Novel EZH2 mutation in a patient with secondary B-cell acute lymphocytic leukemia after deletion 5q myelodysplastic syndrome treated with lenalidomide: A case report

Abstract

Rationale: The gene deletion (5)(q22q35) is reported in 10-20% of myelodysplastic syndrome (MDS) cases and is associated with response to lenalidomide and favorable prognosis. The authors report here a clinical case of MDS transformation to B-cell acute lymphocytic leukemia (B-ALL) with an associated accrual of an additional mutation following treatment with lenalidomide.

Patient concerns: A 69-year-old man presented with progressive anemia, normal white blood cell count, and thrombocytopenia consistent with MDS. He was administered lenalidomide for 27 months, then developed acute B-cell lymphocytic leukemia and acquired a previously unreported mutation in the gene enhancer of zeste homolog 2 (EZH2).

Diagnoses: After 27 months of therapy with lenalidomide, a surveillance bone marrow aspiration (BMA) revealed 90% cellularity with persistent multilineage dysplasia and a population of blasts comprising 54% of all bone marrow elements by morphology, consistent with B-ALL, even though the patient was asymptomatic. Conventional karyotype showed no signs of del(5)(q22q35) MDS, however bone marrow next-generation sequencing (NGS) demonstrated the accrual of a nonsense mutation (c.211del pL71*) in exon 3 of EZH2. A confirmatory BMA yielded 70% blasts and clinical features indicative of B-ALL.

Interventions: Mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m × 4 doses) was administered for 21 days.

Outcomes: A follow-up BMA was performed 2 months after mini-hyper-CVD therapy, showing dysplastic features with 25% ring sideroblasts, but no evidence of B-ALL. The patient is currently receiving monthly-low dose decitabine, ofatumumab, and dexamethasone, and is transfusion independent and asymptomatic after 7 cycles.

Lessons: The present study shows an extremely rare progression of del(5)(q22q35) MDS to B-ALL with accompanying NGS data and a newly described acquisition of an EZH2 frameshift mutation. This case highlights the importance of NGS as a diagnostic and surveillance tool for MDS.

Figure 1

Dynamics of blast percentage, cytogenetic abnormalities, and mutational burdens through the course of therapy. Blast percentages observed by bone marrow morphologic evaluation are represented over time as blue shaded areas with blast populations defined by flow cytometry represented as dotted grey lines (B-ALL flow). Variant allele frequencies (VAFs) of somatic mutations are depicted over time for the EZH2 D185H variant in green and the EZH2 L71∗ in yellow. Frequency of cytogenetic abnormalities are represented as percentages based on the number of metaphases with the abnormality within the total number of evaluated metaphases. The current therapy received by the patient at a given time is specified under the X axis. BM cellularity = bone marrow cellularity, del(5q) = chromosome 5q deletion, mar = marker chromosome.