Treatment with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa can reduce the need for red blood cell (RBC) transfusions in patients with lower-risk myelodysplastic syndromes (MDS) and anemia, according to research published in Leukemia.
Uwe Platzbecker, MD, from the Department of Internal Medicine I at the University Hospital Carl Gustav Carus in Dresden, Germany, and co-authors conducted a randomized, double-blind, placebo-controlled, multicenter, phase III trial to assess the safety and efficacy of darbepoetin alfa in ESA-naïve patients with anemia and low or intermediate-1 risk MDS (per the International Prognostic Scoring System [IPSS]).
Because RBC transfusions “can lead to iron overload, cardiac and liver morbidity, and mortality … prevention or reduction of transfusions [is] the main goal of clinical care in lower-risk MDS,” Dr. Platzbecker and co-authors wrote. According to their findings, “subcutaneous darbepoetin alfa significantly reduced transfusions and increased rates of erythroid response, compared with placebo, with no new safety signals.”
The researchers enrolled 147 patients with MDS (according to the World Health Organization 2008 criteria) with IPSS low or intermediate-1 risk disease from nine European countries between December 2011 and August 2014. Eligible patients had endogenous serum erythropoietin (EPO) ≤500 mU/mL, low transfusion burden (defined as <4 RBC transfusion units in each of two consecutive eight-week periods prior to randomization), no previous treatment with ESAs or disease-modifying treatments, and no bone marrow fibrosis.
Patients were randomized 2:1 to receive 24 weeks of darbepoetin alfa 500 μg (administered subcutaneously every 3 weeks through week 22; n=97) or placebo (n=49). Ten patients in each group discontinued treatment during the double-blind period.
All patients then received 48 weeks of open-label darbepoetin alfa (except those who had dose reductions). Patients who did not require RBC transfusions in the previous four weeks but had a hemoglobin increase of <1.5 g/dL could escalate to darbepoetin alfa 500 μg every two weeks. During the open-label period, 29 patients in the darbepoetin alfa group discontinued or did not receive treatment; in the placebo group, another 13 patients discontinued treatment.
None of the 35 evaluable patients in the placebo group experienced erythroid response (per the International Working Group 2006 criteria) through week 24, compared to 14.7 percent of patients (n=11/75 evaluable patients) in the darbepoetin alfa cohort (p=0.016). In the open-label period, more than one-third of patients in the darbepoetin alfa cohort experienced erythroid response (34.7%; n=34/98).
Transfusion incidence from weeks five through 24 (primary endpoint) was significantly reduced in the darbepoetin alfa cohort, compared with the placebo cohort, with 36.1 percent (n=35/97) of patients requiring red blood cell transfusions versus 59.2 percent (n=29/49; odds ratio = 0.38; 95% CI 0.19-0.79; p=0.008).
Patients receiving darbepoetin alfa had an average of 1.4 transfusion episodes (standard error = 0.2), compared with 2.7 (standard error = 0.5) in the placebo cohort (p<0.001). Patients in each group received an average of 2.2 (standard error = 0.4) and 4.1 (standard error = 0.9) RBC units, respectively (p=0.038).
Dose reductions were required because of a rapid rise in hemoglobin in 18 patients (18%) receiving darbepoetin alfa, at a median hemoglobin of 10.6 g/dL (range = 8.4-12 g/dL). Eleven patients (11%) receiving darbepoetin alfa had a dose withheld, four of whom met criteria for erythroid response.
Twenty-one patients were still responding at their last observation. The mean duration of response was 235 days (standard error = 21 days) during the 24- and 48-week periods. No patients in the placebo cohort required reduced or withheld doses. During the 48-week open-label period, the median average dose of darbepoetin alfa was 500 μg (range not provided).
Adverse events (AEs) leading to treatment discontinuation in the first 24 weeks were reported in two patients receiving placebo (grade 3 pulmonary arterial hypertension and grade 3 renal disease) and three patients receiving darbepoetin alfa (grade 3 pulmonary thrombosis, grade 3 thrombocytopenia, and grade 1 increased blast cell count).
During the 24-week treatment period, the most common AEs across both treatment groups were patient-reported fatigue (17.3% with darbepoetin alfa and 8.3% with placebo), asthenia (12.2% and 10.4%), and exertional dyspnea (6.1% and 10.4%). Three AE-related deaths occurred: two in the placebo group (cardiac failure and cerebral hemorrhage) and one in the darbepoetin alfa group (hemorrhagic proctitis).
AEs reported during the 48-week open-label period were similar, and an additional two deaths occurred: one related to acute myeloid leukemia in a patient who received darbepoetin alfa during the 24-week period and one related to pneumonitis in a patient previously treated with placebo.
The authors noted “the substantial number of patients (42%) with a history of RBC transfusions (albeit still low transfusion burden)” as a potential limitation that may have influenced the outcomes of this trial. The low response rates observed with darbepoetin in this trial (14.7%) will also need to be compared with those achieved in other trials and with other treatments for MDS-associated anemia.
Amgen Inc., conducted and funded the study and all analyses.
Dr. Platzbecker and contributing authors reported honoraria and research funding from Amgen Inc.
Platzbecker U, Symeonidis A, Oliva EN, et al. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 17 June 19. [Epub ahead of print]