Unexpected high incidence of severe toxicities associated with alpha interferon, low-dose cytosine arabinoside and all-trans retinoic acid in patients with chronic myelogenous leukemia

Stefano Sacchi, Hagop M. Kantarjian, Emil J. Freireich, Susan O' Brien, Jorge Cortes, Mary Beth Rios, Steve Kornblau, Francis J. Giles, Charles Koller, James Gajewski, Moshe Talpaz

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Preclinical data have shown that all-trans retinoic acid (ATRA) with interferon-alpha (IFN-α) can exert significant suppressive effects on Philadelphia-chromosome (Ph)-positive cells. The aim of this study combining IFN-α, low-dose cytosine arabinoside (ara-C) and ATRA was to increase the proportion of patients achieving a major cytogenetic response, in comparison with a group of 140 patients previously treated with IFN-α plus low-dose ara-C. Forty three patients with Ph-positive CML in early chronic phase were treated with IFN-α 5 MU/m2 sc daily, low-dose ara-C 10 mg sc daily and ATRA 45 mg/m2 orally daily, for 7 consecutive days every other week. Overall, 76% of patients achieved a complete hematologic response (CHR). A cytogenetic response was in observed 59% (major in 38% and complete in 17%). Compared with patients treated with IFN-α and low-dose ara-C, those receiving additional ATRA had a lower CHR rate (p. 014), but other response rates were similar. Severe toxicities were common with the triple regimen (64%), mostly related to ATRA therapy. Two patients experienced pseudotumor cerebri; two patients had leukocytosis during the week on ATRA treatment, decreasing during the week off (one suffered a severe asthma-like reaction followed by pulmonary edema, resembling ATRA syndrome). Six patients had other unusual side-effects: aseptic necrosis of the hip (1 patient), ataxic syndrome (1 patient), paranoid syndrome (2 patients), syncopal episodes (1 patient), pure red cell aplasia (1 patient). In conclusion the results of IFN-α and low-dose ara-C combined with ATRA in patients with early CML-chronic phase were disappointing, due to excessive toxicity. Whether different ATRA dose schedules may result in fewer side-effects and improve hematologic and cytogenetic response remains to be determined.

Original languageEnglish (US)
Pages (from-to)483-489
Number of pages7
JournalLeukemia and Lymphoma
Volume35
Issue number5-6
StatePublished - 1999
Externally publishedYes

Fingerprint

Cytarabine
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Tretinoin
Interferon-alpha
Incidence
Cytogenetics
Philadelphia Chromosome
Pure Red-Cell Aplasia
Pseudotumor Cerebri
Leukocytosis
Syncope
Pulmonary Edema
Hip
Appointments and Schedules
Necrosis
Asthma

Keywords

  • All-trans retinoic acid
  • Alpha interferon
  • ATRA
  • Chronic myelogenous leukemia
  • CML
  • Low-dose ara-C
  • Severe toxicity

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Unexpected high incidence of severe toxicities associated with alpha interferon, low-dose cytosine arabinoside and all-trans retinoic acid in patients with chronic myelogenous leukemia. / Sacchi, Stefano; Kantarjian, Hagop M.; Freireich, Emil J.; O' Brien, Susan; Cortes, Jorge; Rios, Mary Beth; Kornblau, Steve; Giles, Francis J.; Koller, Charles; Gajewski, James; Talpaz, Moshe.

In: Leukemia and Lymphoma, Vol. 35, No. 5-6, 1999, p. 483-489.

Research output: Contribution to journalArticle

Sacchi, S, Kantarjian, HM, Freireich, EJ, O' Brien, S, Cortes, J, Rios, MB, Kornblau, S, Giles, FJ, Koller, C, Gajewski, J & Talpaz, M 1999, 'Unexpected high incidence of severe toxicities associated with alpha interferon, low-dose cytosine arabinoside and all-trans retinoic acid in patients with chronic myelogenous leukemia', Leukemia and Lymphoma, vol. 35, no. 5-6, pp. 483-489.
Sacchi, Stefano ; Kantarjian, Hagop M. ; Freireich, Emil J. ; O' Brien, Susan ; Cortes, Jorge ; Rios, Mary Beth ; Kornblau, Steve ; Giles, Francis J. ; Koller, Charles ; Gajewski, James ; Talpaz, Moshe. / Unexpected high incidence of severe toxicities associated with alpha interferon, low-dose cytosine arabinoside and all-trans retinoic acid in patients with chronic myelogenous leukemia. In: Leukemia and Lymphoma. 1999 ; Vol. 35, No. 5-6. pp. 483-489.
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abstract = "Preclinical data have shown that all-trans retinoic acid (ATRA) with interferon-alpha (IFN-α) can exert significant suppressive effects on Philadelphia-chromosome (Ph)-positive cells. The aim of this study combining IFN-α, low-dose cytosine arabinoside (ara-C) and ATRA was to increase the proportion of patients achieving a major cytogenetic response, in comparison with a group of 140 patients previously treated with IFN-α plus low-dose ara-C. Forty three patients with Ph-positive CML in early chronic phase were treated with IFN-α 5 MU/m2 sc daily, low-dose ara-C 10 mg sc daily and ATRA 45 mg/m2 orally daily, for 7 consecutive days every other week. Overall, 76{\%} of patients achieved a complete hematologic response (CHR). A cytogenetic response was in observed 59{\%} (major in 38{\%} and complete in 17{\%}). Compared with patients treated with IFN-α and low-dose ara-C, those receiving additional ATRA had a lower CHR rate (p. 014), but other response rates were similar. Severe toxicities were common with the triple regimen (64{\%}), mostly related to ATRA therapy. Two patients experienced pseudotumor cerebri; two patients had leukocytosis during the week on ATRA treatment, decreasing during the week off (one suffered a severe asthma-like reaction followed by pulmonary edema, resembling ATRA syndrome). Six patients had other unusual side-effects: aseptic necrosis of the hip (1 patient), ataxic syndrome (1 patient), paranoid syndrome (2 patients), syncopal episodes (1 patient), pure red cell aplasia (1 patient). In conclusion the results of IFN-α and low-dose ara-C combined with ATRA in patients with early CML-chronic phase were disappointing, due to excessive toxicity. Whether different ATRA dose schedules may result in fewer side-effects and improve hematologic and cytogenetic response remains to be determined.",
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