Relevant subtypes in childhood ALL
Authors: Chloé Arfeuille, Hélène Cavé
Journal: HemaSphere (2019)

Take home messages Genetic lesions define B cell precursor (BCP) ALL subtypes with distinct biology and prognosis. Some of them define “Ph and Ph-like” subtypes that may be treated by tyrosine-kinase inhibitors. CNV signatures (including IKZF1 deletion) have been validated to distinguish subgroups of BCP-ALL statistically defined according to event-free survival. Routine screening of relevant genetic subtypes is now a major tool in clinical practice and improves risk assessment, clinical decision, and implementation of precision medicine in BCP-ALL. Mutually exclusive genetic lesions define ALL subtypes with distinct biology and prognosis Acute lymphoblastic leukemia (ALL) is the most common malignant tumor in children. Despite major improvements in cure rates over the last decades, it remains one of the major causes of cancer-related death in children. ALL uncovers a constellation of different entities characterized by mutually exclusive recurrent genetic alterations establishing the biology of ALLs (Table 1). These entities, which prevalence varies with age and ethnicity, allow the classification of ALLs and often influence response to treatment.1▪,2 Thus, in B cell progenitor ALLs (BCP-ALL), the presence of hyperdiploidy or t(12;21)/ETV6-RUNX1, which are the most frequent alterations in young children, is associated with an excellent prognosis. On the other hand, t(9;22)/BCR-ABL1, KMT2A (MLL) rearrangements, chromosome 21 amplification (iAMP21), t(17/19)/TCF3-HLF and hypodiploidy, are associated with a high risk of relapse and are criteria for therapeutic intensification. Other ALL, including those with t(1;19)/TCF3-PBX1, are considered intermediate risk (Table 1). By allowing the assignment of patients to a risk group and the adjustment of treatment intensity, the identification of classifying genetic abnormalities has led to significant progress in managing children's ALLs and has been a key element in improving children's ALL treatment. However, if increasing the intensity of chemotherapy has been effective in some subgroups (ie, iAMP21), others such as the rare subtype defined by the presence of a t(17;19)/TCF3-HLF remain highly resistant to conventional therapies and alternative therapeutic options based on their specific biology should be considered.3Table 1: Classification of BCP-ALL and Subtype Relevance for Risk Assessment and Clinical DecisionAmong the so-called “B-other ALL,” that is, the fraction of ALLs that still lacks a classifying genetic alteration, pan-genomic studies recently identified novel ALL subtypes (Table 1) defined by specific gene fusions involving several transcription factors such as PAX5, ZNF384, MEF2D, or DUX4 (frequently associated with ERG deletions), each being possibly fused to a variety of partners.1,4,5,6▪,7▪,8 The prognostic value of these genetic lesions remains to be clarified and will require large international studies due to the rarity of each subtype. “Ph and Ph-like” ALL subtypes: The promise of targeted therapies Most precision medicine initiatives so far focus on genetically defined subtypes. Leukemias are no exception to the rule and recently such a type of relevant ALL subgroups has emerged with the development of therapies specifically targeting oncogenic alterations. The detection of t(9;22)/BCR-ABL1 now points to the use of tyrosine-kinase inhibitors (TKI), radically improving the prognosis of these leukemias that are highly resistant to conventional chemotherapy.9,10 More recently, several teams have identified a subpopulation representing 10% to 15% of BCP-ALLs whose gene expression profile (transcriptome) is very similar to that of t(9;22)/BCR-ABL ALLs. This new group of ALLs, called “Ph-like” or “BCR-ABL-like,” has aroused great interest due to the poor prognosis associated with it, in line with the usual persistence of high levels of minimal residual disease (MRD) during induction.11▪,12 These ALLs are characterized by abnormal activation of signaling pathways. This activation is the result of a wide range of genomic translocations leading to gene fusions, some of which have the advantage of providing potential therapeutic targets.1▪,11▪,12 Ph-like ALL can be separated in 2 major groups depending on the type of fusion. Alike BCR-ABL, fusions involving ABL, PDGFR, or CSF1R (ABL-class fusions) are potential targets for tyrosine-kinase inhibitor. Another group of fusions involving or JAK, EPOR, or CRLF2 (JAK-class fusions) are potential targets for JAK inhibitors. Although there is currently no unambiguous transcriptional signature adapted to a prospective identification of these ALLs in the context of care,13 the search for these translocations using techniques such as FISH or RNAseq makes it possible to identify patients for whom therapeutic alternatives can be proposed.6▪,14,15 Several case reports have described the effectiveness of imatinib/dasatinib in the treatment of refractory Ph-like ALL with ABL-class fusions and may help to decrease the use of bone marrow transplant. However, although promising, the beneficial effects of ABL- or JAK-targeted therapies are still based on anecdotal reports. Optimal treatment design as well as potential toxicity in combination with conventional chemotherapy remain an issue but trials are now open that will soon bring more information. CNV signatures distinguishing BCP-ALL with poor outcome Although the so-called “classifying” abnormalities are considered to be the initiators of leukemia, these genetic lesions alone are not sufficient to induce leukemia. Indeed, pan-genomic approaches using DNA microarrays and, more recently, next-generation sequencing applied to the exome or the entire genome have made it possible to identify a number of recurrent mutations that coexist with classifying anomalies.16 These additional lesions frequently alter genes involved in classical oncogenic pathway (RAS, P53, CDKN2A, RB1, etc.) or B-lymphoid development genes (IKZF1, PAX5, EBF1, etc.). Among the latter, deletions of the IKAROS gene (IKZF1), found in 60% to 80% of positive BCR-ABL ALLs as well as in 15% of negative BCR-ABL ALLs, are of note. These deletions are associated with poor prognosis independently of known prognostic factors and therefore represent a promising marker for therapeutic stratification.17 The prognostic power of IKZF1 deletions was shown to be in part context-dependent with an epistatic effect of copy number variations (CNV) of other genes such as ERG.18 Accordingly, several groups subsequently defined CNV-based classifiers, such as the IKZF1+ subgroup, consisting in deletion patterns of 6 to 8 loci including IKZF1 and distinguishing high-risk ALL deserving treatment intensification.19▪,20 Contrary to classifying lesions defining biologically characterized ALL subtypes, these CNV signatures, which are now implemented for risk assessment in ongoing therapeutic trials, can be considered as “pragmatic” prognostic factors, distinguishing statistically defined subgroups associated with low event-free survival and thus providing relevant and robust tools for risk assessment in clinical practice. Future perspectives In ALL, an increasing number of subtypes can be now considered relevant either for their interest in risk assessment in combination with MRD, or because their detection directs patients to protocols that include drugs targeted at these abnormalities. Their prospective screening is now implemented in most up-to-date clinical trials as part of the routine diagnosis workup.15 Targeted therapies are currently limited to the Ph- and Ph-like subtypes but it is likely that precision medicine based on targeted therapies will soon be extended to other ALL subtypes emphasizing the need for strong diagnostic algorithms.