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Costa A, Breccia M. SOHO State of the Art Updates and Next Questions. Atypical Chronic Myeloid Leukemia: Pathogenesis, Diagnostic Challenges, and Therapeutic Strategies. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025:S2152-2650(25)00110-7. [PMID: 40288921 DOI: 10.1016/j.clml.2025.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025]
Abstract
Atypical chronic myeloid leukemia (aCML) is a rare and challenging clonal hematopoietic disorder within the myelodysplastic/myeloproliferative neoplasm (MDS/MPN) spectrum. Over the past two decades, substantial progress has been made in understanding the genetic mechanisms driving aCML, revealing a complex and heterogeneous mutational landscape. Key ancestral mutations, such as ASXL1 and ETNK1, have been identified, providing a foundation for the pathogenesis and for the possible emergence of secondary abnormalities, particularly in epigenetic regulation (eg, SETBP1), and in splicing process (eg, SRSF2). These molecular insights have been integrated into current diagnostic classifications, refining disease characterization and offering potential targets for precision therapies. Despite these advances, significant clinical challenges persist due to the disease's rarity and the lack of randomized clinical trials. Therapeutic strategies remain inadequately defined, with allogeneic stem cell transplantation being the only curative option. This review provides an overview of the molecular, clinical, and therapeutic information that may pave the way for essential advancements in the proper management of this disease.
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Affiliation(s)
- Alessandro Costa
- Hematology Unit, Businco Hospital, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Massimo Breccia
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy.
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Szuber N, Orazi A, Tefferi A. Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management. Am J Hematol 2024; 99:1360-1387. [PMID: 38644693 DOI: 10.1002/ajh.27321] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 03/18/2024] [Indexed: 04/23/2024]
Abstract
Chronic neutrophilic leukemia (CNL) is a rare BCR::ABL1-negative myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis and bone marrow granulocyte hyperplasia. Atypical chronic myeloid leukemia (aCML) (myelodysplastic "[MDS]/MPN with neutrophilia" per World Health Organization [WHO]) is a MDS/MPN overlap disorder featuring dysplastic neutrophilia and circulating myeloid precursors. Both manifest with frequent hepatosplenomegaly and less commonly, bleeding, with high rates of leukemic transformation and death. The 2022 revised WHO classification conserved CNL diagnostic criteria of leukocytosis ≥25 × 109/L, neutrophils ≥80% with <10% circulating precursors, absence of dysplasia, and presence of an activating CSF3R mutation. ICC criteria are harmonized with those of other myeloid entities, with a key distinction being lower leukocytosis threshold (≥13 × 109/L) for cases CSF3R-mutated. Criteria for aCML include leukocytosis ≥13 × 109/L, dysgranulopoiesis, circulating myeloid precursors ≥10%, and at least one cytopenia for MDS-thresholds (ICC). In both classifications ASXL1 and SETBP1 (ICC), or SETBP1 ± ETNK1 (WHO) mutations can be used to support the diagnosis. Both diseases show hypercellular bone marrow due to a granulocytic proliferation, aCML distinguished by dysplasia in granulocytes ± other lineages. Absence of monocytosis, rare/no basophilia, or eosinophilia, <20% blasts, and exclusion of other MPN, MDS/MPN, and tyrosine kinase fusions, are mandated. Cytogenetic abnormalities are identified in ~1/3 of CNL and ~15-40% of aCML patients. The molecular signature of CNL is a driver mutation in colony-stimulating factor 3 receptor-classically T618I, documented in >80% of cases. Atypical CML harbors a complex genomic backdrop with high rates of recurrent somatic mutations in ASXL1, SETBP1, TET2, SRSF2, EZH2, and less frequently in ETNK1. Leukemic transformation rates are ~10-25% and 30-40% for CNL and aCML, respectively. Overall survival is poor: 15-31 months in CNL and 12-20 months in aCML. The Mayo Clinic CNL risk model for survival stratifies patients according to platelets <160 × 109/L (2 points), leukocytes >60 × 109/L (1 point), and ASXL1 mutation (1 point); distinguishing low- (0-1 points) versus high-risk (2-4 points) categories. The Mayo Clinic aCML risk model attributes 1 point each for: age >67 years, hemoglobin <10 g/dL, and TET2 mutation, delineating low- (0-1 risk factor) and high-risk (≥2 risk factors) subgroups. Management is risk-driven and symptom-directed, with no current standard of care. Most commonly used agents include hydroxyurea, interferon, Janus kinase inhibitors, and hypomethylating agents, though none are disease-modifying. Hematopoietic stem cell transplant is the only potentially curative modality and should be considered in eligible patients. Recent genetic profiling has disclosed CBL, CEBPA, EZH2, NRAS, TET2, and U2AF1 to represent high-risk mutations in both entities. Actionable mutations (NRAS/KRAS, ETNK1) have also been identified, supporting novel agents targeting involved pathways. Preclinical and clinical studies evaluating new drugs (e.g., fedratinib, phase 2) and combinations are detailed.
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MESH Headings
- Humans
- Leukemia, Neutrophilic, Chronic/genetics
- Leukemia, Neutrophilic, Chronic/diagnosis
- Leukemia, Neutrophilic, Chronic/therapy
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/diagnosis
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/therapy
- Mutation
- Risk Assessment
- Receptors, Colony-Stimulating Factor/genetics
- Carrier Proteins
- Nuclear Proteins
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Affiliation(s)
- Natasha Szuber
- Department of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
| | - Attilio Orazi
- Department of Pathology, Texas Tech University Health Sciences Center, El Paso, Texas, USA
| | - Ayalew Tefferi
- Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
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Elmakaty I, Saglio G, Al-Khabori M, Elsayed A, Elsayed B, Elmarasi M, Elsabagh AA, Alshurafa A, Ali E, Yassin M. The Contemporary Role of Hematopoietic Stem Cell Transplantation in the Management of Chronic Myeloid Leukemia: Is It the Same in All Settings? Cancers (Basel) 2024; 16:754. [PMID: 38398145 PMCID: PMC10886670 DOI: 10.3390/cancers16040754] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/07/2023] [Accepted: 11/10/2023] [Indexed: 02/25/2024] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) patients has transitioned from the standard of care to a treatment option limited to those with unsatisfactory tyrosine kinase inhibitor (TKI) responses and advanced disease stages. In recent years, the threshold for undergoing HSCT has increased. Most CML patients now have life expectancies comparable to the general population, and therefore, the goal of therapy is shifting toward achieving treatment-free remission (TFR). While TKI discontinuation trials in CML show potential for achieving TFR, relapse risk is high, affirming allogeneic HSCT as the sole curative treatment. HSCT should be incorporated into treatment algorithms from the time of diagnosis and, in some patients, evaluated as soon as possible. In this review, we will look at some of the recent advances in HSCT, as well as its indication in the era of aiming for TFR in the presence of TKIs in CML.
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Affiliation(s)
- Ibrahim Elmakaty
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Giuseppe Saglio
- Department of Clinical and Biological Sciences, University of Turin, 10124 Turin, Italy
| | | | | | - Basant Elsayed
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Mohamed Elmarasi
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | | | - Awni Alshurafa
- Hematology Section, Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation (HMC), Doha P.O. Box 3050, Qatar
| | - Elrazi Ali
- Interfaith Medical Center, Brooklyn, NY 11213, USA
| | - Mohamed Yassin
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
- Hematology Section, Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation (HMC), Doha P.O. Box 3050, Qatar
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Liu L, Song X, Dong W, Li Z, Guo D. Case report: Safety and efficacy of synergistic treatment using selinexor and azacitidine in patients with atypical chronic myeloid leukemia with resistance to decitabine. Front Oncol 2024; 14:1353818. [PMID: 38384813 PMCID: PMC10879427 DOI: 10.3389/fonc.2024.1353818] [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: 12/11/2023] [Accepted: 01/22/2024] [Indexed: 02/23/2024] Open
Abstract
Background Atypical chronic myeloid leukemia (aCML) is a BCR::ABL1 negative myelodysplastic/myeloproliferative neoplasm with poor overall survival. Some patients can be treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) from suitable donors. The effectiveness of decitabine or azacitidine (AZA) has recently been reported; however, their combined efficacy with selinexor has not yet been reported. Case description In this study, we report the case of a patient with aCML who was successfully treated with selinexor combined with AZA. A 67-year-old man with a history of gastric mucosa-associated lymphoid tissue (MALT) lymphoma was admitted to the hospital with fatigue and emaciation. He was diagnosed with aCML and no longer responded to decitabine treatment after undergoing seven cycles. The patient was subsequently administered hydroxyurea (HU), selinexor, and AZA. After four courses of combination therapy, his blood cell counts improved; he no longer required transfusions and was able to discontinue HU. The patient continued receiving selinexor and AZA without severe complications. This case is the first to show that combinatorial selinexor and AZA therapy can effectively treat aCML. Conclusion Our case sheds light on the importance of selinexor and AZA combined therapy in the exploration of new treatment strategies for aCML. Moreover, this treatment approach offers the possibility of bridging with allo-HSCT.
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Affiliation(s)
- Lu Liu
- Department of Hematology, Qilu Hospital (Qingdao) of Shandong University, Qingdao, China
| | - Xiaofeng Song
- Department of Hand and Foot Surgery, Qilu Hospital (Qingdao) of Shandong University, Qingdao, China
| | - Wenhao Dong
- Department of Hematology, Qilu Hospital (Qingdao) of Shandong University, Qingdao, China
| | - Zhao Li
- Department of Hematology, Qilu Hospital (Qingdao) of Shandong University, Qingdao, China
| | - Dongmei Guo
- Department of Hematology, Qilu Hospital (Qingdao) of Shandong University, Qingdao, China
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Klein SK, Huls GA, Visser O, Kluin-Nelemans HC, Dinmohamed AG. Characteristics, primary treatment, and survival of MDS/MPN with neutrophilia: a population-based study. Blood Adv 2023; 7:7554-7563. [PMID: 37934881 PMCID: PMC10761362 DOI: 10.1182/bloodadvances.2023011181] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/02/2023] [Accepted: 10/27/2023] [Indexed: 11/09/2023] Open
Abstract
Myelodysplastic and myeloproliferative neoplasms (MDS/MPN) with neutrophilia, until recently called atypical chronic myeloid leukemia (aCML), being part of the MDS/MPN is a very rare disease with poor prognosis. Although emerging data reveal its cytogenetic and molecular profile, integrated survival and treatment data remain scarce. We analyzed a cohort of 347 adult patients diagnosed with MDS/MPN with neutrophilia, registered in the Netherlands Cancer Registry between 2001 and 2019. Our demographic baseline data align with other cohorts. We observed cytogenetic aberrations exclusively in patients aged >65 years, with trisomy 8 being the most common abnormality. We identified 16 distinct molecular mutations, with some patients (16/101) harboring up to 3 different mutations; ASXL1 being the most frequent one (22%). In a multivariable Cox regression analysis, only age, hemoglobin level and allogeneic hematopoietic stem cell transplant (alloHSCT) were associated with overall survival (aged >65 years; hazard ratio [HR] 1.85; P = .001 and alloHSCT HR, 0.51; P = .039). Because no other treatment modality seemed to affect survival and might cause toxicity, we propose that all patients eligible for alloHSCT should, whenever possible, receive an allogeneic transplant. It is imperative that we strive to improve outcomes for patients who are not eligible for alloHSCT. Tackling this challenge requires international collaborative efforts to conduct prospective intervention studies.
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MESH Headings
- Adult
- Humans
- Aged
- Myelodysplastic Syndromes/diagnosis
- Myelodysplastic Syndromes/therapy
- Myelodysplastic Syndromes/genetics
- Prospective Studies
- Myelodysplastic-Myeloproliferative Diseases/genetics
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/diagnosis
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/therapy
- Chromosome Aberrations
- Leukocytosis
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Affiliation(s)
- Saskia K. Klein
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gerwin A. Huls
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Otto Visser
- Department of Registration, Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands
| | - Hanneke C. Kluin-Nelemans
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Avinash G. Dinmohamed
- Department of Research and Development, Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands
- Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Hematology, Amsterdam UMC, Cancer Center Amsterdam, Amsterdam, The Netherlands
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Breccia M. Atypical CML: diagnosis and treatment. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2023; 2023:476-482. [PMID: 38066919 PMCID: PMC10727105 DOI: 10.1182/hematology.2023000448] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Atypical chronic myeloid leukemia (aCML) is included in the group of myelodysplastic/myeloproliferative neoplasms by the International Consensus Classification and has been renamed as MDS/MPN with neutrophilia by the fifth edition of World Health Organization classification. It is always characterized by morphologic identification of granulocytic dysplasia with >10% circulating immature myeloid cells, 2 distinguished features that differentiate this disease among the others. Somatic mutations may help to diagnose but are not specifically pathognomonic of the disease, with the most detected including ASXL1, SETBP1, NRAS, KRAS, SRSF2, and TET2 and with low-frequency CBL, CSF3R, JAK2, and ETNK1. The genomic landscape of aCML has been recently unravelling, revealing that SETBP1 and ETNK1 are usually not ancestral but secondary events associated with disease progression. Unfortunately, until now, no consensus on risk stratification and treatment has been developed: Mayo Clinic prognostic score identified as adverse events age >67 years, hemoglobin level <10 g/dL, and TET2 mutations. Although some possible genetic markers have been identified, allogeneic transplant remains the only curative strategy.
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MESH Headings
- Humans
- Aged
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/diagnosis
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/therapy
- Myelodysplastic-Myeloproliferative Diseases/diagnosis
- Mutation
- Prognosis
- Disease Progression
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Affiliation(s)
- Massimo Breccia
- Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
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Ilerhunmwuwa NP, Wasifuddin M, Becerra H, Rayapureddy AK, Wang JC. Characteristics and survival outcomes of patients with atypical chronic myeloid leukemia in the United States: A SEER-based analysis. Leuk Res Rep 2023; 20:100383. [PMID: 37592940 PMCID: PMC10428056 DOI: 10.1016/j.lrr.2023.100383] [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: 06/25/2023] [Revised: 07/19/2023] [Accepted: 08/05/2023] [Indexed: 08/19/2023] Open
Affiliation(s)
- Nosakhare Paul Ilerhunmwuwa
- Department of Internal Medicine, One Brooklyn Health/Brookdale University Hospital and Medical Center, Brooklyn, New York, United States of America
| | - Mustafa Wasifuddin
- Department of Internal Medicine, One Brooklyn Health/Brookdale University Hospital and Medical Center, Brooklyn, New York, United States of America
| | - Henry Becerra
- Incoming resident, Department of Internal Medicine, One Brooklyn Health/Brookdale University Hospital and Medical Center, Brooklyn, New York, United States of America
| | - Aditya Keerthi Rayapureddy
- Department of Internal Medicine, One Brooklyn Health/Interfaith Medical Center, Brooklyn, New York, United States of America
| | - Jen Chin Wang
- Department of Hematology and Oncology, One Brooklyn Health/Brookdale University Hospital and Medical Center, Brooklyn, New York, United States of America
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Rinaldi I, Winston K. Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review. J Blood Med 2023; 14:261-277. [PMID: 37051025 PMCID: PMC10084831 DOI: 10.2147/jbm.s382090] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 02/06/2023] [Indexed: 04/14/2023] Open
Abstract
Chronic myeloid leukemia (CML) is one of the most common leukemias occurring in the adult population. The course of CML is divided into three phases: the chronic phase, the acceleration phase, and the blast phase. Pathophysiology of CML revolves around Philadelphia chromosome that constitutively activate tyrosine kinase through BCR-ABL1 oncoprotein. In the era of tyrosine kinase inhibitors (TKIs), CML patients now have a similar life expectancy to people without CML, and it is now very rare for CML patients to progress to the blast phase. Only a small proportion of CML patients have resistance to TKI, caused by BCR-ABL1 point mutations. CML patients with TKI resistance should be treated with second or third generation TKI, depending on the BCR-ABL1 mutation. Recently, many studies have shown that it is possible for CML patients who achieve a long-term deep molecular response to stop TKIs treatment and maintain remission. This review aimed to provide an overview of CML, including its pathophysiology, clinical manifestations, the role of stem cells, CML treatments, and treatment-free remission.
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Affiliation(s)
- Ikhwan Rinaldi
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Cipto Mangunkusumo National General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Correspondence: Ikhwan Rinaldi, Division of Hematology and Medical Oncology, Department of Internal Medicine, Cipto Mangunkusumo National General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia, Email
| | - Kevin Winston
- Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Hospital Medicine, Bhakti Medicare Hospital, Sukabumi, Indonesia
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Elderdery AY, Idris HME, Tebien EM, Diab NA, Hamza SMA, Suliman BA, Alhamidi AH, Omer NE, Mills J. Impact of GSTT1 and GSTM1 Polymorphisms in the Susceptibility to Philadelphia Negative Chronic Myeloid Leukaemia. Curr Cancer Drug Targets 2023; 23:319-324. [PMID: 36305131 DOI: 10.2174/1568009623666221027103845] [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: 06/05/2022] [Revised: 08/30/2022] [Accepted: 09/15/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Our research aimed to clarify the role of genetic polymorphisms in GST (T1 and M1) in the development of Ph-ve CML. MATERIALS AND METHODS We report on a case-control study with 126 participants, divided into 26 patients with Ph-ve CML (57.7% male, 42.3% female) and 100 healthy volunteers (51% male, 49% female) with no medical history of cancer as a control population. All Ph-ve CML patients were diagnosed according to standard hematologic and cytogenetic criteria based on CBC, confirmed by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) to determine the presence or absence of the BCRABL gene, followed by bone marrow (BM) examination. RESULTS Of the 26 studied cases, 50% had the GSTT1 null genotype against 21% of the control group, a statistically significant difference (CI= 1.519 - 9.317; p-value= 0.004). The GSTM1 null genotype was detected in 23.1% of cases and 35% of controls, a difference not statistically significant (OR= 0.557; CI= 0.205-1.515; p-value= 0.252). The distribution of GSTT1 and GSTM1 polymorphisms was also examined according to gender, age and ethnic grouping; these findings revealed no statistically significant differences. CONCLUSION Our study reveals a strong correlation between GSTT1 polymorphism and Ph-ve CML, whereas the data for GSTM1 polymorphisms indicates no role in the initial development of the disease. More studies are required to further clarify these and other genes' roles in disease development.
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Affiliation(s)
- Abozer Y Elderdery
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia.,Health Sciences Research Unit, Jouf University, Sakaka, Saudi Arabia
| | - Hadeil M E Idris
- College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia
| | - Entesar M Tebien
- College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia
| | - Nada Abdalfatah Diab
- University of Khartoum/ Medical Laboratory Science Programme, Alhyatt University College, Khortoum, Sudan
| | - Siddiqa M A Hamza
- Department of Pathology, College of Medicine, Umm Alqura University, Algunfuda, Saudi Arabia
| | - Bandar A Suliman
- College of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia
| | - Abdulaziz H Alhamidi
- Clinical Laboratory Sciences Department, College of Applied Medical Science, King Saud University, Riyadh, Saudi Arabia
| | - Nawal Eltayeb Omer
- Faculty of Medicine, Department of Pathology, Assafa College, Khartoum, Sudan
| | - Jeremy Mills
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
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10
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Moyo TK, Mendler JH, Itzykson R, Kishtagari A, Solary E, Seegmiller AC, Gerds AT, Ayers GD, Dezern AE, Nazha A, Valent P, van de Loosdrecht AA, Onida F, Pleyer L, Cirici BX, Tibes R, Geissler K, Komrokji RS, Zhang J, Germing U, Steensma DP, Wiseman DH, Pfeilstöecker M, Elena C, Cross NCP, Kiladjian JJ, Luebbert M, Mesa RA, Montalban-Bravo G, Sanz GF, Platzbecker U, Patnaik MM, Padron E, Santini V, Fenaux P, Savona MR. The ABNL-MARRO 001 study: a phase 1-2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes. BMC Cancer 2022; 22:1013. [PMID: 36153475 PMCID: PMC9509596 DOI: 10.1186/s12885-022-10073-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 09/09/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).
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Affiliation(s)
- Tamara K Moyo
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA
- Levine Cancer Institute, Charlotte, NC, USA
| | - Jason H Mendler
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | | | - Ashwin Kishtagari
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA
| | - Eric Solary
- Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Adam C Seegmiller
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA
| | | | - Gregory D Ayers
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA
| | | | | | - Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | | | - Francesco Onida
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Lisa Pleyer
- Third Medical Department With Hematology, Medical Oncology, Rheumatology and Infectiology, Paracelsus Medical University, Salzburg, Austria
- Salzburg Cancer Research Institute Center for Clinical Cancer and Immunology Trials, Salzburg, Austria
| | - Blanca Xicoy Cirici
- Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Bellaterr, Spain
| | | | | | | | - Jing Zhang
- University of Wisconsin-Madison, Madison, WI, USA
| | - Ulrich Germing
- Department of Hematology, Oncology, and Clinical Immunology, University of Duesseldorf, Duesseldorf, Germany
| | | | | | - Michael Pfeilstöecker
- Hanusch Hospital and Ludwig Boltzmann Institute for Hematology and Oncology, Vienna, Austria
| | | | | | - Jean-Jacques Kiladjian
- Université de Paris, APHP, Hôpital Saint-Louis, Centre d'Investigations Cliniques, INSERM CIC 1427, Paris, France
| | | | - Ruben A Mesa
- Mays Cancer Center at UT Health San Antonio MD Anderson, San Antonio, TX, USA
| | | | | | | | | | - Eric Padron
- H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | | | | | - Michael R Savona
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA.
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11
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Symeonidis A, Chondropoulos S, Verigou E, Lazaris V, Kourakli A, Tsirigotis P. Allogeneic Hematopoietic Stem Cell Transplantation for Mixed or Overlap Myelodysplastic/Myeloproliferative Disorders. Front Oncol 2022; 12:884723. [PMID: 35992818 PMCID: PMC9389581 DOI: 10.3389/fonc.2022.884723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 05/23/2022] [Indexed: 12/30/2022] Open
Abstract
Chronic myelomonocytic leukemia (CMML) and the remaining, less frequent hybrid, mixed, or overlap myelodysplastic syndromes/myeloproliferative neoplasms (MDSs/MPNs) are difficult to treat neoplastic hematological disorders, exhibiting substantial clinical and prognostic heterogeneity, for which clear therapeutic guidelines or effective treatment options are still missing. CMML has an overall survival ranging from a few months to several years. Although patients with proliferative or dysplastic features may benefit from hydroxyurea and hypomethylating agent treatment, respectively, none of these treatments can establish long-term remission and prevent the inevitable transformation to acute leukemia. Novel targeted treatment approaches are emerging but are still under investigation. Therefore, currently, allogeneic stem cell transplantation (allo-SCT) remains the only treatment modality with a curative potential, but its widespread application is limited, due to significant morbidity and mortality associated with the procedure, especially in the elderly and in patients with comorbidities. Recognition of patient eligibility for allo-SCT is crucial, and the procedure should be addressed to patients with a good performance status without severe comorbidities and mainly to those in intermediate- to high-risk category, with a suitable stem cell donor available. The issues of best timing for performing transplantation, patient and donor eligibility, the type of conditioning regimen, and the outcomes after various allo-SCT procedures are the topics of this review.
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Affiliation(s)
- Argiris Symeonidis
- University of Patras Medical School, Hematology Division, Patras, Greece
- *Correspondence: Argiris Symeonidis, ; orcid.org/0000-0002-0543-046X
| | | | - Evgenia Verigou
- Hematology Division, General University Hospital of Patras, Rion of Patras, Greece
| | - Vasileios Lazaris
- Hematology Division, General University Hospital of Patras, Rion of Patras, Greece
| | - Alexandra Kourakli
- Hematology Division, General University Hospital of Patras, Rion of Patras, Greece
| | - Panagiotis Tsirigotis
- Department of Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
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12
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Atallah EL, Maegawa R, Latremouille-Viau D, Rossi C, Guérin A, Wu EQ, Patwardhan P. Chronic Myeloid Leukemia: Part I-Real-World Treatment Patterns, Healthcare Resource Utilization, and Associated Costs in Later Lines of Therapy in the United States. JOURNAL OF HEALTH ECONOMICS AND OUTCOMES RESEARCH 2022; 9:19-29. [PMID: 35979528 PMCID: PMC9352872 DOI: 10.36469/001c.36975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/25/2022] [Indexed: 06/15/2023]
Abstract
Background: Despite advances in tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia in chronic phase (CML-CP), a sizeable proportion of patients with CML-CP remains refractory or intolerant to these agents. Objectives: Treatment patterns, healthcare resource utilization (HRU), and costs were evaluated among patients with CML who received third or later lines of therapy (3L+), a clinical population that has not been previously well-studied, with unmet treatment needs as TKI therapy has repeatedly failed. Methods: Adult patients with CML who received 3L+ were identified in the IBM® MarketScan® Databases (January 1, 2001-June 30, 2019) and the SEER-Medicare-linked database (January 1, 2006-December 31, 2016). Treatment patterns were observed from CML diagnosis. HRU and direct healthcare costs (payer's perspective, 2019 USD) were measured in a 3L+ setting. Results: Among 296 commercially insured patients with 3L+ (median age, 58.5 years; female, 49.7%), the median duration of first-line (1L), second-line (2L), and 3L therapy was 8.5, 4.2, and 8.3 months, respectively. The annual incidence rate during 3L+ was 3.4 for inpatient days, 30.8 for days with outpatient services, and 1.2 for emergency department visits. Mean per-patient-per-month (PPPM) total healthcare costs (pharmacy + medical costs) were $18 784 in 3L+, $15 206 in 3L, and $19 546 in 4L, with inpatient costs driving most of the difference between 3L and 4L (mean [3L] = $2528 PPPM, mean [4L] = $6847 PPPM). Among 53 Medicare-insured patients with 3L+ (median age, 72.0 years; female, 39.6%), the median duration of 1L, 2L, and 3L therapy was 9.7, 5.0, and 7.0 months, respectively. During 3L+, the annual incidence rate was 10.3 for inpatient days, 61.9 for days with outpatient services, and 1.5 for emergency department visits. Mean PPPM total healthcare costs were $14 311 in 3L+, $15 100 in 3L, and $16 062 in 4L. Discussion: Patients with CML receiving 3L+ rapidly cycled through multiple lines. Costs increased from 3L to 4L; in commercially insured patients, inpatient costs were responsible for most of the cost increase between 3L and 4L, underlying these patients' continued need for care. Conclusions: These findings support the need for better treatment options in patients with CML undergoing later lines of therapy.
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Affiliation(s)
| | - Rodrigo Maegawa
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
| | | | | | | | - Eric Q Wu
- Analysis Group, Inc, Boston, Massachusetts
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13
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Elsayed M, Harry S, Nanua S, Zaidi S, Habib MH, Raza S. Trametinib: Could It Be a Promising Drug to Treat Atypical Chronic Myeloid Leukemia? Cureus 2022; 14:e26619. [PMID: 35949766 PMCID: PMC9356656 DOI: 10.7759/cureus.26619] [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] [Accepted: 07/06/2022] [Indexed: 12/03/2022] Open
Abstract
Atypical chronic myeloid leukemia (aCML) is a rare disease that is currently classified under the myelodysplastic (MDS)/myeloproliferative neoplasm (MPN) disease spectrum. MDS/MPN diseases are characterized by the absence of the Philadelphia (Ph) chromosome and the overlap between bone marrow fibrosis and dysplastic features. The Ph chromosome, resulting from BCR-ABL1 translocation, helps to distinguish aCML from chronic myeloid leukemia (CML). The currently reported incidence of aCML is imprecise because aCML is diagnosed primarily based on morphological features and other unspecified laboratory findings, and there is an especially high chance of under-diagnosis of aCML and other MDS/MPN diseases. Recent advances in next-generation sequencing (NGS) have allowed a greater understanding of the nature of aCML, providing better opportunities to achieve higher diagnostic accuracy and for the use of more targeted treatment to achieve better outcomes. Herein, we present a case of a 68-year-old woman who came to our hospital complaining of shortness of breath, fatigue, and weakness, who was found to have significantly increased leukocytosis, hepatosplenomegaly, and was negative for the Ph chromosome. Further investigations with NGS revealed mutations in ASXL1, GATA2, NRAS, and SRSF2 but not CSF3R. In addition to this, peripheral smear and bone marrow aspiration findings were suggestive of aCML based on specific morphological findings. Since the patient was ineligible for a stem cell transplant (SCT), symptomatic treatment was started with cell transfusion; however, the patient continued to have symptomatic anemia that required multiple transfusions. A trial with trametinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, was later started as a targeted therapy based on one of her genetic mutations. Interestingly, the patient's blood counts stabilized, she reported feeling better, and she did not need any blood transfusions for four consecutive months during treatment with trametinib. Unfortunately, our patient later died from sepsis resulting from secondary infections. In light of the significant advancements in NGS, clinicians should always consider utilizing it as a helpful tool to not only establish a rare diagnosis of aCML but also to offer the best available targeted therapy when applicable. This might alleviate the burden associated with the poor prognosis of aCML.
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Affiliation(s)
- Marwa Elsayed
- Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, USA
| | - Stephanie Harry
- Hematology/Oncology, Saint Francis Cancer Center Warren Clinic, Tulsa, USA
| | - Suprana Nanua
- Oncology, Saint Luke's Cancer Institute, University of Missouri Kansas City, Kansas City, USA
| | - Shayaan Zaidi
- Oncology, University of Kansas School of Medicine, Kansas City, USA
| | - Muhammad H Habib
- Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, USA
| | - Shahzad Raza
- Oncology, Saint Luke's Cancer Institute, University of Missouri Kansas City, Kansas City, USA
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14
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Hassan Z, Iqbal A, Zahoor S, Ali I, Iqbal MM, Bibi R. Hydroxyurea- a cost effective treatment in developing countries for Atypical Chronic Myeloid Leukemia (aCML): Case Report of Two Patients. J Oncol Pharm Pract 2022; 28:1014-1018. [PMID: 35018854 DOI: 10.1177/10781552211073518] [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: 11/16/2022]
Abstract
INTRODUCTION Atypical chronic myeloid leukaemia (aCML) is a rare chronic myeloproliferative disorder with a poor prognosis. CASE REPORT This case report presents two cases of male geriatric patients, both referred from primary care in rural areas and received at an urban clinic in a tertiary care hospital on separate instances. The first patient complained of low-grade fever (on/off), generalized body aches, rapid weight loss and shortness of breath for the last 2 months. The second patient arrived pale looking with symptoms of generalized body aches, dizziness and anorexia. Both patients were diagnosed to have aCML according to the World Health organization criteria. MANAGEMENT & OUTCOME Both the patients were from a low economic bracket and were treated with Hydroxyurea a relatively economic medicine successfully. The follow-up lasted for 12 months in both cases. No progression to acute myeloid leukaemia (AML) or relapse was observed. DISCUSSION This case report shows the promising results of Hydroxyurea in treating aCML and can be a cost effective alternate to other expensive treatments (allogeneic hematopoietic stem cell transplantation) and expensive medicines in lower and middle-income countries especially for resource-limited patients. These two cases show promising evidence for further studies to evaluate and conduct pharmaco-economic evaluations as well as clinical trials to compare hydroxyurea with other available alternative treatments for an affordable therapeutic option towards prevention of relapse and disease free survival after aCML.
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Affiliation(s)
- Zair Hassan
- Department of Cardiology, Lady Reading Hospital, Peshawar, Pakistan
| | - Ayesha Iqbal
- Division of Pharmacy Practice and Policy, School of Pharmacy, University of Nottingham, University park Campus, Nottingham, UK
| | - Saiqa Zahoor
- Department of Hematology, Hayatabad Medical Complex, Peshawar, Pakistan
| | - Iftikhar Ali
- Paraplegic Center, Hayatabad, Peshawar, Pakistan
| | | | - Rashida Bibi
- Lecturer in Clinical Pharmacy, 469633Abbottabad University of Science and Technology, Abbottabad, Pakistan
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15
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Kuendgen A, Kasprzak A, Germing U. Hybrid or Mixed Myelodysplastic/Myeloproliferative Disorders - Epidemiological Features and Overview. Front Oncol 2021; 11:778741. [PMID: 34869027 PMCID: PMC8635204 DOI: 10.3389/fonc.2021.778741] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/25/2021] [Indexed: 11/25/2022] Open
Abstract
The WHO-category Myelodysplastic/Myeloproliferative neoplasms (MDS/MPNs) recognizes a unique group of clonal myeloid malignancies exhibiting overlapping features of myelodysplastic as well as myeloproliferative neoplasms. The group consists of chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, BCR-ABL1-negative (aCML), juvenile myelomonocytic leukemia (JMML), myelodysplastic/myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U). The most frequent entity in this category is CMML, while all other diseases are extremely rare. Thus, only very limited data on the epidemiology of these subgroups exists. An appropriate diagnosis and classification can be challenging since the diagnosis is still largely based on morphologic criteria and myelodysplastic as well as myeloproliferative features can be found in various occurrences. The diseases in this category share several features that are common in this specific WHO-category, but also exhibit specific traits for each disease. This review summarizes published data on epidemiological features and offers a brief overview of the main diagnostic criteria and clinical characteristics of the five MDS/MPN subgroups.
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Affiliation(s)
- Andrea Kuendgen
- Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University Hospital Duesseldorf, Duesseldorf, Germany
| | - Annika Kasprzak
- Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University Hospital Duesseldorf, Duesseldorf, Germany
| | - Ulrich Germing
- Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University Hospital Duesseldorf, Duesseldorf, Germany
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16
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Fontana D, Gambacorti-Passerini C, Piazza R. Molecular Pathogenesis of BCR-ABL-Negative Atypical Chronic Myeloid Leukemia. Front Oncol 2021; 11:756348. [PMID: 34858828 PMCID: PMC8631780 DOI: 10.3389/fonc.2021.756348] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/22/2021] [Indexed: 11/30/2022] Open
Abstract
Atypical chronic myeloid leukemia is a rare disease whose pathogenesis has long been debated. It currently belongs to the group of myelodysplastic/myeloproliferative disorders. In this review, an overview on the current knowledge about diagnosis, prognosis, and genetics is presented, with a major focus on the recent molecular findings. We describe here the molecular pathogenesis of the disease, focusing on the mechanisms of action of the main mutations as well as on gene expression profiling. We also present the treatment options focusing on emerging targeted therapies.
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Affiliation(s)
- Diletta Fontana
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Carlo Gambacorti-Passerini
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy.,Bicocca Bioinformatics, Biostatistics and Bioimaging Centre (B4), University of Milano-Bicocca, Milan, Italy
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17
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Atypical CML with TET2 mutation, associated with NRAS and KRAS: A case report and literature review. Ann Med Surg (Lond) 2021; 71:102980. [PMID: 34840744 PMCID: PMC8606696 DOI: 10.1016/j.amsu.2021.102980] [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: 09/19/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/20/2022] Open
Abstract
Background Atypical chronic myeloid leukemia (BCR-ABL1 negative) is a rare myeloid neoplasm with poor prognosis and no current standard of treatment. It features both myelodysplastic and myeloproliferative characteristics with little data regarding mutations playing a role in the disease. Presentation of case We present a case of a 55-year-old female complaining of fever, cough, general weakness and night sweats. Examinations showed leukocytosis with a left shift, thrombocytopenia, hypercellular bone marrow with marked granulocytic hyperplasia and a negative BCR-ABL. After ruling out myelodysplastic and other myeloproliferative diseases the patient was finally diagnosed as aCML according to the WHO criteria with mutations in the TET2 gene, the NRAS gene and in the KRAS gene. The patient was started on Hydroxyurea for a duration of 9 months with an excellent initial response leading to normalization of her platelets and WBCs. However, in the last month she stopped responding to therapy and her state of health started declining once again. Conclusion Atypical chronic myeloid leukemia (BCR-ABL1 negative with presence of TET2 gene mutation) is an unusual finding in myeloid neoplasms, have unknown prognosis and no current standard of treatment. It features both myelodysplastic and myeloproliferative characteristics with little data regarding mutations playing a role in the disease.
Atypical CML is challenging to diagnose and can be misdiagnosed with CMML. Careful history taking, meticulous physical examination, and investigations are necessary. A treatment is not yet stipulated; however, researchers are working on it.
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18
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Abdulmawjood B, Costa B, Roma-Rodrigues C, Baptista PV, Fernandes AR. Genetic Biomarkers in Chronic Myeloid Leukemia: What Have We Learned So Far? Int J Mol Sci 2021; 22:12516. [PMID: 34830398 PMCID: PMC8626020 DOI: 10.3390/ijms222212516] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/11/2021] [Accepted: 11/18/2021] [Indexed: 12/20/2022] Open
Abstract
Chronic Myeloid Leukemia (CML) is a rare malignant proliferative disease of the hematopoietic system, whose molecular hallmark is the Philadelphia chromosome (Ph). The Ph chromosome originates an aberrant fusion gene with abnormal kinase activity, leading to the buildup of reactive oxygen species and genetic instability of relevance in disease progression. Several genetic abnormalities have been correlated with CML in the blast phase, including chromosomal aberrations and common altered genes. Some of these genes are involved in the regulation of cell apoptosis and proliferation, such as the epidermal growth factor receptor (EGFR), tumor protein p53 (TP53), or Schmidt-Ruppin A-2 proto-oncogene (SRC); cell adhesion, e.g., catenin beta 1 (CTNNB1); or genes associated to TGF-β, such as SKI like proto-oncogene (SKIL), transforming growth factor beta 1 (TGFB1) or transforming growth factor beta 2 (TGFB2); and TNF-α pathways, such as Tumor necrosis factor (TNFA) or Nuclear factor kappa B subunit 1 (NFKB1). The involvement of miRNAs in CML is also gaining momentum, where dysregulation of some critical miRNAs, such as miRNA-451 and miRNA-21, which have been associated to the molecular modulation of pathogenesis, progression of disease states, and response to therapeutics. In this review, the most relevant genomic alterations found in CML will be addressed.
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Affiliation(s)
- Bilal Abdulmawjood
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
| | - Beatriz Costa
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
| | - Catarina Roma-Rodrigues
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
| | - Pedro V. Baptista
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
| | - Alexandra R. Fernandes
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
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19
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Diamantopoulos PT, Viniou NA. Atypical Chronic Myelogenous Leukemia, BCR-ABL1 Negative: Diagnostic Criteria and Treatment Approaches. Front Oncol 2021; 11:722507. [PMID: 34868917 PMCID: PMC8635713 DOI: 10.3389/fonc.2021.722507] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 11/02/2021] [Indexed: 11/25/2022] Open
Abstract
Atypical chronic myelogenous leukemia (aCML), BCR/ABL1 negative is a rare myelodysplastic/myeloproliferative neoplasm, usually manifested with hyperleukocytosis without monocytosis or basophilia, organomegaly, and marked dysgranulopoiesis. In this review, we will discuss the classification and diagnostic criteria of aCML, as these have been formulated during the past 30 years, with a focus on the recent advances in the molecular characterization of the disease. Although this entity does not have a definitive molecular profile, its molecular characterization has contributed to a better understanding and more accurate classification and diagnosis of aCML. At the same time, it has facilitated the identification of adverse prognostic factors and the stratification of patients according to their risk for leukemic transformation. What is more, the molecular characterization of the disease has expanded our therapeutic choices, thoroughly presented and analyzed in this review article.
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Affiliation(s)
- Panagiotis T. Diamantopoulos
- First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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20
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Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms. Blood 2021; 136:1851-1862. [PMID: 32573691 DOI: 10.1182/blood.2019004229] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 05/13/2020] [Indexed: 12/14/2022] Open
Abstract
More than 90% of patients with myelodysplastic/myeloproliferative neoplasms (MDSs/MPNs) harbor somatic mutations in myeloid-related genes, but still, current diagnostic criteria do not include molecular data. We performed genome-wide sequencing techniques to characterize the mutational landscape of a large and clinically well-characterized cohort including 367 adults with MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 119), atypical chronic myeloid leukemia (aCML; n = 71), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 71), and MDS/MPN unclassifiable (MDS/MPN-U; n = 106). A total of 30 genes were recurrently mutated in ≥3% of the cohort. Distribution of recurrently mutated genes and clonal architecture differed among MDS/MPN subtypes. Statistical analysis revealed significant correlations between recurrently mutated genes, as well as genotype-phenotype associations. We identified specific gene combinations that were associated with distinct MDS/MPN subtypes and that were mutually exclusive with most of the other MDSs/MPNs (eg, TET2-SRSF2 in CMML, ASXL1-SETBP1 in aCML, and SF3B1-JAK2 in MDS/MPN-RS-T). Patients with MDS/MPN-U were the most heterogeneous and displayed different molecular profiles that mimicked the ones observed in other MDS/MPN subtypes and that had an impact on the outcome of the patients. Specific gene mutations also had an impact on the outcome of the different MDS/MPN subtypes, which may be relevant for clinical decision-making. Overall, the results of this study help to elucidate the heterogeneity found in these neoplasms, which can be of use in the clinical setting of MDS/MPN.
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21
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Kuykendall AT, Tokumori FC, Komrokji RS. Traipsing Through Muddy Waters: A Critical Review of the Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) Overlap Syndromes. Hematol Oncol Clin North Am 2021; 35:337-352. [PMID: 33641873 DOI: 10.1016/j.hoc.2020.12.005] [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: 11/26/2022]
Abstract
Myelodysplastic syndrome/Myeloproliferative neoplasms (MDS/MPNs) are molecularly complex, clinically heterogeneous diseases that exhibit proliferative and dysplastic features. Diagnostic criteria use clinical, pathologic, and genomic features to distinguish between disease entities, though considerable clinical and genetic overlap persists. MDS/MPNs are associated with a poor prognosis, save for MDS/MPN with ring sideroblasts and thrombocytosis, which can behave more indolently. The current treatment approach is risk-adapted and symptom-directed and largely extrapolated from experience in MDS or MPN. Gene sequencing has demonstrated frequent mutations involving signaling, epigenetic, and splicing pathways, which present numerous therapeutic opportunities for clinical investigation.
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Affiliation(s)
- Andrew T Kuykendall
- Moffitt Cancer Center, 12902 USF Magnolia Drive, CSB 7th Floor, Tampa, FL 33612, USA.
| | - Franco Castillo Tokumori
- University of South Florida, 17 Davis Boulevard, Suite 308, Tampa, FL 33606, USA. https://twitter.com/CTFrancoMD
| | - Rami S Komrokji
- Moffitt Cancer Center, 12902 USF Magnolia Drive, CSB 7th Floor, Tampa, FL 33612, USA. https://twitter.com/Ramikomrokji
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22
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Sampaio MM, Santos MLC, Marques HS, Gonçalves VLDS, Araújo GRL, Lopes LW, Apolonio JS, Silva CS, Santos LKDS, Cuzzuol BR, Guimarães QES, Santos MN, de Brito BB, da Silva FAF, Oliveira MV, Souza CL, de Melo FF. Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review. World J Clin Oncol 2021; 12:69-94. [PMID: 33680875 PMCID: PMC7918527 DOI: 10.5306/wjco.v12.i2.69] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/22/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly - the presence of the Philadelphia chromosome. The advances in cytogenetic and molecular assays are of great importance to the diagnosis, prognosis, treatment, and monitoring of CML. The discovery of the breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) 1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (known as TKIs) are the standard therapy for CML and greatly increase the survival rates, despite adverse effects and the odds of residual disease after discontinuation of treatment. As therapeutic alternatives, the subsequent TKIs lead to faster and deeper molecular remissions; however, with the emergence of resistance to these drugs, immunotherapy appears as an alternative, which may have a cure potential in these patients. Against this background, this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.
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Affiliation(s)
- Mariana Miranda Sampaio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | | | - Glauber Rocha Lima Araújo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Weber Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Jonathan Santos Apolonio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Camilo Santana Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Kauany de Sá Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Beatriz Rocha Cuzzuol
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Mariana Novaes Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Márcio Vasconcelos Oliveira
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Cláudio Lima Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Owojuyigbe TO, Durosinmi MA, Bolarinwa RAA, Salawu L, Akinola NO, Ademosun AA, Bosede OT. Distribution of BCR-ABL1 Transcript Variants in Nigerians with Chronic Myeloid Leukemia. Indian J Hematol Blood Transfus 2020; 36:646-651. [PMID: 33100706 DOI: 10.1007/s12288-020-01264-1] [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: 10/02/2019] [Accepted: 02/15/2020] [Indexed: 11/29/2022] Open
Abstract
The distribution of BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") in Nigerians with chronic myeloid leukemia (CML) had not been previously studied. In addition, there is paucity of data on the impact of BCR-ABL1 transcript variants on clinical presentation and survival in CML patients in Nigeria. The BCR-ABL1 transcript variants were analyzed in 230 Imatinib-treated CML patients at diagnosis. Patients with incomplete data (n = 28), e19a2 (n = 3) and e1a2 (n = 1) were excluded from analysis of transcript variant on disease presentation and survival leaving only 198. The frequencies of BCR-ABL1 transcript variants were 30 (13.0%), 114 (49.6%), 82 (35.7%), three (1.3%) and one (0.4%) for e13a2, e14a2, co-expression of e13a2/e14a2, e19a2 and e1a2, respectively. A significantly higher platelet count was found in patients with e13a2 variant (531.1 ± 563.4 × 109/L) than in those expressing e14a2 (488.2 ± 560.3 × 109/L) or e13a2/e14a2 (320.7 ± 215.8 × 109/L); p = 0.03. No significant differences were found between the variants with regards to gender, age, phase of disease at diagnosis, total white blood cell count, neutrophil percentage, hematocrit, splenomegaly or hepatomegaly. Overall survival was higher but not statistically significant (p = 0.4) in patients with e14a2 variant (134 months) than in e13a2 (119 months) and co-expression of e13a2/e14a2 (115 months). Nigerian CML patients have the highest incidence of co-expression of e13a2 and e14a2. Distinct disease characteristics which contrast with findings from the Western countries were also identified in Nigerians which may be due to genetic factors.
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Affiliation(s)
- Temilola O Owojuyigbe
- Department of Haematology and Blood Transfusion, Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria
| | - Muheez A Durosinmi
- Department of Haematology and Blood Transfusion, Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria
| | - Ramoni A A Bolarinwa
- Department of Haematology and Blood Transfusion, Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria
| | - Lateef Salawu
- Department of Haematology and Blood Transfusion, Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria
| | - Norah O Akinola
- Department of Haematology and Blood Transfusion, Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria
| | - Abdulwaheed A Ademosun
- Department of Haematology and Blood Transfusion, Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria
| | - Oluwayomi T Bosede
- Department of Haematology and Blood Transfusion, Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria
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24
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Atypical Chronic Myeloid Leukemia: Where Are We Now? Int J Mol Sci 2020; 21:ijms21186862. [PMID: 32962122 PMCID: PMC7555965 DOI: 10.3390/ijms21186862] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 12/16/2022] Open
Abstract
Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options.
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25
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Lasho T. Atypical CML- the role of morphology and precision genomics. Best Pract Res Clin Haematol 2019; 33:101133. [PMID: 32460981 DOI: 10.1016/j.beha.2019.101133] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 12/03/2019] [Indexed: 12/20/2022]
Abstract
Atypical chronic myeloid leukemia is an esoteric myeloid malignancy with features of both myeloproliferative and myelodysplastic syndromes. This disease is characterized primarily by morphologic-based criteria, and has clinical and molecular features overlapping with other myeloid malignancies. No one molecular abnormality is specific, and multiple mutations are often present in various combinations, due to the malignant multi-step clonal evolution of myeloid malignancies. In this review, we will address what we know about atypical chronic myeloid leukemia; evaluate how the molecular landscape in myeloid malignancies overlaps, and discuss what we can learn by incorporating individualized precision genomic strategies.
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Affiliation(s)
- Terra Lasho
- Division of Hematology, Mayo Clinic Rochester, USA.
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26
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Strohbehn GW, Ratain MJ. Precision and Accuracy in the Brave New World of Basket Trials. JCO Precis Oncol 2019; 3:1-5. [DOI: 10.1200/po.19.00074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Garth W. Strohbehn
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
| | - Mark J. Ratain
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
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27
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Kong JH, Nam H, Go TH, Hyun SY, Shim KY. Characteristics and survival of patients with atypical chronic myeloid leukemia. Blood Res 2019; 54:233-236. [PMID: 31730680 PMCID: PMC6779938 DOI: 10.5045/br.2019.54.3.233] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/09/2019] [Accepted: 07/15/2019] [Indexed: 11/17/2022] Open
Affiliation(s)
- Jee Hyun Kong
- Division of Oncology and Hematology, Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hohyung Nam
- Division of Oncology and Hematology, Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Tae-Hwa Go
- Center of Biomedical Data Science, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Shin Young Hyun
- Division of Oncology and Hematology, Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kwang Yong Shim
- Division of Oncology and Hematology, Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
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28
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Hueso T, Johnson-Ansah H, Decamp M, Maitre E, Henry A, Mensi S, Vilque JP, Chantepie S, Damaj G. Successful Imatinib therapy as a bridge to transplant in an atypical myeloproliferative neoplasm. Curr Res Transl Med 2019; 67:149-151. [PMID: 31153956 DOI: 10.1016/j.retram.2019.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/12/2019] [Accepted: 04/23/2019] [Indexed: 11/26/2022]
Affiliation(s)
- Thomas Hueso
- Caen University Hospital, Hematology Institute, France
| | | | | | - Elsa Maitre
- Caen University Hospital, Department of Hematological Biology, France
| | | | - Sarah Mensi
- Caen University Hospital, Hematology Institute, France
| | | | | | - Gandhi Damaj
- Caen University Hospital, Hematology Institute, France; Caen Normandy University, School of Medicine, France
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29
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Cassin R, Mattiello V, Viltadi M, D'Aliberti D, Piazza R, Gambacorti-Passerini C, Gianelli U, Neri A, Cortelezzi A, Reda G. Decitabine treatment for an unusual case of atypical chronic myeloid leukemia (aCML) with a concomitant chronic lymphocytic leukemia (CLL). Hematol Oncol 2019; 37:505-507. [PMID: 31102420 DOI: 10.1002/hon.2638] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 05/04/2019] [Accepted: 05/12/2019] [Indexed: 11/05/2022]
Affiliation(s)
- Ramona Cassin
- Hematology Unit, IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Veronica Mattiello
- Hematology Unit, IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Michela Viltadi
- Hematology Unit, IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Deborah D'Aliberti
- Hematology Unit, IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Rocco Piazza
- Hematology Unit, IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Umberto Gianelli
- Hematology Unit, IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Antonino Neri
- Hematology Unit, IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Agostino Cortelezzi
- Hematology Unit, IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Gianluigi Reda
- Hematology Unit, IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
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30
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Belkhair J, Raissi A, Elyahyaoui H, Ameur MA, Chakour M. Atypical chronic myeloid leukemia BCR-ABL 1 negative: A case report and literature review. Leuk Res Rep 2019; 12:100172. [PMID: 31194134 PMCID: PMC6551503 DOI: 10.1016/j.lrr.2019.100172] [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: 12/11/2018] [Revised: 04/25/2019] [Accepted: 05/25/2019] [Indexed: 11/03/2022] Open
Abstract
Atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative is a rare myelodysplastic syndrome/myeloproliferative neoplasm for which no current standard of care exists. The blood smear of patients with aCML showed prominent immature granulocytosis, and granulocytic dysplasia. We admitted a 58-year-old man with splenomegaly, hyperleukocytosis, anemia, and thrombocytopenia; then cytology, cytogenetic and molecular biology analysis of bone morrow were performed and the diagnosis of aCML was made according to 2016 World Health Organization diagnostic criteria. The patient was initially treated by chemotherapy; the patient achieved an aggravation of anemia. This motivated the change of treatment.
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31
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Schwartz LC, Mascarenhas J. Current and evolving understanding of atypical chronic myeloid leukemia. Blood Rev 2019; 33:74-81. [DOI: 10.1016/j.blre.2018.07.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 07/10/2018] [Accepted: 07/27/2018] [Indexed: 12/14/2022]
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32
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Atypical chronic myeloid leukaemia - a rare subtype of myelodysplastic/myeloproliferative neoplasm. Contemp Oncol (Pozn) 2018; 22:14-19. [PMID: 29692658 PMCID: PMC5909725 DOI: 10.5114/wo.2018.74388] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 03/11/2018] [Indexed: 11/17/2022] Open
Abstract
Atypical chronic myeloid leukaemia (aCML) belongs to the group of myelodysplastic/myeloproliferative neoplasms. Changing diagnostic criteria and the rarity of the disease, with incidence approximately 100-times lower than the incidence of BCR-ABL1-positive chronic myeloid leukaemia, result in limited knowledge on aCML. At present the diagnosis is made based on the presence of granulocytic lineage dysplasia and precisely defined quantitative peripheral blood criteria, after exclusion of other molecularly defined myeloid neoplasms. Distinctive cytogenetic and molecular changes for aCML are missing, although recently SETBP1 mutations were described in a significant proportion of patients. The majority of patients are male and elderly. The prognosis of aCML patients is very bad, with median overall survival ranging between 10.8 and 25 months, and acute myeloid leukaemia-free survival amounting to approximately 11 months. No treatment recommendations can be made based upon current evidence, although allogeneic haematopoietic stem cell transplantation seems to be able to induce long-term remission in eligible patients.
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33
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Drozd-Sokołowska J, Mądry K, Waszczuk-Gajda A, Biecek P, Szwedyk P, Budziszewska K, Raźny M, Dutka M, Obara A, Wasilewska E, Lewandowski K, Piekarska A, Bober G, Krzemień H, Stella-Hołowiecka B, Kapelko-Słowik K, Sawicki W, Paszkowska-Kowalewska M, Machowicz R, Dwilewicz-Trojaczek J. Atypical chronic myeloid leukaemia: A case of an orphan disease-A multicenter report by the Polish Adult Leukemia Group. Hematol Oncol 2018; 36:570-575. [PMID: 29512182 DOI: 10.1002/hon.2501] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 01/19/2018] [Accepted: 01/22/2018] [Indexed: 11/08/2022]
Abstract
Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses. Thirteen patients were male, median age 64.6 years (range 40.4-80.9). The median parameters at diagnosis were as follows: white blood cell count 97 × 109 /L (23.8-342) with immature progenitors amounting at 27.5% (12-72), haemoglobin 8.6 g/dL (3.9-14.9), and platelet count 66 × 109 /L (34-833). Cytoreductive treatment was used in all patients, and 2 patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival was 14.1 months (95% CI, 7.2), with median acute myeloid leukaemia-free survival of 13.3 months (95% CI, 3.6-22.6). Cumulative incidence of acute myeloid leukaemia transformation after 1 year in aCML group was 12.5% (95% CI, 0%-29.6%). To conclude, aCML harbours a poor prognosis. Treatment options are limited, with allogeneic hematopoietic stem cell transplantation being the only curative method at present, although only a minority of patients are transplant eligible. Educational measures are needed to improve the quality of diagnoses.
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Affiliation(s)
- Joanna Drozd-Sokołowska
- Department of Hematology, Oncology and Internal Diseases, Medical Univeristy of Warsaw, Warsaw, Poland
| | - Krzysztof Mądry
- Department of Hematology, Oncology and Internal Diseases, Medical Univeristy of Warsaw, Warsaw, Poland
| | - Anna Waszczuk-Gajda
- Department of Hematology, Oncology and Internal Diseases, Medical Univeristy of Warsaw, Warsaw, Poland
| | - Przemysław Biecek
- Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland
| | - Paweł Szwedyk
- Department of Hematology, Ludwik Rydygier Hospital, Cracow, Poland
| | - Katarzyna Budziszewska
- Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Magdalena Raźny
- Department of Hematology, Ludwik Rydygier Hospital, Cracow, Poland
| | - Magdalena Dutka
- Department of Hematology and Transplantology, Medical University of Gdansk, Gdansk, Poland
| | - Agata Obara
- Department of Hematology, Świętokrzyskie Cancer Centre, Kielce, Poland
| | - Ewa Wasilewska
- Department of Hematology, Medical University of Białystok, Białystok, Poland
| | - Krzysztof Lewandowski
- Department of Hematology and Bone Marrow Transplantation, Poznań Medical University, Poznań, Poland
| | - Agnieszka Piekarska
- Department of Hematology and Transplantology, Medical University of Gdansk, Gdansk, Poland
| | - Grażyna Bober
- Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland
| | - Helena Krzemień
- Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland
| | - Beata Stella-Hołowiecka
- Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland
| | - Katarzyna Kapelko-Słowik
- Department and Clinic of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland
| | - Waldemar Sawicki
- Department of Hematology, Military Medical Institute in Warsaw, Warsaw, Poland
| | | | - Rafał Machowicz
- Department of Hematology, Oncology and Internal Diseases, Medical Univeristy of Warsaw, Warsaw, Poland
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Dhakal P, Gundabolu K, Amador C, Rayamajhi S, Bhatt VR. Atypical chronic myeloid leukemia: a rare entity with management challenges. Future Oncol 2017; 14:177-185. [PMID: 29226717 DOI: 10.2217/fon-2017-0334] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The aim of our study was to review the clinicopathologic features and management of atypical chronic myeloid leukemia (aCML). Relevant manuscripts published in English were searched using PubMed. aCML is diagnosed as per WHO 2016 classification in the presence of leukocytosis ≥13 × 109/l with circulating neutrophil precursors ≥10%, monocytes less than 10%, minimal basophils, hypercellular bone marrow with granulocytic proliferation and dysplasia, bone marrow blast less than 20% and absence of BCR/ABL fusion gene. Common cytogenetic features and mutations include trisomy 8, and mutations in SETBP1 and ETNK1. Median survival is 1-2 years. Hematopoietic stem cell transplant may be the only curative option. Ruxolitinib and dasatinib are emerging therapeutic options. Thus, aCML is a rare entity with poor survival. Novel therapies are needed.
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Affiliation(s)
- Prajwal Dhakal
- Department of Medicine, Michigan State University, 788 Service Rd, East Lansing, MI 48824, USA
| | - Krishna Gundabolu
- Department of Internal Medicine, Division of Hematology & Oncology, University of Nebraska Medical Center, NE 68198, USA
| | - Catalina Amador
- Department of Pathology & Microbiology, University of Nebraska Medical Center, NE 68198, USA
| | - Supratik Rayamajhi
- Department of Medicine, Michigan State University, 788 Service Rd, East Lansing, MI 48824, USA
| | - Vijaya Raj Bhatt
- Department of Internal Medicine, Division of Hematology & Oncology, University of Nebraska Medical Center, NE 68198, USA
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35
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Patnaik MM, Barraco D, Lasho TL, Finke CM, Reichard K, Hoversten KP, Ketterling RP, Gangat N, Tefferi A. Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia. Am J Hematol 2017; 92:542-548. [PMID: 28314085 DOI: 10.1002/ajh.24722] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 03/12/2017] [Accepted: 03/14/2017] [Indexed: 12/13/2022]
Abstract
Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8%, and PTPN11 4%. Fifteen patients (60%) had >1 mutation, while 9 (36%) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68%) deaths and 2 (8%) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (P = .02), low hemoglobin (P = .01), red blood cell transfusion dependence (P = .03), high white blood cell count (P = .02), TET2 (P = .03), NRAS (P = .04), PTPN11 (P = .02) mutations and the presence of ≥3 gene mutations (P = .006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (P = .003) [age >67: HR 10.1, 95% CI 1.3-119], low hemoglobin (P = .008) [HB< 10 gm/dL: HR 8.2, 95% CI 1.6-23.2] and TET2 mutations (P = .01) [HR 8.8, 95% CI 1.6-47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dL and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0-1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months, respectively.
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Affiliation(s)
| | - Daniela Barraco
- Division of Hematology; Mayo Clinic; Rochester Minnesota USA
| | | | | | - Kaaren Reichard
- Division of Hematopathology, Department of Laboratory Medicine; Mayo Clinic; Rochester Minnesota USA
| | | | - Rhett P. Ketterling
- Department of Laboratory Medicine and Pathology; Mayo Clinic; Rochester Minnesota USA
| | - Naseema Gangat
- Division of Hematology; Mayo Clinic; Rochester Minnesota USA
| | - Ayalew Tefferi
- Division of Hematology; Mayo Clinic; Rochester Minnesota USA
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36
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Onida F, de Wreede LC, van Biezen A, Eikema DJ, Byrne JL, Iori AP, Schots R, Jungova A, Schetelig J, Finke J, Veelken H, Johansson JE, Craddock C, Stelljes M, Theobald M, Holler E, Schanz U, Schaap N, Bittenbring J, Olavarria E, Chalandon Y, Kröger N. Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Br J Haematol 2017; 177:759-765. [PMID: 28369779 DOI: 10.1111/bjh.14619] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 12/31/2016] [Indexed: 11/29/2022]
Abstract
Atypical chronic myeloid leukaemia (aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who underwent allo-HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen (HLA)-identical siblings in 64% and matched unrelated (MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T-cell depletion was applied in 87% and 26% of transplants from MUD and HLA-identical siblings, respectively. According to the EBMT risk-score, 45% of patients were 'low-risk', 31% 'intermediate-risk' and 24% 'high-risk'. Following allo-HSCT, 87% of patients achieved complete remission. At 5 years, relapse-free survival was 36% and non-relapse mortality (NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse-free survival was higher in MUD than in HLA-identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo-HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates.
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Affiliation(s)
- Francesco Onida
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Liesbeth C de Wreede
- Department of Medical Statistics & Bioinformatics, Leiden University Medical Centre, Leiden, The Netherlands.,DKMS Clinical Trials Unit, Dresden, Germany
| | - Anja van Biezen
- Department of Medical Statistics & Bioinformatics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Diderik-Jan Eikema
- Department of Medical Statistics & Bioinformatics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Jenny L Byrne
- Nottingham University Hospitals Trust, Nottingham, UK
| | - Anna P Iori
- Azienda Policlinico Umberto I, 'La Sapienza' University, Rome, Italy
| | - Rik Schots
- Universitair Ziekenhuis Brussel, Brussels, Belgium
| | | | | | | | - Hendrik Veelken
- Department of Haematology, Leiden University Medical Centre, Leiden, The Netherlands
| | | | | | | | | | | | - Urs Schanz
- University Hospital, Zürich, Switzerland
| | - Nicolaas Schaap
- Radboud University - Nijmegen Medical Centre, Nijmegen, The Netherlands
| | | | | | - Yves Chalandon
- Hematology Division, Hôpitaux Universitaires de Genève and Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Gritsaev SV, Kostroma II, Zapreev IM, Shmidt AV, Tiranova SA, Balashova VA, Martynkevich IS, Chubukina ZV, Semenova NY, Chechetkin AV. [Transformation of secondary myelodysplastic syndrome to atypical chronic myeloid leukemia in a female patient with acute myeloid leukemia]. TERAPEVT ARKH 2017; 88:104-108. [PMID: 27459623 DOI: 10.17116/terarkh2016887104-108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Secondary myeloid neoplasia may be a complication of intensive cytostatic therapy. The most common types of secondary neoplasias are acute myeloid leukemia and myelodysplastic syndrome. The development of secondary atypical chronic myeloid leukemia (aCML) is an extremely rare phenomenon. The paper describes transformation of secondary myelodysplastic syndrome to aCML 6 months after its diagnosis. The development of aCML was accompanied by additional chromosomal aberration as monosomy of chromosome 17. No mutations in the JAK2, MPL, and CalR genes were detected. It is concluded that the clinical course of secondary myeloid neoplasias is variable.
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Affiliation(s)
- S V Gritsaev
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
| | - I I Kostroma
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
| | - I M Zapreev
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
| | - A V Shmidt
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
| | - S A Tiranova
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
| | - V A Balashova
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
| | - I S Martynkevich
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
| | - Zh V Chubukina
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
| | - N Yu Semenova
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
| | - A V Chechetkin
- Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency of Russia, Moscow, Russia
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38
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Wu H, Sun H, Zhang Z, Li X, Li Y, Li L, Xu R, Wang Z, Tian W. Routine blood examinations combined with morphological analysis for the diagnosis of myelodysplastic/myeloproliferative neoplasms. Oncol Lett 2016; 12:4245-4251. [PMID: 27895799 DOI: 10.3892/ol.2016.5165] [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: 09/22/2015] [Accepted: 08/05/2016] [Indexed: 11/06/2022] Open
Abstract
In 2008, the World Health Organization (WHO) introduced a new hematological neoplasm category; myelodysplastic/myeloproliferative neoplasms (MDS/MPN), which included four main subcategories. This disease is often misdiagnosed, which delays effective therapy. The present study evaluated the role of routine blood examinations and morphological analysis of peripheral blood cells in the reliable diagnosis of MDS/MPN. In total, 236 adult MDS/MPN patients were analyzed. The analysis included 10 routine blood parameters measured using a Sysmex XE-2100™, 3 differential percentage parameters and 7 morphological features of peripheral blood cells which were analyzed by optical microscopy, and 3 differential absolute count numbers obtained based on the corresponding differential percentages and absolute count of blood cells. The parameters were compared among the subcategories and a value of P<0.05 was considered to indicate a statistically significant difference. The median white blood cell and hemoglobin counts of the patients were 18.0×109/l and 88 g/l, respectively. The proportion of monocytes increased to 8% (1.82×109/l), the proportion of blast cells increased to 1% (0.5×109/l) and that of neutrophil precursors increased to 10% (1.98×109/l). A total of 87% of all patients presented with hypogranulation and 71% presented with abnormal condensed nuclear chromatin in granulocytes. Atypical monocytes were observed in 73% of all patients and Pseudo-Pelger cells were observed in 60%. Significant differences were detected among the subcategories. The present study demonstrated that combining blood routine parameters and the morphological analysis of peripheral blood cells have an essential role in the reliable diagnosis of MDS/MPN based on WHO categories.
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Affiliation(s)
- Huanling Wu
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Hui Sun
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zhifen Zhang
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xiangli Li
- Department of Clinical Laboratory, Hospital of Traditional Chinese Medicine, Shouguang, Shandong 262700, P.R. China
| | - Yuantang Li
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Li Li
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Rui Xu
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zie Wang
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Wenjun Tian
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Mori N, Ohwashi-Miyazaki M, Okada M, Yoshinaga K, Shiseki M, Tanaka J. Translocation (9;12)(q34.1;p13.?3) Resulted in ETV6-ABL1 Fusion in a Patient with Philadelphia Chromosome-Negative Chronic Myelogenous Leukemia. Acta Haematol 2016; 136:240-243. [PMID: 27710957 DOI: 10.1159/000448984] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 08/07/2016] [Indexed: 01/09/2023]
Affiliation(s)
- Naoki Mori
- Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan
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40
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41
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Giri S, Pathak R, Martin MG, Bhatt VR. Characteristics and survival of BCR/ABL negative chronic myeloid leukemia: a retrospective analysis of the Surveillance, Epidemiology and End Results database. Ther Adv Hematol 2015; 6:308-12. [PMID: 26622999 DOI: 10.1177/2040620715607416] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Smith Giri
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Ranjan Pathak
- Department of Medicine, Reading Health System, Reading, PA, USA
| | - Mike G Martin
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Vijaya Raj Bhatt
- University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology-Oncology, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, USA
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42
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Hausmann H, Bhatt VR, Yuan J, Maness LJ, Ganti AK. Activity of single-agent decitabine in atypical chronic myeloid leukemia. J Oncol Pharm Pract 2015; 22:790-794. [PMID: 26378157 DOI: 10.1177/1078155215605662] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Atypical chronic myeloid leukemia is a rare entity that presents diagnostic and therapeutic challenges. Traditionally utilized therapeutic agents such as hydroxyurea or interferon result in a median survival of approximately two years, thus warranting identification of better options. We report a 49-year-old Caucasian female, who presented with extreme leukocytosis (white blood cells of 148,300/µL) with left shift, severe anemia, and thrombocytopenia. Following a diagnosis of atypical chronic myeloid leukemia, she was started on intravenous decitabine. She subsequently developed paraneoplastic vasculitis of large arteries, which responded to high-dose glucocorticoid. Decitabine therapy resulted in an excellent hematologic response, transfusion independence, and successful transition to an allogeneic peripheral stem cell transplantation. However, the patient subsequently succumbed to the complications of acute graft-versus-host-disease. This case illustrates an association between atypical chronic myeloid leukemia and steroid-responsive paraneoplastic vasculitis and highlights the single-agent disease activity of decitabine in atypical chronic myeloid leukemia, which may be utilized as a bridging therapy to allogeneic stem cell transplantation.
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Affiliation(s)
- Heidi Hausmann
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Vijaya R Bhatt
- Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ji Yuan
- Division of Hematology and Oncology, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Lori J Maness
- Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Apar K Ganti
- Department of Internal Medicine, Veteran's Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
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43
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Tortorella SM, Hung A, Karagiannis TC. The implication of cancer progenitor cells and the role of epigenetics in the development of novel therapeutic strategies for chronic myeloid leukemia. Antioxid Redox Signal 2015; 22:1425-62. [PMID: 25366930 DOI: 10.1089/ars.2014.6096] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE Chronic myeloid leukemia (CML) involves the malignant transformation of hematopoietic stem cells, defined largely by the Philadelphia chromosome and expression of the breakpoint cluster region-Abelson (BCR-ABL) oncoprotein. Pharmacological tyrosine kinase inhibitors (TKIs), including imatinib mesylate, have overcome limitations in conventional treatment for the improved clinical management of CML. RECENT ADVANCES Accumulated evidence has led to the identification of a subpopulation of quiescent leukemia progenitor cells with stem-like self renewal properties that may initiate leukemogenesis, which are also shown to be present in residual disease due to their insensitivity to tyrosine kinase inhibition. CRITICAL ISSUES The characterization of quiescent leukemia progenitor cells as a unique cell population in CML pathogenesis has become critical with the complete elucidation of mechanisms involved in their survival independent of BCR-ABL that is important in the development of novel anticancer strategies. Understanding of these functional pathways in CML progenitor cells will allow for their selective therapeutic targeting. In addition, disease pathogenesis and drug responsiveness is also thought to be modulated by epigenetic regulatory mechanisms such as DNA methylation, histone acetylation, and microRNA expression, with a capacity to control CML-associated gene transcription. FUTURE DIRECTIONS A number of compounds in combination with TKIs are under preclinical and clinical investigation to assess their synergistic potential in targeting leukemic progenitor cells and/or the epigenome in CML. Despite the collective promise, further research is required in order to refine understanding, and, ultimately, advance antileukemic therapeutic strategies.
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Affiliation(s)
- Stephanie M Tortorella
- 1 Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct , Melbourne, Australia
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44
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Penot A, Preux PM, Le Guyader S, Collignon A, Herry A, Dufour V, Monnereau A, Woronoff AS, Troussard X, Pons E, Bordessoule D, Maynadié M. Incidence of chronic myeloid leukemia and patient survival: results of five French population-based cancer registries 1980–2009. Leuk Lymphoma 2015; 56:1771-7. [DOI: 10.3109/10428194.2014.974046] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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45
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Schiffer S, Rosinke R, Jost E, Hehmann-Titt G, Huhn M, Melmer G, Barth S, Thepen T. Targetedex vivoreduction of CD64-positive monocytes in chronic myelomonocytic leukemia and acute myelomonocytic leukemia using human granzyme B-based cytolytic fusion proteins. Int J Cancer 2014; 135:1497-508. [DOI: 10.1002/ijc.28786] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Accepted: 01/30/2014] [Indexed: 02/05/2023]
Affiliation(s)
- Sonja Schiffer
- Department of Experimental Medicine and Immunotherapy; Institute for Biomedical Engineering, University Hospital RWTH Aachen; Aachen Germany
- Department of Pharmaceutical Product Development; Fraunhofer IME; Aachen Germany
| | - Reinhard Rosinke
- Department of Pharmaceutical Product Development; Fraunhofer IME; Aachen Germany
| | - Edgar Jost
- Department of Hematology and Oncology (Internal Medicine IV); University Hospital RWTH Aachen; Germany
| | | | - Michael Huhn
- Department of Experimental Medicine and Immunotherapy; Institute for Biomedical Engineering, University Hospital RWTH Aachen; Aachen Germany
| | | | - Stefan Barth
- Department of Experimental Medicine and Immunotherapy; Institute for Biomedical Engineering, University Hospital RWTH Aachen; Aachen Germany
- Department of Pharmaceutical Product Development; Fraunhofer IME; Aachen Germany
| | - Theo Thepen
- Department of Pharmaceutical Product Development; Fraunhofer IME; Aachen Germany
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46
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Lim SN, Lee JH, Lee JH, Kim DY, Kim SD, Kang YA, Lee YS, Lee KH. Allogeneic hematopoietic cell transplantation in adult patients with myelodysplastic/myeloproliferative neoplasms. Blood Res 2013; 48:178-84. [PMID: 24086937 PMCID: PMC3786277 DOI: 10.5045/br.2013.48.3.178] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Revised: 05/19/2013] [Accepted: 07/01/2013] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND In adults, the 2 main types of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). Both are associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is the only known curative treatment modality for these diseases, but data on outcomes following such treatment are limited. We analyzed the outcomes of patients with MDS/MPN after allogeneic HCT. METHODS This retrospective study included 10 patients with MDS/MPN who received allogeneic HCT at Asan Medical Center from 2002 to 2010. Of these 10 patients, 7 had CMML, 2 had aCML, and 1 had unclassifiable MDS/MPN. Five patients received a myeloablative conditioning (MAC) regimen (busulfan-cyclophosphamide), and 5 received reduced-intensity conditioning (RIC) regimen. RESULTS Neutrophil engraftment was achieved in all patients. After a median follow-up of 47.5 months among surviving patients, 4 had relapsed and 5 had died. There was only 1 treatment-related death. The 5-year rates of overall, relapse-free, and event-free survival were 42.2%, 51.9%, and 46.7%, respectively. Relapse was the leading cause of treatment failure, and all relapses were observed in patients who had received RIC and who did not develop chronic graft-versus-host disease. CONCLUSION Allogeneic HCT can induce durable remission in patients with MDS/MPN, but RIC cannot replace MAC in patients eligible for myeloablative treatments.
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Affiliation(s)
- Sung-Nam Lim
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea
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47
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Wu H, Bian S, Chu J, Zhong X, Sun H, Zhang B, Lu Z. Characteristics of the four subtypes of myelodysplastic/myeloproliferative neoplasms. Exp Ther Med 2013; 5:1332-1338. [PMID: 23737874 PMCID: PMC3671785 DOI: 10.3892/etm.2013.975] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/15/2013] [Indexed: 11/07/2022] Open
Abstract
The aim of the present study was to investigate the characteristics of the four subtypes of myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) in order to improve current knowledge and to aid their diagnosis. A total of 53 cases of MDS/MPNs were analyzed using routine blood cell analysis and morphological, cytogenetic and molecular genetic characteristics were investigated. Numerical data for several groups were compared using a single-factor analysis of variance. The Student-Newman-Keuls test was used to compare the means of two groups. The proportions were compared using a Chi-square test or Fisher’s exact test. Analysis of the patients with MDS/MPNs revealed that 46 patients (86.8%) had paleness and fatigue, and blood analysis revealed hemoglobin (Hb) levels of 83.1±24.6 g/l, a white blood cell (WBC) count of 19.8±8.1×109/l and a platelet (PLT) count of 158.7±108.2×1012/l. Immature neutrophils and monocytes were identified in the peripheral blood at levels of 0.058±0.031 and 0.152±0.034%, respectively. There were 23 cases (43.4%) with dyserythropoiesis and 36 cases (67.9%) had dysgranulopoiesis. Fifteen cases were immunologically characterized using flow cytometry (FCM), of which 13 cases showed abnormalities on blasts and myelocytes. Karyotyping was performed in 27 cases of MDS/MPN and 12 (44.4%) were identified as abnormal. In 23 cases, testing for BCR/ABL1, AML-ETO, CBF-MYH11A, PML-RARA, E2A-PBX1, TEL-AML1, SIL-TAL1 returned negative results. The JAK2V617F mutation was positive in one of five cases. The majority of MDS/MPN cases had anemia, cytosis, low-grade blasts and immature neutrophils in the peripheral blood and dysplasia in the bone marrow. Immunological abnormalities and abnormal karyotypes occurred frequently in MDS/MPNs and although there were no statistical differences between the four subtypes, these were able to aid diagnosis. No specific molecular abnormalities were identified in MDS/MPNs.
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Affiliation(s)
- Huanling Wu
- Clinical Laboratory of Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021
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48
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Prithviraj GK, Mathew BM, Komrokji RK, List AF, Padron E. Chronic myelomonocytic leukemia: a review of the molecular biology, prognostic models and treatment. Int J Hematol Oncol 2013. [DOI: 10.2217/ijh.13.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
SUMMARY Chronic myelomonocytic leukemia (CMML) is a genetically heterogeneous hematologic neoplasm that manifests with features of both a myelodysplastic syndrome and a myeloproliferative neoplasm. Recent advances in the characterization of recurrent genetic markers have resulted in a better understanding of the leukemia-initiating events and have distinguished CMML from other clonal hematopoietic malignancies. Although these mutations may lead to CMML-specific therapies in the relatively near future, the current state of therapy for CMML is based on treatments designed for the myelodysplastic syndromes. Here we review the recurrent genetic mutations and, if known, their clinical significance. We also review the treatment and available CMML-specific prognostic models and novel therapies moving forward.
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Affiliation(s)
- Gopi K Prithviraj
- H Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Blessy M Mathew
- H Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Rami K Komrokji
- H Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Alan F List
- H Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Eric Padron
- H Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
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49
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Salomon O, Holtzman EJ, Beckerman P, Avivi C, Trakhtenbrot L, Kneller A, Tohami T, Kleinbaum Y, Apter S, Amariglio N, Grossman E, Schiby G. Hyperphosphatemia during spontaneous tumor lysis syndrome culminate in severe hypophosphatemia at the time of blast crisis of Phneg CML to acute myelomoncytic leukemia. Exp Hematol Oncol 2012; 1:24. [PMID: 23211092 PMCID: PMC3514108 DOI: 10.1186/2162-3619-1-24] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Accepted: 07/30/2012] [Indexed: 12/16/2022] Open
Abstract
Extreme swing of phosphor from severe hyperphosphatemia to severe hypophosphatemia in a patient with blast crisis of myeloid origin was the result of imbalance between massive apoptosis of leukemic cells in the context of spontaneous tumor lysis syndrome and massive production of leukemic cells with only 1% of blast in peripheral blood. The mutated p53 protein suggested acting as oncogene in the presented case and possibly affecting phosphor status.
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Affiliation(s)
- Ophira Salomon
- The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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50
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Koldehoff M, Steckel NK, Hegerfeldt Y, Ditschkowski M, Beelen DW, Elmaagacli AH. Clinical course and molecular features in 21 patients with atypical chronic myeloid leukemia. Int J Lab Hematol 2011; 34:e3-5. [PMID: 21707937 DOI: 10.1111/j.1751-553x.2011.01351.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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