Page 50 - Haematologica - Vol. 105 n. 6 - June 2020

A. Bazarbachi et al.
has been made in frontline treatments with the incorporation of FLT3 inhibitors and the development of highly sensitive minimal/measurable residual disease assays. Similarly, recent progress in allogeneic hematopoietic SCT includes improvement of transplant techniques, the use of haplo-identical donors in patients lacking an HLA matched donor, and the introduction of FLT3 inhibitors as post-transplant main- tenance therapy. Nevertheless, current transplant strategies vary between centers and differ in terms of transplant indications based on the internal tandem duplication allelic ratio and concomitant nucleophos- min-1 mutation, as well as in terms of post-transplant maintenance/consolidation. This review generated by international leukemia or transplant experts, mostly from the European Society for Blood and Marrow Transplantation, attempts to develop a position statement on best approaches for allogeneic hematopoi- etic SCT for AML with FLT3-internal tandem duplication including indications for and modalities of such transplants and on the potential optimization of post-transplant maintenance with FLT inhibitors.
Introduction
FMS-like tyrosine kinase 3 (FLT3) is a transmembrane ligand-activated receptor tyrosine kinase that is normally expressed by hematopoietic stem cells and early myeloid and lymphoid progenitor cells, and is involved in the pro- liferation, differentiation and apoptosis of hematopoietic cells1 through various signaling pathways, including phos- phatidylinositol 3-kinase (PI3K) and rat sarcoma (RAS) sig- nal-transduction cascades.2-7 FLT3 is mutated in about 25- 30% of newly diagnosed cases of acute myeloid leukemia (AML),8-10 either by internal tandem duplications (FLT3- ITD) of the juxtamembrane domain (19-25%), and/or by a point mutation, usually involving the tyrosine kinase domain (TKD) at D835 or I836 in the activating loop (7- 10%).11-13 Both mutations are more frequent in cytogeneti- cally normal AML and both constitutively activate FLT3 causing dimerization in a ligand-independent manner, resulting in proliferation and survival of leukemia cells.14,15
FLT3-ITD mutations in newly diagnosed AML are asso- ciated with a greater disease burden, manifesting as an ele- vated white blood cell count and a high percentage of blasts at the time of diagnosis as well as a tendency to early relapse and a poor overall prognosis.8,10-12,16,17 Both European LeukemiaNet (ELN) recommendations and National Comprehensive Cancer Network (NCCN) guide- lines incorporate FLT3-ITD mutations in risk-stratifying patients based on allelic burden and nucleophosmin-1 (NPM1) co-mutation.18,19 In cytogenetically normal patients, FLT3-ITD mutations in the presence of a con- comitant NPM1 mutation, mainly when the FLT3-ITD allele ratio is low (<0.5), fare better than those with wild- type NPM1.8,10,16,17,20-22 Despite the great effort to harmonize and cross-validate the FLT3 assays within clinical trials,23 there is still no consensus on the FLT3-ITD allele ratio threshold and there is considerable variability between centers in the assessment of the FLT3-ITD ratio according to the technique used, if one is available. Furthermore, in addition to NPM1 mutations, a significant overlap with other mutations (WT1, IDH1, DNMT3A) as well as NUP98/NSD1 fusions modify outcome as well as response to therapy. Although patients with FLT3-ITD AML respond to conventional induction chemotherapy with remission rates similar to those seen in other sub- types of AML, they are much more likely to relapse and to relapse quickly.11,12,24-28 The prognostic impact of FLT3-TKD is less clear,29-32 but it, too, is influenced substantially by NPM1 co-mutation which confers a better prognosis.33-35
The availability of active FLT3 inhibitors that are able to disrupt the oncogenic signaling initiated by FLT3 has improved the overall survival (OS) of patients with FLT3- mutated AML.36 Midostaurin, a multikinase inhibitor, was granted Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for the treat- ment of patients with newly diagnosed FLT3-mutated AML, in combination with intensive chemotherapy, and by the EMA in addition as maintenance treatment after conventional consolidation therapy. This approval was based on the results of the RATIFY trial, which demon- strated that the combination of midostaurin with standard induction therapy resulted in significantly prolonged OS (not censored for transplant) for AML with either FLT3- ITD or FLT3-TKD mutations.37 The benefit was particular- ly remarkable in patients who went on to receive allo- geneic hematopoietic stem cell transplantation (allo-SCT) in first complete remission (CR1). Following the results of the ADMIRAL trial, gilteritinib, a second-generation FLT3 inhibitor, was recently approved for relapsed/refractory FLT3-mutated AML with FLT3-ITD and FLT3-TKD muta- tions.38 Promising data were also reported for quizartinib and crenolanib.39,40 Finally, because of its long-time avail- ability, sorafenib has been tested, alone or in combination, in various settings in FLT3-ITD AML, such as first-line therapy41,42 or for the treatment of disease relapse,43-45 including after failure of allo-SCT.45-57 However, recent data appear to support incorporating sorafenib into the treatment of patients with FLT3-mutated AML, possibly with induction therapy41,58,59 as well as maintenance thera- py after allo-SCT.43,60-65
Because of the diversity in FLT3-mutated AML, which depends on the type of FLT3 mutation, FLT3-ITD allelic burden, insertion site and co-occurring mutations, the decision regarding whether to perform allo-SCT in CR1 is becoming more challenging.66-75 With the use of more effective therapies, especially with the incorporation of FLT3 inhibitors, deeper responses are being achieved. The assessment of minimal/measurable residual disease (MRD) at the time of response has enabled prediction of outcomes in AML, and tailoring of post-remission thera- peutic strategies accordingly.76-78 Additionally, substantial progress has been made in allo-SCT in recent years, including improvement of transplant techniques, the use of haplo-identical donors in patients lacking an HLA- matched donor,79-81 and post-transplant preventive strate- gies, such as prophylactic or preemptive use of FLT3 inhibitors.63,82-85 Nevertheless, current transplant strategies
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