Educational theme│The genomic landscape, biology, epidemiology, and prognosis of Ph-like ALL

Our educational theme for this quarter is exploring the biology, genomic landscape, epidemiology, and prognosis of a relatively new subtype of acute lymphoblastic leukemia (ALL); Philadelphia chromosome (Ph)-like ALL. This educational theme will also include future articles on the diagnosis and treatment of Ph-like ALL.

Ph-like ALL is a high-risk subtype of B-cell precursor ALL, which is characterized by poor prognosis and outcomes; it harbors diverse genetic alterations (>70 discrete alterations), including a high rate of IKZF1 and other B-cell-associated transcription factor deletions, which activate cytokine receptor genes and kinase signaling pathways.¹ Ph-like ALL occurs commonly in children, as well as adolescents and young adults (AYAs).² Due to associated adverse outcomes, the World Health Organization classifies Ph-like ALL as a provisional leukemia subtype.³ The kinase-activated gene expression patterns of Ph-like ALL are very similar to BCR-ABL1-rearranged or Ph-positive (Ph+) ALL.³

Here, we summarize the biology, epidemiology, and prognosis of Ph-like ALL based on articles published by Tran and Tasian in Best Practice & Research Clinical Hematology in 2021,¹ Tran and Loh Hematology Am Soc Hematol Educ Program in 2016,² Harvey and Tasian in Blood Advances in 2019,³ and Iacobucci and Roberts in Genes in 2021.⁴     

Biology and genomic landscape

The heterogenous genetic alterations in Ph-like ALL are categorized into four genomically-defined subsets based on the similarity of functional fusion partners and underlying kinase-activating lesions (Table 1)¹:

• JAK/STAT pathway gene alterations;
• ABL class alterations;
• Ras pathway mutations; and
• rare kinase fusions.

Table 1. The landscape of Ph-like ALL kinase rearrangements, therapeutic targets, and clinical trials*

The most common alteration in Ph-like ALL is CRLF2 rearrangement, occurring in 64% of children and AYAs. ³ CRLF2 rearrangements may also occur at a lower frequency in children with standard risk (SR) B-ALL and in >50% of trisomy 21/Down syndrome (DS)-associated B-ALL; however, it is rare to discover other Ph‑like ALL-associated kinase fusions in patients with SR ALL.¹

Deletions of IKZF1 and other lymphoid transcription factor genes are also seen in Ph+ ALL, resulting in aberrant marrow stromal adhesion, chemotherapy resistance, and inferior clinical outcomes.¹ In addition, the new IKZF1^plus molecular profile (defined as IKZF1 deletion co-occurring with one or more deletions in CDKN2A, CDKN2B, PAX5, or the pseudoautosomal region 1 [PAR1], and in the absence of ERG deletion) is associated with inferior outcomes, including a higher frequency of relapses, and could be used to refine the risk stratification criteria.¹

Figure 1. Frequency of Ph-like ALL alterations in children, adolescents, and young adults*

CRLF2-R, CRLF2-rearranged; HR, high risk; Ph-like ALL, Philadelphia chromosome-like acute lymphoblastic leukemia; WT, wild-type.
*Adapted from Tran and Loh.² 

Key genomic alterations in Ph-like ALL are presented in Figure 2 and summarized below.

Figure 2. Key genomic alterations in Ph-like ALL*

BCL2i, BCL2 inhibitors; CAR, chimeric antigen receptor; JAKi, JAK inhibitors; mTORi, mTOR inhibitors; Ph-like ALL, Philadelphia chromosome-like acute lymphoblastic leukemia; PI3Ki, PI3K inhibitors; TKi, tyrosine kinase inhibitors; TR, truncated.
*Adapted from Iacobucci I and Roberts KG.^4
†Indicates the occurrence of a mutation.

JAK/STAT pathway gene alterations

Approximately 50% of patients with Ph-like ALL harbor CRLF2 rearrangements that occur either via focal deletion of PAR1 on chromosomes Xp22/Yp11, resulting in the P2RY8-CRLF2 fusion, or via translocation to the immunoglobulin heavy chain enhancer region on chromosome 14, resulting in IGH-CRLF2 rearrangement.¹ P2RY8-CRLF2 fusion occurs more commonly in younger children with National Cancer Institute (NCI)-defined SR B-ALL and in those with DS-associated ALL.¹ On the other hand, IGH-CRLF2 occurs mostly in AYAs, particularly in those of Hispanic/Latino or Native American ethnicity.¹ CRFL2-rearranged (CRLF2-R) accounts for 24% of pediatric patients with NCI SR Ph-like ALL, 55% with high-risk disease, and 50−60% of AYA patients.⁴

Patients with Ph-like ALL, particularly those with CRLF2-R, have an increased risk of relapse due to the GATA3 single nucleotide polymorphism risk allele RS3824662.³ CRLF2-R is also significantly associated with mutations in JAK genes, most commonly the point mutation R683G in the JAK2 pseudokinase domain.¹ Approximately 50−60% of children with DS-associated ALL have JAK2^R683G mutations and CRLF2-R. JAK ^V658F, like the JAK2^V617F mutation observed in adult patients with myeloproliferative neoplasms, occurs much less frequently in CRLF2-R Ph-like ALL.³ IL7R insertions and deletions occur in a small number of patients with CRLF2‑R that lack concomitant JAK1 or JAK2 mutations.³ Of note, 5−10% of patients with CRLF2-R ALL have distinctly different gene expression without the kinase-activated signature and therefore are not considered to have Ph-like disease.³

Mechanisms leading to activation of JAK/STAT signaling include EPOR rearrangements or kinase fusions involving JAK2, which release the normal auto-inhibition of the kinase domain.¹ An increased frequency of EPOR rearrangements is observed with increasing age, with a peak in young adults. Sequence mutations and copy number variations in JAK1, JAK3, ILR7, SH2B3, IL2RB, and TYK2 are also associated with activation of the JAK/STAT pathway and occur more frequently in children compared with adolescents or young adults (14% vs 5% vs 7.3%, respectively). These cases often harbor chromosomal rearrangements expressing fusion oncoproteins involving transcription factor genes (EBF1, PAX5, and ETV6) and/or epigenetic regulators (CREBBP, SETD2, and ASXL1).¹

ABL class alterations

ABL-class alterations account for ~10% of cases and are distinct from CRLF2-R and other JAK pathway-activating alterations.¹ ABL-class alterations are more prevalent in children with NCI high-risk B-ALL compared with AYAs (17% vs 10%).¹ Poor response to chemotherapy is observed in patients with ABL-class fusions, and the EBF1-PDGFRB fusion is associated with induction failure, indicating a potential mechanism for relapse.⁴ In EBF1-PDGFRB Ph‑like ALL, the T681I gatekeeper mutation has been demonstrated to be the most common resistance mutation to imatinib and dasatinib, with a trend towards increased risk of relapse in patients with T681I subclones.⁴  

Ras pathway mutations

Ras pathway mutations are present in ~4% of Ph-like ALL cases, with mutations in the following Ras pathway genes: KRAS, NRAS, NF1, PTPN11, and CBL.¹ These mutations are often subclonal, and commonly occur in hyperdiploid, hypodiploid, KTM2A-rearranged, and relapsed ALL. Ras pathway mutations may occur in conjunction with sentinel Ph-like translocations (e.g., ABL class, CRLF2, EPOR, or JAK2 fusions) or in isolation.¹

Rare kinase fusions

Rare kinase fusions account for 5% of Ph-like ALL cases and involve NTRK3, BLNK, DGKH, FGFR1, PTK2B, FLT3, SH2B3, and TYK2. Among these cases, 1% harbor the ETV6-NTRK3 fusion⁴, which is reported to induce an aggressive ALL with in vitro and in vivo sensitivity to tyrosine receptor kinase inhibitors.¹ As this fusion has been identified in a range of hematologic malignancies it is not unique to Ph-like ALL.¹

Epidemiology and prognosis¹

The prevalence of Ph-like ALL differs according to age, gender, range, ethnicity, and NCI-defined risk group. The pooled prevalence of Ph-like ALL is reported across the spectrum as 15.4%. Figure 3 illustrates the prevalence of Ph-like ALL by age and NCI risk group. Across all age groups, Ph-like ALL occurs more commonly in males than females, at a ratio of 1.5:1. Patients of Hispanic/Latino or Native American ethnicity, particularly those with CRLF2-R, are more predisposed to Ph-like ALL, at least in part due to the increased prevalence of the Ph-like ALL risk variant in GATA3 in this population.

In the pediatric population, the occurrence of Ph-like ALL is three times higher compared with Ph+ ALL.

Figure 3. Prevalence of Ph-like ALL*

AYAs, adolescents and young adults; B-ALL, B-cell acute lymphoblastic leukemia; NCI, National Cancer Institute; Ph-ALL, Philadelphia chromosome-like acute lymphoblastic leukemia.
*Adapted from Tran and Tasian.¹

Furthermore, patients with Ph-like ALL frequently exhibit adverse clinical features; significantly higher rates of hyperleukocytosis at diagnosis, end-induction minimal residual disease (MRD) positivity, and increased risk of treatment failure and relapse have been observed in patients with Ph-like ALL. Aggressive disease course and high rates of end-induction MRD or even induction failure are associated with patients harboring PDGFRB, JAK2, or EPOR fusions.

Compared with patients with Ph+ ALL, patients with Ph-like ALL have inferior survival outcomes across the age spectrum.

Conclusion

Ph-like ALL is emerging as a prevalent subtype of B-ALL, defined by its kinase-activated gene expression signature and associated genetic alterations. The prevalence of Ph-like ALL increases among children and AYAs, reaching a peak in young adults and is associated with a poor prognosis, with high rates of conventional treatment failure and relapse. As the genomic understanding of Ph-like ALL continues to develop, there is an opportunity to consider targeted therapeutic approaches that aim to reduce relapse rates and improve long-term survival for patients with Ph-like ALL across all ages.   

“Look out for our following educational theme articles on the diagnosis and treatment of Ph-like ALL!”