Efficacy of a combination of human recombinant erythropoietin + 13‐cis‐retinoic acid and dihydroxylated vitamin D3 to improve moderate to severe anaemia in low/intermediate risk myelodysplastic syndromes

Abstract

SummaryThe efficacy of human recombinant erythropoietin (rEPO) in myelodysplastic syndromes (MDS) has generally been best in untransfused patients with 'refractory anaemia' according to the World Health Organization (WHO). We treated 63 MDS patients [excluding refractory anaemia with excess blasts, type 2 (RAEB2)] with a previously tested combination of 13-cis-retinoic acid and dihydroxylated vitamin D3 ± 6-thioguanine in addition to rEPO. Most patients were categorized as refractory cytopenia with multilineage dysplasia and RAEB1, with intermediate 1 International Prognostic Scoring System (IPSS) score; all had Hb <95 g/l, and 70% required regular erythrocyte transfusions. Treatment was well tolerated, and erythroid response rate according to new International Working Group criteria was 60%: 50% in RAEB1 and 64% in non-RAEB patients (P ¼ 0AE383). Response rate was not affected by transfusion requirement (63%; 58% in untransfused), IPSS and WHO Prognostic Scoring System scores, and weekly rEPO dosage (30-50 000 U vs. 80 000 U). Median response duration was 16 months. Median survival reached 14 months for RAEB1 and 55 months for non-RAEB patients, with a significant difference in the latter between responders and non-responders (median 82 months vs. 44 months; P ¼ 0AE036). Our combined therapy, independent of rEPO dosage, achieved in patients with unfavourable response predictors, a rate of anaemia improvement comparable to the best obtained in lower risk patients by high-dose rEPO.

The Role of Vitamin D in Hematologic Disease and Stem Cell Transplantation

“…Ferrero and colleagues reported in 2008 on a study of 63 patients with MDS, excluding high risk patients with high numbers of blasts, treated with a combination of recombinant human erythropoietin as well as cis -retinoic acid; 1,25 dihydroxycholecalciferol; and 6-thioguanine if blasts were present [28]. The purpose of this study was primarily to assess erythroid response and compare it to the rates seen with erythropoietin alone or the combination of the two differentiating agents and thioguanine alone, which was approximately 30% for each.…”

“…The purpose of this study was primarily to assess erythroid response and compare it to the rates seen with erythropoietin alone or the combination of the two differentiating agents and thioguanine alone, which was approximately 30% for each. Overall, there was an erythroid response rate of 60% overall, which was better in the low risk patients than those with excess blasts [28]. There was also data for improved survival for the low risk patients who had a response, with 93% of responders vs. 58% of nonresponders alive at three years [28].…”

“…Overall, there was an erythroid response rate of 60% overall, which was better in the low risk patients than those with excess blasts [28]. There was also data for improved survival for the low risk patients who had a response, with 93% of responders vs. 58% of nonresponders alive at three years [28]. Though presented as a positive study, the lack of erythropoietin dose standardization or control arm makes the benefits from the new agents difficult to appreciate.…”

“…Toxicity was generally mild and primarily related to the retinoid agents. Surprisingly, there was little emphasis on the cardiovascular mortality rate of 8/63 patients, which could have been associated with the use of the erythroid stimulating agent [28]. …”

Clinical Experience Using Vitamin D and Analogs in the Treatment of Myelodysplasia and Acute Myeloid Leukemia: A Review of the Literature

“…They treated 63 MDS patients (excluding refractory anaemia with excess blasts, type 2 (RAEB2)) with the combination of 13- cis -retinoic acid and dihydroxy-vitamin D3 with, or without, the further addition of 6-thioguanine. Most patients were categorized as refractory cytopenia with multilineage dysplasia and RAEB1, in the WHO classification scheme, with intermediate 1 International Prognostic Scoring System (IPSS) score [21]. All patients had, at baseline, a hemoglobin of <9.5 gm/dL, and 70% required regular erythrocyte transfusions prior to beginning this therapy.…”