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Cited by 17Chronic Myeloid Leukemia TreatmentsRetinoids in leukemia and cellular processesAcute Myeloid Leukemia Research

All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in the chronic phase

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Russo, D, Regazzi, M, Sacchi, S, Visani, G, Lazzarino, M, Avvisati, G, Pelicci, PG, Dastoli, G +8 more·1998·Leukemia
DOI 10.1038/sj.leu.2400988
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Abstract

Since in vitro observations indicated that all-trans retinoic acid (ATRA), especially in combination with IFNalpha, can exert significant suppressive effects on Ph+ cells, we investigated the effects and the pharmacokinetic profile of ATRA in a selected cohort of patients with Ph+ chronic myeloid leukemia (CML) in chronic phase. Eighteen patients were treated with ATRA at a dose of 80 mg/m2/day (p.o.), divided into two equal doses after meals, for 7 consecutive days every other week for a maximum of 12 courses (1 course = 1 week on and 1 week off). Pharmacokinetic profiles of ATRA were evaluated during intermittent therapy on days 1 and 7 of course 1; on day 1 of course 2; on day 1 of course 6. Out of the 18 patients treated with ATRA, 11 (61%) went off study before the sixth course of treatment because of progressive hyperleukocytosis (seven cases), or thrombocytosis (one case), or refusal (three cases). Seven (39%) patients completed the first six courses (12 weeks) of treatment with ATRA and two of them (11%) maintained a white blood cell (WBC) <10 x 10[9]/l which was induced by the pretreatment with hydroxyurea. One patient completed the 12th course of ATRA maintaining WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpable. The treatment with ATRA was well tolerated and only one patient discontinued the therapy because of non-hematological side-effects. The area under the concentration-time curve (AUC) decreased significantly (P< 0.001) during the first week of therapy. By adopting an intermittent dosing regimen, 1 week on/ 1 week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs equivalent to the ones achieved on day 1 of course 1. In conclusion, our results showed that ATRA alone appeared to be unable to control the WBC expansion in the CML patients in chronic phase. Moreover, it did not induce any remarkable cytoreductive effects on the platelet count and on the hemoglobin level. The major interest of ATRA would be in combination with other therapies. If ATRA was given in combination with IFNalpha or other agents, dose reduction of these would not be planned. On the basis of the pharmacokinetic profile, ATRA should be administered intermittently rather than continuously.

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Authors
Russo, D., Regazzi, M., Sacchi, S., Visani, G., Lazzarino, M., Avvisati, G., Pelicci, P., Dastoli, G., Grandi, C., Iacona, I., Candoni, A., Grattoni, R., Galieni, P., Rupoli, S., Liberati, A., & Maiolo, A.
Affiliations
  • Policlinico San Matteo Fondazione (IT)
  • University of Udine (IT)
  • University of Siena (IT)
  • University of Perugia (IT)
  • University of Milan (IT)
ORCID
Venue
Leukemia
Publisher
Springer Science and Business Media LLC
Published
1998-04-01
Volume
12
Issue
4
Pages
449-454
ISSN
  • 0887-6924 (ISSN-L)
  • 1476-5551
DOI
10.1038/sj.leu.2400988
OpenAlex
W2035639041
Cited by
17
References
25
Citations by year
2026: 1 · 2024: 1 · 2020: 1 · 2018: 1 · 2017: 2
FWCI
1.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Leukemia (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders
  • Centre National de la Recherche Scientifique
  • Associazione Italiana per la Ricerca sul Cancro
Topics
  • Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
all-trans retinoic acid, chronic myeloid leukemia, chronic phase, pharmacokinetics, intermittent dosing, platelet count, treatment tolerability, spleen size reduction, hemoglobin levels, dose reduction
MeSH terms
Adult, Aged, Antineoplastic Agents, Drug Administration Schedule, Female, Humans, Leukocyte Count, Male, Middle Aged, Tretinoin, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myeloid, Chronic-Phase

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