Treatment of acute myeloid leukemia in the elderly with low‐dose cytarabine, hydroxyurea, and calcitriol

Abstract

Twenty-nine patients aged 62-82 years with acute myeloid leukemia (AML) were treated with a 21-day course of continuous infusion cytarabine, oral hydroxyurea, and 1,25-dihydroxyvitamin D3 (calcitriol). Ten patients had an antecedent myelodysplastic syndrome. Calcitriol was continued as the only postremission therapy. Thirteen patients (45%) obtained a complete remission, and 10 patients (34%) had a partial response for an overall 79% response rate. There were three early deaths. The median remission duration was 9.8 months. Overall median survival was 12 months for all patients and 14 months for responding patients. All responding patients had marked bone marrow hypoplasia. Twenty patients received part or all of their chemotherapy as outpatients. This regimen has acceptable toxicity and can result in prolonged remissions in elderly, high-risk patients with AML. The favorable results may be related to the synergistic effect of hydroxyurea, cytarabine, and calcitriol.

Differentiation therapy of leukemia: 3 decades of development

“…Concurrent with the first observations of the differentiating action of retinoids on selected myeloid cell lines, similar promising effects were also demonstrated for the physiologically active form of vitamin D, 1,25 dihydroxy vitamin D 3 [1, [48][49][50] Initial studies also suggested that 1,25(OH) 2 D 3 had cancer-preventive properties in prostate and colon cancers [51][52][53][54] and exerted positive antitumor effects by regulation of proliferation, apoptosis, and angiogenesis. [55][56][57][58] As for the mechanism of action, 1,25(OH) 2 D 3 binds and activates the vitamin D receptor (VDR), which heterodimerizes with the retinoic X receptor and binds to vitamin D-responsive elements (VDREs) in the promoter regions of target genes [59][60][61] ( Figure 1B).…”

Phase II study of doxercalciferol for the treatment of myelodysplastic syndrome

“…Although overall survival was not affected, the patients who received calcitriol had a significantly lower chance of developing AML in a Kaplan-Meyer survival analysis. Slapak et al [12] treated 29 elderly patients with AML using a protocol that combined low-dose cytarabine and hydroxyurea for 21 days with calcitriol (0.25 μg twice per day) until relapse. The CR rate was 45% with median remission duration of 9.8 months.…”

Vitamin D and Acute Myeloid Leukemia

“…Early results were mixed, as single agent VDA induced partial differentiation of myeloid blast cells in a few patients with a paucity of clinical improvements (Mellibovsky, Diez et al 1998). Combination trials with VDA and chemotherapy resulted in mixed results in MDS/AML (Hellstrom, Robert et al 1990;Petrini, Caracciolo et al 1991;Petrini, Dastoli et al 1991;Slapak, Desforges et al 1992;Ferrero, Bruno et al 1996;Siitonen, Timonen et al 2007). Slapak et al (Slapak, Desforges et al 1992) showed promising results in a study of 29 AML patients, who were treated with a regimen of low-dose cytarabine, hydroxyurea, and calcitriol (0.25µg, oral every 12 hours) begun on day 1 of cytarabine and continued until relapse or the patient went off study.…”

“…Combination trials with VDA and chemotherapy resulted in mixed results in MDS/AML (Hellstrom, Robert et al 1990;Petrini, Caracciolo et al 1991;Petrini, Dastoli et al 1991;Slapak, Desforges et al 1992;Ferrero, Bruno et al 1996;Siitonen, Timonen et al 2007). Slapak et al (Slapak, Desforges et al 1992) showed promising results in a study of 29 AML patients, who were treated with a regimen of low-dose cytarabine, hydroxyurea, and calcitriol (0.25µg, oral every 12 hours) begun on day 1 of cytarabine and continued until relapse or the patient went off study. Three patients died within 60 days, and of the remainder, the overall response rate was 79%; 45% achieved CR and 34% achieved partial remission (PR).…”

“…Two patients experienced asymptomatic hypercalcemia (11.2mg/dl and 11.5mg/dl) but did not require treatment. The authors proposed that the favorable results might be due to the synergistic effects of cytarabine, hydroxyurea, and calcitriol, although they did not propose a specific mechanism (Slapak, Desforges et al 1992) , (Trump, Deeb et al 2010). Vitamin D was studied in 19 low-risk MDS patients with a median age of 75 years (Mellibovsky, Diez et al 1998 (Mellibovsky, Diez et al 1998).…”