Page 52 - Haematologica - Vol. 105 n. 6 - June 2020

A. Bazarbachi et al.
found that NPM1-positive AML with low allelic FLT3- ITD still had an unfavorable outcome, with an OS rate of only 41%, but with significant improvements in both relapse-free survival (RFS) and OS for those allografted in CR1.99 This challenges the notion of withholding trans- plant for patients with supposedly favorable outcomes. In that sense, a recent study from the MD Anderson Cancer Center showed that allo-SCT improved leukemia-free sur- vival (LFS) and OS independently of the FLT3-ITD allelic ratio and NPM1 mutation status.100 This fits with recent NCCN guidelines still offering allo-SCT for all patients with FLT3-ITD mutations regardless of allelic ratio or NPM1 mutation status.18
On the other hand, patients with a low allelic ITD ratio lacking an NPM1 mutation (and lacking other adverse risk mutations) are currently considered intermediate risk, hence in a gray prognostic area with no proper consensus on optimal treatment strategy. There is conflict regarding the current practice between proceeding to allo-SCT for these patients or limiting allo-SCT only to those who do not achieve MRD negativity by multiparametric flow cytometry. Indeed, technical limitations prevent the use of FLT3 mutation for assessment of MRD which must there- fore rely on multiparametric flow cytometry.101 Finally, Versluis et al. reported that in patients with wildtype NPM1 AML without FLT3-ITD or with a low allelic ratio of FLT3-ITD, reduced intensity conditioning allo-SCT resulted in better OS and RFS rates as compared with chemotherapy or autologous SCT.89
Overall, limitations to the universal incorporation of FLT3-ITD allelic ratio into routine clinical practice and the treatment algorithm include the lack of a clear cut-off (0.5 in the ELN recommendations, 0.7 in the RATIFY study) and the potential variability of the allelic ratio over time. A global effort is needed to standardize the technique for determining the FLT3-ITD allelic ratio, making it universal with calibration of all laboratories, reminiscent of the glob- al exercise the world did for BCR/ABL1. Similarly, the def- inition of high and low allelic ratio should also be standard- ized with a clear consensus on a cut-off level. Until these technical challenges are addressed, the transplant indica- tion remains controversial in patients with FLT3-ITD who belong to the ELN favorable risk group (low allelic ratio <0.5 with concomitant NPM1 mutation) and who achieve MRD negativity. Many European cooperative groups fol- low the ELN algorithm, deferring allo-SCT in patients with NPM1-mutant FLT3-ITDlow, unless there is molecular per- sistence of NPM1. Thus, performing MRD assessment reg- ularly to decide on allo-SCT timing is crucial when select- ing this approach. Conversely, the NCCN guidelines are still advocating allo-SCT in CR1 in this setting.
Finally, data on the prognosis of FLT3-TKD AML remain conflicting, with some studies suggesting a negative impact of TKD mutations on LFS and OS,11,25,30 while oth- ers suggesting no prognostic effect, or even a benefit when a NPM1 mutation is present.29,32,34,35
Hematopoietic stem cell transplantation and factors predictive of outcome
As stated above, because of the poor prognosis associat- ed with FLT3-ITD mutated AML, allo-SCT was most fre- quently performed in patients in CR166-74,102 including fit patients ≥60 years of age.103 In most studies, the LFS rate at 2 years ranges between 50 to 60% in that setting,66,92,97,104
although a wide variation from 20%70,105 to 70%69 has been reported. There are knowledge gaps about the factors that can predict outcome after allo-SCT.
A previous EBMT study97 reported that patients with
FLT3-ITD mutated AML with concomitant mutated
NPM1 had better post-transplant outcomes compared to
those with wildtype NPM1. Similarly, other studies
reported that the presence of active disease or MRD
before allo-SCT results in poor post-transplant out- comes.106,107
A recent, large EBMT registry study assessed outcomes in 462 allografted FLT3-mutated AML patients with a median follow-up of 39 months for alive patients.63 Forty percent received allo-SCT from matched related donors, 49% from matched unrelated donors and 11% from haploidentical donors. Two-year cumulative incidence of relapse (CIR) and non-relapse mortality rates were 34% and 15%, respectively, whereas LFS, OS and graft-versus-host disease (GvHD)-free. relapse-free survival (GRFS) rates were 51%, 59% and 38%, respectively. On multivariable analysis, the need for more than one induction treatment negatively affected outcome, while prescribing an allo-SCT in CR1 resulted in improved CIR, LFS and OS. Presence of an NPM1 mutation was also associated with better outcomes, including better CIR, LFS, OS and GRFS. Post-transplant maintenance therapy with sorafenib significantly reduced the CIR and improved LFS, OS and GFRS. Outcomes were not affected by the type of donor or conditioning intensity. An important finding from this study was that in vivo T-cell depletion with antithymocyte globulin decreased chronic GvHD and significantly improved LFS, OS and GRFS, with- out an apparent increase in the risk of relapse. This indi- cates that, even in the setting of FLT3-mutated AML, in vivo T-cell depletion does not appear to abrogate the graft-versus- leukemia effect. Finally, the use of haplo-identical donors was associated with improved GRFS compared to that achieved with other types of donors. Given the high risk of rapid relapse of patients with FLT3-mutated AML in CR1 and the poor outcome of allo-SCT in CR2 or beyond,11,12,108 these results and those of a recent EBMT study suggest that, in the absence of a matched sibling donor, performing haplo-identical transplants in CR1 may be considered.109 Furthermore, in another large EBMT study on more than 6,500 adult AML patients allografted in CR1, multivariate analysis confirmed the lack of a statistically significant dif- ference in OS following transplants from matched related donors or 10/10 matched unrelated donors, or haplo-SCT.110 Finally, the results of a CIBMTR, EUROCORD and EBMT collaborative analysis demonstrated that outcomes after umbilical cord blood transplantation are similar to those after allo-SCT from sibling donors for patients with FLT3- ITD AML.110
Post-transplant maintenance in FLT3-mutated acute myeloid leukemia
Even after allo-SCT, FLT3-mutated AML is associated with a higher risk of early relapse (30%-59%) compared to FLT3-wildtype AML.82,92 Indeed, in a CIBMTR analysis of 511 patients (158 with FLT3 mutations), there was an increase in relapse rates in FLT3-mutated AML (38% vs. 28%; P=0.04; relative risk 1.60; 95% CI: 1.15-2.22).74 Satisfactory treatment of patients with FLT3-mutated AML who relapse or progress after allo-SCT, is an unmet need. Chemotherapy or FLT3 inhibitors alone or com-
1510
haematologica | 2020; 105(6)