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Yeon Chae S, Jang SY, Kim J, Hwang S, Malani D, Kallioniemi O, Yun SG, Kim JS, Kim HI. Mechanisms of chemotherapy failure in refractory/relapsed acute myeloid leukemia: the role of cytarabine resistance and mitochondrial metabolism. Cell Death Dis 2025; 16:331. [PMID: 40268906 PMCID: PMC12019594 DOI: 10.1038/s41419-025-07653-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 04/05/2025] [Accepted: 04/09/2025] [Indexed: 04/25/2025]
Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Patients with wild-type FLT3 relapsed or refractory (R/R) AML face significant therapeutic challenges due to the persistent lack of effective treatments. A comprehensive understanding of the mechanisms underlying chemotherapy resistance is needed to the development of effective treatment strategies. Therefore, we investigated the molecular mechanisms underlying cytarabine (Ara-C) resistance and daunorubicin (DNR) tolerance in Ara-C-resistant RHI-1 cells derived from the wild-type FLT3 AML cell line SHI-1. Quantitative analysis of intracellular drug concentrations, proteomics, and phosphoproteomics showed that DNR resistance in Ara-C-resistant RHI-1 cells is driven by metabolic remodeling toward mitochondrial metabolism, upregulation of DNA repair pathways, and enhanced reactive oxygen species (ROS) detoxification rather than reduced drug uptake. Moreover, targeting these compensatory mechanisms, particularly the OXPHOS complex I proteins, significantly improved the efficacy of both Ara-C and DNR. Conclusively, these findings highlight mitochondrial metabolism and DNA repair as critical factors in chemotherapy resistance and offer valuable insights into potential therapeutic targets for enhancing treatment outcomes in patients with wild-type FLT3 R/R AML.
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MESH Headings
- Cytarabine/pharmacology
- Cytarabine/therapeutic use
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/genetics
- Mitochondria/metabolism
- Mitochondria/drug effects
- Drug Resistance, Neoplasm/drug effects
- Cell Line, Tumor
- Daunorubicin/pharmacology
- Reactive Oxygen Species/metabolism
- DNA Repair/drug effects
- Treatment Failure
- Oxidative Phosphorylation/drug effects
- fms-Like Tyrosine Kinase 3/metabolism
- fms-Like Tyrosine Kinase 3/genetics
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Affiliation(s)
- Soo Yeon Chae
- Department of Chemistry, Korea University, Seoul, Republic of Korea
- Center for Proteogenome Research, Korea University, Seoul, Republic of Korea
| | - Se-Young Jang
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
| | - Jinhui Kim
- Department of Chemistry, Korea University, Seoul, Republic of Korea
| | - Sehyun Hwang
- Department of Chemistry, Korea University, Seoul, Republic of Korea
- Center for Proteogenome Research, Korea University, Seoul, Republic of Korea
| | - Disha Malani
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland
| | - Olli Kallioniemi
- Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland
- Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institute, Solna, Sweden
| | - Seung Gyu Yun
- Department of Laboratory Medicine, Korea University College of Medicine, Seoul, Korea.
| | - Jong-Seo Kim
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
- Center for RNA Research, Institute of Basic Science, Seoul National University, Seoul, Korea.
| | - Hugh I Kim
- Department of Chemistry, Korea University, Seoul, Republic of Korea.
- Center for Proteogenome Research, Korea University, Seoul, Republic of Korea.
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2
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Mosialou I, Ali AM, Labella R, Bisikirska B, Cuesta-Dominguez A, Vgenopoulou P, Reyes I, Rao SM, Wang A, Luo N, Galan-Diez M, Zhao J, Chernak BJ, Bewersdorf JP, Fukasawa K, Su J, Higa J, Adams RA, Corper AL, Pampou S, Woods CM, Fan X, Shah RP, Feldstein J, Liu N, Liang C, Heiblig M, Kornblau S, Garcia-Manero G, Berman E, Jurcic JG, Rabadan R, Raza A, Kousteni S. A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies. Cancer Cell 2025:S1535-6108(25)00108-4. [PMID: 40154481 DOI: 10.1016/j.ccell.2025.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 09/14/2024] [Accepted: 03/05/2025] [Indexed: 04/01/2025]
Abstract
Myeloid cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remain resistant to standard of care (SOC) and targeted therapies. In this study, we demonstrate that responsiveness to therapy is associated with activation of β-catenin-JAG1 in osteoblastic cells of patients treated with all-trans-retinoic acid (ATRA). ATRA suppresses β-catenin activity in patients and leukemic mice. Consequently, it inhibits the growth and survival of MDS/AML cells from patients with active β-catenin-JAG1 signaling and promotes their differentiation. This occurs independently of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile to SOC. A human anti-JAG1 antibody improves efficacy in leukemic mice and patient-derived MDS/AML cells. β-catenin activation provides an explanation for the differential response to ATRA and a mechanistic biomarker for ATRA repurposing in myeloid malignancies, potentially evading relapse and extending across a broad range of cancers.
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Affiliation(s)
- Ioanna Mosialou
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA; Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA.
| | - Abdullah M Ali
- Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY 10032, USA; Myelodysplastic Syndromes Center, Columbia University, New York, NY 10032, USA
| | - Rossella Labella
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA
| | - Brygida Bisikirska
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA
| | - Alvaro Cuesta-Dominguez
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA
| | - Paraskevi Vgenopoulou
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA
| | - Ismarc Reyes
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA
| | - Sanjana M Rao
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA
| | - Anqi Wang
- Program for Mathematical Genomics, Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA
| | - Na Luo
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA
| | - Marta Galan-Diez
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA
| | - Junfei Zhao
- Program for Mathematical Genomics, Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA
| | - Brian J Chernak
- Department of Med Hematology & Oncology, Columbia University Medical Center, New York, NY 10032, USA
| | | | - Kazuya Fukasawa
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA
| | - Jiayu Su
- Program for Mathematical Genomics, Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA
| | | | | | | | - Sergey Pampou
- Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA
| | | | | | - Roshan P Shah
- Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA
| | - Julie Feldstein
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Na Liu
- Department of Hematology, Institute of Hematology, First Affiliated Hospital, Naval Medical University, Shanghai 200433, China
| | - Cui Liang
- Department of Hematology, Institute of Hematology, First Affiliated Hospital, Naval Medical University, Shanghai 200433, China
| | - Maël Heiblig
- Department of Hematology Centre Hospitalier Lyon Sud, 69495 Lyon, France
| | - Steven Kornblau
- Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Guillermo Garcia-Manero
- Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ellin Berman
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Joseph G Jurcic
- Department of Med Hematology & Oncology, Columbia University Medical Center, New York, NY 10032, USA
| | - Raul Rabadan
- Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Program for Mathematical Genomics, Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA
| | - Azra Raza
- Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY 10032, USA; Myelodysplastic Syndromes Center, Columbia University, New York, NY 10032, USA; Department of Med Hematology & Oncology, Columbia University Medical Center, New York, NY 10032, USA
| | - Stavroula Kousteni
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA; Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY 10032, USA; Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA.
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Yan L, Li J, Yang Y, Zhang X, Zhang C. Old drug, new use: Recent advances for G-CSF. Cytokine 2024; 184:156759. [PMID: 39293182 DOI: 10.1016/j.cyto.2024.156759] [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: 08/05/2024] [Revised: 09/08/2024] [Accepted: 09/10/2024] [Indexed: 09/20/2024]
Abstract
Granulocyte colony-stimulating factor (G-CSF), also known as colony-stimulating factor 3 (CSF3), is a proinflammatory cytokine that primarily stimulates the survival, proliferation, differentiation and function of neutrophil granulocyte progenitor cells and mature neutrophils. Over the past years, G-CSF has mainly been used to cure patients with neutropenia and as a part of chemotherapy to induct the remission for refractory/relapse leukemia. Recent studies showed that C-CSF can been used as condition regimens and as a part of preventive methods after allogeneic transplantation to improve the survival of patients and also has immunoregulation, and has promote or inhibit the proliferation of solid tumors. Therefore, in this review, we firstly describe the structure for G-CSF. Then its functions and mechanism were reviewed including the neutrophil mobilization, differentiation, migration, and inhibiting apoptosis of neutrophils, and its immunoregulation. Finally, the clinical applications were further discussed.
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Affiliation(s)
- Lun Yan
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing 400037 China; Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037 China; State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037 China
| | - Jing Li
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing 400037 China; Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037 China; State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037 China
| | - Yang Yang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing 400037 China; Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037 China; State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037 China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing 400037 China; Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037 China; State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037 China.
| | - Cheng Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing 400037 China; Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037 China; State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037 China.
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4
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Najima Y, Maeda T, Kamiyama Y, Nakao S, Ozaki Y, Nishio H, Tsuchihashi K, Ichihara E, Miumra Y, Endo M, Maruyama D, Yoshinami T, Susumu N, Takekuma M, Motohashi T, Ito M, Baba E, Ochi N, Kubo T, Uchino K, Kimura T, Tamura S, Nishimoto H, Kato Y, Sato A, Takano T, Yano S. Effectiveness and safety of granulocyte colony-stimulating factor priming regimen for acute myeloid leukemia: A systematic review and meta-analysis of the Clinical Practice Guideline for the use of G-CSF 2022 from the Japan Society of Clinical Oncology. Int J Clin Oncol 2024; 29:899-910. [PMID: 38755516 DOI: 10.1007/s10147-023-02461-4] [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: 09/13/2023] [Accepted: 12/14/2023] [Indexed: 05/18/2024]
Abstract
BACKGROUND The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy. METHODS We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized. RESULTS Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82-1.01), p = 0.08; I2 = 4%, p = 0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS. CONCLUSIONS G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.
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Affiliation(s)
- Yuho Najima
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-8-22 Honkomagome, Bunkyo-Ku, Tokyo, 113-8677, Japan.
| | - Tomoya Maeda
- Department of Hemato-Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Yutaro Kamiyama
- Department of Clinical Oncology/Hematology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shinji Nakao
- Department of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan
| | - Yukinori Ozaki
- Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroshi Nishio
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Kenji Tsuchihashi
- Department of Hematology, Oncology and Cardiovascular Medicine, Fukuoka, Japan
| | - Eiki Ichihara
- Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan
| | - Yuji Miumra
- Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
| | - Makoto Endo
- Department of Orthopaedic Surgery, Kyushu University, Fukuoka, Japan
| | - Dai Maruyama
- Department of Hematology Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tetsuhiro Yoshinami
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Nobuyuki Susumu
- Department of Obstetrics and Gynecology, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | | | - Takashi Motohashi
- Department of Obstetrics and Gynecology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Mamoru Ito
- Department of Hematology, Oncology and Cardiovascular Medicine, Fukuoka, Japan
| | - Eishi Baba
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nobuaki Ochi
- Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan
| | - Toshio Kubo
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Keita Uchino
- Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shinobu Tamura
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Hitomi Nishimoto
- Department of Nursing, Okayama University Hospital, Okayama, Japan
| | - Yasuhisa Kato
- Department of Drug Information, Faculty of Pharmaceutical Sciences, Shonan University of Medical Sciences, Kanagawa, Japan
| | - Atsushi Sato
- Department of Medical Oncology, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Toshimi Takano
- Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shingo Yano
- Department of Clinical Oncology/Hematology, The Jikei University School of Medicine, Tokyo, Japan
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Baba T, Tomaru U, Hirao A, Mukaida N, Johmura Y. Autophagy Inhibition-induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells. CANCER RESEARCH COMMUNICATIONS 2024; 4:849-860. [PMID: 38466568 PMCID: PMC10953625 DOI: 10.1158/2767-9764.crc-23-0507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 01/23/2024] [Accepted: 03/07/2024] [Indexed: 03/13/2024]
Abstract
UNLABELLED Accumulating evidence indicates that various oncogenic mutations interfere with normal myeloid differentiation of leukemogenic cells during the early process of acute myeloid leukemia (AML) development. Differentiation therapy is a therapeutic strategy capable of terminating leukemic expansion by reactivating the differentiation potential; however, the plasticity and instability of leukemia cells counteract the establishment of treatments aimed at irreversibly inducing and maintaining their differentiation states. On the basis of our previous observation that autophagy inhibitor treatment induces the accumulation of cytosolic DNA and activation of cytosolic DNA-sensor signaling selectively in leukemia cells, we herein examined the synergistic effect of cytosolic DNA-sensor signaling activation with conventional differentiation therapy on AML. The combined treatment succeeded in inducing irreversible differentiation in AML cell lines. Mechanistically, cytosolic DNA was sensed by absent in melanoma 2 (AIM2), a cytosolic DNA sensor. Activation of the AIM2 inflammasome resulted in the accumulation of p21 through the inhibition of its proteasomal degradation, thereby facilitating the myeloid differentiation. Importantly, the combined therapy dramatically reduced the total leukemia cell counts and proportion of blast cells in the spleens of AML mice. Collectively, these findings indicate that the autophagy inhibition-cytosolic DNA-sensor signaling axis can potentiate AML differentiation therapy. SIGNIFICANCE Clinical effects on AML therapy are closely associated with reactivating the normal myeloid differentiation potential in leukemia cells. This study shows that autophagosome formation inhibitors activate the cytosolic DNA-sensor signaling, thereby augmenting conventional differentiation therapy to induce irreversible differentiation and cell growth arrest in several types of AML cell lines.
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Affiliation(s)
- Tomohisa Baba
- Division of Cancer and Senescence Biology, Kanazawa University, Kanazawa, Japan
| | - Utano Tomaru
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Atsushi Hirao
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa, Japan
- Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
| | - Naofumi Mukaida
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yoshikazu Johmura
- Division of Cancer and Senescence Biology, Kanazawa University, Kanazawa, Japan
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Khorashad JS, Rizzo S, Tonks A. Reactive oxygen species and its role in pathogenesis and resistance to therapy in acute myeloid leukemia. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:5. [PMID: 38434766 PMCID: PMC10905166 DOI: 10.20517/cdr.2023.125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/24/2024] [Accepted: 02/19/2024] [Indexed: 03/05/2024]
Abstract
Relapse following a short clinical response to therapy is the major challenge for the management of acute myeloid leukemia (AML) patients. Leukemic stem cells (LSC), as the source of relapse, have been investigated for their metabolic preferences and their alterations at the time of relapse. As LSC rely on oxidative phosphorylation (OXPHOS) for energy requirement, reactive oxygen species (ROS), as by-products of OXPHOS, have been investigated for their role in the effectiveness of the standard AML therapy. Increased levels of non-mitochondrial ROS, generated by nicotinamide adenine dinucleotide phosphate oxidase, in a subgroup of AML patients add to the complexity of studying ROS. Although there are various studies presenting the contribution of ROS to AML pathogenesis, resistance, and its inhibition or activation as a target, a model that can clearly explain its role in AML has not been conceptualized. This is due to the heterogeneity of AML, the dynamics of ROS production, which is influenced by factors such as the type of treatment, cell differentiation state, mitochondrial activity, and also the heterogeneous generation of non-mitochondrial ROS and limited available data on their interaction with the microenvironment. This review summarizes these challenges and the recent progress in this field.
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Affiliation(s)
- Jamshid Sorouri Khorashad
- Department of Immunology and inflammation, Imperial College London, London, W12 0NN, UK
- Department of Molecular Pathology, Institute of Cancer Research, Sutton, SM2 5PT, UK
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Sian Rizzo
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Alex Tonks
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
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Röllig C. Improving long-term outcomes with intensive induction chemotherapy for patients with AML. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2023; 2023:175-185. [PMID: 38066853 PMCID: PMC10727094 DOI: 10.1182/hematology.2023000504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Intensive chemotherapy in combination with allogeneic hematopoietic cell transplantation and supportive care can induce long-term remissions in around 50% of acute myeloid leukemia patients eligible for intensive treatment. Several treatment optimization trials helped to refine schedule and dosing of the historic "7 + 3" combination. Together with the addition of novel agents, increased efficacy and tolerability led to improved long-term outcomes. Unsatisfactory outcomes in fit elderly patients and unfavorable genetic subgroups have raised the question of whether less-intensive venetoclax-based approaches may be beneficial as an alternative. Although tempting and worth exploring, this issue will remain controversial until the results of randomized comparisons appear. To date, intensive chemotherapy remains the only evident curative treatment option for long-term disease eradication in a fixed treatment time. With the advent of more novel agents and advances in minimal residual disease (MRD) detection and maintenance approaches, the face of intensive treatment could change in many ways. Several are being explored in clinical trials, such as (1) combinations of more than 1 novel agent with the intensive backbone, (2) head-to-head comparisons of novel agents, (3) replacement or dose reduction of cytotoxic components such as anthracyclines, and (4) MRD-guided escalation and de-escalation strategies. The combination of intensive treatment with individualized tailored innovative strategies will most certainly reduce treatment-related toxicities and increase the chances for long-term remission in the future.
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Affiliation(s)
- Christoph Röllig
- Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany
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Li J, Gao J, Liu A, Liu W, Xiong H, Liang C, Fang Y, Dai Y, Shao J, Yu H, Wang L, Wang L, Yang L, Yan M, Zhai X, Shi X, Tian X, Ju X, Chen Y, Wang J, Zhang L, Liang H, Chen S, Zhang J, Cao H, Jin J, Hu Q, Wang J, Wang Y, Zhou M, Han Y, Zhang R, Zhao W, Wang X, Lin L, Zhang R, Gao C, Xu L, Zhang Y, Fan J, Wu Y, Lin W, Yu J, Qi P, Huang P, Peng X, Peng Y, Wang T, Zheng H. Homoharringtonine-Based Induction Regimen Improved the Remission Rate and Survival Rate in Chinese Childhood AML: A Report From the CCLG-AML 2015 Protocol Study. J Clin Oncol 2023; 41:4881-4892. [PMID: 37531592 PMCID: PMC10617822 DOI: 10.1200/jco.22.02836] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 05/26/2023] [Accepted: 06/14/2023] [Indexed: 08/04/2023] Open
Abstract
PURPOSE Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia (APL). However, the efficacy and safety of HHT-based induction therapy have not been confirmed for childhood AML, and ATRA-based treatment has not been evaluated among patients with non-APL AML. PATIENTS AND METHODS This open-label, multicenter, randomized Chinese Children's Leukemia Group-AML 2015 study was performed across 35 centers in China. Patients with newly diagnosed childhood AML were first randomly assigned to receive an HHT-based (H arm) or etoposide-based (E arm) induction regimen and then randomly allocated to receive cytarabine-based (AC arm) or ATRA-based (AT arm) maintenance therapy. The primary end points were the complete remission (CR) rate after induction therapy, and the secondary end points were the overall survival (OS) and event-free survival (EFS) at 3 years. RESULTS We enrolled 1,258 patients, of whom 1,253 were included in the intent-to-treat analysis. The overall CR rate was significantly higher in the H arm than in the E arm (79.9% v 73.9%, P = .014). According to the intention-to-treat analysis, the 3-year OS was 69.2% (95% CI, 65.1 to 72.9) in the H arm and 62.8% (95% CI, 58.7 to 66.6) in the E arm (P = .025); the 3-year EFS was 61.1% (95% CI, 56.8 to 65.0) in the H arm and 53.4% (95% CI, 49.2 to 57.3) in the E arm (P = .022). Among the per-protocol population, who received maintenance therapy, the 3-year EFS did not differ significantly across the four arms (H + AT arm: 70.7%, 95% CI, 61.1 to 78.3; H + AC arm: 74.8%, 95% CI, 67.0 to 81.0, P = .933; E + AC arm: 72.9%, 95% CI, 65.1 to 79.2, P = .789; E + AT arm: 66.2%, 95% CI, 56.8 to 74.0, P = .336). CONCLUSION HHT is an alternative combination regimen for childhood AML. The effects of ATRA-based maintenance are comparable with those of cytarabine-based maintenance therapy.
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Affiliation(s)
- Jing Li
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Ju Gao
- West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Chronobiology (Sichuan University), National Health Commission of China, Chengdu, China
| | | | - Wei Liu
- Children's Hospital of Henan Province, Zhengzhou, China
| | - Hao Xiong
- Wuhan Children's Hospital, Wuhan, China
| | - Changda Liang
- Jiangxi Provincial Children's Hospital, Nanchang, China
| | - Yongjun Fang
- Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yunpeng Dai
- Shandong First Medical University Affiliated Shandong Provincial Hospital, Jinan, China
| | - Jingbo Shao
- Shanghai Children's Hospital, Shanghai, China
| | - Hui Yu
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingzhen Wang
- Affiliated Hospital of Qingdao University, Qingdao, China
| | - Li Wang
- Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Liangchun Yang
- Department of Pediatrics, Xiangya Hospital Central South University, Changsha, China
| | - Mei Yan
- The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiaowen Zhai
- Children's Hospital of Fudan University, Shanghai, China
| | - Xiaodong Shi
- Capital Institute of Pediatrics' Children's Hospital, Beijing, China
| | - Xin Tian
- Kunming Children's Hospital, Kunming, China
| | - Xiuli Ju
- Qilu Hospital of Shandong University, Jinan, China
| | - Yan Chen
- Children's Hospital of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jing Wang
- Children's Hospital of Shanxi Province, Taiyuan, China
| | - Leping Zhang
- Peking University People's Hospital, Beijing, China
| | - Hui Liang
- Women and Children's Hospital, Qingdao University, Qingdao, China
| | - Sen Chen
- Tianjin Children's Hospital, Tianjin, China
| | | | - Haixia Cao
- Qinghai Women's and Children's Hospital, Xining, China
| | - Jiao Jin
- The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Qun Hu
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junlan Wang
- Northwest Women's and Children's Hospital, Xian, China
| | | | - Min Zhou
- Chengdu Women's and Children's Central Hospital, Chengdu, China
| | - Yueqin Han
- Children's Hospital of Liaocheng, Liaocheng, China
| | - Rong Zhang
- Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Weihong Zhao
- First Hospital, Peking University, Beijing, China
| | | | - Limin Lin
- Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Ruidong Zhang
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Chao Gao
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
- Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Laboratory of Hematologic Diseases, Beijing Pediatric Research Institute, Beijing, China
| | - Liting Xu
- Children's Hospital of Zhejiang University School of Medicine, the Pediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, China
| | - Yuanyuan Zhang
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Jia Fan
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Ying Wu
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Wei Lin
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Jiaole Yu
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Peijing Qi
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Pengli Huang
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Xiaoxia Peng
- Center for Clinical Epidemiology and Evidence-Based Medicine, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Yaguang Peng
- Center for Clinical Epidemiology and Evidence-Based Medicine, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Tianyou Wang
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
| | - Huyong Zheng
- Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
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9
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Schlenk RF, Weber D, Krzykalla J, Kindler T, Wulf G, Hertenstein B, Salih HR, Südhoff T, Krauter J, Martens U, Wessendorf S, Runde V, Tischler HJ, Bentz M, Koller E, Heuser M, Thol F, Benner A, Ganser A, Döhner K, Döhner H. Randomized phase-III study of low-dose cytarabine and etoposide + /- all-trans retinoic acid in older unfit patients with NPM1-mutated acute myeloid leukemia. Sci Rep 2023; 13:14809. [PMID: 37684299 PMCID: PMC10491626 DOI: 10.1038/s41598-023-41964-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 09/04/2023] [Indexed: 09/10/2023] Open
Abstract
The aim of this randomized clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with non-intensive chemotherapy in older unfit patients (> 60 years) with newly diagnosed NPM1-mutated acute myeloid leukemia. Patients were randomized (1:1) to low-dose chemotherapy with or without open-label ATRA 45 mg/m2, days 8-28; the dose of ATRA was reduced to 45 mg/m2, days 8-10 and 15 mg/m2, days 11-28 after 75 patients due to toxicity. Up to 6 cycles of cytarabine 20 mg/day s.c., bid, days 1-7 and etoposide 100 mg/day, p.o. or i.v., days 1-3 with (ATRA) or without ATRA (CONTROL) were intended. The primary endpoint was overall survival (OS). Between May 2011 and September 2016, 144 patients (median age, 77 years; range, 64-92 years) were randomized (72, CONTROL; 72, ATRA). Baseline characteristics were balanced between the two study arms. The median number of treatment cycles was 2 in ATRA and 2.5 in CONTROL. OS was significantly shorter in the ATRA compared to the CONTROL arm (p = 0.023; median OS: 5 months versus 9.2 months, 2-years OS rate: 7% versus 10%, respectively). Rates of CR/CRi were not different between treatment arms; infections were more common in ATRA beyond treatment cycle one. The addition of ATRA to low-dose cytarabine plus etoposide in an older, unfit patient population was not beneficial, but rather led to an inferior outcome.The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2010-023409-37, first posted 14/12/2010).
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Affiliation(s)
- R F Schlenk
- NCT-Trial Center, National Center of Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany.
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
| | - D Weber
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
| | - J Krzykalla
- Division of Biostatistics, German Cancer Research Center Heidelberg, Heidelberg, Germany
| | - T Kindler
- Department of Hematology, Medical Oncology and Pneumology, University Medical Center Mainz, Mainz, Germany
| | - G Wulf
- Department of Hematology and Oncology, University Hospital of Göttingen, Göttingen, Germany
| | - B Hertenstein
- Department of Hematology and Oncology, Klinikum Bremen Mitte, Bremen, Germany
| | - H R Salih
- Department of Hematology and Oncology, Eberhard-Karls University, Tübingen, Germany
| | - T Südhoff
- Department of Hematology and Oncology, Klinikum Passau, Passau, Germany
| | - J Krauter
- Department Hematology and Oncology, Braunschweig Municipal Hospital, Braunschweig, Germany
| | - U Martens
- Department of Hematology and Oncology, Klinikum am Gesundbrunnen, Heilbronn, Germany
| | - S Wessendorf
- Department of Hematology and Oncology, Klinikum Esslingen, Esslingen, Germany
| | - V Runde
- Department of Hematology/Oncology, Wilhelm-Anton Hospital Goch, Goch, Germany
| | - H J Tischler
- Department of Hematology and Oncology, University Hospital of Minden, Minden, Germany
| | - M Bentz
- Department of Hematology and Oncology, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | - E Koller
- Department of Internal Medicine III, Hanuschkrankenhaus Wien, Wien, Austria
| | - M Heuser
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - F Thol
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - A Benner
- Division of Biostatistics, German Cancer Research Center Heidelberg, Heidelberg, Germany
| | - A Ganser
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - K Döhner
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
| | - H Döhner
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
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10
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Nagai Y, Ambinder AJ. The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away. Cancers (Basel) 2023; 15:3535. [PMID: 37509198 PMCID: PMC10377082 DOI: 10.3390/cancers15143535] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/29/2023] [Accepted: 07/03/2023] [Indexed: 07/30/2023] Open
Abstract
Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO). ATRA's success has deepened our understanding of the role of the RARα pathway in normal hematopoiesis and leukemogenesis, and it has influenced a generation of cancer drug development. Retinoids have also demonstrated some efficacy in a handful of other disease entities, including as a maintenance therapy for neuroblastoma and in the treatment of cutaneous T-cell lymphomas; nevertheless, the promise of retinoids as a differentiating therapy in acute myeloid leukemia (AML) more broadly, and as a cancer preventative, have largely gone unfulfilled. Recent research into the mechanisms of ATRA resistance and the biomarkers of RARα pathway dysregulation in AML have reinvigorated efforts to successfully deploy retinoid therapy in a broader subset of myeloid malignancies. Recent studies have demonstrated that the bone marrow environment is highly protected from exogenous ATRA via local homeostasis controlled by stromal cells expressing CYP26, a key enzyme responsible for ATRA inactivation. Synthetic CYP26-resistant retinoids such as tamibarotene bypass this stromal protection and have shown superior anti-leukemic effects. Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.
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Affiliation(s)
- Yuya Nagai
- Department of Hematology, Kobe City Medical Center General Hospital, Kobe 650-0047, Hyogo, Japan
| | - Alexander J Ambinder
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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11
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Dennis M, Copland M, Kaur H, Kell J, Nikolousis E, Mehta P, Palanicawandar R, Potter V, Raj K, Thomas I, Wilson A. Management of older patients with frailty and acute myeloid leukaemia: A British Society for Haematology good practice paper. Br J Haematol 2022; 199:205-221. [PMID: 36000944 DOI: 10.1111/bjh.18369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Mike Dennis
- The Christie NHS Foundation Trust, Manchester, UK
| | - Mhairi Copland
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Harpreet Kaur
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | | | - Priyanka Mehta
- University Hospitals of Bristol and Weston NHS Trust, Bristol, UK
| | | | | | - Kavita Raj
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - Andrew Wilson
- University College London Hospitals NHS Foundation Trust, London, UK
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12
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Othus M, Zhang MJ, Gale RP. Clinical trials: design, endpoints and interpretation of outcomes. Bone Marrow Transplant 2022; 57:338-342. [PMID: 34997213 DOI: 10.1038/s41409-021-01542-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/12/2021] [Accepted: 11/22/2021] [Indexed: 11/12/2022]
Affiliation(s)
- Megan Othus
- Division of Public Health, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
| | - Mei-Jie Zhang
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Robert Peter Gale
- Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK
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13
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Hleihel R, El Hajj H, Wu HC, Berthier C, Zhu HH, Massoud R, Chakhachiro Z, El Sabban M, De The H, Bazarbachi A. A Pin1/PML/P53 axis activated by retinoic acid in NPM-1c acute myeloid leukemia. Haematologica 2021; 106:3090-3099. [PMID: 34047175 PMCID: PMC8634200 DOI: 10.3324/haematol.2020.274878] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 05/03/2021] [Indexed: 11/09/2022] Open
Abstract
Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Promyelocytic, Acute/drug therapy
- Leukemia, Promyelocytic, Acute/genetics
- Leukemia, Promyelocytic, Acute/metabolism
- NIMA-Interacting Peptidylprolyl Isomerase/genetics
- NIMA-Interacting Peptidylprolyl Isomerase/metabolism
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Oncogene Proteins, Fusion/metabolism
- Tretinoin/pharmacology
- Tretinoin/therapeutic use
- Tumor Suppressor Protein p53/genetics
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Affiliation(s)
- Rita Hleihel
- Department of Internal Medicine, American University of Beirut, Beirut, Lebanon; Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon
| | - Hiba El Hajj
- Department of Experimental Pathology, Microbiology and Immunology, Beirut
| | - Hsin-Chieh Wu
- Université de Paris, INSERM UMR 944, CNRS UMR 7212, Equipe labellisée par la Ligue Nationale contre le Cancer, IRSL, Hôpital St. Louis, Paris, College de France, PSL University, CIRB, INSERM UMR 1050, CNRS UMR 7241, Paris
| | - Caroline Berthier
- Université de Paris, INSERM UMR 944, CNRS UMR 7212, Equipe labellisée par la Ligue Nationale contre le Cancer, IRSL, Hôpital St. Louis, Paris; College de France, PSL University, CIRB, INSERM UMR 1050, CNRS UMR 7241, Paris
| | - Hong-Hu Zhu
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou
| | - Radwan Massoud
- Department of Internal Medicine, American University of Beirut, Beirut
| | - Zaher Chakhachiro
- Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut
| | - Marwan El Sabban
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut
| | - Hugues De The
- Université de Paris, INSERM UMR 944, CNRS UMR 7212, Equipe labellisée par la Ligue Nationale contre le Cancer, IRSL, Hôpital St. Louis, Paris; College de France, PSL University, CIRB, INSERM UMR 1050, CNRS UMR 7241, Paris
| | - Ali Bazarbachi
- Department of Internal Medicine, American University of Beirut, Beirut; Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut.
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14
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Kantarjian H, Short NJ, DiNardo C, Stein EM, Daver N, Perl AE, Wang ES, Wei A, Tallman M. Harnessing the benefits of available targeted therapies in acute myeloid leukaemia. Lancet Haematol 2021; 8:e922-e933. [PMID: 34687602 PMCID: PMC8996707 DOI: 10.1016/s2352-3026(21)00270-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/09/2021] [Accepted: 08/19/2021] [Indexed: 12/16/2022]
Abstract
Research has resulted in regulatory approval of nine agents for acute myeloid leukaemia indications by the US Food and Drug Administration since 2017: the Bcl-2 inhibitor, venetoclax; two FLT3 inhibitors, midostaurin and gilteritinib; two IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor); the anti-CD33 antibody-drug conjugate, gemtuzumab ozogamicin; the oral, poorly absorbable hypomethylating agent, azacitidine; the liposomal formulation of cytarabine and daunorubicin (5:1 ratio), CPX-351; and the hedgehog signalling pathway inhibitor, glasdegib. A 100% absorbable oral formulation of the hypomethylating agent decitabine was approved for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukaemia, and might be used as an alternative to parenteral hypomethylating agents. Several of the approvals are as single-agent therapies or in specific combinations for narrow indications, thus offering poor treatment value. In this Review, we discuss ongoing research into combinations containing these commercially available targeted therapies for acute myeloid leukaemia.
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Affiliation(s)
- Hagop Kantarjian
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
| | - Nicholas J Short
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Courtney DiNardo
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Eytan M Stein
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA
| | - Naval Daver
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Alexander E Perl
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Eunice S Wang
- Leukemia Service, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Andrew Wei
- Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, VIC, Australia
| | - Martin Tallman
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA
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15
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All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16. Int J Hematol 2021; 115:43-53. [PMID: 34546543 DOI: 10.1007/s12185-021-03224-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 10/20/2022]
Abstract
All-trans retinoic acid (ATRA)-based therapy for acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), is the most successful example of differentiation therapy. Although ATRA can induce differentiation in some non-APL AML cell lines and primary blasts, clinical results of adding ATRA to standard therapy in non-APL AML patients have been inconsistent, probably due to use of different regimens and lack of diagnostic tools for identifying which patients may be sensitive to ATRA. In this study, we exposed primary blasts obtained from non-APL AML patients to ATRA to test for differentiation potential in vitro. We observed increased expression of differentiation markers, indicating a response to ATRA, in four out of fifteen primary AML samples. Three samples in which CD11b increased in response to ATRA had an inversion of chromosome 16 as well as the CBFB-MYH11 fusion gene, and the fourth sample was from a patient with KMT2A-rearranged, therapy-related AML. In conclusion, we identified a subgroup of non-APL AML patients with inv(16) and CBFB-MYH11 as the most sensitive to ATRA-mediated differentiation in vitro, and our results can help identify patients who may benefit from ATRA treatment.
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16
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Defining the Transcriptional Control of Pediatric AML Highlights RARA as a Super-Enhancer Regulated Druggable Dependency. Blood Adv 2021; 5:4864-4876. [PMID: 34543389 PMCID: PMC9153032 DOI: 10.1182/bloodadvances.2020003737] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 07/11/2021] [Indexed: 11/26/2022] Open
Abstract
The first enhancer mapping of pediatric AML reveals that the most common SE-associated signature is one driven by RARA. A RARA SE is common in pediatric AML and correlates to sensitivity to the retinoid tamibarotene both in vitro and in vivo. Somatic mutations are rare in pediatric acute myeloid leukemia (pAML), indicating that alternate strategies are needed to identify targetable dependencies. We performed the first enhancer mapping of pAML in 22 patient samples. Generally, pAML samples were distinct from adult AML samples, and MLL (KMT2A)–rearranged samples were also distinct from non–KMT2A-rearranged samples. Focusing specifically on superenhancers (SEs), we identified SEs associated with many known leukemia regulators. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort, and a RARA-associated SE was detected in 64% of the study cohort across all cytogenetic and molecular subtypes tested. RARA SE+ pAML cell lines and samples exhibited high RARA messenger RNA levels. These samples were specifically sensitive to the synthetic RARA agonist tamibarotene in vitro, with slowed proliferation, apoptosis induction, differentiation, and upregulated retinoid target gene expression, compared with RARA SE− samples. Tamibarotene prolonged survival and suppressed the leukemia burden of an RARA SE+ pAML patient-derived xenograft mouse model compared with a RARA SE− patient-derived xenograft. Our work shows that examining chromatin regulation can identify new, druggable dependencies in pAML and provides a rationale for a pediatric tamibarotene trial in children with RARA-high AML.
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17
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Weigert N, Rowe JM, Lazarus HM, Salman MY. Consolidation in AML: Abundant opinion and much unknown. Blood Rev 2021; 51:100873. [PMID: 34483002 DOI: 10.1016/j.blre.2021.100873] [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: 05/12/2021] [Revised: 06/24/2021] [Accepted: 08/01/2021] [Indexed: 11/25/2022]
Abstract
Consolidation therapy forms the backbone of post-remission therapy for AML and is uniformly accepted as an integral part of therapy designed to achieve long-term survival. The need for post-remission therapy was initially described over four decades ago and has since undergone many variations in terms of dosage, number of cycles and intensity of therapy. There is much empiricism in the current understanding of consolidation therapy and much that has not been rigorously studied. This review will consider the many aspects of consolidation therapy, focusing on the number of cycles, differences between young and older adults, first and subsequent remission as well as therapy prior to an allogeneic transplant. Emphasis will be given to differentiate strategies that are clearly evidence-based from those that have been incorporated into standard of care while bypassing the need for rigorous data-driven approaches. Finally, consideration will be given to the current ability to assess the minimal measureable residual disease and the impact that this may have on therapeutic paradigms, including superseding many of the time-honored prognostic features.
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Affiliation(s)
- Nir Weigert
- Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Jacob M Rowe
- Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel; Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel; Technion, Israel Institute of Technology, Haifa, Israel.
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18
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Ramsey HE, Stengel K, Pino JC, Johnston G, Childress M, Gorska AE, Arrate PM, Fuller L, Villaume M, Fischer MA, Ferrell PB, Roe CE, Zou J, Lubbock ALR, Stubbs M, Zinkel S, Irish JM, Lopez CF, Hiebert S, Savona MR. Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation. Target Oncol 2021; 16:663-674. [PMID: 34324169 DOI: 10.1007/s11523-021-00830-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis. OBJECTIVE While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML). METHODS Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. RESULTS Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion. CONCLUSIONS JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia.
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Affiliation(s)
- Haley E Ramsey
- Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Kristy Stengel
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - James C Pino
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Bioinformatics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Gretchen Johnston
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Merrida Childress
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Agnieszka E Gorska
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Pia M Arrate
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Londa Fuller
- Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Matthew Villaume
- Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Melissa A Fischer
- Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - P Brent Ferrell
- Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Caroline E Roe
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Jing Zou
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Alexander L R Lubbock
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Bioinformatics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | | | - Sandra Zinkel
- Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.,Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2200 Pierce Avenue, Nashville, TN, 37232, USA
| | - Jonathan M Irish
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Carlos F Lopez
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Bioinformatics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Scott Hiebert
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.,Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2200 Pierce Avenue, Nashville, TN, 37232, USA
| | - Michael R Savona
- Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA. .,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. .,Vanderbilt Center for Immunobiology, Nashville, TN, USA. .,Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2200 Pierce Avenue, Nashville, TN, 37232, USA.
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19
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Borges GSM, Lima FA, Carneiro G, Goulart GAC, Ferreira LAM. All-trans retinoic acid in anticancer therapy: how nanotechnology can enhance its efficacy and resolve its drawbacks. Expert Opin Drug Deliv 2021; 18:1335-1354. [PMID: 33896323 DOI: 10.1080/17425247.2021.1919619] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: All-trans retinoic acid (ATRA, tretinoin) is the main drug used in the treatment of acute promyelocytic leukemia (APL). Despite its impressive activity against APL, the same could not be clinically observed in other types of cancer. Nanotechnology can be a tool to enhance ATRA anticancer efficacy and resolve its drawbacks in APL as well as in other malignancies.Areas covered: This review covers ATRA use in APL and non-APL cancers, the problems that were found in ATRA therapy and how nanoencapsulation can aid to circumvent them. Pre-clinical results obtained with nanoencapsulated ATRA are shown as well as the two ATRA products based on nanotechnology that were clinically tested: ATRA-IV® and Apealea®.Expert opinion: ATRA presents interesting properties to be used in anticancer therapy with a notorious differentiation and antimetastatic activity. Bioavailability and resistance limitations impair the use of ATRA in non-APL cancers. Nanotechnology can circumvent these issues and provide tools to enhance its anticancer activities, such as co-loading of multiple drug and active targeting to tumor site.
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Affiliation(s)
- Gabriel Silva Marques Borges
- Departamento De Produtos Farmacêuticos, Faculdade De Farmácia, Universidade Federal De Minas Gerais, Belo Horizonte, Brazil
| | - Flávia Alves Lima
- Departamento De Produtos Farmacêuticos, Faculdade De Farmácia, Universidade Federal De Minas Gerais, Belo Horizonte, Brazil
| | - Guilherme Carneiro
- Departamento De Farmácia, Faculdade De Ciências Biológicas E Da Saúde, Universidade Federal Dos Vales Do Jequitinhonha E Mucuri, Diamantina, Brazil
| | - Gisele Assis Castro Goulart
- Departamento De Produtos Farmacêuticos, Faculdade De Farmácia, Universidade Federal De Minas Gerais, Belo Horizonte, Brazil
| | - Lucas Antônio Miranda Ferreira
- Departamento De Produtos Farmacêuticos, Faculdade De Farmácia, Universidade Federal De Minas Gerais, Belo Horizonte, Brazil
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20
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Di Francia R, Crisci S, De Monaco A, Cafiero C, Re A, Iaccarino G, De Filippi R, Frigeri F, Corazzelli G, Micera A, Pinto A. Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers. Cancers (Basel) 2021; 13:cancers13050966. [PMID: 33669053 PMCID: PMC7956511 DOI: 10.3390/cancers13050966] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 01/04/2023] Open
Abstract
Simple Summary In this review, the authors propose a crosswise examination of cytarabine-related issues ranging from the spectrum of clinical activity and severe toxicities, through updated cellular pharmacology and drug formulations, to the genetic variants associated with drug-induced phenotypes. Cytarabine (cytosine arabinoside; Ara-C) in multiagent chemotherapy regimens is often used for leukemia or lymphoma treatments, as well as neoplastic meningitis. Chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. The individual variability in clinical response to Leukemia & Lymphoma treatments among patients appears to be associated with intracellular accumulation of Ara-CTP due to genetic variants related to metabolic enzymes. The review provides exhaustive information on the effects of Ara-C-based therapies, the adverse drug reaction will also be provided including bone pain, ocular toxicity (corneal pain, keratoconjunctivitis, and blurred vision), maculopapular rash, and occasional chest pain. Evidence for predicting the response to cytarabine-based treatments will be highlighted, pointing at their significant impact on the routine management of blood cancers. Abstract Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara-CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara-C-based therapies, from biological to clinical practice, maintaining high the interest of both researcher and clinical hematologist. This review could help clinicians in predicting the response to cytarabine-based treatments.
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Affiliation(s)
- Raffaele Di Francia
- Italian Association of Pharmacogenomics and Molecular Diagnostics, 60126 Ancona, Italy;
| | - Stefania Crisci
- Hematology-Oncology and Stem Cell transplantation Unit, National Cancer Institute, Fondazione “G. Pascale” IRCCS, 80131 Naples, Italy; (S.C.); (G.I.); (R.D.F.); (G.C.); (A.P.)
| | - Angela De Monaco
- Clinical Patology, ASL Napoli 2 Nord, “S.M. delle Grazie Hospital”, 80078 Pozzuoli, Italy;
| | - Concetta Cafiero
- Medical Oncology, S.G. Moscati, Statte, 74010 Taranto, Italy
- Correspondence: or (C.C.); (A.M.); Tel.:+39-34-0101-2002 (C.C.); +39-06-4554-1191 (A.M.)
| | - Agnese Re
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Giancarla Iaccarino
- Hematology-Oncology and Stem Cell transplantation Unit, National Cancer Institute, Fondazione “G. Pascale” IRCCS, 80131 Naples, Italy; (S.C.); (G.I.); (R.D.F.); (G.C.); (A.P.)
| | - Rosaria De Filippi
- Hematology-Oncology and Stem Cell transplantation Unit, National Cancer Institute, Fondazione “G. Pascale” IRCCS, 80131 Naples, Italy; (S.C.); (G.I.); (R.D.F.); (G.C.); (A.P.)
- Department of Clinical Medicine and Surgery, Federico II University, 80131 Naples, Italy
| | | | - Gaetano Corazzelli
- Hematology-Oncology and Stem Cell transplantation Unit, National Cancer Institute, Fondazione “G. Pascale” IRCCS, 80131 Naples, Italy; (S.C.); (G.I.); (R.D.F.); (G.C.); (A.P.)
| | - Alessandra Micera
- Research and Development Laboratory for Biochemical, Molecular and Cellular Applications in Ophthalmological Sciences, IRCCS—Fondazione Bietti, 00184 Rome, Italy
- Correspondence: or (C.C.); (A.M.); Tel.:+39-34-0101-2002 (C.C.); +39-06-4554-1191 (A.M.)
| | - Antonio Pinto
- Hematology-Oncology and Stem Cell transplantation Unit, National Cancer Institute, Fondazione “G. Pascale” IRCCS, 80131 Naples, Italy; (S.C.); (G.I.); (R.D.F.); (G.C.); (A.P.)
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21
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Shallis RM, Pollyea DA, Zeidan AM. The complete story of less than complete responses: The evolution and application of acute myeloid leukemia clinical responses. Blood Rev 2021; 48:100806. [PMID: 33531169 DOI: 10.1016/j.blre.2021.100806] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/13/2020] [Accepted: 12/17/2020] [Indexed: 10/22/2022]
Abstract
Complete remission (CR) has long been the critical therapeutic response in acute myeloid leukemia (AML). However, "less than CR" responses have been and continue to be proposed to define clinically meaningful post-therapy outcomes. These responses include CR with incomplete recovery (CRi), CR with incomplete platelet recovery (CRp) and, most recently, CR with partial hematologic recovery (CRh), which has been introduced and subsequently used for regulatory approval. However, the clinical benefits associated with "less than CR" responses have primarily been evaluated in the context of intensive therapies. In an era with sophisticated measurable residual disease (MRD) assessments, including flow-based, cytogenetic and molecular techniques, and an increase in "targeted", non-intensive therapies, the clinical value of responses that are "less than CR" must be reevaluated. Improvements in the rate of CR has not always led to improvements in OS among older patients. As such, MRD techniques might help define a more stringent response criterion (MRD-negative CR) that might better correlate with OS and should be incorporated in future clinical trials. Here we discuss the evolution of CR and "less than CR" responses, data regarding their clinical benefits, and considerations relevant to response assessments with newer therapies.
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Affiliation(s)
- Rory M Shallis
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Yale Cancer Center, New Haven, CT, USA
| | - Daniel A Pollyea
- Division of Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Amer M Zeidan
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Yale Cancer Center, New Haven, CT, USA.
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22
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Tayari MM, Santos HGD, Kwon D, Bradley TJ, Thomassen A, Chen C, Dinh Y, Perez A, Zelent A, Morey L, Cimmino L, Shiekhattar R, Swords RT, Watts JM. Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies. Clin Cancer Res 2021; 27:1893-1903. [PMID: 33495312 DOI: 10.1158/1078-0432.ccr-20-4054] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/07/2020] [Accepted: 01/15/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). PATIENTS AND METHODS Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily). RESULTS ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. CONCLUSIONS These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
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Affiliation(s)
- Mina M Tayari
- Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida
| | - Helena G Dos Santos
- Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida
| | - Deukwoo Kwon
- Sylvester Comprehensive Cancer Center, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida
| | - Terrence J Bradley
- Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
| | - Amber Thomassen
- Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
| | - Charles Chen
- Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
| | - Yvonne Dinh
- Department of Immuno-Oncology, Oncology Division, IQVIA Biotech, Miami, Florida
| | - Aymee Perez
- Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
| | - Arthur Zelent
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology PAS, Warsaw, Poland
| | - Lluis Morey
- Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida
| | - Luisa Cimmino
- Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida
| | - Ramin Shiekhattar
- Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida
| | - Ronan T Swords
- Medical Director, AbbVie Pharmaceuticals, Chicago, Illinois
| | - Justin M Watts
- Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
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23
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Madan V, Koeffler HP. Differentiation therapy of myeloid leukemia: four decades of development. Haematologica 2021; 106:26-38. [PMID: 33054125 PMCID: PMC7776344 DOI: 10.3324/haematol.2020.262121] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023] Open
Abstract
Acute myeloid leukemia is characterized by arrested differentiation, and agents that overcome this block are therapeutically useful, as shown by the efficacy of all-trans retinoic acid in acute promyelocytic leukemia. However, the early promise of differentiation therapy did not translate into clinical benefit for other subtypes of acute myeloid leukemia, in which cytotoxic chemotherapeutic regimens remained the standard of care. Recent advances, including insights from sequencing of acute myeloid leukemia genomes, have led to the development of targeted therapies, comprising agents that induce differentiation of leukemic cells in preclinical models and clinical trials, thus rejuvenating interest in differentiation therapy. These agents act on various cellular processes including dysregulated metabolic programs, signaling pathways, epigenetic machinery and the cell cycle. In particular, inhibitors of mutant IDH1/2 and FLT3 have shown clinical benefit, leading to approval by regulatory bodies of their use. Besides the focus on recently approved differentiation therapies, this review also provides an overview of differentiation- inducing agents being tested in clinical trials or investigated in preclinical research. Combinatorial strategies are currently being tested for several agents (inhibitors of KDM1A, DOT1L, BET proteins, histone deacetylases), which were not effective in clinical studies as single agents, despite encouraging anti-leukemic activity observed in preclinical models. Overall, recently approved drugs and new investigational agents being developed highlight the merits of differentiation therapy; and ongoing studies promise further advances in the treatment of acute myeloid leukemia in the near future.
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Affiliation(s)
- Vikas Madan
- Cancer Science Institute of Singapore, National University of Singapore.
| | - H Phillip Koeffler
- Cancer Science Institute of Singapore, National University of Singapore; Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA; Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital.
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24
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van Gils N, Verhagen HJMP, Rutten A, Menezes RX, Tsui ML, Vermue E, Dekens E, Brocco F, Denkers F, Kessler FL, Ossenkoppele GJ, Janssen JJWM, Smit L. IGFBP7 activates retinoid acid-induced responses in acute myeloid leukemia stem and progenitor cells. Blood Adv 2020; 4:6368-6383. [PMID: 33351133 PMCID: PMC7756998 DOI: 10.1182/bloodadvances.2020002812] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 11/09/2020] [Indexed: 11/20/2022] Open
Abstract
Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) in combination with low doses of arsenic trioxide or chemotherapy leads to exceptionally high cure rates (>90%). ATRA forces APL cells into differentiation and cell death. Unfortunately, ATRA-based therapy has not been effective among any other acute myeloid leukemia (AML) subtype, and long-term survival rates remain unacceptably low; only 30% of AML patients survive 5 years after diagnosis. Here, we identified insulin-like growth factor binding protein 7 (IGFBP7) as part of ATRA-induced responses in APL cells. Most importantly, we observed that addition of recombinant human IGFBP7 (rhIGFBP7) increased ATRA-driven responses in a subset of non-APL AML samples: those with high RARA expression. In nonpromyelocytic AML, rhIGFBP7 treatment induced a transcriptional program that sensitized AML cells for ATRA-induced differentiation, cell death, and inhibition of leukemic stem/progenitor cell survival. Furthermore, the engraftment of primary AML in mice was significantly reduced following treatment with the combination of rhIGFBP7 and ATRA. Mechanistically, we showed that the synergism of ATRA and rhIGFBP7 is due, at least in part, to reduction of the transcription factor GFI1. Together, these results suggest a potential clinical utility of IGFBP7 and ATRA combination treatment to eliminate primary AML (leukemic stem/progenitor) cells and reduce relapse in AML patients.
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Affiliation(s)
- Noortje van Gils
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Han J M P Verhagen
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Arjo Rutten
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Renee X Menezes
- Department of Epidemiology and Biostatistics, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands
| | - Mei-Ling Tsui
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Eline Vermue
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Esmée Dekens
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Fabio Brocco
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Fedor Denkers
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Floortje L Kessler
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Gert J Ossenkoppele
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Jeroen J W M Janssen
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
| | - Linda Smit
- Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands; and
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25
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Hernandez D, Palau L, Norsworthy K, Anders NM, Alonso S, Su M, Petkovich M, Chandraratna R, Rudek MA, Smith BD, Jones RJ, Ghiaur G. Overcoming microenvironment-mediated protection from ATRA using CYP26-resistant retinoids. Leukemia 2020; 34:3077-3081. [PMID: 32152463 PMCID: PMC7483812 DOI: 10.1038/s41375-020-0790-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 02/24/2020] [Accepted: 02/26/2020] [Indexed: 01/20/2023]
Affiliation(s)
- Daniela Hernandez
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA
| | - Laura Palau
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA
| | - Kelly Norsworthy
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA
| | - Nicole M Anders
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA
| | - Salvador Alonso
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA
| | - Meng Su
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA
| | - Martin Petkovich
- Cancer Research Institute, Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | | | - Michelle A Rudek
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA
| | - B Douglas Smith
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA
| | - Richard J Jones
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA
| | - Gabriel Ghiaur
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA.
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Ambinder AJ, Norsworthy K, Hernandez D, Palau L, Paun B, Duffield A, Chandraratna R, Sanders M, Varadhan R, Jones RJ, Douglas Smith B, Ghiaur G. A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML. Front Oncol 2020; 10:587062. [PMID: 33194741 PMCID: PMC7645224 DOI: 10.3389/fonc.2020.587062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 10/05/2020] [Indexed: 12/31/2022] Open
Abstract
Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708.
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Affiliation(s)
- Alexander J. Ambinder
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Kelly Norsworthy
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Daniela Hernandez
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Laura Palau
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Bogdan Paun
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Amy Duffield
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | | | | | - Ravi Varadhan
- Division of Biostatistics and Bioinformatics, Johns Hopkins/Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States
| | - Richard J. Jones
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - B. Douglas Smith
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Gabriel Ghiaur
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1. Oncol Ther 2020; 7:121-130. [PMID: 32699982 PMCID: PMC7359977 DOI: 10.1007/s40487-019-0095-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Indexed: 12/04/2022] Open
Abstract
Introduction EVI1 (MECOM)-positive acute myeloid leukemia (AML) cells have shown in vitro sensitivity to all-trans-retinoic acid (ATRA) by inducing differentiation, cell death, and decreased leukemic engraftment. Methods In this pilot study, we investigated the response to ATRA in 13 high-risk AML patients with overexpression of EVI1. Results Seven of the 13 patients (53.8%) achieved complete remission (CR), and response can be combined with a decreased of the leukemia stem cell pool. Conclusion These primary results tend to confirm in vitro results and suggest that addition of ATRA might be of benefit in the treatment of patients with EVI1-positive AML.
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Vetrie D, Helgason GV, Copland M. The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML. Nat Rev Cancer 2020; 20:158-173. [PMID: 31907378 DOI: 10.1038/s41568-019-0230-9] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/20/2019] [Indexed: 01/21/2023]
Abstract
For two decades, leukaemia stem cells (LSCs) in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR-ABL1 in a haematopoietic stem cell drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukaemic events, adding further layers of context and genetic and cellular heterogeneity to AML LSCs not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standard-of-care therapies and persist in patients, diversify clonally and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal haematopoietic stem cells. These features may represent Achilles' heels against which novel therapies can be developed. Here, we review many of the similarities and differences that exist between LSCs in CML and AML and examine the therapeutic strategies that could be used to eradicate them.
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MESH Headings
- Animals
- Biomarkers, Tumor
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/metabolism
- Disease Management
- Disease Susceptibility
- Drug Development
- History, 20th Century
- History, 21st Century
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/etiology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy
- Leukemia, Myeloid, Acute/diagnosis
- Leukemia, Myeloid, Acute/etiology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/therapy
- Molecular Targeted Therapy
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Research/history
- Research/trends
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Affiliation(s)
- David Vetrie
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
| | - G Vignir Helgason
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Mhairi Copland
- Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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29
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Xu A, Zhang N, Cao J, Zhu H, Yang B, He Q, Shao X, Ying M. Post-translational modification of retinoic acid receptor alpha and its roles in tumor cell differentiation. Biochem Pharmacol 2020; 171:113696. [DOI: 10.1016/j.bcp.2019.113696] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 11/05/2019] [Indexed: 12/22/2022]
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30
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The ATRA-21 gene-expression model predicts retinoid sensitivity in CEBPA double mutant, t(8;21) and inv(16) AML patients. Blood Cancer J 2019; 9:76. [PMID: 31570689 PMCID: PMC6769013 DOI: 10.1038/s41408-019-0241-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/04/2019] [Accepted: 09/17/2019] [Indexed: 11/09/2022] Open
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31
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Buteyn NJ, Fatehchand K, Santhanam R, Fang H, Dettorre GM, Gautam S, Harrington BK, Henderson SE, Merchand-Reyes G, Mo X, Benson DM, Carson WE, Vasu S, Byrd JC, Butchar JP, Tridandapani S. Anti-leukemic effects of all-trans retinoic acid in combination with Daratumumab in acute myeloid leukemia. Int Immunol 2019; 30:375-383. [PMID: 29868798 DOI: 10.1093/intimm/dxy040] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 05/31/2018] [Indexed: 01/07/2023] Open
Abstract
Acute myeloid leukemia (AML) remains a significant health problem, with poor outcomes despite chemotherapy and bone marrow transplants. Although one form of AML, acute promyelocytic leukemia (APL), is successfully treated with all-trans retinoic acid (ATRA), this drug is seemingly ineffective against all other forms of AML. Here, we show that ATRA up-regulates CD38 expression on AML blasts to sufficient levels that promote antibody-mediated fratricide following the addition of anti-CD38 daratumumab (DARA). The combination of ATRA plus DARA induced Fc-dependent conjugate formation and cytotoxicity among AML blasts in vitro. Combination treatment also led to reduction in tumor volume and resulted in increased overall survival in murine engraftment models of AML. These results suggest that, although ATRA does not induce differentiation of non-APL, it may be effective as a therapy in conjunction with DARA.
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MESH Headings
- Antibodies, Monoclonal/chemistry
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Cell Proliferation/drug effects
- Drug Screening Assays, Antitumor
- Drug Therapy, Combination
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Tretinoin/chemistry
- Tretinoin/pharmacology
- Tretinoin/therapeutic use
- Tumor Cells, Cultured
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Affiliation(s)
- Nathaniel J Buteyn
- Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH, USA
| | - Kavin Fatehchand
- Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA
| | - Ramasamy Santhanam
- Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Huiqing Fang
- Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Gino M Dettorre
- Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Shalini Gautam
- Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Bonnie K Harrington
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Sally E Henderson
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Giovanna Merchand-Reyes
- Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH, USA
| | - Xiaokui Mo
- Center for Biostatistics, The Ohio State University, Columbus, OH, USA
| | - Don M Benson
- Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - William E Carson
- Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Sumithira Vasu
- Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - John C Byrd
- Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Jonathan P Butchar
- Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
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32
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Economides MP, McCue D, Borthakur G, Pemmaraju N. Topoisomerase II inhibitors in AML: past, present, and future. Expert Opin Pharmacother 2019; 20:1637-1644. [PMID: 31136213 DOI: 10.1080/14656566.2019.1621292] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Introduction: Topoisomerase II inhibitors have long been used in the frontline and as salvage therapy for AML, with daunorubicin and idarubicin being prototypical agents in this therapeutic class, classically in combination with nucleoside analogs, e.g. cytarabine. Most recently, several other compounds from this drug class have or are being investigated. Areas covered: The current paper reviews older and newer topoisomerase II inhibitors in clinical development for the treatment of AML. The authors discuss the clinical use of these agents, current trials involving them as well as their safety profile. Important side effects of these medications including therapy-related AML (t-AML) are also covered. Expert opinion: Topoisomerase II inhibitors have helped improve outcomes in AML. Recently, the FDA approved several agents including CPX-351 for the treatment of secondary and t-AML. CPX-351 may have applicability in other high-risk myeloid diseases. Future directions include a combination of these agents with other targeted therapies. Finally, the authors believe that small molecule inhibitors, such as venetoclax and possibly immunotherapy options could also be incorporated to our treatment paradigm in selected patients.
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Affiliation(s)
- Minas P Economides
- Department of Internal Medicine, The University of Texas School of Health Sciences at Houston , Houston , TX , USA
| | - Deborah McCue
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Gautam Borthakur
- Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Naveen Pemmaraju
- Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston , TX , USA
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33
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[Study of the effects and mechanism of all-trans retinoic acid on leukemic cell line U937 cells with NPM1 mutation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 38:863-868. [PMID: 29166739 PMCID: PMC7364968 DOI: 10.3760/cma.j.issn.0253-2727.2017.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Objective: To investigate the effect and mechanism of all-trans retinoic acid (ATRA) on leukemic cell line U937 cells with NPM1 mutation. Methods: Human acute myeloid leukemia cell line U937 was explored, NPM1 mutated (A type) plasmids were transfected into U937 to form stable clones A1 and A2, which were identified by Western blot and Co-immunoprecipitation. The cell proliferation was measured by methylthiazolyl tetrazolium bromide (MTT) ; cell cycle and cell apoptosis were explored by flow cytometric; cell colony formation was measured by microscope count, the molecular pathways related to cell proliferation were measured by Western blot. Results: ①The cell proliferations of mutant A1 and A2 were inhibited significantly by 52.6% and 35.8% (P<0.05) , respectively under ATRA exposure. ②The percentages of G(0)/G(1) stage of mutant A1 and A2 increased by 20.1% and 35.8%, respectively under ATRA exposure. ③All the U937 leukemic cells were inhibited under ATRA exposure; the decreased percentages of vector, wild-type and mutant NPM1 cells were 32.7%, 57.9% and 90.9% respectively. ④p-ERK decreased obviously after ATRA exposure in NPM1 mutated leukemic cells. ⑤More mutant NPM1 cells inclined to apoptosis under the exposure of ATRA and cytotoxic drugs than cytotoxic drugs alone, meanwhile more cells apoptosis occurred when ATRA was administrated after cytotoxic drugs exposure. Conclusions: ATRA could inhibit cell proliferation and colony formation, blocked the cell cycle in the G(0)/G(1) stage accompanied by the significant reduction of p-ERK in U937 leukemic cells with NPM1 mutation. Besides, ATRA could synergize with drugs to suppress the leukemic cells survival more effectively when ATRA was administered after the cytotoxic drugs exposure in U937 leukemic cells with NPM1 mutation.
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34
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Megías-Vericat JE, Martínez-Cuadrón D, Sanz MÁ, Poveda JL, Montesinos P. Daunorubicin and cytarabine for certain types of poor-prognosis acute myeloid leukemia: a systematic literature review. Expert Rev Clin Pharmacol 2019; 12:197-218. [PMID: 30672340 DOI: 10.1080/17512433.2019.1573668] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Induction chemotherapy based on anthracyclines and cytarabine (Ara-C) combination remains the standard of care for acute myeloid leukemia (AML) patients who are considered candidate for intensive and curative approaches. However, the toxicity of this regimen is high, with disappointing clinical outcomes among the so-called poor-prognosis AML subsets, which generally refer to patients with adverse cytogenetic risk, secondary AML including therapy-related AML, poor-prognosis mutations, especially FLT3-ITD, and relapse/refractory AML. Areas covered: To the best of our knowledge, the role and efficacy of 7 + 3 schedules containing daunorubicin (DNR) and Ara-C for certain types of poor-prognosis AML has not been systematically assessed. A critical approach to the role of DNR and Ara-C induction could be relevant to establish which patients should be enrolled in clinical trials using novel therapies. Expert commentary: In this regard, a recent randomized clinical trial (RCT) showed improved results in older patients with sAML or high-risk cytogenetics who received CPX-351 compared with standard 7 + 3 combination. We perform a systematic literature review to analyze the clinical outcomes reported with DNR plus Ara-C regimens in adult patients with poor-prognosis AML, the use of liposomal formulations of DNR and Ara-C and the RCTs which compared standard 7 + 3 with the addition of a third drug.
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Affiliation(s)
| | - David Martínez-Cuadrón
- b Servicio de Hematología y Hemoterapia , Hospital Universitari i Politècnic La Fe , Valencia , Spain.,c CIBERONC , Instituto Carlos III , Madrid , Spain
| | - Miguel Ángel Sanz
- b Servicio de Hematología y Hemoterapia , Hospital Universitari i Politècnic La Fe , Valencia , Spain.,c CIBERONC , Instituto Carlos III , Madrid , Spain
| | - José Luis Poveda
- a Servicio de Farmacia, Área del Medicamento , Hospital Universitari i Politècnic La Fe , Valencia , Spain
| | - Pau Montesinos
- b Servicio de Hematología y Hemoterapia , Hospital Universitari i Politècnic La Fe , Valencia , Spain.,c CIBERONC , Instituto Carlos III , Madrid , Spain
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35
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Klobuch S, Steinberg T, Bruni E, Mirbeth C, Heilmeier B, Ghibelli L, Herr W, Reichle A, Thomas S. Biomodulatory Treatment With Azacitidine, All- trans Retinoic Acid and Pioglitazone Induces Differentiation of Primary AML Blasts Into Neutrophil Like Cells Capable of ROS Production and Phagocytosis. Front Pharmacol 2018; 9:1380. [PMID: 30542286 PMCID: PMC6278634 DOI: 10.3389/fphar.2018.01380] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 11/09/2018] [Indexed: 01/06/2023] Open
Abstract
Effective and tolerable salvage therapies for elderly patients with chemorefractory acute myeloid leukemia (AML) are limited and usually do not change the poor clinical outcome. We recently described in several chemorefractory elderly AML patients that a novel biomodulatory treatment regimen consisting of low-dose azacitidine (AZA) in combination with PPARγ agonist pioglitazone (PGZ) and all-trans retinoic acid (ATRA) induced complete remission of leukemia and also triggered myeloid differentiation with rapid increase of peripheral blood neutrophils. Herein, we further investigated our observations and comprehensively analyzed cell differentiation in primary AML blasts after treatment with ATRA, AZA, and PGZ ex vivo. The drug combination was found to significantly inhibit cell growth as well as to induce cell differentiation in about half of primary AML blasts samples independent of leukemia subtype. Notably and in comparison to ATRA/AZA/PGZ triple-treatment, effects on cell growth and myeloid differentiation with ATRA monotherapy was much less efficient. Morphological signs of myeloid cell differentiation were further confirmed on a functional basis by demonstrating increased production of reactive oxygen species as well as enhanced phagocytic activity in AML blasts treated with ATRA/AZA/PGZ. In conclusion, we show that biomodulatory treatment with ATRA/AZA/PGZ can induce phenotypical and functional differentiation of primary AML blasts into neutrophil like cells, which aside from its antileukemic activity may lower neutropenia associated infection rates in elderly AML patients in vivo. Clinical impact of the ATRA/AZA/PGZ treatment regimen is currently further investigated in a randomized clinical trial in chemorefractory AML patients (NCT02942758).
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Affiliation(s)
- Sebastian Klobuch
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Tim Steinberg
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Emanuele Bruni
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Carina Mirbeth
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.,Regensburg Center for Interventional Immunology, University Hospital Regensburg, Regensburg, Germany
| | - Bernhard Heilmeier
- Department of Oncology and Hematology, Hospital Barmherzige Brueder, Regensburg, Germany
| | - Lina Ghibelli
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Wolfgang Herr
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.,Regensburg Center for Interventional Immunology, University Hospital Regensburg, Regensburg, Germany
| | - Albrecht Reichle
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Simone Thomas
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.,Regensburg Center for Interventional Immunology, University Hospital Regensburg, Regensburg, Germany
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Dobrotkova V, Chlapek P, Mazanek P, Sterba J, Veselska R. Traffic lights for retinoids in oncology: molecular markers of retinoid resistance and sensitivity and their use in the management of cancer differentiation therapy. BMC Cancer 2018; 18:1059. [PMID: 30384831 PMCID: PMC6211450 DOI: 10.1186/s12885-018-4966-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 10/17/2018] [Indexed: 12/13/2022] Open
Abstract
For decades, retinoids and their synthetic derivatives have been well established anticancer treatments due to their ability to regulate cell growth and induce cell differentiation and apoptosis. Many studies have reported the promising role of retinoids in attaining better outcomes for adult or pediatric patients suffering from several types of cancer, especially acute myeloid leukemia and neuroblastoma. However, even this promising differentiation therapy has some limitations: retinoid toxicity and intrinsic or acquired resistance have been observed in many patients. Therefore, the identification of molecular markers that predict the therapeutic response to retinoid treatment is undoubtedly important for retinoid use in clinical practice. The purpose of this review is to summarize the current knowledge on candidate markers, including both genetic alterations and protein markers, for retinoid resistance and sensitivity in human malignancies.
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Affiliation(s)
- Viera Dobrotkova
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska 2, 61137 Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, Pekarska 53, 65691 Brno, Czech Republic
| | - Petr Chlapek
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska 2, 61137 Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, Pekarska 53, 65691 Brno, Czech Republic
| | - Pavel Mazanek
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Cernopolni 9, 61300 Brno, Czech Republic
| | - Jaroslav Sterba
- International Clinical Research Center, St. Anne’s University Hospital, Pekarska 53, 65691 Brno, Czech Republic
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Cernopolni 9, 61300 Brno, Czech Republic
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska 2, 61137 Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, Pekarska 53, 65691 Brno, Czech Republic
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Cernopolni 9, 61300 Brno, Czech Republic
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Ni X, Hu G, Cai X. The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit Rev Food Sci Nutr 2018; 59:S71-S80. [PMID: 30277803 DOI: 10.1080/10408398.2018.1509201] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
All-trans retinoic acid (ATRA), an active metabolite of vitamin A, plays important roles in cell proliferation, cell differentiation, apoptosis, and embryonic development. The effects of ATRA are mediated by nuclear retinoid receptors as well as non-genomic signal pathway, such as MAPK and PKA. The great success of differentiation therapy with ATRA in acute promyelocytic leukemia (APL) not only improved the prognosis of APL but also spurred the studies of ATRA in the treatment of other tumors. Since the genetic and physiopathological simplicity of APL is not common in human malignancies, the combination of ATRA with other agents (chemotherapy, epigenetic modifiers, and arsenic trioxide, etc) had been extensively investigated in a variety of tumors. In this review, we will discuss in details about ATRA and its role in cancer treatment.
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Affiliation(s)
- Xiaoling Ni
- a Department of General Surgery , Zhongshan Hospital, Shanghai Medical College, Fudan University , Shanghai , China
| | - Guohua Hu
- a Department of General Surgery , Zhongshan Hospital, Shanghai Medical College, Fudan University , Shanghai , China
| | - Xun Cai
- b Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics , Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
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38
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Küley‐Bagheri Y, Kreuzer K, Monsef I, Lübbert M, Skoetz N, Cochrane Haematological Malignancies Group. Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia (non-APL)). Cochrane Database Syst Rev 2018; 8:CD011960. [PMID: 30080246 PMCID: PMC6513628 DOI: 10.1002/14651858.cd011960.pub2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Acute myeloid leukaemia (AML) is the most common acute leukaemia affecting adults. Most patients diagnosed with AML are at advanced age and present with co-morbidities, so that intensive therapy such as stem cell transplantation (SCT) is impossible to provide or is accompanied by high risks for serious adverse events and treatment-related mortality. Especially for these patients, it is necessary to find out whether all-trans retinoic acid (ATRA), an intermediate of vitamin A inducing terminal differentiation of leukaemic cell lines, added to chemotherapy confers increased benefit or harm when compared with the same chemotherapy alone. OBJECTIVES This review aims to determine benefits and harms of ATRA in addition to chemotherapy compared to chemotherapy alone for adults with AML (not those with acute promyelocytic leukaemia (non-APL)). SEARCH METHODS We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE, study registries and relevant conference proceedings up to July 2018 for randomised controlled trials (RCTs). We also contacted experts for unpublished data. SELECTION CRITERIA We included RCTs comparing chemotherapy alone with chemotherapy plus ATRA in patients with all stages of AML. We excluded trials if less than 80% of participants were adults or participants with AML, and if no subgroup data were available. Patients with myelodysplastic syndrome (MDS) were included, if they had a refractory anaemia and more than 20% of blasts. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and assessed the quality of trials. We contacted study authors to obtain missing information. We used hazard ratios (HR) for overall survival (OS) and disease-free survival (DFS; instead of the pre-planned event-free survival, as this outcome was not reported), and we calculated risk ratios (RR) for the other outcomes quality of life, on-study mortality and adverse events. We presented all measures with 95% confidence intervals (CIs). We assessed the certainty of evidence using GRADE methods. MAIN RESULTS Our search resulted in 2192 potentially relevant references, of which we included eight trials with 28 publications assessing 3998 patients. Overall, we judged the potential risk of bias of the eight included trials as moderate. Two of eight trials were published as abstracts only. All the included trials used different chemotherapy schedules and one trial only evaluated the effect of the hypomethylating agent decitabine, a drug know to affect epigenetics, in combination with ATRA.The addition of ATRA to chemotherapy resulted in probably little or no difference in OS compared to chemotherapy only (2985 participants; HR 0.94 (95% confidence interval (CI) 0.87 to 1.02); moderate-certainty evidence). Based on a mortality rate at 24 months of 70% with chemotherapy alone, the mortality rate with chemotherapy plus ATRA was 68% (95% CI 65% to 71%).For DFS, complete response rate (CRR) and on-study mortality there was probably little or no difference between treatment groups (DFS: 1258 participants, HR 0.99, 95% CI 0.87 to 1.12; CRR: 3081 participants, RR 1.02, 95% CI 0.96 to 1.09; on-study mortality: 2839 participants, RR 1.02, 95% CI 0.81 to 1.30, all moderate-certainty evidence).Three trials with 1428 participants reported the adverse events 'infection' and 'cardiac toxicity': There was probably no, or little difference in terms of infection rate between participants receiving ATRA or not (RR 1.05, 95% CI 0.96 to 1.15; moderate-certainty evidence). We are uncertain whether ATRA decreases cardiac toxicity (RR 0.46, 95% CI 0.24 to 0.90; P = 0.02, very low certainty-evidence, however, cardiac toxicity was low).Rates and severity of diarrhoea and nausea/vomiting were assessed in two trials with 337 patients and we are uncertain whether there is a difference between treatment arms (diarrhoea: RR 2.19, 95% CI 1.07 to 4.47; nausea/vomiting: RR 1.46, 95% CI 0.75 to 2.85; both very low-certainty evidence).Quality of life was not reported by any of the included trials. AUTHORS' CONCLUSIONS We found no evidence for a difference between participants receiving ATRA in addition to chemotherapy or chemotherapy only for the outcome OS. Regarding DFS, CRR and on-study mortality, there is probably no evidence for a difference between treatment groups. Currently, it seems the risk of adverse events are comparable to chemotherapy only.As quality of life has not been evaluated in any of the included trials, further research is needed to clarify the effect of ATRA on quality of life.
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Affiliation(s)
- Yasemin Küley‐Bagheri
- University Hospital of CologneCochrane Haematological Malignancies Group, Department I of Internal MedicineCologneGermany
| | - Karl‐Anton Kreuzer
- University Hospital of CologneDepartment I of Internal MedicineCologneGermany
| | - Ina Monsef
- University Hospital of CologneCochrane Haematological Malignancies Group, Department I of Internal MedicineCologneGermany
| | | | - Nicole Skoetz
- University Hospital of CologneCochrane Haematological Malignancies Group, Department I of Internal MedicineCologneGermany
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van Eijkelenburg NKA, Rasche M, Ghazaly E, Dworzak MN, Klingebiel T, Rossig C, Leverger G, Stary J, De Bont ESJM, Chitu DA, Bertrand Y, Brethon B, Strahm B, van der Sluis IM, Kaspers GJL, Reinhardt D, Zwaan CM. Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study. Haematologica 2018; 103:1484-1492. [PMID: 29773602 PMCID: PMC6119144 DOI: 10.3324/haematol.2017.187153] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 05/16/2018] [Indexed: 12/29/2022] Open
Abstract
Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m2/day × 5 days) and liposomal daunorubicin (40-80 mg/m2/day) were administered with cytarabine (2 g/m2/day × 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), ≥2nd relapse (n=8). Dose level 3 (30 mg/m2clofarabine; 60 mg/m2liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m2 clofarabine with 60 mg/m2 liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine exposure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub) clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.
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Affiliation(s)
- Natasha K A van Eijkelenburg
- Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.,Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.,European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France
| | - Mareike Rasche
- Department of Pediatric Oncology, University Children's Hospital, Essen, Germany
| | - Essam Ghazaly
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK
| | - Michael N Dworzak
- Children's Cancer Research Institute and St. Anna Children's Hospital, Department of Pediatrics, Medical University of Vienna, Austria
| | - Thomas Klingebiel
- Pediatric Hematology/Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - Claudia Rossig
- Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany
| | - Guy Leverger
- Department of Pediatric Hematology and Oncology, AP-HP, GH HUEP, Trousseau Hospital, Paris, France
| | - Jan Stary
- Department of Pediatric Hematology and Oncology, 2Faculty of Medicine, Charles University Prague, University Hospital Motol, Czech Republic
| | - Eveline S J M De Bont
- Department of Pediatric Oncology, University Medical Center Groningen, University of Groningen, the Netherlands
| | - Dana A Chitu
- Clinical Trial Center, Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Yves Bertrand
- Pediatric Hematology Department, IHOP and Claude Bernard University, Lyon, France
| | - Benoit Brethon
- Department of Pediatric Hematology, Robert Debré Hospital, Paris, France
| | - Brigitte Strahm
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Germany
| | - Inge M van der Sluis
- Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.,European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France
| | - Gertjan J L Kaspers
- Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.,Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands.,I-BFM-AML committee, Kiel, Germany
| | - Dirk Reinhardt
- European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France.,I-BFM-AML committee, Kiel, Germany
| | - C Michel Zwaan
- Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands .,Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.,European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France
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40
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Megías-Vericat JE, Martínez-Cuadrón D, Sanz MÁ, Montesinos P. Salvage regimens using conventional chemotherapy agents for relapsed/refractory adult AML patients: a systematic literature review. Ann Hematol 2018; 97:1115-1153. [DOI: 10.1007/s00277-018-3304-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 03/12/2018] [Indexed: 12/26/2022]
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41
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Feng X, Lan H, Ruan Y, Li C. Impact on acute myeloid leukemia relapse in granulocyte colony-stimulating factor application: a meta-analysis. ACTA ACUST UNITED AC 2018. [PMID: 29516766 DOI: 10.1080/10245332.2018.1446811] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES This meta-analysis evaluated the impact of granulocyte colony-stimulating factor (G-CSF) added to chemotherapy on treatment outcomes including survival and disease recurrence in patients with acute myeloid leukemia (AML). METHODS Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 19 September 2016 using search terms. Studies that investigated patients with AML who underwent stem-cell transplantation were included. RESULTS The overall analysis revealed a significant improvement in overall survival (OS) (P = .019) and disease-free survival (DFS) (P = .002) for patients receiving G-CSF with chemotherapy. Among patients without prior AML treatment, there was a significant improvement in DFS (P = .014) and reduction in incidence of relapse (P = .015) for those who received G-CSF. However, subgroup analyses found no significant difference between G-CSF (+) and G-CSF (-) treatments in rates of OS (P = .104) and complete remission (CR) (P = .572) for patients without prior AML treatment. Among patients with relapsed/refractory AML, there was no significant difference found between G-CSF (+) and G-CSF (-) groups for OS (P = .225), DFS (P = .209), and CR (P = .208). DISCUSSION Treatment with chemotherapy plus G-CSF appears to provide better survival and treatment responses compared with chemotherapy alone, particularly for patients with previously untreated AML. ABBREVIATIONS AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; DFS, disease-free survival; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; HR, hazard ratio; MDS, myelodysplastic syndrome; OR, odds ratio; OS, overall survival; RCTs, randomized control trials; RR, relative risk.
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Affiliation(s)
- Xiaoqin Feng
- a Department of Pediatrics , Nanfang Hospital , Guangzhou City , People's Republic of China
| | - He Lan
- a Department of Pediatrics , Nanfang Hospital , Guangzhou City , People's Republic of China
| | - Yongsheng Ruan
- a Department of Pediatrics , Nanfang Hospital , Guangzhou City , People's Republic of China
| | - Chunfu Li
- a Department of Pediatrics , Nanfang Hospital , Guangzhou City , People's Republic of China
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42
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Alonso S, Jones RJ, Ghiaur G. Retinoic acid, CYP26, and drug resistance in the stem cell niche. Exp Hematol 2017; 54:17-25. [PMID: 28754309 PMCID: PMC5603425 DOI: 10.1016/j.exphem.2017.07.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Revised: 07/14/2017] [Accepted: 07/17/2017] [Indexed: 12/25/2022]
Abstract
The bone marrow niche is essential for hematopoietic stem cells to maintain lifelong blood production by balancing their self-renewal and differentiation. Hematologic malignancies have a similar hierarchical organization to their normal counterparts, with rare populations of cancer stem cells that rely on the microenvironment to survive and propagate their differentiated malignant progenitor cells. Cancer cells alter their microenvironment to create a supportive niche, where they endure chemotherapy, survive as minimal residual disease (MRD), and eventually prevail at relapse. Powerful morphogens, such as retinoids, Wnt/βcatenin, Notch, and Hedgehog, control stem cell fates across tissues, including normal and malignant hematopoiesis. The molecular conversations between these pathways and the mechanisms that control their activity and create gradients at cellular scale remain a mystery. Here, we discuss accumulating evidence suggesting that cytochrome P450 (CYP26), the primary retinoid-inactivating enzyme, plays a critical role in the integration of two of these molecular programs: the retinoid and Hedgehog pathways. Induction of stromal CYP26 by either one of these pathways limits retinoic acid concentration in the stem cell niche, with profound effects on tissue homeostasis and drug resistance. Bypassing this gatekeeping mechanism holds promise for overcoming drug resistance and improving clinical outcomes in hematological malignancies and cancer in general.
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MESH Headings
- Antineoplastic Agents/therapeutic use
- Cytochrome P450 Family 26/genetics
- Cytochrome P450 Family 26/metabolism
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Gene Expression Regulation, Neoplastic
- Hedgehog Proteins/genetics
- Hedgehog Proteins/metabolism
- Hematologic Neoplasms/drug therapy
- Hematologic Neoplasms/genetics
- Hematologic Neoplasms/metabolism
- Hematologic Neoplasms/pathology
- Hematopoietic Stem Cells/drug effects
- Hematopoietic Stem Cells/metabolism
- Hematopoietic Stem Cells/pathology
- Humans
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Recurrence, Local/pathology
- Neoplasm, Residual
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Receptors, Notch/genetics
- Receptors, Notch/metabolism
- Signal Transduction
- Stem Cell Niche/drug effects
- Stem Cell Niche/genetics
- Tretinoin/metabolism
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- beta Catenin/genetics
- beta Catenin/metabolism
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Affiliation(s)
- Salvador Alonso
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, Baltimore, Maryland
| | - Richard J Jones
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, Baltimore, Maryland
| | - Gabriel Ghiaur
- Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
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Gao J, Fan M, Xiang G, Wang J, Zhang X, Guo W, Wu X, Sun Y, Gu Y, Ge H, Tan R, Qiu H, Shen Y, Xu Q. Diptoindonesin G promotes ERK-mediated nuclear translocation of p-STAT1 (Ser727) and cell differentiation in AML cells. Cell Death Dis 2017; 8:e2765. [PMID: 28471454 PMCID: PMC5520695 DOI: 10.1038/cddis.2017.159] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 01/26/2017] [Accepted: 03/13/2017] [Indexed: 12/22/2022]
Abstract
Exploration of a new differentiation therapy that extends the range of differentiation for treating acute myeloid leukemia (AML) is attractive to researchers and clinicians. Here we report that diptoindonesin G (Dip G), a natural resveratrol aneuploid, exerts antiproliferative activity by inducing G2/M phase arrest and cell differentiation in AML cell lines and primary AML cells. Gene-profiling experiments showed that treating human leukemia HL-60 cells with Dip G was associated with a remarkable upregulation of STAT1 target gene expression, including IFIT3 and CXCL10. Mechanistically, Dip G activated ERK, which caused phosphorylation of STAT1 at Ser727 and selectively enhanced the interaction of p-STAT1 (Ser727) and p-ERK, further promoting their nuclear translocation. The nuclear translocation of p-STAT1 and p-ERK enhanced the transactivation of STAT1-targeted genes in AML cells. Furthermore, in vivo treatment of HL-60 xenografts demonstrated that Dip G significantly inhibited tumor growth and reduced tumor weight by inducing cell differentiation. Taken together, these results shed light on an essential role for ERK-mediated nuclear translocation of p-STAT1 (Ser727) and its full transcriptional activity in Dip G-induced differentiation of AML cells. Furthermore, these results demonstrate that Dip G could be used as a differentiation-inducing agent for AML therapy, particularly for non-acute promyelocytic leukemia therapy.
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Affiliation(s)
- Jian Gao
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Minmin Fan
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Gang Xiang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Jujuan Wang
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xiong Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Wenjie Guo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Xuefeng Wu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Yang Sun
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Yanhong Gu
- Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Huiming Ge
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Renxiang Tan
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.,Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing 210093, China
| | - Hongxia Qiu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yan Shen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.,Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing 210093, China
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van Gils N, Verhagen HJMP, Smit L. Reprogramming acute myeloid leukemia into sensitivity for retinoic-acid-driven differentiation. Exp Hematol 2017; 52:12-23. [PMID: 28456748 DOI: 10.1016/j.exphem.2017.04.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 04/05/2017] [Accepted: 04/14/2017] [Indexed: 12/29/2022]
Abstract
The success of all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) provides a rationale for using retinoic acid (RA)-based therapy for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may drive leukemic cells efficiently into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation, a FLT3-ITD, an IDH1 mutation, and patients overexpressing EVI-1. Because not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have had disappointing results, the identification of additional biomarkers may help to identify patients who strongly respond to ATRA-based therapy. Searching for response biomarkers might also reveal novel RA-based combination therapies with an efficient differentiation/apoptosis-inducing effect in non-APL AML patients. Preliminary studies suggest that the epigenetic or transcriptional state of leukemia cells determines their susceptibility to ATRA. We hypothesize that reprogramming by inhibitors of epigenetic-modifying enzymes or by modulation of microRNA expression might sensitize non-APL AML cells for RA-based therapy. AML relapse is caused by a subpopulation of leukemia cells, named leukemic stem cells (LSCs), which are in a different epigenetic state than the total bulk of the AML. The survival of LSCs after therapy is the main cause of the poor prognosis of AML patients, and novel differentiation therapies should drive these LSCs into maturity. In this review, we summarize the current knowledge on the epigenetic aspects of susceptibility to RA-induced differentiation in APL and non-APL AML.
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Affiliation(s)
- Noortje van Gils
- Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Han J M P Verhagen
- Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Linda Smit
- Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
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45
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Yılmaz Bengoa Ş, Ataseven E, Kızmazoğlu D, Demir Yenigürbüz F, Erdem M, Ören H. FLAG Regimen with or without Idarubicin in Children with Relapsed/Refractory Acute Leukemia: Experience from a Turkish Pediatric Hematology Center. Turk J Haematol 2017; 34:46-51. [PMID: 27095144 PMCID: PMC5451688 DOI: 10.4274/tjh.2015.0411] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Objective: The optimal therapy to achieve higher rates of survival in pediatric relapsed/refractory acute leukemia (AL) is still unknown. In developing countries, it is difficult to obtain some of the recent drugs for optimal therapy and mostly well-known drugs proven to be effective are used. We assessed the efficacy of the combination of fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG regimen) with or without idarubicin (IDA) in children with relapsed/refractory acute lymphoblastic leukemia and acute myeloid leukemia. Materials and Methods: Between September 2007 and May 2015, 18 children with refractory/relapsed AL attending our center, treated with a FLAG regimen with or without IDA, were included. The primary end point was the remission status of the bone marrow sampled after the first/second course of chemotherapy. The second end point was the duration of survival after hematopoietic stem cell transplantation (HSCT). Results: Complete remission (CR) was achieved in 7 patients (38.8%) after the first cycle, and at the end of the second cycle the total number of patients in CR was 8 (42.1%). All patients in CR underwent HSCT. The CR rate in patients who had IDA in combination therapy was 28.6%, and it was 50% in patients treated without IDA (p=0.36). Mean survival duration in transplanted patients was 24.7±20.8 months (minimum-maximum: 2-70, median: 25 months), and it was 2.7±1.64 months (minimum-maximum: 0-5, median: 3 months) in nontransplanted patients. Five of them (27.7%) were still alive at the end of the study and in CR. The median time of follow-up for these patients was 33 months (minimum-maximum: 25-70 months). Conclusion: FLAG regimens with or without IDA produced a CR of >24 months in 27.7% of children with relapsed/refractory AL and can be recommended as therapeutic options prior to HSCT in developing countries.
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Affiliation(s)
- Şebnem Yılmaz Bengoa
- Dokuz Eylül University Faculty of Medicine, Department of Pediatric Hematology, İzmir, Turkey Phone: +90 505 5252163 E-mail:
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46
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Impact of salvage regimens on response and overall survival in acute myeloid leukemia with induction failure. Leukemia 2017; 31:1306-1313. [PMID: 28138160 DOI: 10.1038/leu.2017.23] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 12/26/2016] [Accepted: 01/05/2017] [Indexed: 12/22/2022]
Abstract
We evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) with induction failure. Between 1993 and 2009, 3324 patients with newly diagnosed AML were enrolled in 5 prospective treatment trials of the German-Austrian AML Study Group. After first induction therapy with idarubicin, cytarabine and etoposide (ICE), 845 patients had refractory disease. In addition, 180 patients, although responding to first induction, relapsed after second induction therapy. Of the 1025 patients with induction failure, 875 (median age 55 years) received intensive salvage therapy: 7+3-based (n=59), high-dose cytarabine combined with mitoxantrone (HAM; n=150), with all-trans retinoic acid (A; A-HAM) (n=247), with gemtuzumab ozogamicin and A (GO; GO-A-HAM) (n=140), other intensive regimens (n=165), experimental treatment (n=27) and direct allo-HCT (n=87). In patients receiving intensive salvage chemotherapy (n=761), response (complete remission/complete remission with incomplete hematological recovery (CR/CRi)) was associated with GO-A-HAM treatment (odds ratio (OR), 1.93; P=0.002), high-risk cytogenetics (OR, 0.62; P=0.006) and age (OR for a 10-year difference, 0.75; P<0.0001). Better survival probabilities were seen in an extended Cox regression model with time-dependent covariables in patients responding to salvage therapy (P<0.0001) and having the possibility to perform an allo-HCT (P<0.0001). FLT3 internal tandem duplication, mutated IDH1 and adverse cytogenetics were unfavorable factors for survival.
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47
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Ma HS, Robinson TM, Small D. Potential role for all- trans retinoic acid in nonpromyelocytic acute myeloid leukemia. Int J Hematol Oncol 2016; 5:133-142. [PMID: 30302214 DOI: 10.2217/ijh-2016-0015] [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: 12/31/2016] [Accepted: 02/08/2017] [Indexed: 11/21/2022] Open
Abstract
All-trans retinoic acid (ATRA) has been very successful in the subtype of acute myelogenous leukemia known as acute promyelocytic leukemia due to targeted reactivation of retinoic acid signaling. There has been great interest in applying this form of differentiation therapy to other cancers, and numerous clinical trials have been initiated. However, ATRA as monotherapy has thus far shown little benefit in nonacute promyelocytic leukemia acute myelogenous leukemia. Here, we review the literature on the use of ATRA in combination with chemotherapy, epigenetic modifying agents and targeted therapy, highlighting specific patient populations where the addition of ATRA to existing therapies may provide benefit. Furthermore, we discuss the impact of recent whole genome sequencing efforts in leading the design of rational combinatorial approaches.
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Affiliation(s)
- Hayley S Ma
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Tara M Robinson
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Donald Small
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA
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48
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Longu F, Fozza C, Dessì L, Longinotti M, Bonfigli S, Careddu MG, Coppola L, Giannico DB, Nieddu RM, Podda L, Pardini S, Dore F, Dore S, Sotgiu G. Fludarabine and Cytarabine Combination in the Induction of Adult Patients with Acute Myeloid Leukaemia. Acta Haematol 2016; 137:15-16. [PMID: 27806360 DOI: 10.1159/000449277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 08/21/2016] [Indexed: 11/19/2022]
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49
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Stahl M, Kim TK, Zeidan AM. Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities. World J Stem Cells 2016; 8:316-331. [PMID: 27822339 PMCID: PMC5080639 DOI: 10.4252/wjsc.v8.i10.316] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 08/11/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
The existence of cancer stem cells has been well established in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells (LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells (HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the self-renewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.
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50
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Schlenk RF, Lübbert M, Benner A, Lamparter A, Krauter J, Herr W, Martin H, Salih HR, Kündgen A, Horst HA, Brossart P, Götze K, Nachbaur D, Wattad M, Köhne CH, Fiedler W, Bentz M, Wulf G, Held G, Hertenstein B, Salwender H, Gaidzik VI, Schlegelberger B, Weber D, Döhner K, Ganser A, Döhner H. All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07-04 study. Ann Hematol 2016; 95:1931-1942. [PMID: 27696203 PMCID: PMC5093206 DOI: 10.1007/s00277-016-2810-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 08/23/2016] [Indexed: 11/29/2022]
Abstract
The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18–60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m2, days 6–8; 15 mg/m2, days 9–21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95).
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Affiliation(s)
- Richard F Schlenk
- Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. .,National Center for Tumor Diseases (NCT), German Cancer Research Center, Heidelberg, Germany.
| | - Michael Lübbert
- Department of Hematology and Oncology, University Hospital of Freiburg, Freiburg, Germany
| | - Axel Benner
- Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
| | - Alexander Lamparter
- Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany
| | - Jürgen Krauter
- Department of Oncology and Hematology, Klinikum Braunschweig, Braunschweig, Germany.,Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Wolfgang Herr
- Department of Medicine III, Johannes Gutenberg-University Mainz, Mainz, Germany.,Department of Internal Medicine III, University of Regensburg, Regensburg, Germany
| | - Hans Martin
- Department of Internal Medicine II, University Hospital, Frankfurt, Germany
| | - Helmut R Salih
- Department of Hematology and Oncology, Eberhard-Karls University, Tübingen, Germany
| | - Andrea Kündgen
- Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Heinz-A Horst
- Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Peter Brossart
- Department of Internal Medicine III, University Hospital of Bonn, Bonn, Germany
| | - Katharina Götze
- Department of Internal Medicine III, Technical University of Munich, Munich, Germany
| | - David Nachbaur
- Department of Internal Medicine V, University Hospital Innsbruck, Innsbruck, Austria
| | - Mohammed Wattad
- Department of Hematology, Oncology and Stem Cell Transplantation, Klinikum Essen Süd, Essen, Germany
| | - Claus-Henning Köhne
- Department of Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany
| | - Walter Fiedler
- Department of Internal Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martin Bentz
- Department of Internal Medicine III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | - Gerald Wulf
- Department of Hematology and Oncology, University Hospital of Göttingen, Göttingen, Germany
| | - Gerhard Held
- Department of Internal Medicine I, University Hospital of Saarland, Homburg, Germany
| | - Bernd Hertenstein
- Department of Internal Medicine I, Klinikum Bremen Mitte, Bremen, Germany
| | - Hans Salwender
- Department of Hematology/Oncology, Asklepios Klinik Altona, Hamburg, Germany
| | - Verena I Gaidzik
- Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany
| | | | - Daniela Weber
- Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany
| | - Konstanze Döhner
- Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany
| | - Arnold Ganser
- Department of Hematology/Oncology, Asklepios Klinik Altona, Hamburg, Germany
| | - Hartmut Döhner
- Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany
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