Mechanism of initial favourable response to decitabine in TP53 mutated MDS/AML and potential mechanisms of subsequent relapses

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with complex and monosomy karyotype (CK/MK) show high prevalence of TP53 mutations, poor response to induction chemotherapy and adverse patient outcome. These diseases may respond to decitabine but the mechanisms are presently unclear. MDS/AML patients were treated with decitabine for 10 days in a Phase II clinical study. In this study, we collected serial samples from patients before and at completion of decitabine treatment, morphologic remission and relapse. The samples were interrogated with targeted myeloid panel sequencing, nanopore DNA cytosine methylation sequencing and single-cell transcriptomics to investigate potential interactions between leukemic and immune populations. The integrative analysis allowed characterization of shifting dynamics within leukemic and immune cell populations in individual patients. Comparison of these trends between TP53 mutated MDS/AML patients who responded to treatment versus TP53 wildtype patients who were refractory to treatment highlighted the complex interplay of leukemic and immune compartments. Single cell transcriptomic analyses confirmed immune activation in TP53m responders after decitabine treatment. At relapse, leukemic populations showed up-regulation of MYC signaling and heat shock response while T-cells showed exhaustion signature. Our work highlighted the complex interplay between leukemic and immune populations in TP53m patients upon decitabine treatment that might account for clinical responses and subsequent relapses. Overall design: Adult patients (age 18 to 65 years old) with newly diagnosed CK-AML were enrolled in a Phase 2 open-labelled clinical trial (ClinicalTrials.gov Identifier: NCT03080766) and received decitabine at 20 mg/m2 for 10 days in 28 day-cycle. Bone marrow (BM) aspiration was performed before treatment and on Day 10 and 28 of the first cycle. Patients with marrow blasts = 5% on Day 28 received 5-day treatment while those with marrow blasts > 5% received 10-day treatment in subsequent cycles until blasts = 5%. Subsequent aspiration was performed at physicians' discretion. Eligible patients with suitable donors could receive allogeneic HSCT.