IGH-CRLF2 fusion

Case: A 20-year-old male with IgH-CRLF2 rearranged leukemia (CRLF2r) presented with relapsed/refractory B-ALL with extramedullary disease (EMD) that was refractory to standard chemotherapy, blinatumomab and inotuzumab. With the rapidly evolving u liza on of immunotherapy, alongside the increasing incidence of LS, Project EVOLVE serves as a collabora ve global approach to profiling these cases and fills an unmet need to op mize outcomes. Collec ng this data will support future physicians and pa ents facing LS diagnoses and unify the field in systema cally iden fying and trea ng such a devasta ng outcome following immunotherapy.

All novel ALL subgroups, except for iAMP21, hyper- and hypodiploid cases were identified. Curiously, we observed higher frequencies of girls within B-'rest' ALLs and boys in PAX5-driven cases.

P1/2, N=26, Not yet recruiting, Princess Maxima Center for Pediatric Oncology

This targeted RNA-seq system showed a reliable and stable performance in detecting various gene fusions occurring in blood cancers, such as leukemia, in clinical laboratories. Also, our targeted RNA-seq system was found to be very useful in diagnosing Ph-like B-ALL compared to the commercial RNA-seq panel.

Here, we retrospectively studied outcomes of adult patients (pts) with r/r B-cell ALL who completed at least one cycle of a novel salvage therapy [blinatumomab (blina), inotuzumab (INO), or CD19CAR T cells (CAR)] at City of Hope from 2012 to 2022 and had post treatment disease assessment. Prior novel therapies did not adversely impact response to subsequent novel therapies. Therefore, the early introduction of novel therapies in pts with Ph-like ALL is of great interest and could potentially lead to improvement in frontline therapy outcomes in this high-risk entity.

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.

In conclusion, in our cohort, a high occurrence of CRLF2 abnormalities was documented, particularly the P2RY8-CRLF2 rearrangement, which might represent a characteristic of the Mexican population. Targeted therapy to treat this group of patients could improve OS.

Clinical molecular testing in our patients revealed gene alterations that provide refinement of diagnosis, prognosis, and risk stratification allowing the use of clinically actionable therapeutic targets in some cases. It also contributes toward a useful data set for further analysis and impactful targeted management. Longer-term follow-up incorporating therapy and outcomes information would be valuable.

While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2 -r ALL cells regardless of RAS mutational status. Our study delineates molecules/pathways relevant for CRLF2 -r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes.

While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status. Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes.

TSLPR expression is not exclusive for CRLF2 translocations and can be seen with various other RGFs, necessitating their testing before its application in diagnostic algorithms. In patients with high TSLPR positivity (> 50%), the testing may be restricted to CRLF2 aberrancies, while patients with 10-50% TSLPR positivity need to be tested for both CRLF2- and non-CRLF2 BCR-ABL1-like CGFs.

Seventy-five of these gene variants have not yet been described in B-cell precursor ALL to date. This study widens existing knowledge of the BCR-ABL1-like and B-other ALL genomic landscape in the adult population, supports previous findings, and identifies a number of novel gene variants.

Development of successful treatment strategies to decrease relapse and to improve survival remains a major therapeutic gap for NCI HR CRLF2+ ALL patients. Current clinical trials are studying the potential efficacy of kinase inhibitor addition to chemotherapy for children, adolescents, and adults with HR Ph-like ALL harboring CRLF2 rearrangements/other JAK pathway alterations or ABL class kinase fusions (NCT0240717, NCT02723994, NCT02883049, NCT03571321).

Whereas CRLF2 and JAK alterations are associated with higher MRD, poorer survival, and increased CIR in patients with high-risk ALL without DS, these alterations do not demonstrate strong adverse prognostic impact in children and AYAs with DS-ALL treated on recent frontline COG trials, although larger sample sizes are needed to adequately assess for possible poorer prognoses associated with the CRLF2+/JAK+ and IGH-CRLF2 subgroups. Regardless, given the frequency of these targetable lesions and the increased risk of relapse and chemotherapy-associated toxicities in patients with DS-ALL, targeted therapies currently under investigation for these genetic lesions may be beneficial to replace some intensive blocks of therapy in DS-ALL with CRLF2 and/or JAK alterations, both to enhance anti-leukemic efficacy and decrease intensive chemotherapy-associated toxicities.