CLINICAL NEWS
Results from Phase III SWOG Trial : 7 + 3 Still the Standard of Care for Patients With Acute Myeloid Leukemia
Remission induction with 7 + 3 chemotherapy ( cytarabine + daunorubicin ) should remain the standard of care for younger patients with acute myeloid leukemia ( AML ), according to results from the phase III SWOG S1203 trial , which evaluated whether adding the histone deacetylase ( HDAC ) inhibitor vorinostat to a regimen of idarubicin and high-dose cytarabine , or whether idarubicin and high-dose cytarabine alone , could improve event-free survival ( EFS ; the study ’ s primary endpoint ) over 7 + 3 alone .
“ A phase II study of vorinostat plus idarubicin and HDAC induction demonstrated an overall response rate of 85 percent and a 4 percent induction mortality rate ,” lead author Guillermo Garcia-Manero , MD , from the University of Texas MD Anderson Cancer Center in Houston , said during his presentation of the results . “ We hypothesized that the addition of vorinostat to idarubicin plus HDAC is superior to 7 + 3 in
In addition , pharmacokinetic analysis revealed that patients receiving the subcutaneous 1,800 mg dose achieved serum trough concentrations similar to or greater than the daratumumab 16 mg / kg IV formulation . Patients in the 1,200 mg dose arm showed lower levels of serum trough concentration , and , based on these results , the recommended dose for the second phase of the PAVO study is subcutaneous daratumumab 1,800 mg .
“ Subcutaneous daratumumab administration appears safe , effective , and convenient for patients in an approximately 30-minute infusion time for the 1,800 mg fixed dose ,” Dr . Usmani told ASH Clinical News . “ There was a lower incidence of IRRs and comparable ORR in the PAVO study , compared with previously published experience with intravenous daratumumab , [ including the ] GEN501 and SIRIUS trials .”
However , Dr . Usmani noted that head-to-head comparative data do not exist between the two formulations , so the results from this trial will need to be demonstrated in randomized clinical trials . In part two of the phase I PAVO study , patients will be randomized 1:1 to receive the recommended dose of daratumumab or intravenous daratumumab 16 mg / kg .
REFERENCE
Usmani SZ , Nahi H , Mateos MV , et al . Open-label , multicenter , dose escalation phase 1b study to assess the subcutaneous delivery of daratumumab in patients ( pts ) with relapsed or refractory multiple myeloma ( PAVO ). Abstract # 1149 . Presented at the 2016 ASH Annual Meeting , December 5 , 2016 ; San Diego , CA . younger patients with AML .”
The SWOG S1203 trial enrolled 738 patients with previously untreated AML ( age range = 15-60 years ) who had preserved cardiac function and no severe comorbidities . Patients with known core-binding factor leukemia or FLT3-mutated leukemia were eligible for inclusion if no other alternative clinical trials existed . Participants ’ median age was 49 years ( range = 18-60 ), and most patients ( 75 %) were between 40 and 60 years . Patients had median white blood cell and platelet counts of 10.8 ( range = 0.3-800 ) and 4 ( range = 3-9,300 ), respectively . Marrow blast percentage was 60 percent .
Patients were randomly assigned to one of three treatment arms : 7 + 3 ( n = 261 ), idarubicin and high-dose cytarabine ( IA ; n = 261 ), and IA plus vorinostat ( IA + V ; n = 216 ).
Most patients had intermediate-risk cytogenetics ( 63 %), while 13 percent had favorable cytogenetics and 22 percent had high-risk cytogenetics . The most common mutation among patients with known mutations was FLT3 ( 21 %), followed by NPM1 ( 20 %).
Induction and consolidation treatment in each arm consisted of :
• 7 + 3 arm : daunorubicin 90 mg / m 2 once daily on days 1-3 plus cytarabine 100 mg / m 2 continuous infusion on days 1-7 , followed by cytarabine 3 g / m 2 every 12 hours on days 1 , 3 , and 5
• IA arm : idarubicin 12 mg / m 2 once daily on days 1-3 plus cytarabine 1.5 g / m 2 continuous infusion on days 4-7 , followed by idarubicin 8 mg / m 2 once daily on days 4-5 plus cytarabine 0.75 g / m 2 continuous infusion on days 4-6
• IA + V arm : IA plus vorinostat 500 mg thrice daily on days 1-3 of induction and consolidation
The number of consolidation cycles each patient received depended on transplant indication , Dr . Garcia-Manero explained , because a secondary aim of the study was to transplant all cytogenetically determined high-risk patients ( results from this analysis were presented in a separate study ).
Contrary to what investigators hypothesized , neither IA nor IA + V was superior to 7 + 3 on all survival endpoints , including EFS , relapse-free survival , and overall survival .
“ The arms were all neutral ,” Dr . Garcia- Manero reported . “ There was no evidence of superiority in the high-dose induction group or the high-dose induction plus vorinostat group .” Outcomes with either of the idarubicin arms were similar , the authors noted .
Rates of complete remission ( CR ) also were similar among all three treatment arms : 75 percent for 7 + 3 , 79 percent for IA , and 77 percent for IA + V ( p = 0.58 ).
In a comparison of outcomes among different cytogenetic and molecular groups , the authors found no differences in outcome for any standard-risk group ; however , in patients with favorable cytogenetics , outcomes were significantly better with 7 + 3 than with IA or IA + V ), which the authors suggest is related to the use of lower doses of cytarabine during postremission therapy .
“ The good news is that the response rates and the survival rates [ in the IA and IA + V arms ] were acceptable , but we were not able to demonstrate superiority of these approaches to 7 + 3 .”
— GUILLERMO GARCIA-MANERO , MD
The rates of adverse events ( AEs ) were similar among all treatment arms , as well , though there was a slightly higher rate of AEs in the vorinostattreated group , which Dr . Garcia-Manero noted “ was to be expected ,” given the known toxicities of this class of drugs . The most common grade ≥3 AEs were blood / lymphatic , gastrointestinal , and infections , and rates of grade 5 AEs in the 7 + 3 , IA , and IA + V arms were 4 percent , 8 percent , and 9 percent , respectively ( p = 0.07 ).
“ The good news is that the response rates and the survival rates [ in the IA and IA + V arms ] were acceptable , but we were not able to demonstrate superiority of these approaches to 7 + 3 ,” he concluded . “ For now , based on this study , a 7 + 3 approach is still the standard of care for patients with AML .”
Future studies , he added , should compare the 7 + 3 regimen with combination treatments that include nucleoside analogues , monoclonal antibodies , or targeted agents .
REFERENCE
Garcia-Manero G , Othus M , Pagel JM , et al . SWOG S1203 : a randomized phase III study of standard cytarabine plus daunorubicin ( 7 + 3 ) therapy versus idarubicin with high dose cytarabine ( IA ) with or without vorinostat ( IA + V ) in younger patients with previously untreated acute myeloid leukemia ( AML ). Abstract # 901 . Presented at the 2016 ASH Annual Meeting , December 5 , 2016 ; San Diego , CA .
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