s00428-022-03465-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 12/07/2022]
Abstract
The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) category includes a heterogeneous group of diseases characterized by the co-occurrence of clinical and pathologic features of both myelodysplastic and myeloproliferative neoplasms. The recently published International Consensus Classification of myeloid neoplasms revised the entities included in the MDS/MPN category as well as criteria for their diagnosis. In addition to the presence of one or more increased peripheral blood cell counts as evidence of myeloproliferative features, concomitant cytopenia as evidence of ineffective hematopoiesis is now an explicit requirement to diagnose the diseases included in this category. The increasing availability of modern gene sequencing has allowed better understanding of the biologic characteristics of these myeloid neoplasms. The presence of specific mutations in the appropriate clinicopathologic context is now included in the diagnostic criteria for some of MDS/MPN entities. In this review, we highlight what has changed in the diagnostic criteria of MDS/MPN from the WHO 2016 classification while providing practical guidance in diagnosing these diseases.
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Affiliation(s)
- Sonam Prakash
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Daniel A Arber
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Carlos Bueso-Ramos
- Division of Pathology and Laboratory Medicine, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert P Hasserjian
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Attilio Orazi
- Department of Pathology, Texas Tech University Health Sciences Center, El Paso, TX, USA.
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19
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Delanghe S, Nguyen TQ, Mazure D, Dendooven A, Speeckaert MM. Immune Complex Glomerulonephritis in a Patient with Myelodysplastic Syndrome with Ring Sideroblasts Treated with Luspatercept. Diagnostics (Basel) 2022; 13:diagnostics13010011. [PMID: 36611303 PMCID: PMC9818993 DOI: 10.3390/diagnostics13010011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/17/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022] Open
Abstract
Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders distinguished by dysplastic bone marrow and peripheral blood cells, ineffective hematopoiesis, and an increased risk of developing acute myeloid leukemia (AML). MDS with ring sideroblasts (MDS-RS) is a favorable outcome subtype with a lower frequency of AML transformation. The FDA recently approved luspatercept for the treatment of patients with very-low-, low-, and intermediate-risk MDS-RS who have failed to correct anemia with an erythropoiesis-stimulating agent (ESA) and require two units of red blood cells over an eight-week period. This drug's pharmacology is based on the critical role of the transforming growth factor-beta (TGF-β) pathway in regulating erythropoiesis. In this case report, we describe for the first time an acute kidney injury caused by membranoproliferative glomerulonephritis (MPGN) in a patient with MDS-RS who was treated with luspatercept. We propose that a multi-hit hypothesis could explain the immunopathogenesis. A first unknown hit may stimulate IgA immune complex production, whereas luspatercept administration acts as a second hit, causing Smad1-5-8 phosphorylation. This intriguing case report on immune-complex-mediated proliferative glomerulonephritis following luspatercept treatment generates hypotheses and stimulates further research in this area.
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Affiliation(s)
- Sigurd Delanghe
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium
| | - Tri Q. Nguyen
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Dominiek Mazure
- Department of Hematology, Ghent University Hospital, 9000 Ghent, Belgium
| | - Amélie Dendooven
- Department of Pathology, Ghent University Hospital, 9000 Ghent, Belgium
- Faculty of Medicine and Health Sciences, University of Antwerp, 2000 Antwerp, Belgium
| | - Marijn M. Speeckaert
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium
- Research Foundation-Flanders (FWO), 1090 Brussels, Belgium
- Correspondence: ; Tel.: +32-933-245-09; Fax: +32-933-238-47
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20
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Gangat N, Chetram D, McCullough K, Al-Kali A, Begna K, Hogan W, Litzow M, Foran J, Badar T, Palmer J, Patnaik M, Pardanani A, Tefferi A. Limited activity of luspatercept in myelofibrosis and myeloid neoplasms other than myelodysplastic syndromes with ring sideroblasts. Am J Hematol 2022; 97:E474-E477. [PMID: 36197043 DOI: 10.1002/ajh.26749] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 09/22/2022] [Accepted: 10/02/2022] [Indexed: 01/31/2023]
Affiliation(s)
- Naseema Gangat
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Deandra Chetram
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Aref Al-Kali
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kebede Begna
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - William Hogan
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Mark Litzow
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - James Foran
- Division of Hematology, Mayo Clinic, Jacksonville, Florida, USA
| | - Talha Badar
- Division of Hematology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jeanne Palmer
- Division of Hematology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Mrinal Patnaik
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Ayalew Tefferi
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
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21
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Ambinder AJ, DeZern AE. Navigating the contested borders between myelodysplastic syndrome and acute myeloid leukemia. Front Oncol 2022; 12:1033534. [PMID: 36387170 PMCID: PMC9650616 DOI: 10.3389/fonc.2022.1033534] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/11/2022] [Indexed: 10/23/2023] Open
Abstract
Myelodysplastic syndrome and acute myeloid leukemia are heterogeneous myeloid neoplasms which arise from the accumulation of mutations in a myeloid stem cell or progenitor that confer survival or growth advantages. These disease processes are formally differentiated by clinical, laboratory, and morphological presentations, especially with regard to the preponderance of blasts in the peripheral blood or bone marrow (AML); however, they are closely associated through their shared lineage as well as their existence on a spectrum with some cases of MDS displaying increased blasts, a feature that reflects more AML-like behavior, and the propensity for MDS to transform into AML. It is increasingly recognized that the distinctions between these two entities result from the divergent patterns of genetic alterations that drive each of them. Mutations in genes related to chromatin-remodeling and the spliceosome are seen in both MDS and AML arising out of antecedent MDS, while mutations in genes related to signaling pathways such as RAS or FLT3 are more typically seen in AML or otherwise are a harbinger of transformation. In this review, we focus on the insights into the biological and genetic distinctions and similarities between MDS and AML that are now used to refine clinical prognostication, guide disease management, and to inform development of novel therapeutic approaches.
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Affiliation(s)
| | - Amy E. DeZern
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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22
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Kontandreopoulou CN, Kalopisis K, Viniou NA, Diamantopoulos P. The genetics of myelodysplastic syndromes and the opportunities for tailored treatments. Front Oncol 2022; 12:989483. [PMID: 36338673 PMCID: PMC9630842 DOI: 10.3389/fonc.2022.989483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Genomic instability, microenvironmental aberrations, and somatic mutations contribute to the phenotype of myelodysplastic syndrome and the risk for transformation to AML. Genes involved in RNA splicing, DNA methylation, histone modification, the cohesin complex, transcription, DNA damage response pathway, signal transduction and other pathways constitute recurrent mutational targets in MDS. RNA-splicing and DNA methylation mutations seem to occur early and are reported as driver mutations in over 50% of MDS patients. The improved understanding of the molecular landscape of MDS has led to better disease and risk classification, leading to novel therapeutic opportunities. Based on these findings, novel agents are currently under preclinical and clinical development and expected to improve the clinical outcome of patients with MDS in the upcoming years. This review provides a comprehensive update of the normal gene function as well as the impact of mutations in the pathogenesis, deregulation, diagnosis, and prognosis of MDS, focuses on the most recent advances of the genetic basis of myelodysplastic syndromes and their clinical relevance, and the latest targeted therapeutic approaches including investigational and approved agents for MDS.
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23
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Rodriguez-Sevilla JJ, Calvo X, Arenillas L. Causes and Pathophysiology of Acquired Sideroblastic Anemia. Genes (Basel) 2022; 13:1562. [PMID: 36140729 PMCID: PMC9498732 DOI: 10.3390/genes13091562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/22/2022] [Accepted: 08/26/2022] [Indexed: 01/19/2023] Open
Abstract
The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia and the presence of ring sideroblasts in the bone marrow. Ring sideroblasts are abnormal erythroblasts with iron-loaded mitochondria that are visualized by Prussian blue staining as a perinuclear ring of green-blue granules. The mechanisms that lead to the ring sideroblast formation are heterogeneous, but in all of them, there is an abnormal deposition of iron in the mitochondria of erythroblasts. Congenital sideroblastic anemias include nonsyndromic and syndromic disorders. Acquired sideroblastic anemias include conditions that range from clonal disorders (myeloid neoplasms as myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with ring sideroblasts) to toxic or metabolic reversible sideroblastic anemia. In the last 30 years, due to the advances in genomic techniques, a deep knowledge of the pathophysiological mechanisms has been accomplished and the bases for possible targeted treatments have been established. The distinction between the different forms of sideroblastic anemia is based on the study of the characteristics of the anemia, age of diagnosis, clinical manifestations, and the performance of laboratory analysis involving genetic testing in many cases. This review focuses on the differential diagnosis of acquired disorders associated with ring sideroblasts.
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Affiliation(s)
| | - Xavier Calvo
- Laboratori de Citologia Hematològica, Department of Pathology, Hospital del Mar, 08003 Barcelona, Spain
- Group of Translational Research on Hematological Neoplasms (GRETNHE), IMIM-Hospital del Mar, 08003 Barcelona, Spain
| | - Leonor Arenillas
- Laboratori de Citologia Hematològica, Department of Pathology, Hospital del Mar, 08003 Barcelona, Spain
- Group of Translational Research on Hematological Neoplasms (GRETNHE), IMIM-Hospital del Mar, 08003 Barcelona, Spain
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Ji YS, Park SK, Jeon BR, Jang MA. Low-level somatic JAK2 V617F mutation in myelodysplastic/myeloproliferative neoplasm with ring sideroblasts, and thrombocytosis with co-mutated SF3B1 and CALR. Blood Res 2022; 57:239-241. [PMID: 35920094 PMCID: PMC9492522 DOI: 10.5045/br.2022.2022105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 11/25/2022] Open
Affiliation(s)
- Young Sok Ji
- Division of Hemato-Oncology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Seong Kyu Park
- Division of Hemato-Oncology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Byung Ryul Jeon
- Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Mi-Ae Jang
- Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
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Girard S, Genevieve F, Rault E, Fenneteau O, Lesesve JF. When Ring Sideroblasts on Bone Marrow Smears Are Inconsistent with the Diagnosis of Myelodysplastic Neoplasms. Diagnostics (Basel) 2022; 12:1752. [PMID: 35885655 PMCID: PMC9320983 DOI: 10.3390/diagnostics12071752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/08/2022] [Accepted: 07/16/2022] [Indexed: 01/19/2023] Open
Abstract
Ring sideroblasts are commonly seen in myelodysplastic neoplasms and are a key condition for identifying distinct entities of myelodysplastic neoplasms according to the WHO classification. However, the presence of ring sideroblasts is not exclusive to myelodysplastic neoplasms. Ring sideroblasts are as well either encountered in non-clonal secondary acquired disorders, such as exposure to toxic substances, drug/medicine, copper deficiency, zinc overload, lead poison, or hereditary sideroblastic anemias related to X-linked, autosomal, or mitochondrial mutations. This review article will discuss diseases associated with ring sideroblasts outside the context of myelodysplastic neoplasms. Knowledge of the differential diagnoses characterized by the presence of ring sideroblasts in bone marrow is essential to prevent any misdiagnosis, which leads to delayed diagnosis and subsequent management of patients that differ in the different forms of sideroblastic anemia.
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Affiliation(s)
- Sandrine Girard
- Laboratory of Hematology, Center of Biology and Pathology East, Hospices Civils de Lyon, 69500 Bron, France
- French-Speaking Cellular Hematology Group, 69500 Bron, France; (F.G.); (E.R.); (O.F.); (J.-F.L.)
| | - Franck Genevieve
- French-Speaking Cellular Hematology Group, 69500 Bron, France; (F.G.); (E.R.); (O.F.); (J.-F.L.)
- Laboratory of Hematology, Angers University Hospital, 49100 Angers, France
| | - Emmanuelle Rault
- French-Speaking Cellular Hematology Group, 69500 Bron, France; (F.G.); (E.R.); (O.F.); (J.-F.L.)
- Department of Biological Hematology, Tours University Hospital, 37081 Tours, France
| | - Odile Fenneteau
- French-Speaking Cellular Hematology Group, 69500 Bron, France; (F.G.); (E.R.); (O.F.); (J.-F.L.)
- Laboratory of Hematology, Robert Debré Hospital, APHP, 75019 Paris, France
| | - Jean-François Lesesve
- French-Speaking Cellular Hematology Group, 69500 Bron, France; (F.G.); (E.R.); (O.F.); (J.-F.L.)
- Laboratory of Hematology, Nancy University Hospital, 54000 Nancy, France
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Lours C, Cottin L, Wiber M, Andrieu V, Baccini V, Baseggio L, Brouzes C, Chatelain B, Daliphard S, Fenneteau O, Geneviève F, Girard S, Leymarie V, Maloum K, Rieu JB, Sebahoun G, Sudaka I, Troussard X, Wagner-Ballon O, Wuilleme S, Bardet V, Lesesve JF. Perls’ Stain Guidelines from the French-Speaking Cellular Hematology Group (GFHC). Diagnostics (Basel) 2022; 12:diagnostics12071698. [PMID: 35885602 PMCID: PMC9318570 DOI: 10.3390/diagnostics12071698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 11/16/2022] Open
Abstract
In order to standardize cellular hematology practices, the French-speaking Cellular Hematology Group (Groupe Francophone d’Hématologie Cellulaire, GFHC) focused on Perls’ stain. A national survey was carried out, leading to the proposal of recommendations on insoluble iron detection and quantification in bone marrow. The criteria presented here met with a “strong professional agreement” and follow the suggestions of the World Health Organization’s classification of hematological malignancies.
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Affiliation(s)
- Camille Lours
- Service d’Hématologie Biologique, Centre de Biologie et de Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France;
- Correspondence:
| | - Laurane Cottin
- Laboratoire d’Hématologie, Centre Hospitalier Universitaire d’Angers, 49100 Angers, France; (L.C.); (M.W.); (F.G.)
| | - Margaux Wiber
- Laboratoire d’Hématologie, Centre Hospitalier Universitaire d’Angers, 49100 Angers, France; (L.C.); (M.W.); (F.G.)
| | - Valérie Andrieu
- Département d’Hématologie et Immunologie, Groupement Hospitalier Bichat Claude Bernard, 75018 Paris, France;
| | - Véronique Baccini
- Laboratoire d’Hématologie Immunologie, Centre Hospitalier Universitaire de Pointe-à-Pitre, 97159 Pointe-à-Pitre, France;
| | - Lucile Baseggio
- Service d’Hématologie Biologique, Centre de Biologie et de Pathologie Sud, Hôpital Lyon Sud, Hospices Civils de Lyon, 69495 Pierre Bénite, France;
| | - Chantal Brouzes
- Service d’Hématologie Biologique, Hôpital Necker, 75015 Paris, France;
| | - Bernard Chatelain
- Laboratoire d’Hématologie, Clinique Universitaire UCL de Mont-Godinne, 5530 Yvoir, Belgium;
| | - Sylvie Daliphard
- Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Rouen, 76000 Rouen, France;
| | - Odile Fenneteau
- Laboratoire d’Hématologie, Hôpital Robert Debré, 75019 Paris, France;
| | - Franck Geneviève
- Laboratoire d’Hématologie, Centre Hospitalier Universitaire d’Angers, 49100 Angers, France; (L.C.); (M.W.); (F.G.)
| | - Sandrine Girard
- Service d’Hématologie Biologique, Centre de Biologie et de Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France;
| | - Vincent Leymarie
- Laboratoire d’Hématologie, Centre Hospitalier d’Avicenne, 93000 Bobigny, France;
| | - Karim Maloum
- Service d’Hématologie Biologique, Hôpital Pitié Salpêtrière, 75013 Paris, France;
| | - Jean-Baptiste Rieu
- Laboratoire d’Hématologie, Institut Universitaire du Cancer—Oncopôle, 31100 Toulouse, France;
| | - Gérard Sebahoun
- Laboratoire d’Hématologie, APHM Hôpital Nord, 13005 Marseille, France;
| | - Isabelle Sudaka
- Laboratoire d’Hématologie, Hôpital Pasteur, 06000 Nice, France;
| | - Xavier Troussard
- Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Caen, 14033 Caen, France;
| | - Orianne Wagner-Ballon
- Département d’Hématologie et d’Immunologie Biologiques, Hôpital Universitaire Henri Mondor, 94000 Créteil, France;
| | - Soraya Wuilleme
- Laboratoire d’Hématologie, Centre Hospitalier de Nantes, 44000 Nantes, France;
| | - Valérie Bardet
- Service d’Hématologie-Immunologie-Transfusion, CHU Ambroise Paré, INSERM UMR 1184, AP-HP, Université Paris Saclay, 92100 Boulogne Billancourt, France;
| | - Jean-François Lesesve
- Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Nancy, 54000 Nancy, France;
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Farrukh F, Chetram D, Al‐Kali A, Foran J, Patnaik M, Badar T, Begna K, Hook C, Hogan W, McCullough KB, Mangaonkar A, He R, Gangat N, Tefferi A. Real-world experience with luspatercept and predictors of response in myelodysplastic syndromes with ring sideroblasts. Am J Hematol 2022; 97:E210-E214. [PMID: 35293000 DOI: 10.1002/ajh.26533] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/10/2022] [Accepted: 03/12/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Faiqa Farrukh
- Division of Hematolog Mayo Clinic Rochester Minnesota USA
| | | | - Aref Al‐Kali
- Division of Hematolog Mayo Clinic Rochester Minnesota USA
| | - James Foran
- Division of Hematolog Mayo Clinic Jacksonville Florida USA
| | - Mrinal Patnaik
- Division of Hematolog Mayo Clinic Rochester Minnesota USA
| | - Talha Badar
- Division of Hematolog Mayo Clinic Jacksonville Florida USA
| | - Kebede Begna
- Division of Hematolog Mayo Clinic Rochester Minnesota USA
| | | | - William Hogan
- Division of Hematolog Mayo Clinic Rochester Minnesota USA
| | | | | | - Rong He
- Division of Hematopathology Mayo Clinic Rochester Minnesota USA
| | - Naseema Gangat
- Division of Hematolog Mayo Clinic Rochester Minnesota USA
| | - Ayalew Tefferi
- Division of Hematolog Mayo Clinic Rochester Minnesota USA
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Liu WB, Ma JX, Tong HX. Successful treatment in one myelodysplastic syndrome patient with primary thrombocytopenia and secondary deep vein thrombosis: A case report. World J Clin Cases 2022; 10:4640-4647. [PMID: 35663076 PMCID: PMC9125256 DOI: 10.12998/wjcc.v10.i14.4640] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/09/2022] [Accepted: 04/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The contradictory process of coagulation and anticoagulation maintains normal physiological function, and platelets (PLTs) play a key role in hemostasis and bleeding. When severe thrombocytopenia and deep vein thrombosis (DVT) occur simultaneously, the physician will be confronted with a great challenge, especially when interventional thrombectomy fails. CASE SUMMARY We describe a 52-year-old woman who suffered from myelodysplastic syndrome with severe thrombocytopenia and protein S deficiency with right lower extremity DVT. In this patient, the treatment of DVT was associated with numerous contradictions due to severe thrombocytopenia, especially when interventional thrombectomy was not successful. Fortunately, fondaparinux sodium effectively alleviated the thrombus status of the patient and gradually decreased the D-dimer level. In addition, no increase in bleeding was noted. The application of eltrombopag stimulated the maturation and differentiation of megakaryocytes and increased the peripheral blood PLT count. The clinical symptoms of DVT in the right lower extremities in this patient significantly improved. The patient resumed daily life activities, and the treatment effects were independent of PLT transfusion. CONCLUSION This is a contradictory and complex case, and fondaparinux sodium and eltrombopag may represent a good choice for the treatment of DVT in patients with severe thrombocytopenia.
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Affiliation(s)
- Wen-Bin Liu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
| | - Jian-Xiong Ma
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 320000, Zhejiang Province, China
| | - Hong-Xuan Tong
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
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Enjeti AK, Agarwal R, Blombery P, Chee L, Chua CC, Grigg A, Hamad N, Iland H, Lane S, Perkins A, Singhal D, Tate C, Tiong IS, Ross DM. Panel-based gene testing in myelodysplastic/myeloproliferative neoplasm- overlap syndromes: Australasian Leukaemia and Lymphoma Group (ALLG) consensus statement. Pathology 2022; 54:389-398. [DOI: 10.1016/j.pathol.2022.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 03/20/2022] [Accepted: 03/23/2022] [Indexed: 11/30/2022]
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Komrokji RS, Platzbecker U, Fenaux P, Zeidan AM, Garcia-Manero G, Mufti GJ, Santini V, Díez-Campelo M, Finelli C, Jurcic JG, Greenberg PL, Sekeres MA, DeZern AE, Savona MR, Shetty JK, Ito R, Zhang G, Ha X, Backstrom JT, Verma A. Luspatercept for myelodysplastic syndromes/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis. Leukemia 2022; 36:1432-1435. [PMID: 35220402 PMCID: PMC9061284 DOI: 10.1038/s41375-022-01521-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 01/06/2022] [Accepted: 02/01/2022] [Indexed: 11/09/2022]
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Myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T): Mayo-Moffitt collaborative study of 158 patients. Blood Cancer J 2022; 12:26. [PMID: 35105856 PMCID: PMC8807827 DOI: 10.1038/s41408-022-00622-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 01/16/2022] [Accepted: 01/20/2022] [Indexed: 11/23/2022] Open
Abstract
The current World Health Organization (WHO) classification of myeloid malignancies includes myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) as a distinct entity. Previous literature on predictors of survival was based on the provisional category of refractory anemia with ring sideroblast and thrombocytosis (RARS-T), which was not subject to MDS/MPN-RS-T exclusionary criteria such as PB blast% ≥1, BM blast% ≥5 or cytogenetic abnormalities such as t(3;3)(q21.2;q26.2), inv(3)(q21.23q26.2) or isolated del(5q). We examined overall (OS) and leukemia-free (LFS) survival and its predictors, among 158 patients with WHO-defined MDS/MPN-RS-T. In univariate analysis, age ≥70 years (P = 0.006), hemoglobin (Hb) ≤10 g/dL (P = 0.03) and abnormal karyotype (excluding -Y, P = 0.008) were associated with shortened OS, which was otherwise not affected by either ASXL1 (P = 0.7), SF3B1 (P = 0.4) or JAK2 V617F (P = 0.7) mutations; in multivariable analysis, Hb ≤ 10 g/dL (P = 0.03) and abnormal karyotype (P = 0.001) remained significant, and thus allowed the development of an operational survival model with low (0 risk factors, median OS 10.5 years), intermediate (1 risk factor, median OS 4.8 years) and high risk (2 risk factors, median OS 1.4 years) categories (P = 0.0009). Comparison of MDS/MPN-RS-T (n = 158) and MDS/MPN-U with BM RS ≥ 15% (MDS/MPN-U-RS; n = 25) did not reveal significant differences in frequency of thrombosis, OS, or LFS, although SF3B1 mutation frequency was higher in the former (93% versus 59%; P = 0.0005). These data suggest limited survival impact for molecular abnormalities and the morphological distinction between MDS/MPN-RS-T and MDS/MPN-U-RS.
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Yang Y, Tang Z, Ji J, Yang C, Chen M, Han B. Recombinant Human Thrombopoietin Accelerates the Recovery of Platelet in Patients With Lower-Risk Myelodysplastic Syndrome: A Proof-of-Concept Study. Front Oncol 2021; 11:721764. [PMID: 34778037 PMCID: PMC8581467 DOI: 10.3389/fonc.2021.721764] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 10/07/2021] [Indexed: 11/13/2022] Open
Abstract
Aim The effect of recombinant human thrombopoietin (rhTPO) is largely unknown in lower-risk myelodysplastic syndrome (LR-MDS). This study aimed at investigating the safety and efficacy of rhTPO in patients with LR-MDS. Methods LR-MDS patients receiving stanozolol (2 mg, t.i.d.) and supportive care alone (non-rhTPO) or additional rhTPO were enrolled in this study prospectively. rhTPO was given at 15,000 U (q.d.) for 7 days/month for at least 3 months. Patients stopped rhTPO if the platelet count was higher than 50 × 109/L or had no effects after 3 months of treatment. The overall response (OR), complete response (CR), platelet response, side effects, clone evolution, and clinical outcome were evaluated. Result Thirty-five patients were enrolled: 20 (57.1%) patients in the rhTPO group and 15 (42.9%) patients in the non-rhTPO group. The demographic and baseline characteristics were balanced between the two groups. Platelet response was higher at 1 and 2 months as compared with that in the non-rhTPO group (p = 0.006 and p = 0.001, respectively). Meanwhile, the rhTPO group had a shorter time to achieve a platelet transfusion-free state compared with the non-rhTPO group (p = 0.034). Hematologic response was higher at 1 and 2 months compared with that in the non-rhTPO group (p = 0.006 and p = 0.001, respectively). There was no significant difference in the overall response or complete response at 1, 2, 3, 6, and 12 months between the two groups. One patient in the rhTPO group evolved into higher-risk MDS at 9 months. No significant difference in disease progression, infection, gastrointestinal disorders, or drug-related liver/renal injuries was found between the two groups (p > 0.05). Conclusion Adding short-term rhTPO can accelerate the early platelet response and decrease platelet transfusion, with no obvious side effects. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT04324060?cond=NCT04324060&draw=2, identifier NCT04324060
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Affiliation(s)
- Yuan Yang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zengwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiang Ji
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chen Yang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Miao Chen
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bing Han
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Lee P, Yim R, Yung Y, Chu HT, Yip PK, Gill H. Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome. Int J Mol Sci 2021; 22:10232. [PMID: 34638574 PMCID: PMC8508686 DOI: 10.3390/ijms221910232] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/17/2021] [Accepted: 09/21/2021] [Indexed: 12/22/2022] Open
Abstract
Myelodysplastic syndrome (MDS) is a heterogeneous, clonal hematological disorder characterized by ineffective hematopoiesis, cytopenia, morphologic dysplasia, and predisposition to acute myeloid leukemia (AML). Stem cell genomic instability, microenvironmental aberrations, and somatic mutations contribute to leukemic transformation. The hypomethylating agents (HMAs), azacitidine and decitabine are the standard of care for patients with higher-risk MDS. Although these agents induce responses in up to 40-60% of patients, primary or secondary drug resistance is relatively common. To improve the treatment outcome, combinational therapies comprising HMA with targeted therapy or immunotherapy are being evaluated and are under continuous development. This review provides a comprehensive update of the molecular pathogenesis and immune-dysregulations involved in MDS, mechanisms of resistance to HMA, and strategies to overcome HMA resistance.
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Affiliation(s)
| | | | | | | | | | - Harinder Gill
- Division of Haematology, Medical Oncology and Haemopoietic Stem Cell Transplantation, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China; (P.L.); (R.Y.); (Y.Y.); (H.-T.C.); (P.-K.Y.)
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EnvIRONmental Aspects in Myelodysplastic Syndrome. Int J Mol Sci 2021; 22:ijms22105202. [PMID: 34068996 PMCID: PMC8156755 DOI: 10.3390/ijms22105202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 11/24/2022] Open
Abstract
Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes and can no longer be generalized. While a certain amount of iron and reactive oxygen species (ROS) are indispensable for proper hematological output, both are harmful if present in excess. Consequently, iron overload has been increasingly recognized as an important player in MDS, which is worth paying attention to. This review focuses on iron- and ROS-mediated effects in the bone marrow niche, their implications for hematopoiesis and their yet unclear involvement in clonal evolution. Moreover, we provide recent insights into hepcidin regulation in MDS and its interaction between erythropoiesis and inflammation. Based on Tet methylcytosine dioxygenase 2 (TET2), representing one of the most frequently mutated genes in MDS, leading to disturbances in both iron homeostasis and hematopoiesis, we highlight that different genetic alteration may have different implications and that a comprehensive workup is needed for a complete understanding and development of future therapies.
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35
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Hasserjian RP, Buckstein R, Patnaik MM. Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes. Am Soc Clin Oncol Educ Book 2021; 41:328-350. [PMID: 34010050 DOI: 10.1200/edbk_320113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPNs) are clonal diseases that differ in morphologic diagnostic criteria but share some common disease phenotypes that include cytopenias, propensity to acute myeloid leukemia evolution, and a substantially shortened patient survival. MDS/MPNs share many clinical and molecular features with MDS, including frequent mutations involving epigenetic modifier and/or spliceosome genes. Although the current 2016 World Health Organization classification incorporates some genetic features in its diagnostic criteria for MDS and MDS/MPNs, recent accumulation of data has underscored the importance of the mutation profiles on both disease classification and prognosis. Machine-learning algorithms have identified distinct molecular genetic signatures that help refine prognosis and notable associations of these genetic signatures with morphologic and clinical features. Combined geno-clinical models that incorporate mutation data seem to surpass the current prognostic schemes. Future MDS classification and prognostication schema will be based on the portfolio of genetic aberrations and traditional features, such as blast count and clinical factors. Arriving at these systems will require studies on large patient cohorts that incorporate advanced computational analysis. The current treatment algorithm in MDS is based on patient risk as derived from existing prognostic and disease classes. Luspatercept is newly approved for patients with MDS and ring sideroblasts who are transfusion dependent after erythropoietic-stimulating agent failure. Other agents that address red blood cell transfusion dependence in patients with lower-risk MDS and the failure of hypomethylating agents in higher-risk disease are in advanced testing. Finally, a plethora of novel targeted agents and immune checkpoint inhibitors are being evaluated in combination with a hypomethylating agent backbone to augment the depth and duration of response and, we hope, improve overall survival.
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Affiliation(s)
| | - Rena Buckstein
- Division of Hematology/Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada
| | - Mrinal M Patnaik
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, MN
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