Transplacental transfer of congenital B‐cell acute lymphoblastic leukemia to the maternal vasculature

Abstract

To the Editor: Monozygotic twin infants with KMT2A-rearranged (KMT2Ar) acute lymphoblastic leukemia (ALL) demonstrate near-uniform disease concordance due to prenatal transfer of pre-leukemic cells via placental vascular anastomoses.1-4 However, despite several historical reports recognizing the presence of fetal nucleated cells in the maternal circulation during pregnancy,5 fetal–maternal dissemination of leukemic clones has not been reported. We present a neonate with congenital KMT2Ar-ALL with documentation of metastasis to the maternal decidual placental vessels without clinical consequence. A newborn infant born at 37 4/7 weeks gestation was found to have leukocytosis (white blood cells 72.1 × 103/μl) with 62% blasts characterized by convoluted nuclear contour, prominent nucleoli, and scant deep-blue cytoplasm. Flow cytometry revealed expression of HLA-DR, CD15, CD19, CD22, CD34, cytoplasmic TdT, and cCD79a, consistent with B-cell ALL. G-banding karyotyping analysis revealed t(4;11)(q21;q23) with a dominant clone (five metaphase cells) containing a (4;11)(q21;q23) translocation and a subclone (one cell) containing an additional copy of der(4). Placental microscopy demonstrated clusters of blasts in both chorionic surface (fetal) vessels and decidual (maternal) vessels (Figure 1). Fluorescence in situ hybridization (FISH) analysis showed these clusters to be positive for the KMT2A rearrangement in both fetal and maternal vessels. These findings indicate that malignant fetal cells had infiltrated the maternal placental vasculature. Unlike in older children and adolescents, the prognosis of ALL in the neonatal age group is dismal.6 Despite intensive therapy, our patient experienced a highly complicated clinical course with eventual decompensation from Enterococcus faecalis bacteremia and infectious rotavirus leading to death on day 47 of life. Notably, throughout the patient's nearly 7-week clinical course, his mother did not demonstrate any clinically apparent findings to suggest sequelae of transplacental leukemia cell transfer. The discovery of leukemia cells of shared clonal lineage between monozygotic twins with ALL supports the so-called “intraplacental metastasis hypothesis”1 and confirms the capacity for pre-leukemic cells to spread from one twin to the other.7 These pre-leukemic cells are thought to transfuse via monochorionic placental vascular anastomoses rather than across the placental membrane barrier itself. Although placental involvement of congenital neuroblastoma has been reported,8 numerous reports of pregnant patients with hematologic malignancies demonstrate a noteworthy absence of clinically apparent transplacental “metastases” to exposed neonates.9-12 For example, in a report of prenatally diagnosed maternal ALL with leukemia cells detected in the cord blood, these cells were efficiently cleared and did not result in leukemic engraftment in the neonate.13 In this report, numerous lymphoblasts characterized by the KMT2A rearrangement were observed in the decidual (maternal) placental blood vessels, suggesting substantial cross-placental infiltration or local proliferation following infiltration. Our findings suggest the capacity for pre-leukemic cells to circumvent the placental membrane barrier as an additional means of transplacental penetration. The absence of a clinical impact on maternal health suggests that infiltrated malignant fetal cells undergo extraplacental maternal immune clearance and do not result in clinical consequence to the exposed mother. The authors declare that there is no conflict of interest.