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A. Burchert
come, RFS, was comparable for midostaurin- and SOC- treated patients. Thus, the RADIUS-trial does not support a role for midostaurin as maintenance drug post HCT in FLT3-ITD-mutated AML.
An uncontrolled phase II study suggested that midostaurin maintenance post HCT was more efficacious than midostaurin maintenance after conventional chemotherapy/midostaurin combination therapy (Table 2). Of interest, only 75 of 134 patients (56%) ultimately proceeded to post-HCT maintenance, and most of these patients (59%) stopped maintenance earlier (after a medi- an of 9 months).49
Gilteritinib and crenolanib
Maintenance trials with gilteritinib and crenolanib are ongoing (Table 2). The placebo-controlled, Astellas-spon- sored trial (MORPHO) plans to randomize 346 FLT3- mutated AML patients who were transplanted in first complete hematologic remission. Recruited patients will be stratified according to minimal residual disease (MRD) levels post HCT. The MORPHO trial is expected to report results in 2025.
Sorafenib
Evidence is available from two recently published ran- domized trials: 1) the placebo controlled SORMAIN trial (recruitment period 2010-2015);63 and 2) an open label phase III trial from China (recruitment period 2015- 2018)64 evaluating whether sorafenib maintenance post HCT improves progression-free survival (PFS) and OS in FLT3-ITD+ AML.
In SORMAIN, 83 patients were recruited. The primary endpoint, RFS, was significantly better with sorafenib. After a median follow-up of 41.8 months in SORMAIN, median RFS was not reached with sorafenib versus 30.9 months with placebo (HR 0.39, 95%CI: 0.18-0.85; P=0.013).63 During the first two years after randomiza- tion, the risk of relapse or death was reduced by 75% (HR 0.25, P=0.002).63 In the Chinese phase III trial, 202 patients were randomized to receive sorafenib versus placebo. The median follow-up duration is 21.3 months.64 The 2-year leukemia-free survival was 78.9% versus 56.6% (HR 0.37, 95%CI: 0.22-0.63; P<0.0001), which is comparable to that in the SORMAIN trial. At 24 months, OS was higher with sorafenib versus placebo in both the SORMAIN trial (90.5% vs. 66.2%; HR 0.24, 95%CI: 0.08- 0.74; P=0.007) and the phase III trial (82.1% vs. 68.0%, HR 0.48, 95%CI: 0.27-0.86; P=0.012).
In both trials, sorafenib was well tolerated because tox- icities could be managed with dose reductions without losing efficacy.
An important aspect of the SORMAIN trial were prospectively acquired MRD data. Although based on a relatively small number of patients, data suggest that sorafenib maintenance is especially beneficial for patients who are already in very good remission at the time of transplantation; among MRD- patients prior to allo-HCT, there were 0 of 9 relapses with sorafenib versus 5 of 12 relapses with placebo (P=0.028).63
Because a large number of retrospective studies had pre-
viously established that MRD levels prior and post HCT inversely correlate with probabilities of RFS and OS,65,66 SORMAIN data lend further support to the notion that achieving MRD-negativity prior to HCT could become an important treatment goal in this high-risk AML subtype. Thus, achievement of low MRD level prior to HCT, such as, for example, through a chemotherapy/ FLT3-TKI com- bination treatment67 (see trials in Table 2), would support the use of sorafenib maintenance post HCT.
Open questions and future directions
SORMAIN data and the phase III results from Xuan et al. establish TKI maintenance treatment post HCT as a novel and efficacious therapy.63,64 Data from these two tri- als reveal an unprecedented therapeutic potency of an FLT3-kinase inhibitor if applied in the context of CR after HCT. In such a context, FLT3-inhibition could maintain CR in the vast majority of patients, who would otherwise relapse. In particular, especially patients with no MRD prior to HCT (but also patients with MRD-positivity after HCT) seem to gain great benefit from FLT3-TKI (sorafenib) maintenance. Thus FLT3-TKI treatment in remission might be a clue as to how to significantly improve the detrimental natural course of FLT3-ITD mutated AML.63
Many important questions remain. For example, what is the mechanism underlying these potentially curative effects of sorafenib? It should be emphasized once again that sorafenib is a multi-targeted TKI and that its efficacy in AML can be also FLT3-ITD independent, as evidenced by the SORAML trial, which treated mainly FLT3-ITD- AML patients.42 Results from ongoing randomized TKI maintenance therapy trials will help clarify whether the benefit of FLT3-TKI maintenance is compound (sorafenib)-specific or whether less promiscuous, highly FLT3-specific inhibitors such as gilteritinib or quizartinib offer comparable or even better benefits (Table 2).
Secondly, the optimal duration of maintenance therapy is unclear: 12 months (as in the phase III study) versus 24 months (as in SORMAIN), or potentially even longer. Finally, it will be important to explore whether the con- cept of targeted maintenance therapy in remission after HCT is generally applicable also to novel, AML-approved signaling inhibitors such as the BCL-2 inhibitor veneto- clax68 or the IDH1/2-inhibitors enasidenib/ivosidenib.69,70 Recent positive results from maintenance trials using the oral hypomethylating compound CC-486,71 azacytidine72 or decitabine73 demonstrate that maintenance chemother- apy can meaningfully improve OS.
Disclosures
AB has received research support from Novartis, BMS, and AOP Orphan. He has received honoraria and sits on the advi- sory boards of BMS, AOP Orphan, Pfizer, and Abbvie.
Funding
AB was supported by the DFG (GRK 2573) and the German Carreras Leukemia Foundation (16R/2019).
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haematologica | 2021; 106(3)