Molecular Monitoring in Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with the Variant e13a3 BCR-ABL1 Fusion

Monitoring BCR-ABL1 transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a widely adopted method to assess response to therapy. However, a small minority of Ph+ ALL patients express variant BCR-ABL1 transcript types, usually due to splicing of alternative BCR or ABL1 exons. Whether patients expressing these rare, variant BCR-ABL1 transcripts have a distinct phenotype or response to therapy is not known due to the limited number of reported cases. Here, we report the presenting features of Ph+ ALL in a young adult with a variant e13a3 BCR-ABL1 fusion. Molecular monitoring reflected the disease response from diagnosis through allogeneic stem cell transplantation which resulted in undetectable e13a3 BCR-ABL1 transcripts. This case highlights the value of molecular monitoring in Ph+ ALL patients with variant BCR-ABL1 transcripts and the requirement for standardization of such assays.


Introduction
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults is an aggressive disease that responds poorly to conventional chemotherapy. Despite improvements in survival with the addition of tyrosine kinase inhibitors (TKI) to chemotherapy, hematopoietic allogeneic stem cell transplantation (ASCT) remains the only curative option in those eligible patients [1]. Molecular monitoring of BCR-ABL1 transcripts is a valuable tool in assessing individual patient response to chemotherapy and ASCT [2][3][4]. e most common BCR-ABL1 transcripts in Ph+ ALL are the e1a2, e13a2, and e14a2 fusions [5]; however, approximately 5% of adult patients express variant BCR-ABL1 transcripts [6]. Of these variants, the e13a3 (b2a3) BCR-ABL1 type is extremely rare with scant information regarding optimal therapeutic approach [7,8].
Characterisation of these rare BCR-ABL1 variants also affords the selection of appropriate primer/probe combinations for reverse-transcriptase quantitative PCR (RT-qPCR) assessment of residual disease. e presentation and clinical course of a patient with e13a3 BCR-ABL1 Ph+ ALL is reported.

Discussion
E13a3 BCR-ABL1 transcripts lack ABL1 exon a2 that encodes part of SH3 domain thought to contribute to leukemogenesis by inhibition of the kinase domain and by STAT5 activation [6]. In chronic myeloid leukemia patients, this transcript results in an indolent and TKI-responsive form of disease [14][15][16]; however, its prognostic significance in adult Ph+ ALL patients remains unknown due to the limited number of annotated cases. While the possibility exists of lymphoid blast crisis in chronic myeloid leukemia (CML), this transformation in e13a3 BCR-ABL1 CML is rare [17]. In the absence of basophilia, thrombocytosis, and splenomegaly, this case likely represents de novo Ph+ ALL. Additional chromosomal abnormalities and complex karyotypes are frequently observed in Ph+ ALL, as witnessed in this case.
ere is some suggestion that in Ph+ ALL, additional cytogenetic abnormalities are associated with a shorter overall survival and might therefore be used for

BCR exon 13
ABL exon 3 2 Case Reports in Hematology stratification purposes [18]. In the post-ASCT setting, monitoring BCR-ABL1 transcript levels is an essential component of Ph+ ALL patient management [19] with effective standardisation of RT-qPCR assays for this and other variant BCR-ABL1 fusion transcripts required [20].
Reporting of further cases would enable identification of any phenotypic characteristics of e13a3 BCR-ABL1 Ph+ ALL and help establishing optimal treatment strategies for patients with this rare genotype. Case Reports in Hematology 3