Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis

Abstract

We studied acute myeloid leukemia (AML) patients with lympho-myeloid clonal hematopoiesis (LM-CH), defined by the presence of DNA methyltransferase 3A (DNMT3A) mutations in both the myeloid and lymphoid T-cell compartment. Diagnostic, complete remission (CR) and relapse samples were sequenced for 34 leukemia-related genes in 171 DNMT3A mutated adult AML patients. AML with LM-CH was found in 40 patients (23%) and was associated with clonal hematopoiesis of indeterminate potential years before AML, older age, secondary AML and more frequent MDS-type co-mutations (TET2, RUNX1 and EZH2). In 82% of AML patients with LM-CH, the preleukemic clone was refractory to chemotherapy and was the founding clone for relapse. Both LM-CH and non-LM-CH MRD-positive AML patients who achieved CR had a high risk of relapse after 10 years (75% and 75%, respectively) compared with patients without clonal hematopoiesis in CR with negative MRD (27% relapse rate). Long-term survival of patients with LM-CH was only seen after allogeneic hematopoietic stem cell transplantation (HSCT). We define AML patients with LM-CH as a distinct high-risk group of AML patients that can be identified at diagnosis through mutation analysis in T cells and should be considered for HSCT.

Figure 1. AML with LM-CH is associated with secondary AML and MDS-type mutations.

(A) Variant allele frequency of DNMT3A mutations at diagnosis in mononuclear and sorted T cells for AML patients with LM-CH and without LM-CH. (B) Comparison of median age at diagnosis in AML patients with and without LM-CH. (C) Frequency of de novo and secondary AML in patients with and without LM-CH. (D) Mutational landscape of patients with LM-CH or without LM-CH as identified by targeted sequencing analysis. (E) Unsupervised hierarchical clustering of all 158 patients based on genes that are mutated in at least 10 patients. LM-CH patients (yellow) cluster on the left side and are enriched for MDS-type mutations.

Figure 2. The preleukemic LM-CH clone is refractory to chemotherapy.

(A) Schematic overview of DNMT3A mutated AML patients according to their DNMT3A mutation status in T cells at diagnosis and in mononuclear cells at CR. (B) and (C) Comparison of mean variant allelic frequency of DNMT3A at time of diagnosis and CR (B) as well as CR and relapse (C)

Figure 3. AML with LM-CH is preceded by CHIP.

(A) Comparison of mean variant allelic frequency of DNMT3A years prior to AML diagnosis in healthy condition (CHIP), at time of diagnosis and during disease course in two patients with LM-CH and available samples prior to diagnosis (B) Blood counts of the two patients from (A) at time of CHIP and AML diagnosis

Figure 4. AML patients with LM-CH have a high risk of relapse.

(A) Mutation pattern of paired diagnosis and relapse samples of 20 DNMT3A mutated patients. (B) Cumulative incidence of relapse (CIR) in patients with LM-CH, patients without LM-CH who are DNMT3A mutated in CR (M-CH), and patients without LM-CH who are DNMT3A wildtype in CR.

Figure 5. Long term survival of AML patients with LM-CH requires allogeneic stem cell transplantation.

(A) Overall survival in intensively treated AML patients with or without LM-CH. (B) Relapse-free survival in intensively treated AML patients with or without LM-CH. (C) Proportion of surviving patients with or without LM-CH who received either chemotherapy alone or an allogeneic transplantation during their course of treatment. Only patients are considered who received intensive induction chemotherapy. (D) Overall survival of AML patients with or without LM-CH who were treated with intensive induction chemotherapy, achieved CR and were transplanted in CR1.