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While 10.6 % of cases had arterial complications ( n = 25 ), no difference was found between the two groups in the arterial complication rate ( 12.4 % vs . 9 %; p = 0.83 ). Additionally , 2.1 % of patients experienced venous complications other than PVT recurrence , with no difference between the two groups ( 2.7 % vs . 1.6 %; p = 0.67 ).
There was also no significant difference between the two groups in terms of graft ( p = 0.11 ), patient survival ( p = 0.44 ), or the incidence of arterial complications ( 12.4 % vs . 9 %; p = 0.83 ).
In a univariate analysis , researchers found that the only significant risk factor for PVT recurrence was recipient age ( odds ratio = 0.94 ; 95 % CI 0.89-0.99 ; p = 0.03 ).
“ [ These findings ] provide valuable data regarding the usefulness of therapeutic anticoagulation pre- and post-transplant .”
— Isabel Bos , MD
In a subgroup analysis that considered only patients who presented with Yerdel grade 2 PVT ( n = 88 ), a significantly greater proportion of patients who received therapeutic anticoagulation experienced bleeding events ( 27.3 % vs . 3 %; p < 0.01 ), but there were no differences in the need for surgical revision between the two groups ( 10.9 % vs . 3 %; p = 0.25 ).
The study was limited by its retrospective nature , differences in recipient and graft characteristics between the two groups , and exclusion of patients with extensive grade III / IV PVT . Despite these limitations , the researchers concluded that the findings “ provide valuable data regarding the usefulness of therapeutic anticoagulation in the pre- and post-transplant period that will help clinicians in their decisions .”
The authors report no relevant conflicts of interest .
Reference Bos I , Blondeau M , Wouters D , et al . Therapeutic anticoagulation after liver transplantation is not useful among patients with pre-transplant Yerdel-grade I / II portal vein thrombosis : A two-center retrospective study [ published online ahead of print , 2021 Jul 23 ]. J Thromb Haemost . doi : 10.1111 / jth . 15472 .
Study Explores Molecular Landscape , Prognostic Impact of FLT3-ITD Insertion Site in Patients With AML
In an analysis of the phase III RATIFY trial published in Leukemia , researchers examined the molecular landscape of FLT3 internal tandem duplication ( ITD ) mutations in acute myeloid leukemia ( AML ), confirming this subtype ’ s distinct heterogeneity and the negative prognostic impact of the tyrosine kinase domain-1 ( TKD1 ) insertion site ( IS ).
The retrospective study , led by Frank Rücker , MD , of the University Hospital of Ulm in Germany , looked at the prognostic impact of FLT3-ITD IS in 452 patients with AML who participated in the randomized , placebo-controlled RATIFY trial , which evaluated the effects of midostaurin plus intensive chemotherapy in 717 patients with AML and activating FLT3 mutations .
In the current analysis , patients assigned to placebo more often had a normal karyotype , compared to those who received midostaurin ( 80.1 % vs . 62.2 %; p < 0.001 ). Placebo-treated patients also more often had an NPM1 mutation ( NPM- 1 mut ; 64.3 % vs . 50.0 %; p = 0.008 ), and favorable genotype NPM1 mut / FLT3-ITD low ( 23.9 % vs . 14.7 %; p = 0.031 ).
A total of 908 ITDs were identified with next-generation sequencing ( NGS ), including 643 insertions in the juxtamembrane domain ( JMD ), as well as 265 insertions in the TKD1 . Based on IS , patients were classified as :
• JMDsole ( n = 251 ; 55 %)
• JMD and TKD1 ( JMD / TKD1 ; n = 117 ; 26 %)
• TKD1sole ( n = 84 ; 19 %)
Overall , there were no significant differences between the three groups in regard to clinical variables .
Approximately 55 % of FLT3-ITD + patients with AML ( n = 452 ) died during a median follow-up of 60.6 months . The median overall survival ( OS ) rate was 24.4 months , and the estimated four-year OS probability was 0.43 . The estimated four-year OS probabilities were significantly greater among patients in the JMD / TKD1 group ( 0.50 ) compared with the JMDsole ( 0.44 ) and TKD1sole ( 0.30 ) groups ( p = 0.032 ).
Cox regression analyses revealed the following unfavorable factors for OS :
• higher white blood cell ( WBC ) count ( HR = 1.12 ; 95 % CI 1.03-1.23 ; p = 0.010 )
• advancing age ( HR = 1.17 ; 95 % CI 1.02-1.43 ; p = 0.029 )
In contrast , favorable factors for OS were NPM- 1 mut ( HR = 0.58 ; 95 % CI 0.43-0.78 ; p < 0.001 ) and hematopoietic cell transplantation ( HCT ) in first complete remission ( HR = 0.46 ; 95 % CI 0.30-0.70 ; p < 0.001 ). The use of multikinase inhibitor midostaurin demonstrated no beneficial effect on OS , the researchers noted .
Looking at the risk for relapse , the researchers found that FLT3-ITD IS in TKD1sole ( vs . JMDsole ), higher WBC count , and higher NGS-based calculated FLT3-ITD allelic ratio per patient were associated with a greater cumulative incidence of relapse . In contrast , NPM1 mut and HCT in first complete remission were associated with a reduced risk of relapse . Again , midostaurin showed no impact on relapse risk .
The authors also observed superior outcomes among patients with the JMDsole / NPM1 mut genotype who received additional treatment with midostaurin . In this genotype , the four-year rates for OS and relapse with either midostaurin or placebo were 65 % versus 44 % ( p = 0.016 ) and 30 % versus 53 % ( p = 0.018 ), respectively . The JMDsole / NPM1wt genotype was the only other genotype that benefited from additional treatment with midostaurin , they added .
“ The results from this retrospective analysis of the RATIFY trial further classify the molecular landscape of FLT3-ITD ,” the authors wrote . The data also show that the negative impact of TKD1 insertions might not be overcome by treatment with the multikinase inhibitor midostaurin . This clinical observation “ does not only confirm the known resistance to chemotherapy of patients with TKD1 insertions , but also to tyrosine kinase inhibitor ( TKI ) treatment , which is in line with preclinical data ,” they added .
“ Furthermore , the significantly higher [ relapse ] rate for patients with TKD1 insertions compared to patients with JMDsole insertions might reflect different patterns of clonal evolution and acquired co-mutations mediating secondary resistance to TKIs between these groups .”
The authors report no relevant conflicts of interest .
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• FLT3-ITD IS in TKD1sole vs . JMDsole ( hazard ratio [ HR ] = 1.61 ; 95 % CI 1.10-2.34 ; p = 0.014 )
• JMD / TKD1 ( HR = 2.17 ; 95 % CI 1.29-3.67 ; p = 0.004 )
Reference Rücker FG , Du L , Luck TJ , et al . Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia : RATIFY study results [ published online ahead of print , 2021 Jul 28 ]. Leukemia . doi : 10.1038 / s41375-021-01323-0 .
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