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Eltrombopag Reduces Thrombocytopenic Events in Patients With AML and MDS , But Not as Much as Expected
Compared with placebo , the oral thrombopoietic receptor agonist eltrombopag significantly lowered the incidence of thrombocytopenic events in patients with acute myeloid leukemia ( AML ) or myelodysplastic syndromes ( MDS ) who had thrombocytopenia , according to a phase III , placebo-controlled study . However , the difference between the two treatment groups was less than 30 percent , which was lower than expected , the researchers noted .
The three-part , randomized , placebo-controlled ASPIRE ( A Study of eltromboPag In myelodysplastic syndRomes and acutE myeloid leukemia ) trial enrolled patients from 61 international hospitals and medical centers . Lead author Moshe Mittelman , MD , of Tel Aviv Sourasky Medical Center and Tel Aviv University in Israel , and colleagues published the findings from part one ( open-label phase ) and part two ( randomized phase ) in The Lancet Haematology .
Patients with intermediate-2 or high-risk ( per International Prognostic Scoring System ) MDS or AML who had grade 4 thrombocytopenia because of bone marrow ( BM ) insufficiency ( defined as < 25 × 10 9 / L ), or grade 4 thrombocytopenia before platelet transfusion , with platelet counts of ≥25 × 10 9 / L after transfusion were included in the study . Participants were also required to have at least one of the following within four weeks of the screening period : platelet transfusion , symptomatic bleeding , or platelet count of < 10 × 10 9 / L . People with thrombocytopenia for reasons other than BM insufficiency , leukocyte count ≥25 × 10 9 / L , or previous treatment with a thrombopoietin receptor agonist were excluded .
In part one , 17 patients ( mean age = 71.5 years ; standard deviation [ SD ] = 10.8 years ; 9 with MDS and 8 with AML ) received eltrombopag for eight weeks , with 11 completing all planned treatment .
In the randomized , double-blind , placebocontrolled , multicenter second part of the study , 145 patients were stratified based on baseline platelet count (< 10 × 10 9 / L vs . ≥10 × 10 9 / L ) and disease ( MDS vs . AML ) to receive 12 weeks of either :
• eltrombopag 100 to 300 mg / day ( n = 98 ; mean age = 72.3 years ; SD = 8.9 years )
• placebo ( n = 47 ; mean age = 70.6 years ; SD = 10.7 years )
Forty-three and 27 patients , respectively , completed all planned treatment . Discontinuation of eltrombopag was primarily related to adverse events ( AEs ; n = 31 ; 32 %), while discontinuation of placebo was mainly due to physician ’ s decision ( n = 8 ; 17 %).
In the overall study population , patients received a median eltrombopag dose of 108.5 mg / day ( interquartile range [ IQR ] = 50-122 mg / day ) over a mean duration of 8.1 weeks ( SD = 4.2 weeks ); mean duration of placebo was 9.6 weeks ( SD = 3.7 weeks ).
During weeks five to 12 of treatment , eltrombopagtreated patients experienced significantly fewer clinically relevant thrombocytopenic events ( CRTEs ; primary endpoint ; defined as one of the following , either alone or in combination : grade ≥3 hemorrhagic AEs , platelet counts of < 10 × 10⁹ / L , and platelet transfusions ), compared with placebo : 54 percent versus 69 percent ( odds ratio [ OR ] = 0.20 ; 95 % CI 0.05-0.87 ; p = 0.032 ). Although the weekly average proportion of CRTE was lower in the eltrombopag group for all 12 study weeks , the difference did not meet criteria for clinically meaningful efficacy ( defined as 30 % absolute difference between the groups ).
The average proportion of patients with weekly platelet counts < 10 × 10 9 / L during treatment was significantly lower in the eltrombopag group ( 27 % vs . 50 %; p = 0.0013 ); however , patients in each treatment group still required weekly platelet transfusions at a similar rate ( 51 % vs . 52 %; p = 0.83 ).
Maximum mean platelet transfusion independence duration during weeks five through 12 also did not differ significantly between the eltrombopag and placebo cohorts : 26.3 days ( SD = 21.47 days ) versus 25.4 days ( SD = 15.5 days ).
Few responses were reported : one marrow complete response ( CR ) in the eltrombopag group and one morphologic CR in the placebo group ( OR = 0.47 ; 95 % CI 0.03-7.75 ; p = 0.59 ). Eighteen patients in the eltrombopag group ( 18 %) and 10 in the placebo group ( 21 %) experienced stable disease , although 36 and 98 patients in each cohort , respectively , were non-evaluable , “ which could have influenced the lower disease progression rate observed in eltrombopag recipients ,” the authors noted .
Sixty-one eltrombopagtreated patients ( 62 %) and 36 placebo-treated patients ( 77 %) experienced disease progression .
At all weekly evaluations following treatment , the proportion of patients with no bleeds was higher in the eltrombopag group
( n = 21 / 40 ; 53 %), compared with the placebo group ( n = 6 / 27 ; 22 %; p values not reported ).
Median BM blast counts and median peripheral blood blast counts did not differ between treatment groups . Any hematologic improvement also was similar between groups ( n = 10 [ 10 %] and n = 4 [ 9 %], respectively ; OR = 1.26 ; 95 % CI 0.37-4.30 ).
“ The bleeding and CRTE reductions in ASPIRE were not accompanied by hematologic improvement or improved platelet transfusion independence ,” the authors noted . “ This , and that only 48 percent of the 145 patients [ receiving eltrombopag completed ] the study , could be explained by the advanced disease stage of enrolled patients .”
During part two , 47 deaths ( 48 %) were reported in the eltrombopag arm and 18 ( 38 %) in the placebo arm , with 35 ( 36 %) and 13 ( 28 %) deaths , respectively , within 30 days of final treatment dose ( p values not reported ). The primary cause of death in both groups was underlying disease ( n = 41 [ 87 %] and n = 17 [ 94 %], respectively ).
In part two , the median overall survival did not differ between groups : 4.3 months ( IQR = 1.5-12.0 months ) with eltrombopag and 4.6 months ( IQR = 2.4- 8.5 months ) with placebo ( hazard ratio [ HR ] = 0.97 ; 95 % CI 0.64-1.48 ; p = 0.89 ). Median progressionfree survival was also similar between both groups : 1.08 ( IQR = 0.48-2.73 months ) and 0.94 months
TABLE 1 . Most Common Adverse Events (> 10 %) in Overall Patient Population
Eltrombopag ( n = 97 )
Any event 44 ( 45 %)
Alanine aminotransferase increased 7 ( 7 %)
Nausea 7 ( 7 %)
Diarrhea 8 ( 8 %)
Blood bilirubin increased 5 ( 5 %)
Decreased appetite 6 ( 6 %)
Fatigue 5 ( 5 %)
Aspartate aminotransferase increased 1 ( 1 %)
Blood creatinine increased 3 ( 3 %)
Bone pain 3 ( 3 %)
Hyperbilirubinemia 3 ( 3 %)
Placebo ( n = 47 )
12 ( 26 %)
4 ( 9 %)
3 ( 6 %)
1 ( 2 %)
1 ( 2 %)
0
0
3 ( 6 %)
0
0
0
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