CRLF2 mutation

Compared to Ph-negative, Ph-like patients were more likely to have a refractory disease (20.6% vs. 6.2% P=0.006) and require Blinatumomab (67.2% vs. 39.3% P<0.001), with a non-significant trend towards lower rates of CR (84.1% vs 90.9% P=0.21)... Ph-like B- Cell ALL represents a high-risk disease subtype of adult B-ALL, with poor EFS and frequent treatment failure. CRLF2 translocation confers worse CIR and EFS within Ph-like patients and requires novel treatment approaches.

This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No IMI001-07. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Single-cell RNA sequencing and digital spatial profiling enable the identification of rare cell subpopulations, characterization of clonal evolution dynamics, and exploration of the tumor microenvironment's role. These approaches may help identify new druggable targets and tailor therapeutic interventions based on distinct molecular profiles, ultimately improving patient outcomes with the potential to guide personalized medicine approaches and the development of targeted therapies.

Our studies provide a crucial role of glycosylation in the cell surface expression of receptors.

In patients with CRLF2 expression, other molecular rearrangements should be searched to determine the proper risk group.

Furthermore, concomitant CNA of IKZF1 in CRLF2 positive patients was associated with a greater hazard for poor overall and event free survival, compared to patients without these alterations or presence of any one of them. Our findings demonstrate that the surface CRLF2 expression in association with IKZF1 copy number alteration can be used to risk stratify pediatric B-ALL patients.

However, long-term efficacy remains to be determined and it is under evaluation in clinical trials.1,22,23 Preclinical and more recent clinical studies have shown variable activity of JAK inhibitors in JAK-STAT activating ALL17,24 and the need to simultaneously inhibit multiple pathways, including phosphoinositide 3-kinase (PI3K)/mTOR or mitogen-activated protein kinase (MEK)/ receptor tyrosine kinases (e.g. FLT3) to block the growth of leukemic blasts.25–27 Promising alternative approaches to TKIs are represented by antibody-based (e.g. blinatumomab or inozutumab) and cellular (CAR T-cell therapy) immunotherapy which have shown discernable efficacy in BCR::ABL1-like ALL among other subtypes.28–30 Moreover, the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAK231 or GSPT1/2 degraders32 has been recently reported in preclinical models of CRLF2-rearranged and other JAK-activated BCR::ABL1-like ALL. Conclusions BCR::ABL1-like ALL is driven by numerous targetable kinase fusions whose diagnosis requires the use of comprehensive assays. The incorporation of TKIs and/or different immunotherapies is reversing the historically poor outcome of this ALL subtype.

We demonstrate the use of a single-tube multimodal NGS assay for comprehensive genomics profiling that simultaneously screens DNA and RNA for expression and variants. It is a powerful and cost-effective tool to help classify PhL B-ALL subgroup for clinical management and guiding therapeutic intervention.

The combination of ruxolitinib plus blinatumomab or inotuzumab is a promising chemotherapyfree salvage regimen given outpatient for relapsed Ph-like ALL. It achieved CR in our patient prior to allo SCT with a limited side effect profi le. Further clinical trials adding ruxolitinib to front-line and next-line therapies are needed.

Blinatumomab is an available immunotherapy, and there are currently a few ongoing clinical trials to treat CRLF2 B-ALL. This review focuses on the role of CRLF2 in B-ALL and summarizes the literature regarding its molecular pathways, clinical significance, incidence rates across demographics, therapies, and areas of further research.

The identification of the CRLF2 antigen using the MFC, based on the percentage of positivity and MFI values, is a useful tool for predicting JAK2 mutations and CRLF2-r.

CRLF2 expression was significantly higher in Egyptian precursor B-ALL pediatric patients. CRLF2 overexpression was associated with a number of unfavorable prognostic factors with high tumor load, but was not an adverse independent parameter in pediatric BCP-ALL patients. Some patients with CRLF2 overexpression display JAK2 mutation, which may benefit from targeted therapy by kinase inhibitors.

A 2nd relapse, 5m later, was treated with Blinatumomab (4 cycles) and 2 DLIs achieving CR. After 3m a 3rd relapse at bone marrow (BM) and pelvic nodes (PET-scan: SUV10) was treated with Inotuzumab-Ozogamicin (6 cycles) and radiotherapy reaching MRD-neg and nodal partial response (PET-scan: SUV2.9)... Abnormal activation in JAK/STAT pathway is thought to play an important role in maligcies and in particular in ALL pathogenesis. These alterations translate in modified transcription of genes involved in cell survival, proliferation and differentiation including STAT3, STAT5 and BCL2. In our pt we found JAK/STAT pathway alterations in terms of JAK1 KD-mutation and MPL, STAT5B downregulation.

Furthermore, patients with CRLF2-high/IKZF1del had a poorer prognosis in the RELLA05 protocol (p = 0.067, 36.1 months, 95%CI 0.0-85.9) and adult cohort (p = 0.094, 29.7 months, 95%CI 11.8-47.5). In this study, we show that IKZF1 status is associated with CRLF2-high and dismal outcomes in B-ALL patients regardless of age.