BCR/ABL1–like acute lymphoblastic leukemia: How to diagnose and treat?

Abstract

BCR/ABL1–like acute lymphoblastic leukemia (ALL) accounts for 15% to 30% of B‐lineage ALL, with a peak of incidence occurring in adolescence. This subgroup of patients is characterized by a peculiar transcriptional profile that resembles that of true BCR/ABL1–positive cases, and have a heterogeneous genetic background and a poor outcome. Next‐generation sequencing studies have demonstrated that the majority of patients carry rearrangements of tyrosine kinases or cytokine receptors and mutations of janus kinase (JAK)/signal transducer and activator of transcription (STAT), thus opening the way to the possible use of targeted therapeutic approaches. However, several issues remain unresolved at both the diagnostic and therapeutic level, such as the definition of a standardized method to identify BCR/ABL1–like ALL and the design of ad hoc clinical trials examining tyrosine kinase inhibitors or other tailored treatments. These aspects are discussed in this review.

Philadelphia chromosome‐like acute lymphocytic leukemia: Perspectives on diagnosis

“…It should be noted that Ph‐L ALL is an umbrella term and by no means defines a single entity. Not only is this disease subset characterized by a wide array of potentially targetable kinase and cytokine rearrangements, the definition of Ph‐L ALL itself is not standardized—with the gold standard diagnosis consisting of 2 different probe sets . It may be best to think of Ph‐L ALL as a group of BCP‐ALL that shows poor response to conventional chemotherapy with persistence of minimal residual disease and, as with Ph+ ALL, contains potentially therapeutically targetable genetic alterations.…”

“…This is done using one of the two independently developed large scale microarrays. The first is a 110 gene probe developed by the Dutch Children's Oncology Group, and the second, a 257 gene probe set developed by the Children's Oncology Group (COG) . The caveat with GEP testing is the lack of universal availability—these large scale Affymetrix‐based microarrays are only available at select research laboratories and thus not a practical screening method …”

“…An alternative to GEP diagnosis of Ph‐L ALL is an 8 or 15 gene low density array (LDA) that has been developed. Both LDAs have high sensitivities and specificities for screening for Ph‐L ALL and have been validated when compared to RNA seq and the gold standard gene expression profiling . The LDA is currently being used in frontline National Cancer Trial Network (NCTN) studies for both pediatric and adult cooperative groups in the United States, but it is not currently commercially available as a diagnostic test .…”

“…Both LDAs have high sensitivities and specificities for screening for Ph‐L ALL and have been validated when compared to RNA seq and the gold standard gene expression profiling . The LDA is currently being used in frontline National Cancer Trial Network (NCTN) studies for both pediatric and adult cooperative groups in the United States, but it is not currently commercially available as a diagnostic test . Even if this test is available, it is important to realize that the LDA only identifies the presence of the Ph‐L signature, and additional diagnostic work is needed to identify the specific Ph‐L subset for potential targeting …”

“…At the University of Chicago Medical Center we use FISH given our concerns for RT‐PCR missing certain translocations based on variations in splicing and break points . Nonetheless, studies have demonstrated the efficacy of RT‐PCR in screening for Ph‐L ALL, and several proposed algorithms use RT‐PCR as a step in Ph‐L ALL diagnosis . As mentioned previously, neither FISH nor RT‐PCR will specifically identify Ph‐L ALL—as this can only be done with GEP testing—but they will identify mutations commonly seen with this disease.…”