Page 53 - Haematologica - Vol. 105 n. 6 - June 2020

EBMT ALWP recommendation for allo-SCT for FLT3 AML
bined with donor lymphocyte infusions are rarely effec- tive in the long term,45-50 even though a small proportion of patients who relapse after allo-SCT can achieve long- lasting responses with sorafenib.52,54,55,57 A second allo-SCT can be offered to only a small percentage of patients and is associated with a rather high non-relapse mortality rate.111 Several studies have, therefore, investigated the use of post-transplant maintenance with FLT3 inhibitors as a strategy aimed to reduce relapse after allo-SCT.112
Midostaurin was not offered as maintenance therapy to recipients of allo-SCT in the RATIFY study,113 but the RADIUS phase II randomized trial compared post-trans- plant midostaurin maintenance with standard care in 60 adult patients.114 Estimated relapse rates at 18 months were 24% in the standard care group and 11% in the midostaurin group (P=0.27).114 In another prospective phase II study, maintenance midostaurin was also offered to FLT3-mutated AML patients undergoing allo-SCT in CR1. In a landmark analysis in patients who were event free at day 100 after transplant (n=116), those who start- ed maintenance therapy within 100 days after their trans- plant (n=72) had a significantly better OS than those who did not.115 The main cause of early discontinuation of maintenance midostaurin after allo-SCT (23%) was poor tolerability, mainly as a result of gastrointestinal toxici- ty.114
Sorafenib has been studied as maintenance therapy fol- lowing allo-SCT, demonstrating benefit with regards to survival and improved outcomes in a phase I study, a pilot study, a single-center study, a multicenter study, a registry study and a randomized study.60-65,116 A phase I trial (NCT01398501) was conducted in which 22 FLT3-ITD AML patients received twelve 28-day cycles of sorafenib 45-120 days after allo-SCT.61 The maximum tolerated dose was established at 400 mg twice daily. The 1-year progression-free survival (PFS) rate was 85% with a cor- responding 1-year OS of 95%. In a pilot study, six patients with FLT3-ITD AML received sorafenib (n=5 maintenance, n=1 salvage) after allo-SCT with similarly encouraging results.116 Five of these patients developed cutaneous corticosteroid-sensitive GvHD within a few days after sorafenib initiation, suggesting a possible immunomodulatory effect, and remarkably all patients had sustained molecular remissions.
In a single-institution, observational study on FLT3-ITD AML patients transplanted in CR1, 26 patients who received sorafenib as maintenance treatment after allo- SCT were compared to 55 historical controls who did not.62 The sorafenib cohort had a better 2-year OS rate (81% vs. 62%), improved PFS (82% vs. 53%), and lower relapse incidence (8% vs. 38%).
In a multicenter study, 27 FLT3-mutated AML patients (aged 15-57 years) received maintenance therapy with sorafenib as a single agent after allo-SCT.60 At a median follow-up of 18 months, 25 patients were in complete remission with full donor chimerism, with 1-year PFS and OS rates reaching 92%. Updated results after a median follow-up of 40 months further demonstrated favorable long-term outcomes in patients receiving sorafenib main- tenance therapy, with 2-year PFS and OS rates reaching 73% and 80%, respectively, with an acceptable toxicity profile.65
A recent large EBMT registry study assessed outcomes in 462 allografted FLT3-mutated AML patients over a median follow-up of 39 months for surviving patients.63
Twenty-eight patients received post-transplant sorafenib maintenance treatment, initiated at a median of 55 days after transplantation (range, 1-173) at a median dose of 800 mg/day (range, 200-800 mg/day). Thirteen patients in the sorafenib group had chronic GvHD at a median time of 76 days after the initiation of sorafenib (range, 9-194 days). Chronic GvHD was limited in seven patients and extensive in six. On multivariate analysis, post-transplant maintenance with sorafenib significantly reduced the relapse incidence (HR=0.39; P=0.05), and improved LFS (HR=0.35; P=0.01), OS (HR=0.36; P=0.03) and GFRS (HR=0.44; P=0.02). Matched-pair analysis was also per- formed on 52 patients (26 in the sorafenib group and 26 controls) who engrafted and survived after allo-SCT with no relapse or grade II-IV acute GvHD until sorafenib ini- tiation. The 2-year LFS and OS rates were 79% and 83%, respectively, in the sorafenib group (P=0.02) versus 54% and 62%, respectively, in the controls (P=0.007).
More recently, preliminary conclusions of a double- blind, prospective trial (SORMAIN) that randomized patients to either maintenance treatment with sorafenib or placebo introduced during the first 60-100 days after allo-SCT provided further support for the use of this drug in this high-risk setting.64 Eighty transplanted FLT3-ITD adult AML patients were randomized 1:1 to receive either sorafenib (up to 400 mg twice daily) or placebo for up to 24 months. After a median follow-up of 42 months, the median RFS was 31 months in the placebo group whereas it was ‘not reached’ in the sorafenib group (corresponding to a 2-year RFS of 53% vs. 85%: HR 0.39; P=0.01). Sorafenib was well-tolerated with toxicities that were generally manageable, mostly by dose reduction. These findings build on previously reported data and confirm that sorafenib maintenance therapy after allo-SCT in FLT3-ITD AML patients is both safe and efficient in sig- nificantly reducing CIR and improving survival.
In addition to sorafenib’s direct anti-leukemic effect, a possible synergism between the drug and alloreactive donor T cells in facilitating long-term disease control has been suggested,117 and has also been proposed in murine models in which sorafenib apparently exacerbated GvHD.118 A recent study demonstrated that sorafenib pro- motes graft-versus-leukemia activity in mice and humans through interleukin-15 production in FLT3-ITD leukemia cells.119
Gilteritinib is also currently being prospectively assessed for maintenance use in FLT3-ITD AML after allo- SCT in a phase III, randomized, double-blind, placebo- controlled multicenter trial (NCT02997202).120 This study aims to enroll 346 adult patients with AML in CR1, ran- domized 1:1, to receive either gilteritinib 120 mg or place- bo for 2 years. In addition, a large phase III randomized study (NCT04027309) by a consortium of several cooper- ative study groups, including HOVON, AMLSG, SAKK, ALFA, CETLAM, PETHEMA, FILO and ALLG, is antici- pated to start enrolling by the end of 2019: patients will be randomized to midostaurin or gilteritinib added to standard induction and consolidation treatment. Patients who achieve complete remission will continue mainte- nance with either midostaurin or gilteritinib.
Finally, the recent approval of midostaurin for frontline treatment of FLT3-mutated AML in the USA and Europe may challenge the role of post-transplant maintenance therapies, including sorafenib. Accordingly, new data should be generated in this setting.121,122 Most FLT3-mutat-
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