Randomized phase-III study of low-dose cytarabine and etoposide + /- all-trans retinoic acid in older unfit patients with NPM1-mutated acute myeloid leukemia.

T Südhoff, H Döhner, K Döhner, F Thol, E Koller, M Bentz, H J Tischler, V Runde, S Wessendorf, U Martens, J Krauter, A Ganser, H R Salih, B Hertenstein, G Wulf, T Kindler, J Krzykalla, D Weber, R F Schlenk, A Benner, M Heuser

Journal: Scientific reports 2023;13(1):14809

PMID: 37684299

Free Full Text on Nature Publishing Group View on PubMed

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/m, days 8-28; the dose of ATRA was reduced to 45 mg/m, days 8-10 and 15 mg/m, 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).

Address: NCT-Trial Center, National Center of Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany. [email protected].; Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. [email protected].; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.; Division of Biostatistics, German Cancer Research Center Heidelberg, Heidelberg, Germany.; Department of Hematology, Medical Oncology and Pneumology, University Medical Center Mainz, Mainz, Germany.; Department of Hematology and Oncology, University Hospital of Göttingen, Göttingen, Germany.; Department of Hematology and Oncology, Klinikum Bremen Mitte, Bremen, Germany.; Department of Hematology and Oncology, Eberhard-Karls University, Tübingen, Germany.; Department of Hematology and Oncology, Klinikum Passau, Passau, Germany.; Department Hematology and Oncology, Braunschweig Municipal Hospital, Braunschweig, Germany.; Department of Hematology and Oncology, Klinikum am Gesundbrunnen, Heilbronn, Germany.; Department of Hematology and Oncology, Klinikum Esslingen, Esslingen, Germany.; Department of Hematology/Oncology, Wilhelm-Anton Hospital Goch, Goch, Germany.; Department of Hematology and Oncology, University Hospital of Minden, Minden, Germany.; Department of Hematology and Oncology, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.; Department of Internal Medicine III, Hanuschkrankenhaus Wien, Wien, Austria.; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

DOI: 10.1038/s41598-023-41964-y

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MeSH Terms: Humans, Aged, Etoposide, Leukemia, Myeloid, Acute, Cytarabine, Tretinoin, Nuclear Proteins