Monitoring Pre-Malignant Clones May Predict Development of Therapy-Related Myeloid Neoplasms

Post-transplant development of therapy-related myeloid neoplasms (tMNs) originates in hematopoietic stem cells (HSCs) with tMN mutations that are present years before disease onset, according to a whole-exome sequencing (WES) study published in Blood. In addition, post-autologous hematopoietic cell transplantation (AHCT) treatment can influence the selection of these clones.

Gerbrig Berger, BSc, of the Department of Hematology at the University of Groningen in the Netherlands, and co-authors studied the mutational landscape of tMNs and the clonal dynamics preceding tMN diagnosis. The study included 18 patients who developed tMN between 1999 and 2013, 17 of whom were diagnosed with tMN following AHCT (the other had tMN following peripheral blood [PB] stem cell apheresis).

Patients received HCT conditioning therapy that included high-dose melphalan for those with plasma cell dyscrasia (n=5) or BEAM (carmustine, etoposide, cytarabine, melphalan) combination therapy for those with lymphoma (n=13).

The median time from AHCT to tMN diagnosis was three years (range = 0.18-16.2 years), and the median age at tMN diagnosis was 61 years (range = 41-71 years). The most commonly observed cytogenetic abnormalities were complex karyotypes (44%) and isolated abnormalities of chromosome 7 (28%).

Researchers performed WES at the time of diagnosis on bone marrow (BM) mononuclear cells (MNC; n=6) or PB MNC (n=1). WES revealed a median of 27 somatically acquired mutations (range = 9-29 mutations). TP53 was the most common mutation among seven patients who developed tMN after AHCT (n=4).

“We observed that tMNs are characterized by significantly increased mutation load, [compared with] de novo myelodysplastic syndromes (MDS),” the authors wrote. For de novo MDS, there was no correlation between Revised International Prognostic Scoring System assessment and total number of mutations (median = 12 for both very low/low and intermediate/high; p=0.9266). However, there was a significantly higher number of mutations identified in tMN versus de novo MDS (median = 27 vs. 12; p=0.001).

The researchers also performed a mutational signature analysis (n=7 for tMN and n=11 for de novo MDS) and observed that “the mutations found in tMN did not carry a clear aging-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism.”

Clonal hematopoiesis of indeterminate potential (CHIP) at the time of AHCT was demonstrated in seven of 10 cases (70%), and variant allele frequencies (VAFs) ranged between 0.1 and 8 percent. “Our data suggest that determination of CHIP following AHCT becomes even more important when there is the intention to treat the patient with agents that could impose an extra selective pressure on the hematopoietic system,” the authors concluded.

Next, researchers tracked all mutations detected by WES at tMN diagnosis (n=7 cases) using targeted deep sequencing. Transformation from MDS to acute myeloid leukemia (AML) was accompanied by the acquisition of mutations.

Four years post-AHCT, all mutations present at AML diagnosis could be detected at VAFs of 12 to 25 percent. Reconstruction of clonal patterns based on VAFs showed that pre-malignant clones can be present more than seven years before tMN diagnosis.

The researchers also examined the presence of high p53-protein expressing cells (p53++) for specific tMN cases. Patients who displayed 5 percent or greater p53++ cells had confirmed TP53 mutation. Pre-leukemic biopsies were evaluated for p53 expression, and in all cases clear clusters of p53++ cells were detected up to three years prior to tMN diagnosis, which demonstrates that “small pre-leukemic clones are present in the BM of patients years before tMN diagnosis.”

Treatment also impacted mutations, “by both causing stabilization or outgrowth of pre-leukemic clones,” the authors noted.

“The presence of CHIP may be correlated to a more general dysfunction of the HSC compartment and the surrounding microenvironment that may favor the outgrowth of pre-leukemic clones,” the researchers concluded. “Our results would argue for regular monitoring of patients’ PB counts following AHCT.”

The study is limited by its small patient population. Also, this analysis was restricted to WES-identified mutations that could be confirmed by targeted deep sequencing; considering all mutations found by whole-genome sequencing may identify different mutational profiles.

“Future research, preferentially based on prospective studies using large patient numbers, is necessary to identify mutations and clinical parameters that are predictive for risk of tMN development after AHCT,” the authors added.

The authors report no financial conflicts.


Reference

Berger G, Kroeze LI, Koorenhof-Scheele TN, et al. Early detection and evolution of pre-leukemic clones in therapy-related myeloid neoplasms following autologous SCT. Blood. 2018 January 8. [Epub ahead of print]

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