High Response Rate to Darbopoetin Alfa in “Low Risk” MDS : Results of a Phase II Study.

Background : Recombinant Erythopoietin (EPO) alfa or beta, when used alone at 10 to 20 000 units, three times weekly, improves anemia in 25 to 30 % of low risk MDS. By combining G-CSF to EPO, the response rate increases to 40 to 45 %. Darbopoietin alfa is a highly glycosylated form of EPO with prolonged half life, allowing weekly (or even once every second week) administration. We report results of a phase II study of Darbopoietin alpha in low risk MDS.

Patients and Treatment : Inclusion criteria were (i) MDS with < 10 % marrow blasts (ii) anemia requiring transfusion or Hb < 10g/dl (iii) serum epo level < 500 mU/ml (iiii) exclusion of other causes of anemia. Patients were treated with Darbopoietin 300 μg/week during at least 12 weeks. In the absence of response, G-CSF (lenograstim 150 μg, 3 times weekly) was added to Darbopoietin and a new evalution made after 12 weeks. Response was evaluated based on IWG criteria. In patients responding to Darbopoietin, intervals between 300 μg injections were adjusted to maintain Hb levels between 11 and 13g/dl. 55 patients were included. 2 were inevaluable due to severe sepsis (unrelated to darbopoietin) after 4 weeks of treatment and 13 were too early for evaluation. The 40 patients who received at least 12 weeks of darbopoietin included 20M/20F, median age was 77, morphology : 15 RA, 12 RARS, 12 RAEB1, 1 CMML ; Karyotype was favorable (21 %), intermediate (76 %), unfavorable (3%). IPSS was low (38 %), int 1 (52 %), int 2 (10 %), serum epo levels ranged from 10 to 490 mU/ml (median 68). Median interval from diagnosis of MDS was 12 months (range 3–136), 6 patients had previously received EPO alfa or beta without success.

Results: 24 of the evaluable patients (60 %) responded at 12 weeks with Darbopoietin alone including HI - E major (n=19) and HI - E minor (n=5). No response was seen on granulocytes and platelets. 6 patients reached Hb > 15g/dl and 2 Hb > 16g/dl. Of the non responders at 12 weeks , 8 received further Darbopoietin + G-CSF and 2 of them responded after 12 weeks of combined treatment. 16 of the responders were evaluable for maintenance treatment (during 8 to 24 weeks) and intervals between injections required to maintain response could be prolonged to 2 or 3 weeks in 9 of them. 2 relapses were seen during maintenance, in 2 patients with HI-E minor. No side effects were observed. Pretreatment serum epo level, Karyotype and IPSS had no prognostic value on response. Response rates were 67 %, 42 % 67 % for RA, RARS and RAEB1, respectively (p=NS). 2/3 patients with 5 q- syndrome responded. Finally, 3 of the 6 patients previously unresponsive to EPO responded to darbopoietin.

Conclusion : Results obtained with Darbopoietin alfa alone on the anemia of low risk MDS may be superior to those obtained with conventional EPO alone, and the drug is well tolerated. Randomized studies are obviously required to compare the effect of the different types of EPO on the correction of anemia of MDS patients.