Safety and Efficacy of Maintenance Treatment Following Allogeneic Hematopoietic Cell Transplant in Acute Myeloid Leukemia and Myelodysplastic Syndrome - a Systematic Review and Meta-Analysis
Authors: Bewersdorf Jan Philipp , Tallman Martin S. , Cho Christina , Zeidan Amer M. , Stahl Maximilian 
Published: February 2021

Background: Prognosis of patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who relapse after allogeneic hematopoietic cell transplant (allo-HCT) is extremely poor and strategies to reduce the risk of disease relapse are warranted. Hypomethylating agents (HMA) or FLT3 inhibitors have been used in several studies for relapse prevention following allo-HCT with mixed results leaving the question regarding the safety and efficacy of this strategy unanswered.
Methods: We conducted a systematic review and meta-analysis and searched MEDLINE, EMBASE, Web of Science and CENTRAL from inception to 8/2020 for studies using the following combination of free-text terms linked by Boolean operators: [Acute myeloid leukemia OR AML OR MDS OR Myelodysplastic syndrome] AND [transplant OR allogeneic stem cell transplant OR hematopoietic stem cell transplantation] AND [maintenance OR maintenance therapy OR maintenance treatment]. Titles and abstracts were reviewed and excluded if they were review or basic research articles, not on post-allo-HCT maintenance in AML or MDS, no English full-text was available, or if they were clinical trials without published results. Full-texts were reviewed and excluded if (I) duplicate publications from the same patient cohort, (II) insufficient reporting of endpoints, (III) studies not on FLT3 inhibitors or HMA, (IV) case series with &lt;5 pts, or (V) commentaries without original independent data. Studies using FLT3 inhibitors or HMA for pre-emptive treatment of imminent relapse based on positive minimal residual disease (MRD) testing were excluded. Outcomes of interest were the rates of 2-year overall survival (OS) and relapse-free survival (RFS) as well as incidence of acute and chronic graft-versus-host disease (GVHD). The study protocol was registered on PROSPERO (CRD42020187298).
Results: The search strategy retrieved 1388 unique citations (Figure 1). After application of additional exclusion criteria, 22 studies were included in the meta-analysis. A total of 829 pts was included with 462 and 367 receiving post-allo-HCT treatment with FLT3 inhibitors or HMA, respectively. All pts treated with FLT3 inhibitors had AML, while 231 AML and 112 MDS pts were treated with HMA, respectively. Among studies on FLT3 inhibitors, sorafenib was used in 10 studies with midostaurin and quizartinib being used in 1 study each. Azacitidine was used in 8 studies, decitabine in 3 studies and 1 study used both azacitidine and decitabine. Patient, transplant, and treatment characteristics of the included studies are shown in Table 1.
Reporting of outcomes was variable among the included studies (Figure 2;Panels A-D). Among pts treated with FLT3 inhibitors, 2-year OS and RFS rates were 81.7% (95% confidence interval [CI]: 70.0 - 89.5%), and 82.9% (95% CI: 76.9 - 87.5%), respectively. Acute and chronic GVHD occurred in 10.4% (95% CI: 0.5 - 73.3%) and 38.4% (95% CI: 13.4 - 71.5%) of pts, respectively.
In HMA-treated pts, 2-year OS and RFS rates were 65.6% (95% CI: 54.7 - 75.1%) and 56.2% (42.4 - 69.2%), respectively. Acute and chronic GVHD occurred in 39.9% (95% CI: 29.2 - 51.6%) and 44.4% (95% CI: 34.1 - 55.2%) of pts, respectively.
Study quality was limited by retrospective design employed by 10 studies, small sample sizes in some of the analyses, and heterogenous patient populations, reporting of outcomes, and transplant characteristics which were limiting cross-study comparisons.
Discussion: Maintenance therapy with FLT3 inhibitors or HMA following allo-HCT in AML and MDS pts appears to be safe and can potentially be associated with prolonged RFS and OS although its efficacy needs to be verified in randomized trials. Careful patient selection is necessary as both the rates of GVHD and the burden on pts related to extended treatment following allo-HCT can be substantial. Selecting pts based on high-risk genetic (e.g. presence of TP53 mutations) and other disease characteristics (MRD-positivity at time of allo-HCT) could be options for patient selection but require additional validation. Various clinical trials investigating the role of post allo-HCT maintenance therapy are ongoing and our data could serve as a reference when interpreting the results of those trials.

Disclosures
Tallman: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Orsenix: Research Funding; Cellerant: Research Funding; ADC Therapeutics: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafael: Research Funding; Glycomimetics: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees. Zeidan:Incyte: Consultancy, Honoraria, Research Funding; CCITLA: Other; Astex: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Aprea: Research Funding; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Takeda: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; MedImmune/Astrazeneca: Research Funding; Jazz: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding.