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Novel targeted therapies post-HSCT for AML/MDS

May 19, 2021

Despite advances in the treatments for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), relapse remains the main cause of treatment failure. Patients with AML or MDS are more susceptible to early relapse after hematopoietic stem cell transplantation (HSCT) due to FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations and unfavorable cytogenetics. The majority of relapses occur during the 6 month period following HSCT; to limit this, treatment is required to assist the graft-versus-leukemia effect, provide sufficient control of minimal residual disease (MRD), and ultimately protect against relapse.

At the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Gesine Bug presented a summary of novel targeted therapies, including FLT3 inhibitors and hypomethylating agents (HMAs), for patients with AML or MDS post-HSCT.1 The presentation is summarized here, including further information on some of the trials that have previously been covered by the AML Hub.

Existing targeted therapies post-HSCT

The evidence on existing targeted therapies post-HSCT was presented as three types based on the intention of each targeted therapy: salvage therapy (used in hematologic relapse after transplant), pre-emptive therapy (used in the presence of MRD donor chimerism), and maintenance therapy (used in the absence of any trace of the disease). Here, we present a brief description of the trials investigating FLT3 inhibitors and HMAs used in these three types of therapies.

Salvage therapy

In 2019, Perl et al.2 published the results of their randomized phase III trial (ADMIRAL; NCT02421939) in The New England Journal of Medicine, which compared gilteritinib to salvage chemotherapy in patients with FLT3-mutated relapsed/refractory AML (N = 371). The primary endpoints were overall survival and complete remission (CR) with full or partial hematologic recovery (CRi). The trial concluded that gilteritinib resulted in a significantly longer overall survival (9.3 months) compared with salvage chemotherapy (5.6 months), and 19.9% of the patients included had undergone prior allogeneic-HSCT (allo-HSCT). The CR/CRi rate was higher in the gilteritinib arm compared with the salvage chemotherapy arm (34.0% vs 15.3%, respectively). See a detailed summary of this study here.

Pre-emptive therapy

Azacitidine was the first drug to be approved for use post-HSCT owing to its significant antileukemic activity. In 2018, Platzbecker et al.3 published the results of the prospective phase II RELAZA2 trial (NCT01462578) in Lancet Oncology, which investigated azacitidine in patients with MDS or AML in CR after receiving either standard chemotherapy or allo-HSCT (N = 198). The primary endpoint was relapse-free survival (RFS) at 6 months from the start of MRD. Over half of the patients (58%) in the MRD-guided azacitidine therapy arm were relapse free (p < 0.0001). The AML Hub has previously summarized key findings from this trial.

Maintenance therapy

The primary results of the phase II RADIUS trial (NCT01883362) were recently published in Bone Marrow Transplantation by Maziarz et al.4 This trial evaluated standard-of-care (SoC) treatment with or without midostaurin in patients with AML following allo-HSCT (N = 60). The primary endpoint was RFS at 18 months following allo-HSCT. In total, 89% of patients in the midostaurin arm achieved RFS, suggesting a favorable primary endpoint; however, the result was not statistically significant compared with the SoC arm. Although, an improved RFS was associated with inhibition of FLT3 phosphorylation to <70% of baseline. The findings from this study have previously been summarized on the AML Hub.

The results from the SORMAIN trial were published in the Journal of Clinical Oncology in 2020 by Burchert et al.5 This trial evaluated the use of sorafenib, a tyrosine kinase inhibitor, as a maintenance therapy vs placebo in patients with FLT3-ITD-positive AML following HSCT (N = 83). The primary endpoint was RFS. Patients in the sorafenib arm showed a higher probability of RFS compared with those in the placebo arm (85.0% vs 53.3%; p = 0.002). Patients with MRD-negative AML prior to HSCT benefitted the most from sorafenib. The findings from this trial have previously been summarized here.

Xuan et al.6 evaluated sorafenib as a maintenance therapy vs SoC in patients with FLT3-ITD-positive AML in CR prior and after HSCT (N = 202). This was a phase III randomized trial (NCT02474290) and the primary endpoint was 1-year cumulative incidence of relapse. Patients in the sorafenib arm had a significantly lower rate of relapse (7%; 95% confidence interval [CI], 3.1–13.1) compared with those in the SoC arm (24.5%; 95% CI, 16.6–33.2). The median follow-up post-HSCT was 21.3 months (interquartile range, 15.0–37.0).

Another azacitidine maintenance therapy trial has also previously been summarized on the AML Hub. Oran et al.7 conducted a phase III trial of azacitidine maintenance therapy in patients with high-risk AML/MDS achieving CR following HSCT (N = 187). The primary endpoint was RFS, defined as time from HSCT to relapse or death. There was no difference in the outcome in both arms. However, only 24 patients completed 12 cycles of treatment.

Gao et al.8 published the results of their trial in Journal of Clinical Oncology, investigating the effect of recombinant human granulocyte colony-stimulating factor combined with minimal decitabine (G-Dec). This was a phase II, multicenter, randomized controlled trial including patients with high-risk AML (N = 204). The primary endpoint was relapse after transplantation. Patients in the G-Dec arm had an estimated 2-year cumulative incidence of relapse of 15% (95% CI, 8.0–22.1) compared with 38.3% (95% CI, 28.8–47.9) in the non-G-Dec arm (p < 0.01).

Several other trials evaluating FLT3 inhibitors as maintenance therapy are ongoing (as shown in Table 1). Some of these trials have also been summarized on the AML Hub in the editorial theme that discussed combination therapies for AML.

Table 1. Further trials evaluating FLT3 inhibitors as post-transplant maintenance*

Investigational drug

Sample size, N

Type of AML

Primary endpoint identifier





















AML, acute myeloid leukemia; EFS, event-free survival; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication; RFS, relapse-free survival.
*Adapted from Bug.1

Ongoing targeted therapy post-HSCT

Examples of ongoing salvage and maintenance therapy trials were also presented, and these are listed in Table 2.

Table 2. Ongoing salvage and maintenance therapy trials for R/R AML or MDS*

Investigational drug

Trial phase (sample size, N)

Patient population identifier

Salvage therapy

Azacitidine + lenalidomide + DLI

Phase II (50)

Relapsed MDS, sAML


Bortezomib + lenalidomide

Phase I (22)



Daratumumab + DLI

Phase I/II (30)

Relapsed AML


Nivolumab + ipilimumab

Phase I (55)




Phase I/II (26)

R/R myeloid malignancies



Phase I/II (60)

R/R myeloid malignancies with IDH2-mutation


Maintenance therapy

Oral azacitidine (CC-486)

Phase III (324)



Azacitidine + venetoclax

Phase III (424)



Azacitidine + venetoclax

Phase II (125)



PF-04449913 Hedgehog inhibitor

Phase II (35)



AML, acute myeloid leukemia; DLI, donor lymphocyte infusion; IDH2, isocitrate dehydrogenase 2; MDS, myelodysplastic syndromes; R/R, relapsed/refractory; sAML, secondary AML.
*Adapted from Bug.1


Currently, post-HSCT-targeted interventions are focused on FLT3 inhibitors and HMAs. More recent trials have investigated maintenance therapies, and evidence from these trials is suggestive of a reduced relapse rate and improved RFS. Evidence on pre-emptive therapy is limited and future trials should focus on maintenance and pre-emptive strategies to maximize the impact on RFS.

  1. Bug G. Novel targeted therapy post-HSCT for AML/MDS. Oral abstract E5-2. 47th Annual Meeting of the European Society for Blood and Marrow Transplantation; Mar 16, 2021; Virtual.
  2. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740. DOI: 1056/NEJMoa1902688
  3. Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent hematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicenter, phase 2 trial. Lancet Oncol. 2018;19(12):1668-1679. DOI: 1016/S1470-2045(18)30580-1
  4. Maziarz RT, Levis M, Patnaik MM, et al. Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. Bone Marrow Transplant. 2020;56(5):1180-1189. DOI: 1038/s41409-020-01153-1
  5. Burchert A, Bug G, Fritz LV, et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN). J Clin Oncol. 2020;38(26):2993-3002. DOI: 1200/JCO.19.03345
  6. Xuan L, Wang Y, Huang F, et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicenter, randomized phase 3 trial. Lancet Oncol. 2020;21(9):1201-1212. DOI: 1016/S1470-2045(20)30455-1
  7. Oran B, de Lima M, Garcia-Manero G, et al. A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients. Blood Adv. 2020;4(21):5580-5588. DOI: 1182/bloodadvances.2020002544
  8. Gao L, Zhang Y, Wang S, et al. Effect of rhG-CSF combined with decitabine prophylaxis on relapse of patients with high-risk MRD-negative AML after HSCT: An open-label, multicenter, randomized controlled trial. J Clin Oncol. 2020;38(36):4249-4259. DOI: 1200/JCO.19.03277