Literature Scan
Randomized Study of Darbepoetin Alfa Shows Modest Reduction in RBC Transfusions in Patients With MDS and Anemia
Treatment with the erythropoiesis-stimulating agent ( ESA ) darbepoetin alfa can reduce the need for red blood cell ( RBC ) transfusions in patients with lowerrisk 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 , placebocontrolled , 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 .
REFERENCE
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 ]
Study Finds Low Incidence of Intracranial Bleeding With Preventive Low-Dose Aspirin
The protective effect of low-dose aspirin against ischemic cardiovascular ( CV ) events and colorectal cancer ( CRC ) appears to outweigh the risks of major bleeding , including intracranial bleeding ( ICB ), according to results from a populationbased study published in the Journal of Thrombosis and Haemostasis . However , factors such as age , sex , and indication for low-dose aspirin prescription were associated with different ICB incidence rates .
Using data from The Health Improvement Network ( THIN ), the United Kingdom ’ s primary-care database , Lucía Cea Soriano , from the Department of Preventive Medicine and Public Health at the Complutense University of Madrid in Spain , and co-authors estimated an ICB incidence of 0.8 per 100 person-years among new users of low-dose aspirin .
“ There is increasing interest in the balance of overall benefits and risks of lowdose aspirin as a preventive agent , for both CV [ disease ( CVD )] and CRC prevention ,” the authors wrote . “[ Our ] results provide valuable measures for incorporation into benefit-risk assessments of low-dose aspirin use in [ both settings ].”
To estimate the incidence of ICB , the researchers selected adult patients enrolled in THIN who had a registered primarycare physician for at least two years and had at least one clinical visit within three years of enrollment . Included patients had never been prescribed low-dose aspirin ( 75 or 300 mg ) for primary or secondary prevention of CV events or CRC . Patients with a diagnosis of cancer , alcohol abuse , coagulopathies , esophageal varices , or chronic liver disease at any time prior to study entry were excluded .
The researchers identified 199,079 patients ( mean age = 63.9 years ). Beginning with the first date of low-dose aspirin prescription , patients were followed for as long as 14 years ( median = 5.58 years ).
During follow-up , 881 patients had confirmed ICB events : 407 intracerebral hemorrhages ( ICHs ), 283 subdural hematomas ( SDHs ), and 191 subarachnoid hemorrhages ( SAHs ).
26 ASH Clinical News August 2017