Clonal Evolution of Acute Myeloid Leukemia with CEBPA Double Mutations after Long-Term Remission: Case Report and a Literature Review

To the Editor,

Mutations in the CEBPA gene occur in 7%-15% of all acute myeloid leukemia (AML) patients [1,2]. However, we found that the frequency of such mutation may be high in Chinese AML patients [3,4]. Although AML with CEBPA double mutations (CEBPA^dm) indicates a favorable outcome, recent data show that more than 50% of patients finally relapsed when consolidated with chemotherapy alone [5]. Clonal evolution (CE) is an important factor for relapse [6]. However, studies discussing CE in AML patients with CEBPA^dm are limited [7,8]. Here, we report CE in two patients with CEBPA^dm determined by sensitive next-generation sequencing (NGS).

Two female AML patients were diagnosed in our hospital in January 2012 and September 2013. Standard ‘3+7’ induction chemotherapy was administered. Both of them achieved CR after induction therapy. Patient 1 received consolidation therapy with one course of DA (daunorubicin + cytarabine), four courses of high-dose cytarabine (HD-Ara-C), and one course of DA. Patient 2 received consolidation therapy with three courses of HD-Ara-C and two courses of immunotherapy. After long-term remissions (63 and 40 months), they both relapsed. Cytogenetic and fusion gene analyses indicated no difference from diagnosis. NGS analysis indicated altered mutations sites of the CEBPA gene in Patient 2 (Figure 1). New co-occurring mutations emerged at relapse: SETD2 mutation in Patient 1 and WT1 mutation in Patient 2 (Table 1). After relapse, Patient 1 achieved CR with a DA regimen and Patient 2 refused treatment.

Figure 1.

CEBPA gene mutations of these two patients at diagnosis and relapse.

Table 1. CEBPA and co-occurring mutations at diagnosis and relapse.

The first report for CE in patients with CEBPA^dm included two patients [7]. In the first patient, the amino-terminal frame-shift mutation was duplicated and found on both alleles at relapse. In the second patient, the amino-terminal frame-shift mutation and a mutation in the fork region were found either alone or combined on the same allele, suggesting a subclone formation [7]. Another study reported CE in 22 patients; two of them lost mutations and none acquired new mutation at relapse [8]. Twenty patients harboring CEBPA mutations relapsed with identical mutation patterns; three of them had a second relapse that also exhibited the same patterns as their initial diagnosis and first relapse [8]. Two patients had concomitant FLT3-ITD mutations at diagnosis and one was lost at relapse. Two patients acquired FLT3-TKD mutations at relapse. N-RAS mutations were detected in three patients at diagnosis and two of them retained the identical mutation at relapse [8]. In this case report, we found mutation site alteration in the CEBPA gene and two newly emerged co-occurring mutations.

CE of patients with CEBPA^dm can be summarized as follows: 1) allele alteration of CEBPA gene: acquire or lose mutation site in allele; 2) mutation site alteration in CEBPA gene: acquire or lose mutation site in CEBPA gene other than allele; 3) co-occurring mutation alteration: acquire or lose co-occurring mutation. One issue that needs to be resolved is the relationship between time and CE after CR. In this case report, these two patients relapsed after long-term remissions, and new co-occurring mutations emerged in both of them. Hence, whether late relapse is associated with new co-occurring mutations is unknown.