A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy.

Szczegóły
Abstrakt

Tytuł:: A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy.
Autorzy:: Wass M; Department of Hematology and Oncology, University Hospital Halle, Halle (Saale), Germany. .
Göllner S; Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
Besenbeck B; Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
Schlenk RF; Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
Mundmann P; Department of Hematology and Oncology, Paracelsus-Klinik, Osnabrück, Germany.
Göthert JR; Department of Hematology, University Hospital Essen, Essen, Germany.
Noppeney R; Department of Hematology, University Hospital Essen, Essen, Germany.
Schliemann C; Department of Medicine A, University Hospital Münster, Münster, Germany.
Mikesch JH; Department of Medicine A, University Hospital Münster, Münster, Germany.
Lenz G; Department of Medicine A, University Hospital Münster, Münster, Germany.
Dugas M; Department of Medicine A, University Hospital Münster, Münster, Germany.
Wermke M; Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Germany.
Röllig C; Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Germany.
Bornhäuser M; Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Germany.
Serve H; Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt/Main, Germany.
Platzbecker U; Department of Medicine I, Hematology, Cellular Therapy, Hemostaseology, University of Leipzig, Leipzig, Germany.
Foerster KI; Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany.
Burhenne J; Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany.
Haefeli WE; Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany.
Müller LP; Department of Hematology and Oncology, University Hospital Halle, Halle (Saale), Germany.
Binder M; Department of Hematology and Oncology, University Hospital Halle, Halle (Saale), Germany.
Pabst C; Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Müller-Tidow C; Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Corporate Authors:: Study Alliance Leukemia (SAL)
Źródło:: Leukemia [Leukemia] 2021 Mar; Vol. 35 (3), pp. 701-711. Date of Electronic Publication: 2020 Jun 19.
Typ publikacji:: Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: 2000- : London : Nature Publishing Group, Specialist Journals
Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987-
MeSH Terms:: Proof of Concept Study*
Salvage Therapy*
Drug Resistance, Neoplasm/*drug effects
Leukemia, Myeloid, Acute/*drug therapy
Neoplasm Recurrence, Local/*drug therapy
Tranylcypromine/*therapeutic use
Tretinoin/*therapeutic use
Adult ; Aged ; Antidepressive Agents/therapeutic use ; Antineoplastic Agents/therapeutic use ; Arabidopsis Proteins ; DNA-Binding Proteins ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Humans ; Leukemia, Myeloid, Acute/pathology ; Male ; Middle Aged ; Neoplasm Recurrence, Local/pathology ; Prognosis ; Prospective Studies ; Survival Rate ; Transcription Factors ; Young Adult
References:: Abdel-Wahab O, Levine RL. Recent advances in the treatment of acute myeloid leukemia. F1000 Med Rep. 2010;2:55. (PMID: 10.3410/M2-55)
Berglund L, Björling E, Oksvold P, Fagerberg L, Asplund A, Szigyarto CA, et al. A genecentric Human Protein Atlas for expression profiles based on antibodies. Mol Cell Proteom. 2008;7:2019–27. (PMID: 10.1074/mcp.R800013-MCP200)
Dart RC, editor. Medical toxicology. 3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2003.
Schenk T, Chen WC, Göllner S, Howell L, Jin L, Hebestreit K, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18:605–11. (PMID: 10.1038/nm.2661)
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–9. (PMID: 10.1200/JCO.2003.04.036)
Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74. (PMID: 10.1182/blood-2009-07-235358)
Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109:1114–24. (PMID: 10.1002/cncr.22496)
Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28:562–9. (PMID: 10.1200/JCO.2009.23.8329)
Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126:291–9. (PMID: 10.1182/blood-2015-01-621664)
Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30:2670–7. (PMID: 10.1200/JCO.2011.38.9429)
Schlenk RF, Müller-Tidow C, Benner A, Kieser M. Relapsed/refractory acute myeloid leukemia: any progress? Curr Opin Oncol. 2017;29:467–73. (PMID: 10.1097/CCO.0000000000000404)
Stahl M, DeVeaux M, Montesinos P, Itzykson R, Ritchie EK, Sekeres MA, et al. Hypomethylating agents in relapsed and refractory AML: outcomes and their predictors in a large international patient cohort. Blood Adv. 2018;2:923–32. (PMID: 10.1182/bloodadvances.2018016121)
DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378:2386–98. (PMID: 10.1056/NEJMoa1716984)
Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–31. (PMID: 10.1182/blood-2017-04-779405)
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21. (PMID: 10.1056/NEJMoa1516192)
Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase ii study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Disco. 2016;6:1106–17. (PMID: 10.1158/2159-8290.CD-16-0313)
DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17. (PMID: 10.1182/blood-2018-08-868752)
Yang GJ, Lei PM, Wong SY, Ma DL, Leung CH. Pharmacological inhibition of LSD1 for cancer treatment. Molecules. 2018;23:3194. (PMID: 10.3390/molecules23123194)
Magliulo D, Bernardi R, Messina S. Lysine-specific demethylase 1A as a promising target in acute myeloid leukemia. Front Oncol. 2018;8:255. (PMID: 10.3389/fonc.2018.00255)
Fang J, Ying H, Mao T, Fang Y, Lu Y, Wang H, et al. Upregulation of CD11b and CD86 through LSD1 inhibition promotes myeloid differentiation and suppresses cell proliferation in human monocytic leukemia cells. Oncotarget. 2017;8:85085–101. (PMID: 10.18632/oncotarget.18564)
Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012;21:473–87. (PMID: 10.1016/j.ccr.2012.03.014)
McGrath JP, Williamson KE, Balasubramanian S, Odate S, Arora S, Hatton C, et al. Pharmacological inhibition of the histone lysine demethylase KDM1A suppresses the growth of multiple acute myeloid leukemia subtypes. Cancer Res. 2016;76:1975–88. (PMID: 10.1158/0008-5472.CAN-15-2333)
Morera L, Lübbert M, Jung M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics. 2016;8:57. (PMID: 10.1186/s13148-016-0223-4)
Barth J, Abou-El-Ardat K, Dalic D, Kurrle N, Maier AM, Mohr S, et al. LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML. Leukemia. 2019;33:1411–26. (PMID: 10.1038/s41375-018-0375-7)
Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J, Versteeg R, et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res. 2009;69:2065–71. (PMID: 10.1158/0008-5472.CAN-08-1735)
Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem Biol. 2006;13:563–7. (PMID: 10.1016/j.chembiol.2006.05.004)
Thase ME, Madhukar HT, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacol. 1995;12:185–219. (PMID: 10.1016/0893-133X(94)00058-8)
Aristo Pharma GmbH. Fachinformation Jatrosom 10 mg. Aristo Pharma GmbH, 2010. https://www.fachinfo.de/ .
Huang Y, Stewart TM, Wu Y, Baylin SB, Marton LJ, Perkins B, et al. Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin Cancer Res. 2009;15:7217–28. (PMID: 10.1158/1078-0432.CCR-09-1293)
Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SG, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2014;28:2155–64. (PMID: 10.1038/leu.2014.119)
Substance Nomenclature:: 0 (Antidepressive Agents)
0 (Antineoplastic Agents)
0 (Arabidopsis Proteins)
0 (DNA-Binding Proteins)
0 (LSD1 protein, Arabidopsis)
0 (Transcription Factors)
3E3V44J4Z9 (Tranylcypromine)
5688UTC01R (Tretinoin)
Entry Date(s):: Date Created: 20200621 Date Completed: 20210322 Latest Revision: 20210617
Update Code:: 20240105
PubMed Central ID:: PMC7303943
DOI:: 10.1038/s41375-020-0892-z
PMID:: 32561840
: Czasopismo naukowe

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.

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