Common molecular genetic mutations in AML
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September 2009 and December 2010 .
Patients were randomized 1:1 to receive a five-day schedule of azacitidine 75 mg / m 2 daily , with or without three daily doses of vorinostat 200 mg . Treatment continued for 12 cycles unless disease progression or intercurrent illness occurred or if patients requested discontinuation . After 12 cycles , patients could continue to receive azacitidine alone .
The median follow-up was 7.4 months ( range = 0.3-29 months ), with patients
TP53 2 %
PTEN 2 %
KRAS 2 %
PHF6 3 %
ASXL1 3 %
MLL-PTD 5 %
RUNX1 5 %
KIT 6 %
IDH1 7 %
IDH2 8 % receiving a median of 3.5 treatment cycles ( range = 1-12 cycles ).
Sixty-day survival ( the study ’ s primary endpoint ) was 83 percent ( n = 24 ); the stopping rule for survival was never met .
Patients with AML and MDS experienced similar levels of overall survival ( OS ; 5.9 vs . 7.9 months ; hazard ratio [ HR ] = 0.67 ; 95 % CI 0.32-1.4 ; p = 0.308 ) and event-free survival ( EFS ; 3.5 vs . 4.4 months ; HR = 0.74 ; 95 % CI 0.34-1.57 ;
Common molecular genetic mutations in AML
WT1 8 %
TET2 8 %
FLT3 ( ITD , TKD ) 37 %
CEBPA 9 %
NRAS 10 % p = 0.432 ). The overall response rate ( ORR ) was 40 percent ( n = 12 ), with 27 percent of patients ( n = 8 ) achieving CR . Two patients went on to receive allogeneic hematopoietic cell transplantation ( alloHCT ).
Most patients ( 70 %; n = 21 ) experienced at least one AE , the most common of which were gastrointestinal toxicity and febrile neutropenia . Eight patients ( 27 %) had treatment held or withdrawn due to AEs . At four and eight weeks , early
DNMT3A 23 %
NPM1 29 %
Adapted from Patel 2012 . 5
Molecular genetic testing may be an important factor that can be utilized to facilitate clinical decision-making 4
References : 1 . National Cancer Institute . SEER Stat Fact Sheets : Acute Myeloid Leukemia ( AML ). http :// seer . cancer . gov / statfacts / html / amyl . html . Accessed September 20 , 2016 . 2 . Deschler B , Lübbert M . Acute myeloid leukemia : epidemiology and etiology . Cancer . 2006 ; 107 ( 9 ): 2099-2107 . 3 . Ferrara F , Schiffer CA . Acute myeloid leukaemia in adults . Lancet . 2013 ; 381 ( 9865 ): 484-495 . 4 . Referenced with permission from the NCCN Clinical Practice Guidelines In Oncology ( NCCN Guidelines ® ) for Acute Myeloid Leukemia V . 2.2016 . © National Comprehensive Cancer Network , Inc 2016 . All rights reserved . Accessed September 20 , 2016 . To view the most recent and complete version of the guideline , go online to NCCN . org . NATIONAL COMPREHENSIVE CANCER NETWORK ® , NCCN ® , NCCN GUIDELINES ® , and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network , Inc . 5 . Patel JP , Gönen M , Figueroa ME , et al . Prognostic relevance of integrated genetic profiling in acute myeloid leukemia . N Engl J Med . 2012 ; 366 ( 12 ): 1079-1089 .
mortality was 10 percent and 20 percent , respectively .
The authors noted that the presence of more than one eligibility criteria ( what are typically considered exclusion criteria in clinical trials ) was associated with a lower likelihood of 60-day survival ( p = 0.04 ). They added that “ a majority of patients were able to complete at least one cycle of therapy without major toxicity and obtain clinical benefit with acceptable responses and survival despite their high comorbidity burden .”
The authors expanded the study to include 79 patients who were enrolled between September 2011 and March 2014 and who were randomized to receive azacitidine ( n = 27 ; 34 %) or azacitidine plus vorinostat ( n = 52 ; 66 %).
The median follow-up was 22.7 months ( range = 12.6-47.5 months ), with patients receiving a median of three treatment cycles ( range = 1-12 cycles ). Seventy-nine percent of patients were alive at 60 days ( n = 62 ), and , unlike in the exploratory study , patients with MDS in this expanded study experienced longer median OS with a trend toward significance ( 10.6 vs . 4.4 months ; HR = 0.5 ; 95 % CI 0.1-8.3 ; p = 0.07 ) and significantly longer EFS ( 5.7 vs . 2.9 months ; HR = 0.1 ; 95 % CI 0.3-0.8 ; p = 0.04 ), compared with patients with AML . The ORR was slightly higher in the expanded patient cohort ( 47 %; n = 37 ), with 25 percent of patients achieving CR ( n = 20 ). Patients responded after receiving a median of two treatment cycles ( range = 1-12 cycles ), and the mediation duration of response was 7.4 months ( range = 4.9-9.9 months ).
Most patients ( 82 %; n = 65 ) experienced at least one AE , with grade 3 fatigue , dyspnea , and neutropenic fever being the most common . However , the stopping rule for toxicity was not met .
At the time of the study ’ s publication , 85 percent of patients ( n = 67 ) had died , with four- and eight-week early mortality at 10 percent and 19 percent , respectively .
“ These findings suggest relaxation of [ organ dysfunction , poor performance status , and other comorbidities ] exclusion criteria may increase the pool of clinical trial candidates and allow access to potential beneficial therapies for patients with an otherwise dismal prognosis ,” the authors concluded . “ These [ exclusion ] criteria are in place more to protect the drug or intervention being studied as opposed to the patients .”
Limitations include the heterogeneous patient population , which limits the ability to extrapolate outcomes to specific patient populations . In addition , quality of life was not assessed , which is an important clinical outcome in a patient population with high comorbidities and decreased expected survival . ●
REFERENCE
Montalban Bravo G , Huang X , Jabbour E , et al . A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials . Leukemia . 2016 ; 30:303-8 .
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