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  • Flow cytometric immunophenotyping showed the circulating bla

    2019-05-23

    Flow cytometric immunophenotyping showed the circulating blasts expressed CD19, CD20, CD22, CD24 partial, HLA -DR, CD34, and TdT. There was variable expression of the myeloid markers CD15 and CD33. The blasts were negative for CD3, CD10, MPO, and all other T-cell, myeloid, and monocytic markers evaluated, including CD14, CD64, and CD7 (Fig. 1C). A diagnosis of B-lymphoblastic leukemia was made. Cytogenetics testing did not reveal any karyotypic abnormalities, and FISH studies were negative for MLL rearrangement (break apart probes), BCR-ABL fusion, ETV6-RUNX1 fusion, and showed disomy for chromosomes 4, 10 and 17. A cerebrospinal fluid sample taken at diagnosis was positive for lymphoblasts (700 WBC/mm3, 39% blasts; 64,000 RBC/mm3). Because the lumber puncture was traumatic, the patient did not meet criteria for CNS3 disease based on the Steinherz/Bleyer algorithm where the CSF WBC/RBC needs to be greater than 2 times blood WBC/RBC. Therefore, the patient was classified as CNS2c. One month later the patient developed leukocytosis (WBC 46K/µL) with 70% blasts and was re-induced to treat the persistent B-lymphoblastic leukemia. A post re-induction bone marrow performed at day +130 found 6% lymphoblasts with the same flow cytometric immunophenotype found at diagnosis. However, karyotyping demonstrated a subset of opioid receptor with clonal evolution: 46, XY,+6[2]/46, XY[18]. The chemotherapy was then modified to a regimen of vinorelbine, mitoxanthrone, dexamethasone and Bortezomib[4]. A bone marrow evaluation following re-induction with the modified regimen (day +180) revealed 33% blasts, this time with monocytic features by morphology (Fig. 1B). Rare lymphoblasts were also present; cytochemical staining for MPO was negative in all blasts. A repeat RT-PCR for t(11;19)(q23;p13) was again positive. Flow cytometric immunophenotyping confirmed the morphologic impression of blast monocytic lineage; there was a small subset of blasts with an immunophenotype consistent with the original B-ALL, and a much larger subset of blasts expressing CD2 dim, CD4 partial, CD7, CD56, CD22 dim, CD13 partial, CD15, CD33, CD117 partial, CD14, CD64, and CD38 bright. These blasts were negative for CD19, CD10, CD24, and TdT, and expressed dim MPO, an immunophenotype consistent with monocytic blasts (Fig. 1D). A subsequent cerebrospinal fluid (CSF) specimen demonstrated significant leukocytosis (36 WBC/mm3; 1 RBC/mm3) with 96% promonocytes with atypical morphologic features, suggesting CNS involvement by the lineage switched leukemia. We performed chromosomal microarray analysis (CMA) analysis using CytoScan HD arrays from Affymetrics (Affymetrics, Santa Clara, CA) on the patient\'s sample obtained at the time of relapse, (day +180) to interrogate the MLL and MLLT1 loci for deletions and duplications that may have arisen during the rearrangement which created the MLL-MLLT1 fusion detected by RT-PCR. This analysis revealed a copy number gain (duplication), involving the entire chromosome 6, which was consistent with the presence of the clone with trisomy 6 observed by karyotyping. No deletions or duplications were observed at the MLL and MLLT1 loci. Similarly, CMA analysis did not reveal any pathogenic, disease associated copy number abnormalities (CNA) at other genomic regions, consistent with the previously reported low CNA burden in MLL-rearranged ALL in infants [5]. The patient was able to attain a MRD negative remission, as determined by flow cytometric immunophenotyping, following an experimental infant relapse protocol at an outside facility. However, his chemotherapy course overall was marked by multiple bacterial and fungal infections, and despite all therapeutic efforts, the patient succumbed to infection at day +320 of life and passed away. He received a total anthracycline dose of 100mg/m2 daunomycin and 20mg/m2 mitoxanthrone.
    Discussion Congenital B-ALL is a rare disease with a poor prognosis, a high rate of MLL rearrangements, and has a variable rate of CNS involvement. In one recent study, there was only a 17% survival rate, with 93% of patients having a detectable MLL rearrangement by FISH or RT-PCR, and just 10% having CNS involvement [2]. Just a handful of previous case reports and small case series have described lineage switch in cases of congenital leukemia [6–12]. Interestingly, one case described a congenital leukemia with t(11;19), with a lineage switch from lymphoid to monocytoid heralded by the acquisition of trisomy 6, as in the current case [9].