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

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/m2 × 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.

Treatment-Associated Acute Lymphoblastic Leukemia Following Autologous Hematopoietic Stem Cell Transplant and Lenalidomide Maintenance in Patients With Multiple Myeloma

“… 8 The other studies revealed 2 cases of ALL after lenalidomide exposure to be positive for CD34 and CD79a. 9 - 11 The most consistent genetic abnormality found across studies is the 11q23 ( KMT2A ) rearrangement, followed by monosomies of chromosomes 5, 7, and/or 17, hypodiploidy. 12 This patient lacked the 11q23 (KMT2A) rearrangement and the monosomy of chromosome 5.…”

HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia

“…Conventional treatment regimens do not relieve their symptoms. The prognosis of MDS is related to many factors that are very complex [19]. Some studies have suggested that decitabine may be effective against high-risk MDS [20, 21].…”

Prognostic Markers of Myelodysplastic Syndromes

“…Although MDS transforms to AML often, it can also transform to other leukemias, including acute lymphocytic leukemia (ALL). The presence of del(5q) and mutations in TP53 or EZH2 are associated with the emergence of the ALL clone [ 79 ]. Deletion of the long arm of chromosome 20, too, is an occurrence in MDS and is detected at a frequency of 3–7%, often co-occurring with anemia and thrombocytopenia [ 80 , 81 ].…”