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 Human recombinant erythropoietin (rEPO) improved anemia, in most of casistics, in about 30–35% of myelodysplastic syndrome (MDS) patients without BM blast excess. More recent sudies, employing either higher rEPO doses (70–80.000 U/week) or combinations of rEPO + G-CSF or all trans retinoic acid reported erythroid responses in 40–50% of patients. However, responses were quite less frequent in transfusion-dependent patients. On the basis of a previous our study (D. Ferrero et al.: Leuk Res1996; 20: 867–876; Blood1999; 94 suppl.1: 307) reporting more than 50% transfusion reduction in 30% of MDS patients treated with a combination of 13-cis retinoic acid (RA) + dihydroxylated vitamin D3 (D3), we employed in a new protocol the same combination of differentiating agents + rEPO. Thirty-two MDS patients, 19 males and 13 females, with a median age of 74.5 (46–90) entered the sudy. Diagnosis, according to W.H.O. classification was RA in 10, RARS in 3, RCMD in 7, 5q- syndrome in 2, RAEB1 in 10. IPSS score, available in 21, was: low risk in 4, intermediate-1 risk in 14, intermediate-2 risk in 3. Cytogenetic abnormalities were evidenced in 7/21 patients. Twenty-two/32 patients were transfusion- dependent with a median requirement of 2 U/month (1 – 7). All patients received a combination of RA (20 – 40 mg/day) + D3 (1 microgram/day) + human rEPO (either alpha or beta epoetin), starting from 30–40,000 U/week up to 70 – 80,000 U/week (median maximal dose: 70,000 U). Six/10 RAEB1 patients also received intermittent courses of low-dose 6-thioguanine and 2 patients received G-CSF for coexisting severe neutropenia. Erythroid responses were scored as major in the case of 100% reduction in transfusion requirements or greater than 2 g/dl increase in Hb level in untransfused patients, minor in the case of at least 50% reduction in transfusion requirements or 1–2 g/dl increase in Hb level without transfusions. Erytroid responses (13 major, 7 minor) were detected in 20/32 (62.5%) patients, without significant differences between patients without blast excess (14/22: 63.6% responsive) and RAEB1 patients (6/10: 60% responsive). Responses were observed in 13/22 (59%) transfusion-dependent and in 7/10 (70%) untransfused patients. EPO serum level were tested in 19 patients: 15 had values below 200 U/l and 12 of them (80%) responded, 4 had values greater than 200 U/l and no one of them responded. Median response duration was 9 months (2 – 27+) and 35% of responses are projected to be maintained at 15 – 27 months. Median survival was 12.5 months (6.5 – 25+) in RAEB1 patients, unreached (52% projected alive at 4 years) in patients without blast excess. Therapy was well tolerated, with only mild RA- induced mucosal dryness. In conclusion, our combination of rEPO + differentiating agents seems to be more effective than either treatment alone in ameliorating anemia of MDS patients, particularly in transfusion- dependent patients. However, the efficacy is probably low in patients with very high serum EPO levels.

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THERAPY WITH HUMAN RECOMBINANT ERYTHROPOIETIN IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES

British Journal of Haematology ◽

10.1111/j.1365-2141.1992.tb03014.x ◽

1992 ◽

Vol 81 (4) ◽

pp. 628-630 ◽

Cited By ~ 9

Author(s):

Monica Razzano ◽

Corrado Caslini ◽

Sergio Cortelazzo ◽

Vittorio Battistel ◽

Alessandro Rambaldi ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Recombinant Erythropoietin ◽

Human Recombinant Erythropoietin

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Long Term Follow-up of a Population of Low-Intermediate Risk Myelodisplastyc Syndrome Patients Treated with a Combination of Recombinant Erythropoietin, 13-Cis-Retinoic Acid and Dihydroxylated Vitamin D3 Confirms the Positive Role of Erythroid Response on Survival

Blood ◽

10.1182/blood.v116.21.4968.4968 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4968-4968

Author(s):

Dario Ferrero ◽

Elena Crisà ◽

Antonella Darbesio ◽

Cristina Foli ◽

Valentina Giai ◽

...

Keyword(s):

Retinoic Acid ◽

Median Survival ◽

Vitamin D3 ◽

Recombinant Erythropoietin ◽

Positive Role ◽

Erythroid Response ◽

Long Term Follow Up

Abstract Abstract 4968 In our previous paper (Ferrero et al, BJH 2009) we reported the treatment of 63 MDS patients (median age 75, 16 RAEB1, 47 non RAEB) with a combination of human recombinant erythropoietin (alfa or beta epoetin, 30–80000 U/ week, median 65000U/week), 13-cis-retinoic acid (20 mg day) and dihydroxylated vitamin D3 (1 ug day). Eleven of the 16 RAEB1 patients also received intermittent, low dose of 6-thioguanine. In spite of adverse prognostic factors for response to erythropoietin (all patients with Hb <9.5 g/dl, 70% transfusion dependent, 51% IPSS intermediate 1 or 2) 64% of non RAEB and 50% of RAEB1 displayed an erythroid response according to Cheson et al (Blood 2006). At previous evaluation (41 months of follow-up) a survival advantage was evident for non RAEB patients with erythroid response. Now we updated the casistic after 3 years from the previous evaluation. Median follow up for alive patients is now 64 months (5 months - 12 years). Median duration of erythroid response is now increased to 25 (2-88+) months for non RAEB and 6 (2.5-34.5+) months for RAEB1, 32.5% of responses in non RAEB patients have lasted more than 3 years. Twenty-nine/46 non RAEB and 14/16 RAEB1 patients died, with a median survival respectively of 57 and 15 months. Acute myeloid leukemia evolution occurred to 10 patients (5 RAEB1 and 5 non RAEB patients). Although the erythroid response did not correlate with known risk factors such as IPSS score, caryotype and transfusion requirement, it confirmed its positive prognostic role for survival in non RAEB patients (p 0.04, HR 2.06): median survival 71.5 months (range 12–150+) for responders, 30.6 months (range 5–149) for non responders. A trend towards a better survival for responder was also observed among RAEB1 patients (median survival 17 months for responders, 10 months for non responders), however, due to the low numbers of patients in this group, the difference was not statistically significant, even if border line (p 0.052, HR 2.52). In conclusion our long term follow-up confirmed the positive role of our combined treatment for response duration and survival in a group of non RAEB patients, most of them with unfavorable prognostic features.Figure 1.Overall survival of myelodisplastyc patients according to erythroid response: A. Non-RAEB patients:“___” responsive patients, “—” not responsive patients (p 0.04, HR 2.06) B. RAEB patients: “___” responsive patients, “—” not responsive patients (p 0.05, HR 2.52)Figure 1. Overall survival of myelodisplastyc patients according to erythroid response: A. Non-RAEB patients:“___” responsive patients, “—” not responsive patients (p 0.04, HR 2.06) B. RAEB patients: “___” responsive patients, “—” not responsive patients (p 0.05, HR 2.52) Disclosures: Off Label Use: The use of 13-cis retinoic acid and 1; 25(OH)2 vitamin D3 in myelodisplastyc syndrome is off-label. In our study we used that drugs in combination with erythropoietin as differentiative agents.

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