Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for correcting anaemia in patients with myelodysplastic syndromes

Abstract

Patients with myelodysplastic syndromes (MDS) often develop anaemia resulting in frequent transfusions and fatigue. Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anaemia. This single-arm, phase 2 study examined the efficacy of darbepoetin alfa 500 microg every 3 weeks (Q3W) for treating anaemia in low-risk MDS patients (after 6 weeks, poor responders received darbepoetin alfa 500 microg every 2 weeks). The primary end-point was the incidence of erythroid responses (International Working Group criteria) after 13 weeks of therapy. Secondary end-points included the incidence of erythroid responses at weeks 28 and 55, [or weeks 27 and 53 for dose escalations to every two weeks (Q2W)], and safety parameters. Analyses were stratified by the patient's previous ESA therapy status [ESA-naïve (n = 144) vs. prior ESA-treated (n = 62)]. After 13 weeks of therapy, 49% of ESA-naïve patients and 26% of prior ESA-treated patients achieved a major erythroid response. After 53/55 weeks, 59% of ESA-naïve patients and 34% of prior ESA-treated patients achieved a major erythroid response; 82% of ESA-naïve patients and 55% of prior ESA-treated patients achieved target haemoglobin of 110 g/l. Thromboembolic or related adverse events occurred in 2% of patients; no pulmonary embolisms were reported. In conclusion, darbepoetin alfa, 500 microg Q3W appeared well tolerated and increased haemoglobin levels in low-risk MDS patients.

Trial registration: ClinicalTrials.gov NCT00095264.

Fig 1

Study schema. Darbepoetin alfa was administered at 500 μg every 3 weeks (Q3W). After 6 weeks (at week 7), the dosing frequency could be escalated to every 2 weeks (Q2W). Treatment was withheld when a patient's haemoglobin reached ≥130 g/l. Darbepoetin alfa treatment was not to exceed 52 weeks, and end of study was planned for 3 weeks (at week 55 for Q3W dosing) or 2 weeks (at week 53 for Q2W dosing) after the last dose of darbepoetin alfa was administered. Study day 1 (the first day of darbepoetin alfa administration) to week 13 was designated as ‘test period’, study day 1 to week 27/28 was designated as ‘treatment period’ and study day 1 to week 52 was designated as ‘extended-treatment period’.

Fig 2

Patients who achieved an erythroid response by 13 and 53/55 weeks. A major erythroid response was defined as: i) an increase in Hb concentration of ≥20 g/l from baseline or ii) transfusion-independent for patients who were transfusion-dependent at screening. A minor erythroid response was defined as: i) an increase in Hb concentration of ≥10 and <20 g/l from baseline or ii) ≥50% decrease in transfusion requirements for patients who were transfusion-dependent at screening. (A) Percentage of patients achieving an erythroid response after 13 weeks of darbepoetin alfa therapy (the primary end-point). (B) The percentage of patients with an erythroid response after 53/55 weeks of darbepoetin alfa therapy. Error bars indicate the upper 95% CL. ESA, erythropoiesis-stimulating agent; CL, confidence limit.

Fig 3

Kaplan–Meier plots of the time to haemoglobin response and of the time to target haemoglobin over the 28-week treatment period. (A) The time to haemoglobin response for erythropoiesis-stimulating agent (ESA)-naïve patients and prior ESA-treated patients. (B) The time to target haemoglobin for ESA-naïve patients and prior ESA-treated patients. n below each graph represents the number of patients at risk for an event (patients were censored after an end-point was achieved).

Fig 4

Change in haemoglobin from baseline to week 53/55. Data are presented from an analysis using the last-value-carried-forward (LVCF) approach and from an analysis using available data. The mean change in haemoglobin is shown by baseline haemoglobin category. Error bars indicate the upper and lower 95% CL. ESA, erythropoiesis-stimulating agent; CL, confidence limit.

Fig 5

Major and minor erythroid responses during the 13-week test period by IPSS classification. The percentage of patients achieving an erythroid response during the 13-week test period is shown for patients with Low and Intermediate-1 (Int-1) IPSS classifications, and stratified by prior ESA treatment status. IPSS, International Prognostic Scoring System; ESA, erythropoiesis-stimulating agent; CL, confidence limit.

Fig 6

Change in Functional Assessment of Cancer Therapy-Fatigue (FACT-F) score from baseline. The mean change in the FACT-F score from baseline to weeks 13 and 25 is shown by mean changes in haemoglobin levels. Error bars indicate the upper or lower 95% CL. ESA, erythropoiesis-stimulating agent; CL, confidence limit; Hb, haemoglobin.