Hypomethylating Agent-Based Combination Therapies to Treat Post-Hematopoietic Stem Cell Transplant Relapse of Acute Myeloid Leukemia

Abstract

Allogeneic stem cell transplantation still represents the best curative option for most patients with acute myeloid leukemia, but relapse is still dramatically high. Due to their immunologic activity and safety profile, hypomethylating agents (HMAs) represent an interesting backbone for combination therapies. This review reports mechanism of action, safety, and efficacy data on combination strategies based on HMAs in the setting of post-allogeneic stem cell transplant relapse. Several studies highlighted how HMAs and donor lymphocyte infusion (DLI) combination may be advantageous. The combination strategy of HMA with venetoclax, possibly in association with DLI, is showing excellent results in terms of response rate, including molecular responses. Lenalidomide, despite its well-known high rates of severe graft-versus-host disease in post-transplant settings, is showing an acceptable safety profile in association with HMAs with a competitive response rate. Regarding FLT3 internal tandem duplication (ITD) mutant AML, tyrosine kinase inhibitors and particularly sorafenib have promising results as monotherapy and in combination with HMAs. Conversely, combination strategies with gemtuzumab ozogamicin or immune checkpoint inhibitors did not show competitive response rates and seem to be currently less attractive strategies. Associations with histone deacetylase inhibitors and isocitrate dehydrogenase 1 and 2 (IDH1/2) inhibitors represent new possible strategies that need to be better investigated.

Increasing Role of Targeted Immunotherapies in the Treatment of AML

“…This mechanism may crucially contribute to the development of drug resistance [ 94 ]. In summary, their immunomodulatory properties make them an interesting backbone for combination therapies [ 95 ]. Especially since combination therapies might comprise the possibility to bypass drug resistance mechanisms.…”

“…Combination trials of ivosidenib or enasidenib with AZA in relapsed or refractory AML (NCT03683433) as well as in first-line therapy of IDH mut AML with enasidenib (AML005-trial) or ivosidenib (AGIL-trial) in combination with AZA (NCT02677922) are currently ongoing [ 97 , 98 ]. Even in the posttransplant setting several studies showed the benefit of the combination of DLIs and AZA, further randomized trials are, up to date, still lacking [ 95 ]. Additionally, the therapy with DLIs and AZA can be enhanced with venetoclax in the posttransplant setting [ 95 ].…”

“…Even in the posttransplant setting several studies showed the benefit of the combination of DLIs and AZA, further randomized trials are, up to date, still lacking [ 95 ]. Additionally, the therapy with DLIs and AZA can be enhanced with venetoclax in the posttransplant setting [ 95 ]. Another combination partner with HMAs in the posttransplant setting is lenalidomide [ 95 ].…”

“…Additionally, the therapy with DLIs and AZA can be enhanced with venetoclax in the posttransplant setting [ 95 ]. Another combination partner with HMAs in the posttransplant setting is lenalidomide [ 95 ]. While lenalidomide as a single agent caused high rates of GvHD, there were acceptable side effects and good response rates when combined with HMAs [ 95 ].…”

Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy

“…However, relapse remains the primary cause of mortality in patients receiving allo-HSCT for MDS or AML ( 3 , 4 ). Epigenetic agents, mainly including hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDACi), have become widely used in the pretransplant, transplant, and posttransplant stages for MDS or AML ( 5 – 9 ) and are regarded as candidates to reduce the tumor burden, as they have tolerable toxicity and mitigate graft-versus-host disease (GvHD) without influencing graft versus leukemia (GvL) ( 9 , 10 ). Furthermore, HMAs have been proven effective in exerting an antitumor effect by promoting cell differentiation and apoptosis in leukemia cells ( 11 , 12 ) and by reactivating silent tumor suppressor antigens like MAGE-1 and WT-1 to improve the response to other therapeutic hematologic malignancies ( 10 , 13 , 14 ).…”