Concentrations of endogenous EPO in patients with MDS may be suboptimally increased for the degree of their anemia. The rationale of rHuEPO therapy is to provide pharmacologic doses of the cytokine to increase serum EPO concentrations and to enhance the proliferation and maturation of marrow erythroid precursors. The clinical objective is to increase Hb concentrations and to reduce the risks associated with transfusion therapy, including infection, red cell alloimmunization, and secondary hemochromatosis. Although various criteria have been used to define response to rHuEPO therapy, and the proportion of low- and high-risk FAB (French-American-British) subtypes differs in each study, the cumulative response rate of numerous published small trials is approx 20% (14-26). The Italian Cooperative Study Group has performed the only double-blind, placebo-controlled, randomized study of rHuEPO in MDS to date (27). Patients with <10% marrow blasts received either placebo or rHuEPO 150 U/kg/d for 8 wk. A statistically significant Hb response was observed in the rHuEPO group, but benefit was limited to the refractory anemia (RA) subtype, and patients with either no prior transfusion requirements or basal endogenous EPO < 200 U/L. Other nonrandomized studies have cited serum EPO < 100 U/L, female sex, or normal karyotype as predictors of response to rHuEPO (24,28). A recent study found that baseline serum EPO concentration predicted survival (29). Patients with serum EPO > 50 U/L experienced a median survival of 17 mo compared with 65 mo in patients with serum EPO < 50 U/L.

Using red blood cell transfusion independence as the minimal criteria for response, one meta-analysis of 115 patients from 10 trials (30) and a second meta-analysis of 205 patients from 17 published reports (31) reported response rates of 23.5% and 16%, respectively. In the latter analysis, patients with RARS showed a significantly lower response rate (7.5%) than all other patients (21%). Other factors favoring response were the absence of transfusion need (44% vs. 10%) and serum EPO concentration < 200 U/L. Patients without a transfusion requirement and MDS patients other than RARS showed a response rate > 50% irrespective of the serum EPO concentration. No dose-response relationship and no correlation between maximal dose and time to

Table 1

Clinical Trials of rHuEPO ± rHuG-CSF in MDS"


No. of patients Responses (%)b


rHuEPO alone

350 U/kg/wk 16

450-900 U/kg/wk 20

18,000-72,000 U/wk 14

800 U/kg/wk 23

210-1680 U/kg/wk 10

225-750 U/kg/wk 13

300-1200 U/kg/wk 20

450-900 U/kg/wk 100

450-900 U/kg/wk 12

450-900 U/kg/wk 41

1050 U/kg/wk 38

150 U/kg 3x/wk 281

150-200 U/kg 3x/wk 68

Various doses and schedulesc 110

Various doses and schedulesc 205

rHuG-CSF and rHuEPO

13% 50% 8% 29% 30% 20% 38% 26% 35% 28% 58% 32% 37% 45% 33% 24% 16%

16 18

20 21 22 28

26 27 33

Abbreviations: rHuEPO, recombinant human erythropoietin; rHuG-CSF, recombinant human granulocyte colony-stimulating factor; MDS, myelodysplastic syndromes.

a Clinical trials enrolling 10 or more patients are shown.

b Response criteria differ between studies.

c Metaanalysis.

d Twenty-five patients evaluated in 12-wk follow-up with 61% response rate; 28 evaluated in 36-wk follow-up with 80% response rate.

response was seen. The optimal dose was generally in the range of 450-1000 U/kg/wk. The limited clinical efficacy of rHuEPO in these trials partly reflects the suboptimal responsiveness of myelodysplastic BFU-E to rHuEPO in vitro (9,10).

Durability of rHuEPO response has been studied in two trials. In a small study of 18 primarily low-risk MDS patients treated with rHuEPO 10,000 U three times weekly, three patients were still responding at 30, 41, and 56 mo (32). Two of these patients were maintained on a lower rHuEPO dose, and one was still responding 48 mo after rHuEPO had been discontinued. In seven patients, anemia recurred with tapering of the initial rHuEPO dose, and a second course of rHuEPO resulted in responses in 5 of 6 retreated patients. The remaining eight patients died during or soon after the initial treatment period, three from transformation to AML. At the time of follow-up, five patients maintained Hb responses with a median duration of 36+ mo.

A phase 2 study of 281 patients evaluated whether response rates to rHuEPO increase with prolonged administration (33). Using a dose of 150 U/kg three times weekly, the overall erythroid response rate was 18.1% at 12 wk and increased to 45.1% at 26 wk. The median duration of response was 68 wk. Significant predictors of response included serum EPO < 150 U/L, good cytogenetic risk group by International Prognostic Scoring System (IPSS) criteria, and RA compared with RARS and RAEB FAB subtypes.

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