Synchronous del5q myelodysplastic syndrome (del5qMDS) and adult B‐cell acute lymphoblastic leukemia (B‐ALL) with <i>TET2</i> and <i>TP53</i> mutations
Authors: Preetesh Jain, Guilin Tang, Sergej N. Konoplev, Rashmi Kanagal‐Shamanna, Sa A Wang, Naveen Pemmaraju, Naval Daver, Zeev Estrov
Journal: American Journal of Hematology (2015)

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 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 (Image 1A,B). Immunohistochemistry showed that the neoplastic cells expressed CD19, CD22, CD34, CD79a, CD20, and TdT (Image 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 (Image 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-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 two 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-cell acute lymphoblastic leukemia (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, and dexamethasone) was administered. A day-28 BM showed no morphologic evidence of leukemia, rare hypolobated megakaryocytes and flow cytometry showed minimal residual disease 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). 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 ALL 6, 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. P.J., T.G., S.K., R.K., S.W., and Z.E., collected and analyzed pathology and wrote the paper. N.D., N.P., and Z.E. managed the patient. 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) (Wright–Giemsa stain, ×500). (B) Sheets of immature medium size cells are seen interspersed with monolobated megakaryocytes (H&E, ×500). (C, D) Immunohistochemistry showing strongly positive CD20 and terminal deoxynucleotidyl transferase (TdT) (×500). (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.