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Gómez, Hidalgo G.1, 2; Gabarros, M.1, 2; Blanco, A.2; Tazón, B.2; Palacio, C.2; Gallur, L.2; Martínez, N.2; Aznar, M.2; Altimiras, L.2; Dapena, J. L.3; Ortega, M.2

doi: 10.1097/01.HS9.0000564876.31182.9b
Publication Only: Acute lymphoblastic leukemia - Biology & translational research

1Experimental Hematology Group, Vall d'Hebron Institute of Oncology (VHIO)

2Integrated Diagnosis Unit, Hematology Service

3Pediatric Oncology and Hematology Service, Vall d'Hebron University Hospital, Barcelona, Spain

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B-cell precursor acute lymphoblastic leukemia cases with immature phenotype (nuclear TdT (NuTdT)+, CD34+, surface immunoglobulins (IgS)-) represent 90% of total ALL cases. In contrast, B mature phenotype (NuTdT-, IgS+) is characteristic of Burkitt's leukemia/lymphoma with L3 morphology and MYC rearrangements. KMT2A rearrangements appear in 4% of B-cell ALL pediatric patients and in 80% of infants younger than one-year-old. These rearrangements are associated with immature phenotype and bad prognosis.

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Two cases of pediatric ALL with mature phenotype and KMT2A rearrangements are presented.

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Immunophenotyping by flow cytometry, G-banded, fluorescent in situ hybridization (FISH) and RT-PCR assays were performed on bone marrow samples according to standardized procedures.

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CASE 1: A 4-year-old boy was admitted due to the presence of a scalp mass. The hemoglobin was 9.2 g/dl, the white blood cell count was 3.68 × 109/L and the platelets count was 46 × 109/L. The bone marrow study confirmed a 13% of pathologic cells with B mature phenotype: CD45+, CyCD79a+, CD19+, CD10+, CyIgμ+, IgS lambda+ and absence of CD34, NuTdT, CD20 or other myeloid related antigens. Karyotype analysis resulted in 46,XY,t(9;11)(p21;q23)[5]/47,idem,+5[3]/48,idem,+5,+21[2]/46,XY,der(9)del(9)(q22q32)t(9;11)(p21;q23)[2]/47,XY,+5,der(9)del(9)(q22q32)t(9;11)(p21;q23)[2]/48,XY,+5,der(9)del(9)(q22q32)t(9;11)(p21;q23),+21[4]/46,XY[3]. FISH study showed KMT2A rearrangements in 13% of the nucleus. The presence of MLLT3-KMT2A transcripts was confirmed by real-time PCR. He was treated following the Interfant 2006 protocol, achieving complete remission with negative minimal residual disease (MRD). Six months later, the patient suffered a combined relapse in bone marrow and central nervous system (CNS). He received a new induction treatment but showed no response and died 11 months after the initial diagnosis.

CASE 2: A 2-year-old girl was diagnosed with pre-B lymphoblastic lymphoma without medullar infiltration in a different hospital and she was treated following the EURO-LB02 protocol. After achieving remission, she suffered an early relapse in CNS and was transferred to our hospital to receive rescue therapy. The patient reached complete remission with negative MRD. One month after receiving an allogeneic hematopoietic stem cell transplantation from an unrelated donor, she relapsed for the second time. At this moment, the hemogram showed a hemoglobin count of 9.8 g/dL, a white blood cell count of 12.2 × 109/L and a platelets count of 71 × 109/L. The bone marrow study revealed an 88.7% of pathologic cells with B mature phenotype: CD45+, CyCD79a+, CD79b+, CD19+, CD10+, CyIgμ+, IgS lambda+, and absence of CD34, NuTdT, CD20 or other myeloid related antigens. The cytogenetic analysis revealed the following karyotype: 46,XX,t(9;11)(p21;q23)[20]. The KMT2A rearrangement was confirmed by FISH and the presence of MLLT3-KMT2A transcripts. The patient initiated palliative care and died 6 months after the diagnosis.

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There have already been reported 21 cases of B-cell ALL with mature phenotype and KMT2A rearrangements. 50% of these cases had t(9;11)(p21;q23), presented early relapse and bad prognosis. Due to the frequent association between these clinical and biological characteristics, the patients presenting these could probably represent a new subtype inside the WHO entity “B lymphoblastic leukemia/lymphoma with KMT2A rearrangements”. In order to identify these patients, it is important to include on the ALL diagnosis protocol the analysis of IgS, specially for the cases with t(9;11)/MLLT3-KMT2A.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.