CD56-positive B cell precursor acute lymphoblastic leukemia harboring KMT2A-AFF1 rearrangement developed in a pregnant woman successfully treated with allogeneic hematopoietic cell transplantation

Although aberrant T/NK-cell antigen expression is observed approximately 10% of B cell precursor acute lymphoblastic leukemia (BCP-ALL), the bright positivity of CD56 is exceedingly rare [1–3]. Here, we describe the first reported case, at least to our knowledge, of KMT2A-AFF1-rearranged BCPALL that co-expressed CD34, CD19, cytoplasmic (cyt) CD79a, and CD56 without any other lineage markers developed in a pregnant woman and successfully treated by allogeneic hematopoietic cell transplantation. A 33-year-old woman in her third trimester was referred to our department because of extreme hyperleukocytosis reaching 300 × 10/L with 96% of leukemic blasts (Fig. 1a). Flow cytometric analysis of bone marrow leukemic cells revealed the bright surface expression of CD34 and CD56 as well as the positivity of CD19, CD38, and HLA-DR with partial expression of cyt CD79a, while CD3, CD10, cyt myeloperoxidase, cyt CD3, cyt CD22, and cyt μ heavy chain were found to be negative (Fig. 1b). CD4 was also negative (data not shown) and there was nomorphological findings that suggest monocytic differentiation. Cytogenetic analysis showed a 47, XX, +X, t(4;11)(q21;11q23.3) karyotype suggesting a diagnosis of KMT2A-rearranged BCP-ALL, which was confirmed by the molecular detection of KMT2A-AFF1 fusion transcript. After delivery of a female newborn by Cesarean section at 32 weeks pregnant, she had started to receive intensive chemotherapy by use of the hyper-CVAD regimen [2], which led her disease to sustained molecular remission. The delivered infant did not show any hematologic abnormalities that denied the possibility of fetal cell–derived maternal leukemia. Considering the high-risk nature of KMT2A-AFF1-rearranged BCP-ALL with hyperleukocytosis, we decided to perform allogeneic peripheral blood stem-cell transplantation from her HLA identical sister usingmyeloablative conditioning consisting of fludarabine 120mg/m, intravenous busulfan 12.8 mg/kg, and melphalan 140 mg/m as a consolidative treatment. She has maintained molecular remission with good performance status with mild skin chronic GVHD more than 2 years after transplantation. Aberrant expression of CD56 is commonly observed in acute myeloid leukemia, whereas its expression in lymphoblastic leukemia is a relatively rare event. BCP-ALLwithKMT2A-AFF1 is a common subtype ofKMT2A-rearranged leukemia characterized by frequent occurrence in infants with dismal clinical course [4]. In a more recent study, KMT2A-AFF1 was also shown to be the most prevalent translocation in adult patients with Philadelphia chromosome-negative BCP-ALL and associated with a worse outcome independent of age [5]. Although its etiology and cellular origin remain an enigma, KMT2A-AFF1 fusion gene was shown to be present in primitive CD34+CD19− lymphoid progenitors [6]. Because those common lymphoid progenitors usually differentiate into innate lymphoid cells via expression of CD56 [7], aberrant CD56 expression in our patient might suggest the bidirectional differentiation potential of very early B cell * Tatsuo Ichinohe tatsuo.ichinohe@gmail.com

showed a 47, XX, +X, t(4;11)(q21;11q23.3) karyotype suggesting a diagnosis of KMT2A-rearranged BCP-ALL, which was confirmed by the molecular detection of KMT2A-AFF1 fusion transcript. After delivery of a female newborn by Cesarean section at 32 weeks pregnant, she had started to receive intensive chemotherapy by use of the hyper-CVAD regimen [2], which led her disease to sustained molecular remission. The delivered infant did not show any hematologic abnormalities that denied the possibility of fetal cell-derived maternal leukemia. Considering the high-risk nature of KMT2A-AFF1-rearranged BCP-ALL with hyperleukocytosis, we decided to perform allogeneic peripheral blood stem-cell transplantation from her HLA identical sister using myeloablative conditioning consisting of fludarabine 120 mg/m 2 , intravenous busulfan 12.8 mg/kg, and melphalan 140 mg/m 2 as a consolidative treatment. She has maintained molecular remission with good performance status with mild skin chronic GVHD more than 2 years after transplantation.
Aberrant expression of CD56 is commonly observed in acute myeloid leukemia, whereas its expression in lymphoblastic leukemia is a relatively rare event. BCP-ALL with KMT2A-AFF1 is a common subtype of KMT2A-rearranged leukemia characterized by frequent occurrence in infants with dismal clinical course [4]. In a more recent study, KMT2A-AFF1 was also shown to be the most prevalent translocation in adult patients with Philadelphia chromosome-negative BCP-ALL and associated with a worse outcome independent of age [5]. Although its etiology and cellular origin remain an enigma, KMT2A-AFF1 fusion gene was shown to be present in primitive CD34+CD19− lymphoid progenitors [6]. Because those common lymphoid progenitors usually differentiate into innate lymphoid cells via expression of CD56 [7], aberrant CD56 expression in our patient might suggest the bidirectional differentiation potential of very early B cell progenitors characterized by CD34+CD10−CD19+ phenotype, a putative origin of KMT2A-AFF1-rearranged BCP-ALL. It is also important to note here that CD34+CD10−CD19+ B cell precursors might arise from distinct developmental pathways from CD34+CD10+CD19+ pro-B cells [8]. Because the promoter of CD56 gene contains sequences that allow binding of various transcription factors such as RUNX1, BTB3, Pax5, MMSET, and Cyclin D1 [9], more simple explanation of aberrant CD56 expression in this particular case might be dysregulated transcriptome of leukemic cells. Finally, although the prognostic impact of CD56 expression in KMT2A-AFF1-rearranged BCP-ALL has yet to be elucidated, our present experience suggests that sustained remission can be achieved by allogeneic hematopoietic cell transplantation performed at an appropriate timing.
Acknowledgments We thank all of the staff in our department and members of Hiroshima University Hospital who dedicatedly provided the best care for this patient and her infant. We also thank Emi Kurita, Sachiko Fukumoto, Nanae Nakaju, Sajeda Chowdhury, Sanae Furuya, and Masako Ninomiya for their excellent technical and secretarial assistance.

Compliance with ethical standards
All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent for writing and publishing this report was obtained from the patient included in the study. T. Ichinohe has received speaker honoraria from Bristol-Myers Squibb, Celgene, Janssen Pharmaceutical K.K., and Kyowa Kirin Co. and research funding from Astellas Pharma, Chugai Pharmaceutical Co., CSL Behring, Eisai Co., FUJIFILM Wako Chemicals., Kyowa Kirin Co., Ono Pharmaceutical Co., Pfizer, Nippon Shinyaku Co., MSD, Otsuka Pharmaceutical Co., Repertoire Genesis Inc., Sumitomo Dainippon Pharma Co., Taiho Pharmaceutical Co., Takara Bio Inc., Takeda Pharmaceutical Co., and Zenyaku Kogyo Co. All other authors declare that they have no conflict of interest.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.