Page 51 - Haematologica - Vol. 105 n. 6 - June 2020

EBMT ALWP recommendation for allo-SCT for FLT3 AML
vary between centers and differ in terms of indications for the transplants and treatments following them. This review provides a consensus from European Society for Blood and Marrow Transplantation (EBMT) experts on best approaches to allo-SCT in AML with FLT3-ITD including the indications for and modalities of allo-SCT and on potential optimization of post-transplant mainte- nance therapy with FLT3 inhibitors.
The consensus process
Two chairpersons (AB and MM) appointed a panel of 32 physicians (hereafter referred to as the Panel) selected mostly from the EBMT) for their expertise in research and clinical practice in AML and allo-SCT. A physician with expertise in clinical epidemiology (ML) ensured the methodological correctness of the process. The objective of the Panel was to identify practical issues pertinent to all physicians involved in the therapeutic management of patients undergoing allo-SCT for AML with FLT3 muta- tions and to generate best practice recommendations on indications for and modalities of allo-SCT and on potential optimization of post-transplant maintenance with FLT3 inhibitors. This was done through a number of questions according to the Delphi technique.86 A search for relevant literature in English was performed in the MEDLINE, EMBASE and PubMed databases (up to August 2019). Most of the studies used for these recommendations are retrospective cohort studies or phase II trials, with only a few prospective randomized trials. Three panelists drafted statements that addressed the key questions identified, and the remaining panelists scored their agreement with those statements and provided suggestions for rephrasing them.
The evaluation of evidence and the subsequent recom- mendations were graded according to the system used by Couriel.87 The strength of the recommendations (Online Supplementary Table S1) and evidence levels (Online Supplementary Table S2) were rated by all participants of the consensus process.
Overview of prognosis and current indications for allogeneic stem-cell transplantation in FLT3-mutated acute myeloid leukemia
The indication for allo-SCT in FLT3-ITD AML depends largely on FLT3 variables (allelic burden, insertion site and co-occurring mutations), on disease status (including MRD), and on the use of FLT3 inhibitors during induc- tion/consolidation treatment, in addition to other patient-, donor- and graft-related factors. Unfortunately, there are no prospective randomized trials evaluating the best post-remission therapeutic strategy in FLT3-mutated AML, taking in consideration all the diverse combinations.
Several recent reports have suggested that allele burden might affect prognosis of FLT3-ITD AML treated with standard induction chemotherapy.17,22,88,89 Indeed, the pres- ence of a high allelic burden of FLT3-ITD mutations (≥0.5) confers a poor prognosis.12,27,90,91 Several studies have demonstrated that allo-SCT significantly improves sur- vival outcomes in this category69, 92-95 and that the negative impact of high allele burden might be overcome when patients undergo allo-SCT in CR1.17 Therefore, all patients with FLT3-ITDhigh should be considered for allo-SCT in CR1.66,69,92-96 These patients still face higher rates of early
relapse and poor responses to further therapy and eventu- ally poor long-term survival.92,97 The worst prognosis is observed in patients who relapse after allo-SCT, who have predicted 1-year OS rates below 20%.98 However, a sub- category of patients with FLT3-ITDhigh/NPM1 mutation of the ELN intermediate-risk group treated with FLT3 inhibitors, and who achieve MRD negativity, may be offered the possibility of post-remission consolidation with longitudinal MRD monitoring of NPM1.91 This approach should be undertaken with caution, and prefer- ably within a clinical trial, since recent data suggest the possible extinction of the NPM1 clone after chemothera- py while the FLT3-ITD clone persists.
Additional mutations may, however, influence the prog- nosis of AML with FLT3-ITD. For example, the co-exis- tence of NPM1 mutation with FLT3-ITD is associated with improved outcomes, particularly in patients with a low FLT3 allelic ratio (<0.5).8,10,16,20 According to the 2017 ELN recommendations, this subcategory is stratified as favorable risk, advocating against the need for allo-SCT.91 Nonetheless, the good prognosis of a low allelic ratio is not universally recognized, with data suggesting better outcome for allografted patients regardless of NPM1 mutation status.99 A threshold for FLT3 allelic burden is also controversial and differs according to studies. It was mainly based on the median of the mutant-to-wildtype ratio found in different retrospective studies. For example, in one study evaluating the prognostic factors of newly diagnosed AML, a FLT3 ratio above 0.78 was associated with worse survival, whereas in another study the thresh- old was 0.51.11,17 Therefore, the allelic burden has a contin- uous effect on survival outcomes and a ratio of 0.5 is a chosen threshold based on maximum clinical prognostic data. With the advent of FLT3 inhibitors in the frontline treatment of FLT3-mutated AML, the OS has improved regardless of the allelic burden and the use of allo-SCT. Whether NPM1-mutant FLT3-ITDlow AML warrants post- remission allo-SCT in CR1 or not is still debatable. Although some studies analyzing the effect of allo-SCT in patients with NPM1-mutant FLT3-ITDlow found no improvement in OS or relapse risk, we must take into con- sideration the retrospective nature of the analysis and the small number of patients with a non-statistically signifi- cant improvement in OS and relapse risk.17,22 Interestingly, patients with newly diagnosed AML with NPM1-mutant FLT3-ITDlow treated with frontline midostaurin and inten- sive chemotherapy, had a 3-year OS rate of around 75%. In a retrospective subgroup analysis, the benefit of allo- SCT was only seen in the adverse ELN subgroup [hazard ratio (HR)=0.39; P=0.003], but not in the favorable (HR=0.78; P=0.62) and intermediate risk subgroups (HR=0.81; P=0.53).91 These findings should, however, be interpreted with caution as the RATIFY trial was not pow- ered to demonstrate a difference of benefit of allo-SCT among diverse FLT3-ITD/NPM1 genotypes. For example, the total number of patients in the favorable ELN sub- group was 85 and these patients were divided into four small groups according to whether they did or did not receive midostaurin and/or allo-SCT in CR1.91
The deleterious effect of FLT3-ITD was most clinically relevant in patients with concomitant NPM1 and DNMT3A mutations, suggesting that AML patients with NPM1, FLT3-ITD and DNMT3A mutations (triple-positive AML) should be transplanted regardless of the FLT3-ITD allelic ratio.8 A recent study conducted on 147 patients
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