Philadelphia chromosome‐like acute lymphocytic leukemia: Perspectives on diagnosis

Abstract

Philadelphia chromosome-like acute lymphocytic leukemia (Ph-L ALL) is a heterogenous subset of ALL defined within the past decade. As its name implies, this entity shares a similar gene expression profile (GEP) with Philadelphia chromosome positive ALL (Ph+ ALL), but lacks the BCR-ABL1 fusion. 1-3 This similarity in GEP is due to the presence of kinase activations, usually resulting from the presence of chromosomal micro-deletions and insertions that result in oncogenic fusions that drive the development of both types of leukemia. 4-7 The vast majority of Ph-L ALL cases contain at least one activating kinase alteration and, as with Ph+ ALL, >70% of Ph-L ALL cases possess defects in the transcription factor IKZF1. 8-10 Defects in IKZF1 are associated with the development of B-cell precursor ALL (BCP-ALL) and, more specifically, high risk BCP-ALL that possess activated tyrosine kinase profiles. Interestingly, IKZF1 mutations have been described to affect downstream signaling pathways that ultimately result in treatment resistance and poor response to conventional chemotherapy. 9 It is not surprising then, that a large majority of both Ph-L and Ph+ ALL contain these mutations. Unlike Ph+ ALL, however, as mentioned above, this subset lacks the classic t[9;22].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. 1,8,11 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. Generally speaking, Ph-L ALL can be further divided into 3 broad groups: ABL class fusions (consisting of rearrangements in ABL1, ABL2, CSF1R, PDGFRB), JAK/STAT pathway alterations (consisting of CRLF2 ± JAK mutation, isolated JAK 1-3 mutations, EPOR, IL2RB, TSLP), and a miscellaneous category consisting of a multitude of less common rearrangements, including Ras pathway mutations. 3,4,8 The frequency of these mutations varies by age group. While always more predominant than other subtypes of Ph-L ALL, alterations in the JAK/STAT pathway (including CRLF2 overexpression) occur more frequently with advancing age from pediatric to the young and older adult populations. The converse is true of ABL class fusions, with a decline in frequency as we progress from pediatric to adult subgroups. 3,10 Averaged among all age groups, alterations in the JAK/ STAT pathway are seen in >70% of Ph-L ALL cases, with ABL class fusions occurring in roughly 10% of cases. 3,12 Thus, a significant majority of Ph-L ALL could, at least in theory, be managed with JAK inhibitors (JAKi) and ABL inhibitors (ABLi). Individuals with Ph-L ALL tend to have higher WBC counts at diagnosis, higher rates of induct...