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Olieslagers TI, Groeneweg M, van Gorkom GNY, Beckers EAM, Wieten L, Voorter CEM. Somatic Genomic Alterations in Haematological Tumours Can Interfere With Accurate HLA and Chimerism Diagnostics. HLA 2025; 105:e70093. [PMID: 40071308 PMCID: PMC11897862 DOI: 10.1111/tan.70093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 02/05/2025] [Accepted: 02/14/2025] [Indexed: 03/15/2025]
Abstract
Tumour cells, which are often found in the peripheral blood of patients with acute leukaemia, may harbour multiple somatic alterations throughout the genome, including changes in the HLA region and short tandem repeat (STR) regions. We investigated whether such somatic alterations interfere with HLA and chimerism diagnostics conducted in preparation for an allogeneic haematopoietic stem cell transplantation (allo-HSCT). This study describes 10 patient-based cases for which laboratory diagnostics were performed prior to a possible stem cell transplant in the Maastricht University Medical Center. In three acute leukaemia patients, somatic alterations were detected within the HLA region in peripheral blood samples: one case showed a complete loss of an HLA haplotype, while two cases exhibited somatic mutations affecting a single HLA class I gene. Additionally, seven patients with haematological malignancies revealed somatic variations within the STR regions, indicated by the presence of a third allele or the partial or complete loss of an allele in pre-transplant peripheral blood samples. In all patients, these somatic variations were confirmed by repeating the tests using buccal swab samples from patients or samples from family members. Furthermore, our study demonstrated that somatic alterations within STR regions used for chimerism testing occurred in 6% of the 176 patients who received an allo-HSCT between 2017 and 2022. This study underscores the clinical relevance of detecting somatic alterations prior to allo-HSCT, as they may interfere with HLA and STR analysis, potentially leading to HLA mistyping or incorrect chimerism detection. Additionally, it highlights the frequency with which genetic changes in tumour cells can affect chimerism diagnostics. The findings emphasise the vital importance of selecting the appropriate sample source for typing purposes and considering the patient's karyotype when choosing STRs, especially when tumour cells are present in the peripheral blood of patients with haematological malignancies.
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Affiliation(s)
- Timo I. Olieslagers
- Department of Transplantation ImmunologyMaastricht University Medical CenterMaastrichtthe Netherlands
- GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtthe Netherlands
| | - Mathijs Groeneweg
- Department of Transplantation ImmunologyMaastricht University Medical CenterMaastrichtthe Netherlands
- GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtthe Netherlands
| | - Gwendolyn N. Y. van Gorkom
- GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtthe Netherlands
- Department of Internal Medicine, Division of HematologyMaastricht University Medical CenterMaastrichtthe Netherlands
| | - Erik A. M. Beckers
- Department of Internal Medicine, Division of HematologyMaastricht University Medical CenterMaastrichtthe Netherlands
| | - Lotte Wieten
- Department of Transplantation ImmunologyMaastricht University Medical CenterMaastrichtthe Netherlands
- GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtthe Netherlands
| | - Christina E. M. Voorter
- Department of Transplantation ImmunologyMaastricht University Medical CenterMaastrichtthe Netherlands
- GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtthe Netherlands
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2
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Okuda R, Ochi Y, Saiki R, Yamanaka T, Terao C, Yoshizato T, Nakagawa MM, Zhao L, Ohyashiki K, Hiramoto N, Sanada M, Handa H, Kasahara S, Miyazaki Y, Sezaki N, Shih LY, Kern W, Kanemura N, Kitano T, Imashuku S, Watanabe M, Creignou M, Chonabayashi K, Usuki K, Ishikawa T, Gotoh A, Atsuta Y, Shiraishi Y, Mitani K, Chiba S, Takaori-Kondo A, Miyano S, Kamatani Y, Haferlach T, Hellström-Lindberg E, Matsuda K, Yoshida Y, Makishima H, Nannya Y, Ogawa S. Genetic analysis of myeloid neoplasms with der(1;7)(q10;p10). Leukemia 2025; 39:760-764. [PMID: 39715854 PMCID: PMC11879841 DOI: 10.1038/s41375-024-02494-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 11/26/2024] [Accepted: 11/29/2024] [Indexed: 12/25/2024]
Grants
- JP15cm0106056h0005 Japan Agency for Medical Research and Development (AMED)
- JP19cm0106501h0004 Japan Agency for Medical Research and Development (AMED)
- JP16ck0106073h0003 Japan Agency for Medical Research and Development (AMED)
- JP19ck0106250h0003 Japan Agency for Medical Research and Development (AMED)
- 19ck0106470h0001 Japan Agency for Medical Research and Development (AMED)
- hp170227 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- hp180198 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- hp190158 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- hp200138 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- hp210167 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- JP1505909 MEXT | Japan Society for the Promotion of Science (JSPS)
- JP26221308 MEXT | Japan Society for the Promotion of Science (JSPS)
- JP19H05656 MEXT | Japan Society for the Promotion of Science (JSPS)
- JP22J23598 MEXT | Japan Society for the Promotion of Science (JSPS)
- JP22K16320 MEXT | Japan Society for the Promotion of Science (JSPS)
- JP19H01053 MEXT | Japan Society for the Promotion of Science (JSPS)
- JPMJFR220L MEXT | Japan Science and Technology Agency (JST)
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Affiliation(s)
- Rurika Okuda
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yotaro Ochi
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Ryunosuke Saiki
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshiyuki Yamanaka
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Chikashi Terao
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
- The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Tetsuichi Yoshizato
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masahiro M Nakagawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Lanying Zhao
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuma Ohyashiki
- Department of Hematology, Tokyo Medical University, Tokyo, Japan
| | - Nobuhiro Hiramoto
- Department of Hematology, Kobe City Medical Center General Hospital, Hyogo, Japan
| | - Masashi Sanada
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Advanced Diagnosis, Clinical Research Center, NHO Nagoya Medical Center, Nagoya, Japan
| | - Hiroshi Handa
- Department of Hematology, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Senji Kasahara
- Department of Hematology, Gifu Municipal Hospital, Gifu, Japan
| | - Yasushi Miyazaki
- Japan Adult Leukemia Study Group, and Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Nobuo Sezaki
- Department of Hematology, Chugoku Central Hospital, Hiroshima, Japan
| | - Lee-Yung Shih
- Division of Hematology-Oncology, Chang Gung Memorial Hospital-Linkou, Chang Gung University, Taoyuan, Taiwan
| | | | - Nobuhiro Kanemura
- Department of Hematology and Infectious Disease, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Toshiyuki Kitano
- Department of Hematology, Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - Shinsaku Imashuku
- Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Japan
| | - Mitsumasa Watanabe
- Department of Hematology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan
| | - Maria Creignou
- Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
- Center for Clinical Cancer Studies, Phase 1 Unit, Karolinska University Hospital, Stockholm, Sweden
| | - Kazuhisa Chonabayashi
- Department of Cell Growth and Differentiation, Center for iPS Research and Application, Kyoto University, Kyoto, Japan
- Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kensuke Usuki
- Department of Hematology, NTT Medical Center Tokyo, Tokyo, Japan
| | - Takayuki Ishikawa
- Department of Hematology, Kobe City Medical Center General Hospital, Hyogo, Japan
| | - Akihiko Gotoh
- Department of Hematology, Tokyo Medical University, Tokyo, Japan
| | - Yoshiko Atsuta
- The Japanese Data Center for Hematopoietic Cell Transplantation, Aichi, Japan
- Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Aichi, Japan
| | - Yuichi Shiraishi
- Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kinuko Mitani
- Department of Hematology and Oncology, Dokkyo Medical University, Tochigi, Japan
| | - Shigeru Chiba
- Department of Hematology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Akifumi Takaori-Kondo
- Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoru Miyano
- Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoichiro Kamatani
- Department of Computational Biology and Medical Sciences, Graduate Schools of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | | | - Eva Hellström-Lindberg
- Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
| | - Koichi Matsuda
- Department of Computational Biology and Medical Sciences, Graduate Schools of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Yoshinori Yoshida
- Department of Cell Growth and Differentiation, Center for iPS Research and Application, Kyoto University, Kyoto, Japan
| | - Hideki Makishima
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yasuhito Nannya
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
- Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
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Rørvik SD, Torkildsen S, Bruserud Ø, Tvedt THA. Acute myeloid leukemia with rare recurring translocations-an overview of the entities included in the international consensus classification. Ann Hematol 2024; 103:1103-1119. [PMID: 38443661 PMCID: PMC10940453 DOI: 10.1007/s00277-024-05680-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 02/19/2024] [Indexed: 03/07/2024]
Abstract
Two different systems exist for subclassification of acute myeloid leukemia (AML); the World Health Organization (WHO) Classification and the International Consensus Classification (ICC) of myeloid malignancies. The two systems differ in their classification of AML defined by recurrent chromosomal abnormalities. One difference is that the ICC classification defines an AML subset that includes 12 different genetic abnormalities that occur in less than 4% of AML patients. These subtypes exhibit distinct clinical traits and are associated with treatment outcomes, but detailed description of these entities is not easily available and is not described in detail even in the ICC. We searched in the PubMed database to identify scientific publications describing AML patients with the recurrent chromosomal abnormalities/translocations included in this ICC defined patient subset. This patient subset includes AML with t(1;3)(p36.3;q21.3), t(3;5)(q25.3;q35.1), t(8;16)(p11.2;p13.3), t(1;22)(p13.3;q13.1), t(5;11)(q35.2;p15.4), t(11;12)(p15.4;p13.3) (involving NUP98), translocation involving NUP98 and other partner, t(7;12)(q36.3;p13.2), t(10;11)(p12.3;q14.2), t(16;21)(p11.2;q22.2), inv(16)(p13.3q24.3) and t(16;21)(q24.3;q22.1). In this updated review we describe the available information with regard to frequency, biological functions of the involved genes and the fusion proteins, morphology/immunophenotype, required diagnostic procedures, clinical characteristics (including age distribution) and prognostic impact for each of these 12 genetic abnormalities.
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Affiliation(s)
- Synne D Rørvik
- Department of Cardiology, Haukeland University Hospital, Bergen, Norway
| | - Synne Torkildsen
- Department of Haematology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Øystein Bruserud
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, Bergen, Norway
- Section for Hematology, Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Zheng L, Zhang FJ. Adult rhabdomyosarcoma combined with acute myeloid leukemia: A case report. World J Clin Cases 2024; 12:582-586. [PMID: 38322472 PMCID: PMC10841940 DOI: 10.12998/wjcc.v12.i3.582] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 12/17/2023] [Accepted: 01/04/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Rhabdomyosarcoma is a tumor of mesenchymal origin. Secondary leukemia is a complication of previous transformation to other hematologic disorders or is a treatment-related acute myeloid leukemia secondary to cytotoxic chemotherapy or radiation therapy for other malignancies. CASE SUMMARY We present the case of a 36-year-old female patient who was diagnosed with rhabdomyosarcoma and acute myeloid leukemia. Further disease progression was observed after multiline chemotherapy. Eventually, the patient suffered cerebral hemorrhage, which resulted in death. CONCLUSION The incidence of rhabdomyosarcoma in adults is extremely low, and secondary leukemia caused by rhabdomyosarcoma is even rarer. Secondary leukemia has a very poor prognosis and a low overall survival rate.
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Affiliation(s)
- Lu Zheng
- Department of Hematology, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
| | - Fen-Juan Zhang
- Department of Hematology, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
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Gao Y, Han N, Jiang Y, Lu Z. Transformation from acute promyelocytic leukemia in pregnancy to acute myeloid leukemia with MLL-AF9 fusion gene: A case report and literature review. Medicine (Baltimore) 2023; 102:e36403. [PMID: 38050244 PMCID: PMC10695569 DOI: 10.1097/md.0000000000036403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 11/10/2023] [Indexed: 12/06/2023] Open
Abstract
RATIONALE Because there are few evidence-based guidelines and an extremely low incidence rate, managing and treating patients who have transitioned from acute promyelocytic leukemia (APL), which was diagnosed during pregnancy, to acute myeloid leukemia (AML), can be difficult. PATIENT CONCERNS In this case, a 34-year-old pregnant patient was diagnosed with APL in medium-risk group in June 2017. After the all-trans retinoic acid and arsenic trioxide-based full-course treatment, the patients achieved complete remission (CR) and were well-tolerated. After 5 years, the patient complained of fatigue for 3 months. DIAGNOSIS Bone marrow examination revealed hypercellularity with approximately 50% immunophenotypic abnormal myeloblasts with MLL-AF9 fusion gene. Based on the AML diagnosis criteria of the World Health Organization, the patient was eventually diagnosed with a rare transformation from APL to AML. INTERVENTIONS The patient was treated with two cycles of induction chemotherapy and an allogeneic hematopoietic stem cell transplantation (allo-HSCT). OUTCOMES Until now, the patient is in continuous remission with no signs of APL and AML. LESSIONS Despite the rarity of APL to AML transformation, it is crucial to track the disease's progress and administer treatment on time. It remains uncertain whether the risk stratification and clinical outcomes of secondary AML with MLL-AF9 are equivalent to those of de novo AML with MLL-AF9. The management and treatment of these patients should be personalized and require further observation.
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MESH Headings
- Adult
- Female
- Humans
- Pregnancy
- Hematopoietic Stem Cell Transplantation
- Leukemia, Myeloid, Acute/complications
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Promyelocytic, Acute/diagnosis
- Leukemia, Promyelocytic, Acute/genetics
- Leukemia, Promyelocytic, Acute/therapy
- Myeloid-Lymphoid Leukemia Protein/genetics
- Oncogene Proteins, Fusion/genetics
- Remission Induction
- Tretinoin/therapeutic use
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Affiliation(s)
- Yang Gao
- Department of Hematology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Hematology, General Hospital of PLA Southern Theater Command, Guangzhou, China
| | - Na Han
- Department of Hematology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Hematology, General Hospital of PLA Southern Theater Command, Guangzhou, China
| | - Yu Jiang
- Department of Hematology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Ziyuan Lu
- Department of Hematology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Auger N, Douet-Guilbert N, Quessada J, Theisen O, Lafage-Pochitaloff M, Troadec MB. Cytogenetics in the management of myelodysplastic neoplasms (myelodysplastic syndromes, MDS): Guidelines from the groupe francophone de cytogénétique hématologique (GFCH). Curr Res Transl Med 2023; 71:103409. [PMID: 38091642 DOI: 10.1016/j.retram.2023.103409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/04/2023] [Accepted: 09/14/2023] [Indexed: 12/26/2023]
Abstract
Myelodysplastic neoplasms (MDS) are clonal hematopoietic neoplasms. Chromosomal abnormalities (CAs) are detected in 40-45% of de novo MDS and up to 80% of post-cytotoxic therapy MDS (MDS-pCT). Lately, several changes appeared in World Health Organization (WHO) classification and International Consensus Classification (ICC). The novel 'biallelic TP53 inactivation' (also called 'multi-hit TP53') MDS entity requires systematic investigation of TP53 locus (17p13.1). The ICC maintains CA allowing the diagnosis of MDS without dysplasia (del(5q), del(7q), -7 and complex karyotype). Deletion 5q is the only CA, still representing a low blast class of its own, if isolated or associated with one additional CA other than -7 or del(7q) and without multi-hit TP53. It represents one of the most frequent aberrations in adults' MDS, with chromosome 7 aberrations, and trisomy 8. Conversely, translocations are rarer in MDS. In children, del(5q) is very rare while -7 and del(7q) are predominant. Identification of a germline predisposition is key in childhood MDS. Aberrations of chromosomes 5, 7 and 17 are the most frequent in MDS-pCT, grouped in complex karyotypes. Despite the ever-increasing importance of molecular features, cytogenetics remains a major part of diagnosis and prognosis. In 2022, a molecular international prognostic score (IPSS-M) was proposed, combining the prognostic value of mutated genes to the previous scoring parameters (IPSS-R) including cytogenetics, still essential. A karyotype on bone marrow remains mandatory at diagnosis of MDS with complementary molecular analyses now required. Analyses with FISH or other technologies providing similar information can be necessary to complete and help in case of karyotype failure, for doubtful CA, for clonality assessment, and for detection of TP53 deletion to assess TP53 biallelic alterations.
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Affiliation(s)
- Nathalie Auger
- Gustave Roussy, Génétique des tumeurs, 144 rue Edouard Vaillant, Villejuif 94805, France
| | - Nathalie Douet-Guilbert
- Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest F-29200, France; CHRU Brest, Laboratoire de Génétique Chromosomique, Service de génétique, Brest, France
| | - Julie Quessada
- Laboratoire de Cytogénétique Hématologique, CHU Timone Aix Marseille University, Marseille, France
| | - Olivier Theisen
- Hematology Biology, Nantes University Hospital, Nantes, France
| | | | - Marie-Bérengère Troadec
- Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest F-29200, France; CHRU Brest, Laboratoire de Génétique Chromosomique, Service de génétique, Brest, France.
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Belhabri A, Heiblig M, Morisset S, Vila L, Santana C, Nicolas‐Virelizier E, Hayette S, Tigaud I, Plesa A, Labussiere‐Wallet H, Sobh M, Michallet A, Marie B, Nicolini F, Guillermin Y, Gaëlle F, Lebras L, Rey P, Jauffret‐Bertholon L, Laude M, Sandrine L, Michallet M. Clinical outcome of therapy-related acute myeloid leukemia patients. Real-life experience in a University Hospital and a Cancer Center in France. Cancer Med 2023; 12:16929-16944. [PMID: 37548369 PMCID: PMC10501294 DOI: 10.1002/cam4.6322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 06/17/2023] [Accepted: 06/27/2023] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND t-AML occurs after a primary malignancy treatment and retains a poor prognosis. AIMS To determine the impact of primary malignancies, therapeutic strategies, and prognostic factors on clinical outcomes of t-AML. RESULTS A total of 112 adult patients were included in this study. Fifty-Five patients received intensive chemotherapy (IC), 33 non-IC, and 24 best supportive care. At t-AML diagnosis, 42% and 44% of patients presented an unfavorable karyotype and unfavorable 2010 ELN risk profile, respectively. Among treated patients (n = 88), 43 (49%) achieved complete remission: four out of 33 (12%) and 39 out of 55 (71%) in non-IC and IC groups, respectively. With a median follow-up of 5.5 months, the median overall survival (OS) and disease-free survival (DFS) for the whole population were 9 months and 6.3 months, respectively, and for the 88 treated patients 13.5 months and 8.2 months, respectively. Univariate analysis on OS and DFS showed a significant impact of high white blood cells (WBC) and blast counts at diagnosis, unfavorable karyotype and ELN classification. Multivariate analysis showed a negative impact of WBC count at diagnosis and a positive impact of chemotherapy on OS and DFS in the whole population. It also showed a negative impact of previous auto-HCT and high WBC count on OS and DFS and of IC on OS in treated patients which disappeared when we considered only confounding variables (age, previous cancers, marrow blasts, and 2010 ELN classification). In a pair-matched analysis comparing IC treated t-AML with de novo AML, there was no difference of OS and DFS between the two populations. CONCLUSION We showed, in this study that t-AML patients with unfavorable features represented almost half of the population. Best outcomes obtained in patients receiving IC must be balanced by known confounding variables and should be improved by using new innovative agents and therapeutic strategies.
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Affiliation(s)
- Amine Belhabri
- Department of HematologyLeon Berard Cancer CenterLyonFrance
| | - Mael Heiblig
- Department of HematologyUniversity Hospital Lyon SudPierre BeniteFrance
| | | | - Liliana Vila
- Department of HematologyLeon Berard Cancer CenterLyonFrance
| | | | | | - Sandrine Hayette
- Department of biology – GHSUniversity Hospital Lyon SudPierre BeniteFrance
| | - Isabelle Tigaud
- Department of biology – GHSUniversity Hospital Lyon SudPierre BeniteFrance
| | - Adriana Plesa
- Department of biology – GHSUniversity Hospital Lyon SudPierre BeniteFrance
| | | | - Mohamad Sobh
- Research Advisor, Faculty of MedicineUniversity of OttawaOttawaCanada
| | | | - Balsat Marie
- Department of HematologyUniversity Hospital Lyon SudPierre BeniteFrance
| | | | | | - Fossard Gaëlle
- Department of HematologyUniversity Hospital Lyon SudPierre BeniteFrance
| | - Laure Lebras
- Department of HematologyLeon Berard Cancer CenterLyonFrance
| | - Philippe Rey
- Department of HematologyLeon Berard Cancer CenterLyonFrance
| | | | | | - Loron Sandrine
- Department of HematologyUniversity Hospital Lyon SudPierre BeniteFrance
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8
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Lomov NA, Viushkov VS, Rubtsov MA. Mechanisms of Secondary Leukemia Development Caused by Treatment with DNA Topoisomerase Inhibitors. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:892-911. [PMID: 37751862 DOI: 10.1134/s0006297923070040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/14/2023] [Accepted: 04/20/2023] [Indexed: 09/28/2023]
Abstract
Leukemia is a blood cancer originating in the blood and bone marrow. Therapy-related leukemia is associated with prior chemotherapy. Although cancer therapy with DNA topoisomerase II inhibitors is one of the most effective cancer treatments, its side effects include development of secondary leukemia characterized by the chromosomal rearrangements affecting AML1 or MLL genes. Recurrent chromosomal translocations in the therapy-related leukemia differ from chromosomal rearrangements associated with other neoplasias. Here, we reviewed the factors that drive chromosomal translocations induced by cancer treatment with DNA topoisomerase II inhibitors, such as mobility of ends of double-strand DNA breaks formed before the translocation and gain of function of fusion proteins generated as a result of translocation.
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Affiliation(s)
- Nikolai A Lomov
- Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
| | - Vladimir S Viushkov
- Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
| | - Mikhail A Rubtsov
- Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
- Department of Biochemistry, Center for Industrial Technologies and Entrepreneurship Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119435, Russia
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9
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Portuguese AJ, Albittar A, Gooley TH, Deeg HJ. Transplantation for myeloid neoplasms with antecedent solid tumor. Cancer 2023; 129:142-150. [PMID: 36316954 DOI: 10.1002/cncr.34517] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/07/2022] [Accepted: 09/19/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Definitive treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN) involves allogeneic hematopoietic stem cell transplantation (allo-HSCT), either with myeloablative (MAC) or reduced-intensity conditioning (RIC). These diseases may arise in patients with a prior solid tumor. The impact of antecedent solid tumor on transplantation decision-making and outcomes is not well defined. METHODS The authors performed a retrospective cohort study to address this question. A total of 1193 patients who underwent allo-HSCT for AML, MDS, or MPN between January 1, 2010 and December 31, 2018 were included, 102 of whom had a history of prior solid tumor. RESULTS Patients with prior solid tumor were older (median age, 62.5 vs. 54.9 years; p < .00001) and more frequently were conditioned with RIC (52.5% vs. 27.2%; p < .00001). A higher incidence of acute graft-versus-host disease was observed in patients with prior solid tumor (73.5% vs 66.4%; adjusted odds ratio, 1.65; 95% confidence interval, 1.03-2.65; p = .037), yet overall survival and relapse did not significantly differ. Cytogenetic risk was the dominant risk factor for survival. CONCLUSIONS Analysis by the authors suggests that patients with antecedent solid tumor and respective therapy can be transplanted successfully. Although selection bias is likely to be a factor, the results are encouraging for patients who come to transplantation after surviving a prior cancer.
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Affiliation(s)
- Andrew Jay Portuguese
- University of Washington, Seattle, Washington, USA.,Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Aya Albittar
- University of Washington, Seattle, Washington, USA
| | - Ted H Gooley
- University of Washington, Seattle, Washington, USA.,Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Hans Joachim Deeg
- University of Washington, Seattle, Washington, USA.,Fred Hutchinson Cancer Center, Seattle, Washington, USA
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10
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Marques FK, Sabino ADP. Myelodysplastic neoplasms: An overview on diagnosis, risk-stratification, molecular pathogenesis, and treatment. Biomed Pharmacother 2022; 156:113905. [DOI: 10.1016/j.biopha.2022.113905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/10/2022] [Accepted: 10/19/2022] [Indexed: 11/02/2022] Open
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11
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Nguyen-Khac F, Bidet A, Daudignon A, Lafage-Pochitaloff M, Ameye G, Bilhou-Nabéra C, Chapiro E, Collonge-Rame MA, Cuccuini W, Douet-Guilbert N, Eclache V, Luquet I, Michaux L, Nadal N, Penther D, Quilichini B, Terre C, Lefebvre C, Troadec MB, Véronèse L. The complex karyotype in hematological malignancies: a comprehensive overview by the Francophone Group of Hematological Cytogenetics (GFCH). Leukemia 2022; 36:1451-1466. [DOI: 10.1038/s41375-022-01561-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/24/2022] [Accepted: 03/28/2022] [Indexed: 12/16/2022]
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12
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Tariq H, Barnea Slonim L, Coty Fattal Z, Alikhan MB, Segal J, Gurbuxani S, Helenowski IB, Zhang H, Sukhanova M, Lu X, Altman JK, Chen QC, Behdad A. Therapy-related myeloid neoplasms with normal karyotype show distinct genomic and clinical characteristics compared to their counterparts with abnormal karyotype. Br J Haematol 2022; 197:736-744. [PMID: 35304738 DOI: 10.1111/bjh.18154] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/05/2022] [Accepted: 03/08/2022] [Indexed: 01/13/2023]
Abstract
Therapy-related myeloid neoplasms (t-MNs) are a complication of treatment with cytotoxic chemotherapy and/or radiation therapy. The majority of t-MNs show chromosomal abnormalities associated with myelodysplastic syndrome (MDS) or KMT2A rearrangements and are characterized by poor clinical outcomes. A small but substantial subset of patients have normal karyotype (NK) and their clinical characteristics and mutational profiles are not well studied. We retrospectively studied patients diagnosed with t-MN at three institutions and compared the mutational profile and survival data between t-MNs with NK and t-MNs with abnormal karyotype (AK). A total of 204 patients with t-MN were identified including 158 with AK and 46 with NK. NK t-MNs, compared to AK, were enriched for mutations in TET2 (p < 0.0001), NPM1 (p < 0.0001), ASXL1 (p = 0.0003), SRSF2 (p < 0.0001), RUNX1 (p = 0.0336) and STAG2 (p = 0.0099) and showed a significantly lower frequency of TP53 mutations (p < 0.0001). Overall survival (OS) was significantly lower in AK t-MNs as compared to NK cases (p = 0.0094). In our study, NK t-MNs showed a significantly better OS, a higher prevalence of MN-associated mutations and a lower frequency of TP53 mutations compared to their AK counterparts. The distinct clinical and mutational profile of NK t-MNs merits a separate classification.
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Affiliation(s)
- Hamza Tariq
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | | | - Zachary Coty Fattal
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Mir B Alikhan
- Department of Pathology, NorthShore University Health System, Evanston, Illinois, USA
| | - Jeremy Segal
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
| | - Sandeep Gurbuxani
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
| | - Irene B Helenowski
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Hui Zhang
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Madina Sukhanova
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Xinyan Lu
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Jessica K Altman
- Department of Medicine (Hematology and Oncology), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Qing C Chen
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Amir Behdad
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.,Department of Medicine (Hematology and Oncology), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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13
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Pommier Y, Nussenzweig A, Takeda S, Austin C. Human topoisomerases and their roles in genome stability and organization. Nat Rev Mol Cell Biol 2022; 23:407-427. [PMID: 35228717 PMCID: PMC8883456 DOI: 10.1038/s41580-022-00452-3] [Citation(s) in RCA: 213] [Impact Index Per Article: 71.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2022] [Indexed: 12/15/2022]
Abstract
Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and TOP3B) topoisomerases. In this Review, we discuss their biochemistry and their roles in transcription, DNA replication and chromatin remodelling, and highlight the recent progress made in understanding TOP3A and TOP3B. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. We also discuss the physiological and pathological formation of irreversible topoisomerase cleavage complexes (TOPccs) as they generate topoisomerase DNA–protein crosslinks (TOP-DPCs) coupled with DNA breaks. We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer. Topoisomerases have essential roles in transcription, DNA replication, chromatin remodelling and, as recently revealed, 3D genome organization. However, topoisomerases also generate DNA–protein crosslinks coupled with DNA breaks, which are increasingly recognized as a source of disease-causing genomic damage.
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14
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Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study. Blood Adv 2021; 6:1278-1295. [PMID: 34794172 PMCID: PMC8864639 DOI: 10.1182/bloodadvances.2021005335] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 10/12/2021] [Indexed: 11/20/2022] Open
Abstract
The large PETHEMA registry shows that secondary AML represents 27% of AML cases and confirms its independent adverse prognostic value. Subcategories of secondary AML were analyzed, including MSD/MPN and therapy-related cases, with different features and outcomes. Secondary acute myeloid leukemia (sAML) comprises a heterogeneous group of patients and is associated with poor overall survival (OS). We analyze the characteristics, treatment patterns, and outcomes of adult patients with sAML in the Programa Español de Tratamientos en Hematología (PETHEMA) registry. Overall, 6211 (72.9%) were de novo and 2310 (27.1%) had sAML, divided into myelodysplastic syndrome AML (MDS-AML, 44%), MDS/myeloproliferative AML (MDS/MPN-AML, 10%), MPN-AML (11%), therapy-related AML (t-AML, 25%), and antecedent neoplasia without prior chemotherapy/radiotherapy (neo-AML, 9%). Compared with de novo, patients with sAML were older (median age, 69 years), had more Eastern Cooperative Oncology Group ≥2 (35%) or high-risk cytogenetics (40%), less FMS-like tyrosine kinase 3 internal tandem duplication (11%), and nucleophosmin 1 (NPM1) mutations (21%) and received less intensive chemotherapy regimens (38%) (all P < .001). Median OS was higher for de novo than sAML (10.9 vs 5.6 months; P < .001) and shorter in sAML after hematologic disorder (MDS, MDS/MPN, or MPN) compared with t-AML and neo-AML (5.3 vs 6.1 vs 5.7 months, respectively; P = .04). After intensive chemotherapy, median OS was better among patients with de novo and neo-AML (17.2 and 14.6 months, respectively). No OS differences were observed after hypomethylating agents according to type of AML. sAML was an independent adverse prognostic factor for OS. We confirmed high prevalence and adverse features of sAML and established its independent adverse prognostic value. This trial was registered at www.clinicaltrials.gov as #NCT02607059.
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15
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Vasudevan Nampoothiri R, Viswabandya A. Allogeneic Hematopoietic Stem Cell Transplantation in Therapy Related Acute Leukemia. Indian J Hematol Blood Transfus 2021; 37:521-527. [PMID: 34744336 PMCID: PMC8523613 DOI: 10.1007/s12288-020-01334-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/07/2020] [Indexed: 12/19/2022] Open
Abstract
Therapy related acute leukemia consists of a unique subset of acute leukemia with an increased frequency of high risk cytogenetic and molecular abnormalities, dismal response to therapy, higher relapse rates and poor overall survival. Therapy related acute myeloid leukemia (t-AML) is a better defined disease entity than therapy related acute lymphoid leukemia (t-ALL). However, in recent times, t-ALL is also being increasingly recognized and extensively studied. Therapy related acute myeloid leukemia is usually classified together with therapy related myelodysplastic syndrome. However, the management of these two diseases maybe different regarding needs of induction chemotherapy and eligibility for upfront allogeneic hematopoietic stem cell transplantation (Allo HSCT). There is also evidence regarding differences in prognosis and outcomes between these two entities. Allo HSCT offers a potential for cure in t-AML and t-ALL. However, existing literature on the same is confounded by inclusion of t-MDS and secondary acute leukemias. Here we review the current evidence on the outcomes and predictors of outcomes of Allo HSCT in the management of therapy related acute leukemias. We also shed light into the under-representation of therapy related leukemias in clinical trials. This stresses the need for prospective trials incorporating measurable residual disease monitoring and sequential next generation sequencing based genomic data for accurate prognostication and management of therapy related acute leukemia.
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Affiliation(s)
- Ram Vasudevan Nampoothiri
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9 Canada
| | - Auro Viswabandya
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9 Canada
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16
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Nampoothiri RV, Law AD, Lam W, Chen C, Al-Shaibani Z, Loach D, Michelis FV, Kim DDH, Mattsson J, Kumar R, Lipton JH, Viswabandya A. Predictors of outcomes of therapy-related acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther 2021; 15:27-35. [PMID: 33775624 DOI: 10.1016/j.hemonc.2021.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/06/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/OBJECTIVE Existing literature on allogeneic hematopoietic stem cell transplantation (allo-HSCT) in therapy-related acute myeloid leukemia (t-AML) is confounded by the inclusion of patients with secondary AML and t-MDS. We aim to report our 20-year experience of HSCT in t-AML. METHODS We retrospectively reviewed patients with t-AML who underwent HSCT. Patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival (RFS), overall survival (OS), and predictors of outcomes. RESULTS In total, 68 patients (59.9% female; median age, 56.5 years) underwent HSCT. Acute and chronic graft-versus-host disease (GVHD) occurred in 39 (57.4%) and 23 (33.8%) patients, respectively. Cumulative incidence of relapse, nonrelapse mortality, RFS, and OS at 2 years were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Significant predictors of reduced OS were presence of 11q23 rearrangement (hazard ratio [HR], 3.24), using induction regimens other than FLAG-Ida or 7 + 3 (HR, 3.65), haploidentical donors (HR, 3.48), Eastern Cooperative Oncology Group performance status 2 or higher (HR, 5.83), and using cyclosporine A-methotrexate as GVHD prophylaxis (HR, 2.41). A significant decrement in survival was seen with an increasing number of any of these prognostic factors. CONCLUSION Outcomes of t-AML are satisfactory after allo-HSCT. Patients with t-AML with good-risk karyotypes, good performance status, having HLA-matched donors, and receiving intensive induction regimens have better outcomes after HSCT.
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Affiliation(s)
- Ram Vasudevan Nampoothiri
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Arjun Datt Law
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Wilson Lam
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Carol Chen
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Zeyad Al-Shaibani
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - David Loach
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Fotios V Michelis
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Dennis Dong Hwan Kim
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Jonas Mattsson
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Rajat Kumar
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Jeffrey Howard Lipton
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Auro Viswabandya
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
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17
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Luedke C, Zhao Y, McCracken J, Maule J, Yang LH, Jug R, Galeotti J, Siddiqi I, Gong J, Lu CM, Wang E. Myeloid neoplasms in the setting of chronic lymphocytic leukaemia/chronic lymphocytic leukaemia-like disease: a clinicopathological study of 66 cases comparing cases with prior history of treatment to those without. J Clin Pathol 2021; 75:292-301. [PMID: 33542108 DOI: 10.1136/jclinpath-2020-207334] [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: 12/10/2020] [Revised: 01/16/2021] [Accepted: 01/19/2021] [Indexed: 11/04/2022]
Abstract
AIMS Myeloid neoplasms occur in the setting of chronic lymphocytic leukaemia (CLL)/CLL-like disease. The underlying pathogenesis has not been elucidated. METHODS Retrospectively analysed 66 cases of myeloid neoplasms in patients with CLL/CLL-like disease. RESULTS Of these, 33 patients (group 1) had received treatment for CLL/CLL-like disease, while the other 33 patients (group 2) had either concurrent diagnoses or untreated CLL/CLL-like disease before identifying myeloid neoplasms. The two categories had distinct features in clinical presentation, spectrum of myeloid neoplasm, morphology, cytogenetic profile and clinical outcome. Compared with group 2, group 1 demonstrated a younger age at the diagnosis of myeloid neoplasm (median, 65 vs 71 years), a higher fraction of myelodysplastic syndrome (64% vs 36%; OR: 3.1; p<0.05), a higher rate of adverse unbalanced cytogenetic abnormalities, including complex changes, -5/5q- and/or -7/7q- (83% vs 28%; OR: 13.1; p<0.001) and a shorter overall survival (median, 12 vs 44 months; p<0.05). CONCLUSIONS Myeloid neoplasm in the setting of CLL/CLL-like disease can be divided into two categories, one with prior treatment for CLL/CLL-like disease and the other without. CLL-type treatment may accelerate myeloid leukaemogenesis. The risk is estimated to be 13-fold higher in patients with treatment than those without. The causative agent could be attributed to fludarabine in combination with alkylators, based on the latency of myeloid leukaemogenesis and the cytogenetic profile.
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Affiliation(s)
- Catherine Luedke
- Pathology, Duke University Medical Center, Durham, North Carolina, USA
| | - Yue Zhao
- Pathology, Duke University Medical Center, Durham, North Carolina, USA .,Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, China
| | - Jenna McCracken
- Pathology, Duke University Medical Center, Durham, North Carolina, USA
| | - Jake Maule
- Pathology, Duke University Medical Center, Durham, North Carolina, USA
| | - Lian-He Yang
- Pathology, Duke University Medical Center, Durham, North Carolina, USA.,Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, China
| | - Rachel Jug
- Pathology, Duke University Medical Center, Durham, North Carolina, USA
| | - Jonathan Galeotti
- Pathology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Imran Siddiqi
- Pathology, University of Southern California, Los Angeles, California, USA
| | - Jerald Gong
- Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Chuanyi Mark Lu
- Laboratory Medicine, University of California San Francisco, San Francisco, California, USA
| | - Endi Wang
- Pathology, Duke University Medical Center, Durham, North Carolina, USA
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18
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Prognostic Markers of Myelodysplastic Syndromes. ACTA ACUST UNITED AC 2020; 56:medicina56080376. [PMID: 32727068 PMCID: PMC7466347 DOI: 10.3390/medicina56080376] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/23/2020] [Accepted: 07/24/2020] [Indexed: 12/26/2022]
Abstract
Myelodysplastic syndrome (MDS) is a clonal disease characterized by multilineage dysplasia, peripheral blood cytopenias, and a high risk of transformation to acute myeloid leukemia. In theory, from clonal hematopoiesis of indeterminate potential to hematologic malignancies, there is a complex interplay between genetic and epigenetic factors, including miRNA. In practice, karyotype analysis assigns patients to different prognostic groups, and mutations are often associated with a particular disease phenotype. Among myeloproliferative disorders, secondary MDS is a group of special entities with a typical spectrum of genetic mutations and cytogenetic rearrangements resembling those in de novo MDS. This overview analyzes the present prognostic systems of MDS and the most recent efforts in the search for genetic and epigenetic markers for the diagnosis and prognosis of MDS.
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19
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Higgins A, Shah MV. Genetic and Genomic Landscape of Secondary and Therapy-Related Acute Myeloid Leukemia. Genes (Basel) 2020; 11:E749. [PMID: 32640569 PMCID: PMC7397259 DOI: 10.3390/genes11070749] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/02/2020] [Accepted: 07/02/2020] [Indexed: 12/22/2022] Open
Abstract
A subset of acute myeloid leukemia (AML) arises either from an antecedent myeloid malignancy (secondary AML, sAML) or as a complication of DNA-damaging therapy for other cancers (therapy-related myeloid neoplasm, t-MN). These secondary leukemias have unique biological and clinical features that distinguish them from de novo AML. Over the last decade, molecular techniques have unraveled the complex subclonal architecture of sAML and t-MN. In this review, we compare and contrast biological and clinical features of de novo AML with sAML and t-MN. We discuss the role of genetic mutations, including those involved in RNA splicing, epigenetic modification, tumor suppression, transcription regulation, and cell signaling, in the pathogenesis of secondary leukemia. We also discuss clonal hematopoiesis in otherwise healthy individuals, as well as in the context of another malignancy, and how it challenges the conventional notion of sAML/t-MN. We conclude by summarizing the current and emerging treatment strategies, including allogenic transplant, in these complex scenarios.
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20
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Winer ES. Secondary Acute Myeloid Leukemia: A Primary Challenge of Diagnosis and Treatment. Hematol Oncol Clin North Am 2020; 34:449-463. [PMID: 32089222 DOI: 10.1016/j.hoc.2019.11.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Secondary acute myeloid leukemia (sAML) is a complex diagnosis that includes AML caused by either an antecedent hematologic disease (AML-AHD) or from previous treatment with chemotherapy or radiation. This disease carries a poor prognosis and is historically chemorefractory; additionally, often patients are ineligible for standard chemotherapy because of advanced age and other comorbidities. The advances of molecular diagnostics and reclassification of World Health Organization criteria have aided in the categorization of this disease. This article describes the etiology and pathophysiology of sAML, and delves into past successful treatments as well as promising new treatments.
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Affiliation(s)
- Eric S Winer
- Adult Leukemia Program, Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
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21
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Acute Myeloid Neoplasms. Genomic Med 2020. [DOI: 10.1007/978-3-030-22922-1_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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22
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Murray NP, Orrego S, López MA, Munoz L, Minzer S. Common B-cell acute lymphoblastic leukaemia in a 70-year-old woman presenting 2 years after carboplatin-taxane radiotherapy for endometrial cancer. Ecancermedicalscience 2019; 13:972. [PMID: 31921343 PMCID: PMC6834386 DOI: 10.3332/ecancer.2019.972] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Indexed: 11/16/2022] Open
Abstract
Therapy-related acute lymphoblastic leukaemia (t-ALL) is a poorly defined entity and is not featured in the World Health Organization classification as a distinct clinical entity from acute lymphoblastic leukaemia (ALL), thus differing from therapy-related acute myeloid leukaemia and myelodysplasia. We present a case of t-ALL occurring 18 months after treatment for metastatic endometrial cancer with a regimen of carboplatin, paclitaxel and radiotherapy. The patient presented with severe pancytopenia and diagnosed with common-B ALL, and the cytogenetic analysis showed a previously unreported deletion in chromosome 19 (q13.1) in 100% of the blast cells. The patient declined further therapy and died 1 month later. This rare but serious side effect of chemo-radiotherapy should be considered when deciding on treatment options for gynaecological cancers.
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Affiliation(s)
- Nigel P Murray
- Consultant Haematologist, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile.,Professor Haematology, Faculty of Medicine, University Finis Terrae, Av Pedro de Valdivia 1509, Providencia, Santiago
| | - Shenda Orrego
- Physician General Medicine, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile.,Tutor, Faculty of Medicine, University Mayor, Renato Sánchez 4369, Las Condes, Santiago, 27550224, Chile
| | - Marco Antonio López
- Physician General Medicine, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile.,Tutor, Faculty of Medicine, University Mayor, Renato Sánchez 4369, Las Condes, Santiago, 27550224, Chile
| | - Lorena Munoz
- Tutor, Faculty of Medicine, University Mayor, Renato Sánchez 4369, Las Condes, Santiago, 27550224, Chile.,Consultant Internal Medicine, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile
| | - Simona Minzer
- Physician General Medicine, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile
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23
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Gollapudi P, Bhat VS, Eastmond DA. Concentration-response studies of the chromosome-damaging effects of topoisomerase II inhibitors determined in vitro using human TK6 cells. Mutat Res 2019; 841:49-56. [PMID: 31138411 DOI: 10.1016/j.mrgentox.2019.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/13/2019] [Accepted: 05/14/2019] [Indexed: 11/28/2022]
Abstract
Topoisomerase II (topo II) inhibitors are commonly used as chemotherapy to treat multiple types of cancer, though their use is also associated with the development of therapy related acute leukemias. While the chromosome-damaging effects of etoposide, a topo II poison, have been proposed to act through a threshold mechanism, little is known about the chromosome damaging effects and dose responses for the catalytic inhibitors of the enzyme. The current study was designed to further investigate the potencies and concentration-response relationships of several topoisomerase II inhibitors, including the topoisomerase II poison etoposide, as well as catalytic inhibitors aclarubicin, merbarone, ICRF-154 and ICRF-187 using both a traditional in vitro micronucleus assay as well as a flow-cytometry based version of the assay. Benchmark dose (BMD) analysis was used to identify models that best fit the data and estimate a BMD, in this case the concentration at which a one standard deviation increase above the control frequency would be expected. All of the agents tested were potent in inducing micronuclei in human lymphoblastoid TK6 cells, with significant increases seen at low micromolar, and in the cases of aclarubicin and etoposide, at low nanomolar concentrations. Use of the anti-kinetochore CREST antibody with the microscopy-based assay demonstrated that the vast majority of the micronuclei originated from chromosome breakage. In comparing the two versions of the micronucleus assay, significant increases in micronucleated cells were observed at similar or lower concentrations using the traditional microscopy-based assay. BMD modeling of the data exhibited several advantages and proved to be a valuable alternative for concentration-response analysis, producing points of departure comparable to those derived using traditional no-observed or lowest-observed genotoxic effect level (NOGEL or LOGEL) approaches.
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Affiliation(s)
- P Gollapudi
- Environmental Toxicology Graduate Program and Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA
| | - V S Bhat
- Environmental Toxicology Graduate Program and Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA
| | - D A Eastmond
- Environmental Toxicology Graduate Program and Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA.
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Hartmann L, Haferlach C, Meggendorfer M, Kern W, Haferlach T, Stengel A. Myeloid malignancies with isolated 7q deletion can be further characterized by their accompanying molecular mutations. Genes Chromosomes Cancer 2019; 58:698-704. [PMID: 30994218 DOI: 10.1002/gcc.22761] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 04/16/2019] [Indexed: 01/22/2023] Open
Abstract
Deletions in the long arm of chromosome 7 (del(7q)) are recurrent cytogenetic aberrations in myeloid neoplasms. They occur either isolated or as part of a complex karyotype and are associated with unfavorable prognosis in certain disease entities. We performed detailed cytogenetic analysis, molecular analysis, and array comparative genomic hybridization in a cohort of 81 patients with a variety of myeloid malignancies and del(7q) as sole chromosomal alteration. In 70% (57/81) of patients, we identified a commonly deleted region (size: 18 Mb) involving the genomic region 101 912.442 (7q22.1)-119 608.824 (7q31.31). Furthermore, in 80 patients, we analyzed 17 genes commonly mutated in myeloid neoplasms and identified high mutation frequencies in ASXL1 34% (27/80), TET2 33% (26/80), RUNX1 25% (20/80), DNMT3A 25% (20/80), while TP53 was rarely affected (5%, 4/80). ASXL1 and TET2 showed similar mutation frequencies across all analyzed entities while RUNX1, CBL, and JAK2 were specifically mutated in patients with acute myeloid leukemia (AML), chronic myelomonocytic leukemia, and myeloproliferative neoplasms, respectively. We detected a significantly higher frequency of RUNX1 (42% vs 13%, P = .0001) and ASXL1 (32% vs 14%, P = .008) mutations in AML patients with del(7q) compared to other AML patients in the Medical Research Council unfavorable risk group (n = 464), indicating a cooperative leukemogenic potential. Our data provide further insight into the pathomechanism of this cytogenetic subgroup.
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Affiliation(s)
- Luise Hartmann
- MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich, 81377, Germany
| | - Claudia Haferlach
- MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich, 81377, Germany
| | - Manja Meggendorfer
- MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich, 81377, Germany
| | - Wolfgang Kern
- MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich, 81377, Germany
| | - Torsten Haferlach
- MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich, 81377, Germany
| | - Anna Stengel
- MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich, 81377, Germany
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25
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Ganster C, Müller-Thomas C, Haferlach C, Strupp C, Ogata K, Germing U, Hildebrandt B, Mallo M, Lübbert M, Müller C, Solé F, Götze KS, Vandenberghe P, Göhring G, Steinmetz T, Kröger N, Platzbecker U, Söling U, Raynaud S, Shirneshan K, Schanz J, Haase D. Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes. Genes Chromosomes Cancer 2019; 58:689-697. [PMID: 30994215 DOI: 10.1002/gcc.22760] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/15/2019] [Accepted: 04/15/2019] [Indexed: 11/10/2022] Open
Abstract
The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the new comprehensive cytogenetic scoring system for MDS, chromosome 7 anomalies are no longer generally assigned to poor risk features but are thoroughly separated. However, der(1;7)(q10;p10), hereinafter der(1;7), is merged into the group labeled "any other single" and belongs to the intermediate risk group, just by definition due to lack of adequate clinical data. The aim of our international collaborative was to clarify the "real" prognostic impact of der(1;7) on a homogenous and well-documented data base. We performed detailed analysis of 63 MDS patients with isolated der(1;7) constituting the largest cohort hitherto reported. Furthermore, clinical data are compared with those of patients with isolated del(7q) and isolated monosomy 7. Median overall survival (OS) of patients with der(1;7) is 26 months (hazard ratio (HR) 0.91 for del(7q) vs der(1;7) and 2.53 for monosomy 7 vs der(1;7)). The der(1;7) is associated with profound thrombocytopenia most probably causing the reduced OS which is in striking contrast to the low risk for AML transformation (HR 3.89 for del(7q) vs der(1;7) and 5.88 for monosomy 7 vs der(1;7)). Molecular karyotyping indicates that der(1;7) is generated in a single step during mitosis and that a chromosomal imbalance rather than a single disrupted gene accounts for malignancy. Thus, the current cytogenetic scoring system assigning isolated der(1;7) to the intermediate risk group is now confirmed by a sufficient data set.
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Affiliation(s)
- Christina Ganster
- Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Catharina Müller-Thomas
- Department of Hematology and Medical Oncology III, Technische Universität München, Munich, Germany
| | | | - Corinna Strupp
- Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-Universität, Düsseldorf, Germany
| | - Kiyoyuki Ogata
- Metropolitan Research and Treatment Center for Blood Disorders (MRTC Japan), Tokyo, Japan
| | - Ulrich Germing
- Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-Universität, Düsseldorf, Germany
| | - Barbara Hildebrandt
- Institute of Human Genetics and Anthropology, Heinrich-Heine-Universität, Düsseldorf, Germany
| | - Mar Mallo
- Josep Carreras Leukemia Research Institute (IJC), ICO-Hospital GermansTrias i Pujol, Universitat Autonòma de Barcelona, Barcelona, Spain
| | - Michael Lübbert
- Division of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg, Freiburg, Germany
| | - Christel Müller
- Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Leipzig, Germany
| | - Francesc Solé
- Josep Carreras Leukemia Research Institute (IJC), ICO-Hospital GermansTrias i Pujol, Universitat Autonòma de Barcelona, Barcelona, Spain
| | - Katharina S Götze
- Department of Hematology and Medical Oncology III, Technische Universität München, Munich, Germany
| | | | - Gudrun Göhring
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Tilman Steinmetz
- Onkologie Köln, Outpatient Clinic for Hematology and Oncology, Köln, Germany
| | - Nicolaus Kröger
- Department of Stem Cell Transplantation, University of Hamburg-Eppendorf, Hamburg, Germany
| | - Uwe Platzbecker
- Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Leipzig, Germany
| | - Ulrike Söling
- Outpatient Clinic for Hematology and Oncology, Kassel, Germany
| | - Sophie Raynaud
- Département d'hématologie biologique, Hôpital Pasteur, Nice, France
| | - Katayoon Shirneshan
- Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Julie Schanz
- Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Detlef Haase
- Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany
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26
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Tweats D, Eastmond DA, Lynch AM, Elhajouji A, Froetschl R, Kirsch-Volders M, Marchetti F, Masumura K, Pacchierotti F, Schuler M. Role of aneuploidy in the carcinogenic process: Part 3 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2019; 847:403032. [PMID: 31699349 DOI: 10.1016/j.mrgentox.2019.03.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 02/10/2019] [Accepted: 03/13/2019] [Indexed: 12/13/2022]
Abstract
Aneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical aneugens; and chemotherapy-related malignant neoplasms. Aneuploidy is seen at various stages in carcinogenesis. However, the relationship between induced aneuploidy occurring after exposure and clonal aneuploidy present in tumours is not clear. Recent evidence indicates that the induction of chromosomal instability (CIN), may be more important than aneuploidy per se, in the carcinogenic process. Down Syndrome, trisomy 21, is associated with altered hematopoiesis in utero which, in combination with subsequent mutations, results in an increased risk for acute megakaryoblastic and lymphoblastic leukemias. In contrast, there is reduced cancer risk for most solid tumours in Down Syndrome. Mouse models with high levels of aneuploidy are also associated with increased cancer risk for particular tumours with long latencies, but paradoxically other types of tumour often show decreased incidence. The aneugens reviewed that induce cancer in humans and animals all possess other carcinogenic properties, such as mutagenicity, clastogenicity, cytotoxicity, organ toxicities, hormonal and epigenetic changes which likely account for, or interact with aneuploidy, to cause carcinogenesis. Although the role that aneuploidy plays in carcinogenesis has not been fully established, in many cases, it may not play a primary causative role. Tubulin-disrupting aneugens that do not possess other properties linked to carcinogenesis, were not carcinogenic in rodents. Similarly, in humans, for the tubulin-disrupting aneugens colchicine and albendazole, there is no reported association with increased cancer risk. There is a need for further mechanistic studies on agents that induce aneuploidy, particularly by mechanisms other than tubulin disruption and to determine the role of aneuploidy in pre-neoplastic events and in early and late stage neoplasia.
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Affiliation(s)
| | | | | | | | | | | | - Francesco Marchetti
- Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada
| | - Kenichi Masumura
- Division of Genetics and Mutagenesis, National Institute of Health Sciences, Kanagawa, Japan
| | - Francesca Pacchierotti
- Health Protection Technology Division, Laboratory of Biosafety and Risk Assessment, ENEA, CR Casaccia, Rome, Italy
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27
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Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum. Blood 2019; 133:2718-2724. [PMID: 30914417 DOI: 10.1182/blood-2019-01-895698] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
There is a Blood Commentary on this article in this issue.
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28
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The leukemia strikes back: a review of pathogenesis and treatment of secondary AML. Ann Hematol 2019; 98:541-559. [PMID: 30666431 DOI: 10.1007/s00277-019-03606-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/04/2019] [Indexed: 12/17/2022]
Abstract
Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.
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29
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Yang WJ, Nie DN, Ma LP, Wang XJ, Wu YD, Xie SF, Xiao J, Wang JY, Liu HY, Huang KZ. [Lineage switch from B cell to myeloid cell in the course of lymphoma treatment: three cases and literature review]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2018; 39:518-520. [PMID: 30032573 PMCID: PMC7342913 DOI: 10.3760/cma.j.issn.0253-2727.2018.06.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Indexed: 12/04/2022]
Affiliation(s)
| | - D N Nie
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
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30
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Liu P, Li P, Lei T, Qu L, Huang H, Mu Q. Acute lymphoblastic leukemia following temozolomide treatment in a patient with glioblastoma: A case report and review of the literature. Oncol Lett 2018; 15:8663-8668. [PMID: 29805603 DOI: 10.3892/ol.2018.8422] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 09/22/2016] [Indexed: 01/24/2023] Open
Abstract
Temozolomide (TMZ) is a second-generation oral alkylating agent that functions against a number of central nervous system neoplasms, and is generally used to treat high-grade gliomas, including anaplastic astrocytoma and glioblastoma multiforme. Therapy-related secondary myelodysplastic syndrome and acute myeloid leukemia have been reported in patients following prolonged exposure to TMZ. However, TMZ-related acute lymphoblastic leukemia (ALL) is extremely rare. The present study describes the case of an 11-year-old boy with a 3-day history of generalized tonic-clonic seizures and a contrast-enhanced lesion in the left temporooccipital region with focal cystic degeneration, as detected by magnetic resonance imaging. The patient underwent craniotomy and gross-total resection andpathological analysis confirmed the diagnosis of giant cell glioblastoma. Postoperatively, the patient received TMZ-based concurrent chemoradiation during radiotherapy, and developed B-cell ALL 6 months following TMZ treatment. A thorough literature search identified only six published cases of TMZ-related ALL. The chemotherapeutic efficacy of TMZ has been identified, however, its leukemogenic potential should be emphasized among practitioners and patients. Further studies are required to determine the specific pathogenic mechanism of TMZ-related ALL. Close hematological monitoring of patients following TMZ treatment is vital and a high index of suspicion is necessary.
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Affiliation(s)
- Pengfei Liu
- Department of Neurosurgery The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China.,Department of Neurosurgery, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China.,Department of Neurosurgery, Guangdong 999 Brain Hospital, Guangzhou, Guangdong 510510, P.R. China
| | - Peiwen Li
- Department of Neurosurgery The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Ting Lei
- Department of Neurosurgery The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Limei Qu
- Department of Pathology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Haiyan Huang
- Department of Neurosurgery The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Qingchun Mu
- Department of Neurosurgery, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
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31
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Inoue Y, Nakamura T, Nakanishi H, Oishi M, Hongo F, Okihara K, Mizutani S, Kuroda J, Ukimura O. Therapy-related acute myeloid leukemia and myelodysplastic syndrome among refractory germ cell tumor patients. Int J Urol 2018; 25:678-683. [PMID: 29752743 DOI: 10.1111/iju.13597] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 04/03/2018] [Indexed: 11/29/2022]
Abstract
OBJECTIVES To analyze cases of therapy-related acute myeloid leukemia and myelodysplastic syndrome diagnosed after chemotherapy for refractory testicular and extragonadal germ cell tumor in our experience. METHODS A total of 171 consecutive patients who were diagnosed and treated as refractory germ cell tumor and had records of detailed chemotherapy doses between April 1998 and December 2015 were retrospectively reviewed. RESULTS Four testicular tumor patients (4/171, 2.3%) developed therapy-related acute myeloid leukemia and myelodysplastic syndrome. Three of them were affected after complete remission of the primary testicular tumor. A median time interval from a start of chemotherapy to a secondary tumor development was 6.8 years (range 3.7-11.5 years). The median total dose of etoposide, ifosfamide, cisplatin and nedaplatin were 3640 mg/m2 (range 2906-4000 mg/m2 ), 42.7 g (range 19.5-54.0 g), 1100 mg/m2 (range 600-1500 mg/m2 ) and 500 mg/m2 (range 300-1600 mg/m2 ), respectively. Etoposide had the only significant relationship between a cumulative dose and leukemogenesis in univariate analysis (P < 0.05). One patient had complete remission, but the other three patients died. CONCLUSIONS The present findings show that refractory germ cell tumor patients have an increased risk of therapy-related acute myeloid leukemia and myelodysplastic syndrome. A cumulative dose of etoposide is a significant risk of leukemogenesis. As therapy-related acute myeloid leukemia and myelodysplastic syndrome has a poor prognosis, close follow up is required for refractory germ cell tumor patients.
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Affiliation(s)
- Yuta Inoue
- Department of Urology, Kyoto Prefecture University of Medicine, Kyoto, Japan
| | | | | | - Masakatsu Oishi
- Department of Urology, Kyoto Prefecture University of Medicine, Kyoto, Japan
| | - Fumiya Hongo
- Department of Urology, Kyoto Prefecture University of Medicine, Kyoto, Japan
| | - Koji Okihara
- Department of Urology, Kyoto Prefecture University of Medicine, Kyoto, Japan
| | - Shinsuke Mizutani
- Division of Hematology and Oncology, Kyoto Prefecture University of Medicine, Kyoto, Japan
| | - Junya Kuroda
- Division of Hematology and Oncology, Kyoto Prefecture University of Medicine, Kyoto, Japan
| | - Osamu Ukimura
- Department of Urology, Kyoto Prefecture University of Medicine, Kyoto, Japan
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Clinical Features and Outcomes of 666 Cases with Therapy-Related Myelodysplastic Syndrome (t-MDS). Indian J Hematol Blood Transfus 2018; 34:83-90. [PMID: 29398804 DOI: 10.1007/s12288-017-0813-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 04/03/2017] [Indexed: 12/15/2022] Open
Abstract
Therapy-related myelodysplastic syndrome (t-MDS) is a serious complication of chemoradiotherapy for primary diseases. This cohort was aimed to determine the clinical features and outcomes of t-MDS in comparison with de novo MDS. I retrieved data of 666 cases with t-MDS, and 29,703 cases with de novo MDS diagnosed between 2001 and 2012 from the database of U.S. National Cancer Institute. Survival curves were estimated, and Cox proportional hazards model was constructed. Compared with patients with de novo MDS, patients with t-MDS tended to be young (median age; 65 vs. 76 years, p < 0.001), and were more likely to be female-sex (51.4 vs. 44.7%, p = 0.001). Median overall survival (OS) and 5-year OS rate are significantly poorer in t-MDS than de novo MDS (17.2 months and 22% vs. 31 months and 32%, respectively, p < .001). In t-MDS cases, with a median follow-up of 16 months (range 1-143 months), 521 cases (78.2%) had died. Of which, 78 (15%) cases had died from acute myeloid leukemia, and 66 (12.7%) cases had died from solid cancers. Of the total 66 cases died from solid cancers; 19 cases (28.8%) died from cancer of lung/bronchus, 11 cases (16.7%) breast cancers, and 10 cases (15.2%) ovarian cancer. In a multivariate analysis adjusted for clinical features, calendar period and radiotherapy, the hazard of mortality was significantly low in de novo MDS compared with t-MDS (hazard ratio 0.59; p < .001). In conclusions, t-MDS is a distinct entity of MDS in terms of clinical characteristics and prognosis.
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Wu B, Ingersoll K, Jug R, Yang LH, Luedke C, Lo A, Su P, Liu X, Rehder C, Gong J, Lu CM, Wang E. Myeloid Neoplasms Following Solid Organ Transplantation: Clinicopathologic Studies of 23 Cases. Am J Clin Pathol 2017; 149:55-66. [PMID: 29228125 DOI: 10.1093/ajcp/aqx133] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVES Myeloid neoplasms (MNs) after solid organ transplant are rare, and their clinicopathologic features have not been well characterized. METHODS We retrospectively analyzed 23 such cases. RESULTS The ages ranged from 2 to 76 years, with a median of 59 years at the diagnosis. The median interval between the transplant and diagnosis was 56 months (range, 8-384 months). The transplanted organs included liver in five, kidney in six, lung in five, heart in six, and heart/lung in one case(s). The types of MN included acute myeloid leukemia (AML) in 12, myelodysplastic syndrome (MDS) in five, chronic myelogenous leukemia (CML) in four, and myeloproliferative neoplasms (MPNs) in two cases. Cytogenetics demonstrated clonal abnormalities in 18 (78.3%) cases, including unbalanced changes in 10 (55.6%), Philadelphia chromosome in four (22.2%), and other balanced aberrations in four (22.2%) cases. Thirteen (56.5%) patients died, with an estimated median survival of 9 months. With disease stratification, AML and MDS have short median survivals (3.5 and 7 months, respectively), with an initial precipitous decline of the survival curve. CONCLUSIONS Posttransplant MNs have a latency period between that seen in AML/MDS related to alkylators and that associated with topoisomerase II inhibitors. The cytogenetic profile suggests a mutagenic effect on leukemogenesis. The clinical outcome for AML/MDS is dismal, with death occurring at an early phase of treatment.
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MESH Headings
- Adult
- Aged
- Bone Marrow/pathology
- Child, Preschool
- Cytogenetics
- Humans
- Kaplan-Meier Estimate
- Kidney/pathology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/mortality
- Leukemia, Myeloid, Acute/pathology
- Liver/pathology
- Lung/pathology
- Middle Aged
- Mutation
- Myelodysplastic Syndromes/genetics
- Myelodysplastic Syndromes/mortality
- Myelodysplastic Syndromes/pathology
- Myeloproliferative Disorders/genetics
- Myeloproliferative Disorders/mortality
- Myeloproliferative Disorders/pathology
- Myocardium/pathology
- Organ Transplantation/adverse effects
- Retrospective Studies
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Affiliation(s)
- Bin Wu
- Division of Hematology, Department of Medicine, Shengjing Hospital affiliated to China Medical University, Shenyang, China
- Department of Pathology, Duke University Medical Center, Durham, NC
| | | | - Rachel Jug
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Lian-He Yang
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Catherine Luedke
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Amanda Lo
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Pu Su
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Xin Liu
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Catherine Rehder
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Jerald Gong
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA
| | - Chuanyi Mark Lu
- Department of Laboratory Medicine, University of California, San Francisco
| | - Endi Wang
- Department of Pathology, Duke University Medical Center, Durham, NC
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34
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Horai M, Satoh S, Matsuo M, Iwanaga M, Horio K, Jo T, Takasaki Y, Kawaguchi Y, Tsushima H, Yoshida S, Taguchi M, Itonaga H, Sawayama Y, Taguchi J, Imaizumi Y, Hata T, Moriuchi Y, Haase D, Yoshiura KI, Miyazaki Y. Chromosomal analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki. Br J Haematol 2017; 180:381-390. [DOI: 10.1111/bjh.15050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/09/2017] [Indexed: 11/30/2022]
Affiliation(s)
- Makiko Horai
- Department of Haematology; Atomic Bomb Disease and Hibakusha Medicine Unit; Atomic Bomb Disease Institute; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
| | - Shinya Satoh
- Department of Haematology; Atomic Bomb Disease and Hibakusha Medicine Unit; Atomic Bomb Disease Institute; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
| | - Masatoshi Matsuo
- Department of Internal Medicine; Nagasaki Harbour Medical Centre City Hospital; Nagasaki Japan
| | - Masako Iwanaga
- Department of Frontier Life Science; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
| | - Kensuke Horio
- Department of Haematology; Japanese Red Cross Nagasaki Genbaku Hospital; Nagasaki Japan
| | - Tatsuro Jo
- Department of Haematology; Japanese Red Cross Nagasaki Genbaku Hospital; Nagasaki Japan
| | - Yumi Takasaki
- Department of Internal Medicine; St. Francis Hospital; Nagasaki Japan
| | - Yasuhisa Kawaguchi
- Department of Internal Medicine; Nagasaki Harbour Medical Centre City Hospital; Nagasaki Japan
| | - Hideki Tsushima
- Department of Internal Medicine; Nagasaki Harbour Medical Centre City Hospital; Nagasaki Japan
| | - Shinichiro Yoshida
- Department of Internal Medicine; National Hospital Organization Nagasaki Medical Centre; Ohmura Japan
| | - Masataka Taguchi
- Department of Haematology; Sasebo City General Hospital; Sasebo Japan
| | - Hidehiro Itonaga
- Department of Haematology; Atomic Bomb Disease and Hibakusha Medicine Unit; Atomic Bomb Disease Institute; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
| | - Yasushi Sawayama
- Department of Haematology; Atomic Bomb Disease and Hibakusha Medicine Unit; Atomic Bomb Disease Institute; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
| | - Jun Taguchi
- Department of Haematology; Atomic Bomb Disease and Hibakusha Medicine Unit; Atomic Bomb Disease Institute; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
| | - Yoshitaka Imaizumi
- Department of Haematology; Atomic Bomb Disease and Hibakusha Medicine Unit; Atomic Bomb Disease Institute; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
| | - Tomoko Hata
- Department of Haematology; Atomic Bomb Disease and Hibakusha Medicine Unit; Atomic Bomb Disease Institute; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
| | | | - Detlef Haase
- Clinic of Haematology and Medical Oncology; University Medical Centre Goettingen; Goettingen Germany
| | - Koh-Ichiro Yoshiura
- Department of Human Genetics; Atomic Bomb Disease Institute; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
| | - Yasushi Miyazaki
- Department of Haematology; Atomic Bomb Disease and Hibakusha Medicine Unit; Atomic Bomb Disease Institute; Nagasaki University Graduate School of Biomedical Sciences; Nagasaki Japan
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Abstract
PURPOSE OF REVIEW Adverse karyotype acute myeloid leukemia is a disease particularly of older patients, but also observed in younger patients. Despite all efforts, standard chemotherapy is still generally applied in fit patients, as already for decades, and for nearly all different subtypes of acute myeloid leukemia. Lack of more specifically targeted therapy and the often older age of the patients are complicating treatment, and in the subgroup of patients achieving a complete remission, the strikingly high frequency of relapse is a characteristic of this disease. This review aims to give an overview of current treatment approaches as well as emerging therapies. RECENT FINDINGS Currently, the approach of a targeted therapy specific to the genetic and/or epigenetic aberrations detected in the individual patient is still not possible, and a 'one treatment fits all' course of action is still used, with allografting as curative consolidation. However, first immunotherapeutic approaches are emerging as treatment options and first phase 1 and 2 studies are described. SUMMARY Treatment of acute myeloid leukemia with adverse karyotype is still not individualized, most treatment options currently not being curative. This can change in the near future, but recent findings will have to be implemented into larger phase 3 studies before being standard of care.
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Kerzic PJ, Irons RD. Distribution of chromosome breakpoints in benzene-exposed and unexposed AML patients. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2017; 55:212-216. [PMID: 28926803 DOI: 10.1016/j.etap.2017.08.033] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 08/30/2017] [Indexed: 06/07/2023]
Abstract
Results of laboratory studies and investigations of occupationally exposed healthy individuals have been used to develop a mode of action for benzene-induced leukemia that mirrors disease following treatment with chemotherapeutic agents. Recently we have described series of AML and MDS cases with benzene exposure history, and have provided cytogenetic, molecular, and pathologic evidence that these cases differ significantly in many features from therapy-related disease. Here we have extended this work, and describe chromosome breakpoints across 441 identifiable regions, in terms of gains or losses, in 710 AML cases collected during the Shanghai Health Study, which include 75 with a history of benzene exposure. Using FISH and cytogenetic analysis, we developed prevalence information and risk ratios for benzene exposure across all regions with a lesion in at least one exposed and unexposed case. These results indicate that AML following benzene exposure mirrors de novo disease, and supports a mechanism for development of hematopoietic disease that bears no resemblance to therapy-related disease.
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Affiliation(s)
- Patrick J Kerzic
- California Environmental Protection Agency, 9211 Oakdale Ave, Chatsworth, CA, 91311, USA.
| | - Richard D Irons
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China; Anschutz Medical Center, University of Colorado, Aurora, CO, USA
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37
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Cytogenetic Evolution in Myeloid Neoplasms at Relapse after Allogeneic Hematopoietic Cell Transplantation: Association with Previous Chemotherapy and Effect on Survival. Biol Blood Marrow Transplant 2017; 23:782-789. [DOI: 10.1016/j.bbmt.2017.02.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 02/06/2017] [Indexed: 01/21/2023]
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38
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Abstract
MicroRNAs are small, noncoding, RNAs known for their powerful modulation of molecular processes, making them a major focus for studying pathological mechanisms. The human miR-146 family of microRNAs consists of two member genes, MIR146A and MIR146B These two microRNAs are located on different chromosomes and exhibit differential regulation in many cases. However, they are nearly identical in sequence, sharing a seed region, and are thus predicted to target the same set of genes. A large proportion of the microRNA (miR)-146 literature focuses on its role in regulating the innate immune response in the context of various pathologies by modulating two widely studied target genes in the toll-like receptor signaling cascade. A growing subset of the literature reports a role of miR-146 in cardiovascular and renal disease, and data suggest there is exciting potential for miR-146 as a diagnostic and therapeutic target. Nevertheless, the published literature is confounded by unclear and imprecise language concerning the specific effects of the two miR-146 family members. The present review will compare the genomic origin and regulation of miR-146a and miR-146b, discuss some approaches to overcome analytical and experimental challenges, and summarize findings in major areas of miR-146 research. Moving forward, careful evaluation of miR-146a/b specificity in analytical and experimental approaches will aid researchers in elucidating the functional relevance of differential regulation of the miR-146 family members in health and disease.
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Affiliation(s)
- Mark R Paterson
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and
| | - Alison J Kriegel
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and
- Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
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39
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Daraki A, Zachaki S, Rosmaraki F, Kalomoiraki M, Aleporou-Marinou V, Sambani C, Kollia P, Manola KN. Association of GSTP1 inactivating polymorphism with acute myeloid leukemia and its specific chromosomal abnormalities. Leuk Lymphoma 2017; 58:2505-2507. [PMID: 28278696 DOI: 10.1080/10428194.2017.1295148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Aggeliki Daraki
- a Laboratory of Health Physics, Radiobiology & Cytogenetics , National Center for Scientific Research (NCSR) "Demokritos" , Athens , Greece
| | - Sophia Zachaki
- b Genesis Genoma Lab, Genetic Diagnosis , Clinical Genetics & Research , Athens , Greece
| | - Faidra Rosmaraki
- a Laboratory of Health Physics, Radiobiology & Cytogenetics , National Center for Scientific Research (NCSR) "Demokritos" , Athens , Greece
| | - Marina Kalomoiraki
- a Laboratory of Health Physics, Radiobiology & Cytogenetics , National Center for Scientific Research (NCSR) "Demokritos" , Athens , Greece
| | - Vassiliki Aleporou-Marinou
- c Department of Genetics & Biotechnology, Faculty of Biology , National and Kapodistrian University of Athens , Athens , Greece
| | - Constantina Sambani
- a Laboratory of Health Physics, Radiobiology & Cytogenetics , National Center for Scientific Research (NCSR) "Demokritos" , Athens , Greece
| | - Panagoula Kollia
- c Department of Genetics & Biotechnology, Faculty of Biology , National and Kapodistrian University of Athens , Athens , Greece
| | - Kalliopi N Manola
- a Laboratory of Health Physics, Radiobiology & Cytogenetics , National Center for Scientific Research (NCSR) "Demokritos" , Athens , Greece
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40
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Atwal M, Lishman EL, Austin CA, Cowell IG. Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy. Mol Pharmacol 2017; 91:49-57. [PMID: 27974636 PMCID: PMC5198516 DOI: 10.1124/mol.116.106054] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 11/08/2016] [Indexed: 01/17/2023] Open
Abstract
Myeloperoxidase is expressed exclusively in granulocytes and immature myeloid cells and transforms the topoisomerase II (TOP2) poisons etoposide and mitoxantrone to chemical forms that have altered DNA damaging properties. TOP2 poisons are valuable and widely used anticancer drugs, but they are associated with the occurrence of secondary acute myeloid leukemias. These factors have led to the hypothesis that myeloperoxidase inhibition could protect hematopoietic cells from TOP2 poison-mediated genotoxic damage and, therefore, reduce the rate of therapy-related leukemia. We show here that myeloperoxidase activity leads to elevated accumulation of etoposide- and mitoxantrone-induced TOP2A and TOP2B-DNA covalent complexes in cells, which are converted to DNA double-strand breaks. For both drugs, the effect of myeloperoxidase activity was greater for TOP2B than for TOP2A. This is a significant finding because TOP2B has been linked to genetic damage associated with leukemic transformation, including etoposide-induced chromosomal breaks at the MLL and RUNX1 loci. Glutathione depletion, mimicking in vivo conditions experienced during chemotherapy treatment, elicited further MPO-dependent increase in TOP2A and especially TOP2B-DNA complexes and DNA double-strand break formation. Together these results support targeting myeloperoxidase activity to reduce genetic damage leading to therapy-related leukemia, a possibility that is enhanced by the recent development of novel specific myeloperoxidase inhibitors for use in inflammatory diseases involving neutrophil infiltration.
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Affiliation(s)
- Mandeep Atwal
- Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne. United Kingdom
| | - Emma L Lishman
- Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne. United Kingdom
| | - Caroline A Austin
- Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne. United Kingdom
| | - Ian G Cowell
- Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne. United Kingdom
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41
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Abou Zahr A, Kavi AM, Mukherjee S, Zeidan AM. Therapy-related myelodysplastic syndromes, or are they? Blood Rev 2016; 31:119-128. [PMID: 27923516 DOI: 10.1016/j.blre.2016.11.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 09/14/2016] [Accepted: 11/22/2016] [Indexed: 12/12/2022]
Abstract
The incidence of therapy-related myelodysplastic syndromes (t-MDS) is increasing as the number of cancer survivors is increasing. While t-MDS is currently defined descriptively by prior receipt of chemotherapy and/or radiotherapy, some forms of MDS that occur post localized radiation monotherapy, biologically and clinically resemble de novo (d)-MDS more than t-MDS, and therefore may not be truly therapy-related. Although patients with t-MDS, as a group, fare worse than patients with d-MDS, a variation in individual outcomes of patients with t-MDS has increasingly been appreciated. As such, accurate risk stratification is important for counseling of patients and for clinical decision making. Most of the current clinical tools used for prognostication in t-MDS were developed for d-MDS and were not specifically validated in patients with t-MDS. The management of patients with t-MDS remains challenging, highlighting the importance of developing effective prevention strategies as well as newer, targeted, and rationally-designed therapeutic interventions.
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Affiliation(s)
- Abdallah Abou Zahr
- Section of Hematology/Oncology, Department of Internal Medicine, Mount Sinai Beth Israel, New York City, New York, NY, USA
| | - Ami M Kavi
- Department of Internal Medicine, Mount Sinai Beth Israel, New York City, New York, NY, USA
| | - Sudipto Mukherjee
- Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA
| | - Amer M Zeidan
- Section of Hematology, Department of Medicine, Yale University, New Haven, CT, USA.
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42
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Matsuo M, Iwanaga M, Kondo H, Soda M, Jo T, Horio K, Takasaki Y, Kawaguchi Y, Tsushima H, Imaizumi Y, Imanishi D, Taguchi J, Sawayama Y, Hata T, Miyazaki Y. Clinical features and prognosis of patients with myelodysplastic syndromes who were exposed to atomic bomb radiation in Nagasaki. Cancer Sci 2016; 107:1484-1491. [PMID: 27487572 PMCID: PMC5084675 DOI: 10.1111/cas.13025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/19/2016] [Accepted: 07/27/2016] [Indexed: 01/19/2023] Open
Abstract
There is evidence that radiation exposure is a causative factor of myelodysplastic syndromes (MDS). However, little is known about whether radiation exposure is also a prognostic factor of MDS. We investigated the impact of radiation exposure on the prognosis of MDS in Nagasaki atomic bomb survivors using the International Prognostic Scoring System (IPSS) and the revised version (IPSS‐R). Subjects were 140 patients with primary MDS diagnosed between 1985 and 2011 and evaluable for IPSS, IPSS‐R, and exposure distance. Of those, 31 were exposed at <1.5 km, 35 at 1.5–2.99 km, and 74 at ≥3.0 km. By the end of March 2014, 47 patients (34%) progressed to overt leukemia and 106 (75.7%) died. By comparing with patients exposed at ≥3.0 km, those exposed at <1.5 km had significantly higher frequencies of abnormal chromosome (P = 0.02), intermediate/poor IPSS, and intermediate/poor/very poor IPSS‐R cytogenetic category (P = 0.0001, and P < 0.0001, respectively). As with de novo MDS, multivariate Cox regression analyses revealed that cytogenetic abnormalities, IPSS karyotype, and IPSS‐R cytogenetics were significantly associated with poor survival, and cumulative incidence of leukemic transformation in MDS among atomic bomb survivors, but exposure distance was not associated with any poor outcomes. These suggest that exposure to the greater dose of atomic bomb radiation is associated with developing poor cytogenetic abnormalities in MDS, which might consequently lead to overt leukemia among atomic bomb survivors.
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Affiliation(s)
- Masatoshi Matsuo
- Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.,Department of Hematology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masako Iwanaga
- Department of Frontier Life Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Hisayoshi Kondo
- Division of Scientific Data Registry, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Midori Soda
- Nagasaki Prefectural Cancer Registry, Nagasaki, Japan.,Department of Epidemiology, Radiation Effects Research Foundation, Nagasaki, Japan
| | - Tatsuro Jo
- Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan
| | - Kensuke Horio
- Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan
| | - Yumi Takasaki
- Department of Internal Medicine, St. Francis Hospital, Nagasaki, Japan
| | - Yasuhisa Kawaguchi
- Department of Internal Medicine, Nagasaki Harbor Medical Center City Hospital, Nagasaki, Japan
| | - Hideki Tsushima
- Department of Internal Medicine, Nagasaki Harbor Medical Center City Hospital, Nagasaki, Japan
| | | | - Daisuke Imanishi
- Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan
| | - Jun Taguchi
- Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.,Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan
| | - Yasushi Sawayama
- Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan
| | - Tomoko Hata
- Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.,Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan
| | - Yasushi Miyazaki
- Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan. .,Department of Hematology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. .,Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.
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43
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Zahid MF, Parnes A, Savani BN, Litzow MR, Hashmi SK. Therapy-related myeloid neoplasms - what have we learned so far? World J Stem Cells 2016; 8:231-242. [PMID: 27621757 PMCID: PMC4999650 DOI: 10.4252/wjsc.v8.i8.231] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 07/15/2016] [Accepted: 08/08/2016] [Indexed: 02/07/2023] Open
Abstract
Therapy-related myeloid neoplasms are neoplastic processes arising as a result of chemotherapy, radiation therapy, or a combination of these modalities given for a primary condition. The disease biology varies based on the etiology and treatment modalities patients receive for their primary condition. Topoisomerase II inhibitor therapy results in balanced translocations. Alkylating agents, characteristically, give rise to more complex karyotypes and mutations in p53. Other etiologies include radiation therapy, high-dose chemotherapy with autologous stem cell transplantation and telomere dysfunction. Poor-risk cytogenetic abnormalities are more prevalent than they are in de novo leukemias and the prognosis of these patients is uniformly dismal. Outcome varies according to cytogenetic risk group. Treatment recommendations should be based on performance status and karyotype. An in-depth understanding of risk factors that lead to the development of therapy-related myeloid neoplasms would help developing risk-adapted treatment protocols and monitoring patients after treatment for the primary condition, translating into reduced incidence, early detection and timely treatment.
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44
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Goswami RS, Wang SA, DiNardo C, Tang Z, Li Y, Zuo W, Hu S, Li S, Medeiros LJ, Tang G. Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms. Mod Pathol 2016; 29:727-34. [PMID: 27056073 DOI: 10.1038/modpathol.2016.67] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 02/22/2016] [Accepted: 02/23/2016] [Indexed: 01/13/2023]
Abstract
Deletion 7q is a common chromosomal abnormality in myeloid neoplasms. Detection of del(7q) in patients following cytotoxic therapies is highly suggestive of an emerging therapy-related myeloid neoplasm. In this study, we describe 39 patients who acquired del(7q) as a sole abnormality in their bone marrow following cytotoxic therapies for malignant neoplasms. The median interval from cytotoxic therapies to detection of del(7q) was 40 months (range, 4-190 months). Twenty-eight patients showed an interstitial and 11 showed a terminal 7q deletion. Fifteen patients (38%) had del(7q) as a large clone and 24 (62%) as a small clone. With a median follow-up of 21 months (range, 1-135 months), 18 (46%) patients developed therapy-related myeloid neoplasms, including all 15 patients with a large del(7q) clone and 3/24 (12.5%) with a small clone. Of the remaining 21 patients with a small del(7q) clone, 16 showed no evidence of therapy-related myeloid neoplasms and 5 had an inconclusive pathological diagnosis. We conclude that isolated del(7q) emerging in patients after cytotoxic therapy may not always be associated with therapy-related myeloid neoplasms in about half of patients. The clone size of del(7q) is critical; a large clone is almost always associated with therapy-related myeloid neoplasms, whereas a small clone can be a clinically indolent or transient finding.
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Affiliation(s)
- Rashmi S Goswami
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Laboratory Hematology, University Health Network, Toronto General Hospital, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Sa A Wang
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Courtney DiNardo
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhenya Tang
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yan Li
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wenli Zuo
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shimin Hu
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shaoying Li
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - L Jeffrey Medeiros
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guilin Tang
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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45
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Cytogenetic profiles of 2806 patients with acute myeloid leukemia—a retrospective multicenter nationwide study. Ann Hematol 2016; 95:1223-32. [DOI: 10.1007/s00277-016-2691-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 05/09/2016] [Indexed: 10/21/2022]
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46
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Something Old, New, Borrowed, Blue: Anthracenedione Agents for Treatment of Multiple Sclerosis. Clin Neuropharmacol 2016; 39:102-11. [PMID: 26966886 DOI: 10.1097/wnf.0000000000000137] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE This study aimed to present anthracenedione agents that have been used to treat multiple sclerosis (MS), problems related to their use, and knowledge gained from our experiences using these agents to develop more efficacious drugs with fewer adverse effects. METHODS We review preclinical and clinical data during the development mitoxantrone, an anthracycline, for the treatment of MS; benefits and potential risks; and strategies to reduce complications of anthracyclines. RESULTS Mitoxantrone had unacceptable and greater-than-anticipated toxicity for use in a chronic disease such as MS. Adverse effects included cardiotoxicity, treatment-associated leukemia, and amenorrhea. Toxicity was identified primarily in retrospect. Structurally related compounds include pixantrone (BBR2278) and BBR3378. Pixantrone is in clinical development in oncology. BBR3378 prevents the development of autoimmunity and experimental autoimmune encephalomyelitis and blocks experimental autoimmune encephalomyelitis even when given after the onset of autoimmunity. CONCLUSIONS There remains a need for effective MS treatment, particularly for nonrelapsing forms of MS. Mitoxantrone was the first nonbiologic drug approved by the Food and Drug Administration for use in MS. Chromophore modification of anthracenedione agents yielded a novel class of DNA binding agents (aza-anthracenediones such as pixantrone and aza-anthrapyrazoles such as BBR3378) with the potential for less cardiotoxicity compared with mitoxantrone. There is a need for long-term observation for delayed toxicity among humans enrolled in pixantrone trials. Preclinical toxicity studies for delayed toxicities in rodents and other models are warranted before consideration of derivatives of anthracenediones, aza-anthrazenediones, or aza-anthrapyrazoles for use in human MS clinical trials.
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47
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Shan Y, Cortopassi G. Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. Mitochondrion 2015; 26:94-103. [PMID: 26702583 DOI: 10.1016/j.mito.2015.12.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 09/04/2015] [Accepted: 12/11/2015] [Indexed: 01/30/2023]
Abstract
Mitochondrial iron-sulfur cluster (ISC) biogenesis provides iron-sulfur cofactors to several mitochondrial proteins, but the extent to which ISC biogenesis regulates hematopoiesis has been unclear. The blood disease Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis, and the disease overlaps with the gene Hspa9/Mortalin in multiple ways: the HSPA9 locus maps to 5q31.2 that is frequently deleted in human MDS; mutant Hspa9 causes zebrafish MDS; and Hspa9 knockdown mice have decreased hematopoiesis. We show here that HSPA9 functions in mitochondrial ISC biogenesis, and is required for erythroid differentiation. HSPA9 interacts with and stabilizes the mitochondrial ISC biogenesis proteins frataxin, Nfs1, ISCU, and Nfu. MDS-causing mutations in HSPA9 protein change its interactions with ISC biogenesis proteins. Depletion of HSPA9 decreases aconitase activity, which requires an ISC at its active site, but not that of the non-ISC requiring malate dehydrogenase, and increases IRP1 binding activity. In erythroid cell lines, Hspa9 depletion inhibited erythroid differentiation, post-transcriptionally regulating the expression of Alas2 and FeCH, as expected through known ISC control of the IRE response elements in these genes. By contrast, the Alas2 open reading frame rescued the Hspa9-dependent defect in erythroid differentiation, but not when uncoupled from its 5'-IRE sequence. Thus, Hspa9 depletion causes a mitochondrial ISC deficit, altering IRP1-IRE binding and FeCH stability, which consequently inhibits Alas2 translation, heme synthesis, and erythroid differentiation, i.e.: Hspa9->ISC->IRP/IRE->Alas2->heme synthesis->erythroid differentiation. Thus Hspa9 regulates erythroid differentiation through ISC cluster assembly, providing a pathophysiological mechanism for an MDS subtype characterized by HSPA9 haploinsufficiency, and suggests hemin and other pharmacological stimulators of ISC synthesis as potential routes to therapy.
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Affiliation(s)
- Yuxi Shan
- University of California, Davis, VM: Dept. of Molecular Biosciences, One Shields Ave., Davis 95616, USA.
| | - Gino Cortopassi
- University of California, Davis, VM: Dept. of Molecular Biosciences, One Shields Ave., Davis 95616, USA.
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48
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Oluwasanjo A, Pathak R, Ukaigwe A, Alese O. Therapy-related acute myeloid leukemia following radioactive iodine treatment for thyroid cancer. Cancer Causes Control 2015; 27:143-6. [PMID: 26453198 DOI: 10.1007/s10552-015-0682-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 10/03/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Therapy-related acute myeloid leukemia (t-AML) associated with radioiodine treatment (RAI) is emerging as an important clinical entity with the rise in incidence of thyroid cancer. DESIGN AND METHODS We conducted an electronic search of MEDLINE and EMBASE, and also searched reference lists of articles and abstracts from conference proceedings for case reports and review articles on t-AML following radioiodine therapy. A total of 37 patients with acute myeloid neoplasms following radioiodine treatment were analyzed. RESULTS The median RAI dose was 324 mCi, and median age was 47.5 years with M/F ratio of 1:3. Latency period was 1-4 years, and the median time from RAI exposure to diagnosis of t-AML was 2.9 years. FAB M2 and M3 were the two most common t-AML subtypes reported. Seventy-one percent of the cases that reported cytogenetic abnormalities were classified as unfavorable. The most commonly reported abnormalities were del 5q and t(15:17). Survival outcomes were not reported due to lack of patient-level data. CONCLUSIONS T-AML following radioiodine therapy for thyroid cancer appears to have a shorter latency period than other types of t-AML, which is an important consideration for post-therapy surveillance. Reporting of cases and outcomes will help provide data for further research. Identifying biomarkers that help risk-stratify patients prior to therapy and specific genetic-guided therapies may help improve outcomes.
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Affiliation(s)
- Adetokunbo Oluwasanjo
- Department of Medicine, Reading Health System, Sixth Avenue and Spruce Street, West Reading, PA, 19611, USA.
| | - Ranjan Pathak
- Department of Medicine, Reading Health System, Sixth Avenue and Spruce Street, West Reading, PA, 19611, USA
| | - Anene Ukaigwe
- Department of Medicine, Reading Health System, Sixth Avenue and Spruce Street, West Reading, PA, 19611, USA
| | - Olatunji Alese
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Suite 5010, Atlanta, GA, 30322, USA
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Loghavi S, Kutok JL, Jorgensen JL. B-acute lymphoblastic leukemia/lymphoblastic lymphoma. Am J Clin Pathol 2015; 144:393-410. [PMID: 26276770 DOI: 10.1309/ajcpan7bh5dnywzb] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES This session of the 2013 Society of Hematopathology/European Association for Haematopathology Workshop was dedicated to B-acute lymphoblastic leukemia (B-ALL)/lymphoblastic lymphoma (LBL) with recurrent translocations and not otherwise specified. METHODS In this review, we summarize the cases discussed during the workshop, review the pertinent and most recent literature on the respective topics, and provide a few key points that may aid in the workup of patients with B-ALL/LBL. RESULTS Many of the submitted cases showed interesting diagnostic, immunophenotypic, or clinical aspects of B-ALL with BCR/ABL1, MLL-associated, and other recurrent chromosomal abnormalities. Several cases showed rare aberrancies such as coexistent IGH/BCL2 and MYC rearrangements and raised issues in classification. Other cases had unusual clinical presentations, including B-ALL with hypereosinophilia and therapy-related B-ALL. Several cases highlighted the role of flow cytometry immunophenotyping in distinguishing benign B-cell precursors from aberrant lymphoblasts, and other cases raised questions regarding the clinical importance of myeloperoxidase positivity in acute lymphoblastic leukemia. CONCLUSIONS The complexity and spectrum of cases presented in this review highlight the importance of clinicopathologic correlation and the value of ancillary studies in the classification and workup of patients with B-ALL/LBL.
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Affiliation(s)
- Sanam Loghavi
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston; and
| | | | - Jeffrey L. Jorgensen
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston; and
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Granfeldt Østgård LS, Medeiros BC, Sengeløv H, Nørgaard M, Andersen MK, Dufva IH, Friis LS, Kjeldsen E, Marcher CW, Preiss B, Severinsen M, Nørgaard JM. Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study. J Clin Oncol 2015; 33:3641-9. [PMID: 26304885 DOI: 10.1200/jco.2014.60.0890] [Citation(s) in RCA: 322] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age. PATIENTS AND METHODS In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs. RESULTS Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61). CONCLUSION Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.
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Affiliation(s)
- Lene Sofie Granfeldt Østgård
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA.
| | - Bruno C Medeiros
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Henrik Sengeløv
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Mette Nørgaard
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Mette Klarskov Andersen
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Inge Høgh Dufva
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Lone Smidstrup Friis
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Eigil Kjeldsen
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Claus Werenberg Marcher
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Birgitte Preiss
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Marianne Severinsen
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
| | - Jan Maxwell Nørgaard
- Lene Sofie Granfeldt Østgård, Mette Nørgaard, Eigil Kjeldsen, and Jan Maxwell Nørgaard, Aarhus University Hospital, Aarhus; Henrik Sengeløv, Mette Klarskov Andersen, and Lone Smidstrup Friis, The University Hospital Rigshospitalet, Copenhagen; Inge Høgh Dufva, Herlev University Hospital, Herlev; Claus Werenberg Marcher and Birgitte Preiss, Odense University Hospital, Odense; Marianne Severinsen, Aalborg University Hospital, Aalborg, Denmark; and Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA
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