Synchronous del5q myelodysplastic syndrome (del5qMDS) and adult B cell acute lymphoblastic leukemia (B-ALL) with TET2 and TP53 mutations

An 81 year old female presented with a 3 month history of progressive weakness, fatigue and shortness of breath. Initial physical examination was unremarkable except for pallor. Her hemoglobin was 4.9 g/L, white blood cell (WBC) 2.5 ×10⁹/L, platelets 78 ×10⁹/L and MCV 99 fl. Peripheral blood smear showed anisopoikilocytosis, giant platelets and tear drop cells. A bone marrow (BM) aspiration and biopsy revealed a hypercellular marrow (80-100%) with sheets of blasts. Aspirate smears showed medium sized blasts (about 80%), with open nuclear chromatin, and scant agranular basophilic cytoplasm without Auer rods. There was multilineage dysplasia. Numerous small monolobated megakaryocytes were noted (Figure1A-B). Immunohistochemistry showed that the neoplastic cells expressed CD19, CD22, CD34, CD79a, CD20 and TdT (Figure 1C-D) but not CD3, CD10, CD61 and MPO. BM flow cytometry analysis identified a distinct population of blasts expressing CD19, CD20, CD22, TdT, and dim CD13, CD33, CD34, CD45, and HLA-DR. The blasts did not express CD10, CD25, CRLF2, CD5, CD15, T/NK-cell or other myeloid markers. In addition, a small population of aberrant myeloid blasts (9% of the CD34-positive cells) was also detected. Conventional cytogenetic analysis showed 46, XX, del (5) (q13q33) in 14/20 metaphases. Fluorescent in-situ hybridization (FISH) analysis using dual color probe LSI EGR1/D5S23, D5S721 showed that 14.5% of the interphases harbor del(5)(q31). MYC and BCR-ABL rearrangement were absent. Combined morphologic/FISH analysis shows del(5q) only in dysplastic myelocytes and granulocytes, and not in the blasts (Figure 1E-F). Microarray-based comparative genomic hybridization (array CGH) demonstrated loss of chromosome 5 (q14.3-q34) with no other alterations. A next generation sequencing (NGS)-based analysis was performed using the patient’s BM DNA extract. In addition to a point mutation in exon 5 of the TP53 gene (Y126C), a 2 base pair deletion leading to a frameshift mutation was present in exon 11 of the TET2 gene, , both at an allelic frequency of about 20%. Blasts were not detected in the patient’s cerebrospinal fluid. Because FISH analysis suggested that these two processes were not clonally related, a diagnosis of B-ALL and MDS with isolated del5q was rendered. Induction chemotherapy of decitabine for 5 days followed by rituximab-mini-HyperCVAD chemoimmunotherapy (Cyclophosphamide, mesna, vincristine, dexamethasone) was administered. A day-28 BM showed no morphologic evidence of leukemia, rare hypolobated megakaryocytes and flow cytometry showed minimal residual disease (MRD) with 0.01% B-ALL leukemia cells. Cytogenetic analysis detected 1/20 metaphases with del(5)(q13q33) and Sanger sequencing detected TP53 mutation (p.Y126C).

Figure 1.

(A-F) – Features of the bone marrow aspirate/biopsy and Cytogenetics/FISH – A) Markedly increased blasts with open nuclear chromatin, inconspicuous nucleoli, and scant agranular basophilic cytoplasm. Dysplastic erythrocytes noted in the background (arrows) (arrows) (Wright-Giemsa stain, 500x) B) Sheets of immature medium size cells are seen interspersed with monolobated megakaryocytes (H&E, 500x) C-D) Immunohistochemistry showing strongly positive CD20 and TdT (Terminal deoxynucleotidyl transferase) (500x)E-F) Combined morphologic and FISH analysis - FISH with D5S721, D5S23/EGR1 probes. Arrow: dysplastic myelocytes and granulocyte, showing two green and one red signals, indicating 5q31 deletion; Arrow head: Blasts, showing two green and two red signals – normal pattern

MDS with deletion 5q is a distinct entity and is considered as a ribosomopathy.¹ It is characterized by macrocytic anemia, hypolobulated megakaryocytes, a normal or high platelet count and a good prognosis with approximately 10% of patients transforming to AML. Generally, patients with 5q- MDS and TP53 mutations have a poor prognosis, higher risk of leukemic transformation and do not respond well to lenalidomide.^2,3 Except for anecdotal case reports^4,5 with transformation of 5q- MDS into ALL⁶, synchronous presentation of 5q- MDS with adult B-ALL has not been reported. Whether the MDS clone was preexisting in this patient and later evolved into B-ALL is unclear. The patient remains in remission and is due to receive consolidation chemotherapy.