CRLF2 rearrangement

Upon ruxolitinib withdrawal, TSLPRCART functionality recovered in vivo with clearance of subsequent ALL rechallenge. These translational studies demonstrate an effective two-pronged therapeutic strategy that mitigates acute CART-induced hyperinflammation and provides potential anti-leukemia 'maintenance' relapse prevention for CRLF2-rearranged Ph-like and DS-ALL.

Genomic IKZF1 plus with any IKZF1 deletion, IKZF1 deletion of exon 4-7, and unfavorable subtype confer increased risk of relapse. The type of IKZF1 alteration, together with the subtype, are informative for risk stratification and predict response in patients with B-ALL.

Blinatumomab was not used during consolidation therapy in the reported patients. Its incorporation in the routine therapy of newly diagnosed patients may increase the proportion of patients receiving AHCT in a MRD negative state and further improve outcomes in this historically poor risk patient population.

NGS detects very low-level (<0.001%) residual clonal sequences in 22% of patients and the clinical significance remains a matter of investigation. These data suggest that MFC and NGS are complementary and provide more powerful insight into the biology and clinical outcome of B-ALL than either assay alone.

To our knowledge, these are the first cases of LS to be reported in patients with CRLF2 rearranged acute lymphoblastic leukemia. In addition to raising awareness that this genetic mutation may associate with lineage plasticity, our cases illustrate the importance of multi-modal disease surveillance in the diagnosis of LS.

In real-world cohorts, it may be clinically useful to prioritise limited early FISH in B-cell ALL (B-ALL) diagnostic algorithms to identify Ph-like abnormalities that respond to locally available kinase inhibitors to promote and prioritise broad access to effective targeted treatment. Additional studies are required to provide adequately powered validations and verifications of targeted Ph-like FISH panels to confirm sensitivity and specificity against side-by-side gold standard methods, and to define optimal local approaches.

Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high-risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph-like ALL.

This is a preliminary report of the results of NGS analysis of a group of pediatric patients that will allow riskstratification and will provide recommendations of diverse therapeutical approaches within the concept ofpersonalized medicine. The 198 genes panel is ample and identified mutations present in a cluster of 8 genes in the entire set of cases(46/46). We will correlate the obtained mutational profile with response to treatment and relapse considering eternalfactors as nutritional status and access to medical services and medication.

Our study shows enrichment of high-risk genetic variants in H/L B-ALL and raises consideration for novel therapeutic targets.

Our study provides important insights into the demographic and clinical characteristics of patients with ALL and highlights notable disparities between non-Hispanic and Hispanic patients. A higher proportion of Hispanic patients lacked any form of health insurance coverage at the time of diagnosis. Interestingly, the incidence of Philadelphia-positive ALL was found to be higher among non-Hispanic patients, whereas other cytogenetic abnormalities were more prevalent among Hispanic patients.

P1, N=15, Recruiting, University of Chicago | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2023 --> Sep 2026

Overall, our findings indicate that Latino children are significantly less likely to have favorable cytogenetic subtypes, TCF3::PBX1 and iAMP21 and prognostically neutral cytogenetics. Further evaluation of cytogenetic subtypes and race/ethnicity may elucidate their contribution to outcome disparities.

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.

Among 21 drugs, seven showed significant differences in overall LC50 between children and adults (P<0.05 after Bonferroni correction): children displayed higher sensitivity to asparaginase, prednisolone, mercaptopurine, daunorubicin, and inotuzumab, while adults showed higher sensitivity to dasatinib and nelarabine...In the KMT2A subtype, cases in C-a exhibited an over-representation of the KMT2A::AFF1 fusion, and resistance to mercaptopurine (P=0.029), prednisolone (P=0.0039), vincristine (P=0.046) and cytarabine (P=0.0037)...In conclusion, these studies have revealed important new insights into the pharmacogenomic basis of age-related differences in B-ALL treatment response. These results indicate that both inter- and intra-subtype heterogeneity contribute to inferior prognosis in adults with ALL, but also point to therapeutic opportunities to improve their outcomes.

In 8/15 patients ponatinib was used as single agent or in association with steroids or intrathecal chemotherapy only, in 4 it was administered in combination with chemotherapy and in 3 with blinatumomab; 7 patients started ponatinib after having failed an allogeneic transplant (6 hematologic relapses and 1 molecular relapse). In a pre-transplant setting, ponatinib was effective as a bridge to cellular therapies in 7 out of 8 patients as intention-to-treat (ITT), thus suggesting that this strategy may represent an effective bridge to further therapies. To our knowledge, this is the largest cohort of adult Ph-like ALL cases treated with ponatinib so far reported.

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.

Acknowledgments This is an independent academic early phase I clinical trial conducted under the sponsor role of the Goethe University, Frankfurt, Germany. It received financial support and supply of Venetoclax by AbbVie Inc..

To test sensitivity, primary or PDX cells were exposed ex vivo to a concentration range of gilteritinib (FLT3 inhibitor), trametinib (MEK1/2 inhibitor), or ruxolitinib (JAK1/2 inhibitor). This might also explain the observed sensitivity to RAS-pathway inhibition irrespective of secondary lesions. These results suggest that further research into FLT3 and RAS signalling inhibitors might lead to better treatment options for pediatric iAMP21 BCP-ALL.

Identification of recurrent gene abnormalities (RGA) B-acute lymphoblastic leukemia (B-ALL) cases using multiplex-reverse transcriptase polymerase chain reaction. Identification and characterization of Philadelphia (Ph)-like ALL cases using nCounter NanoString gene expression profiling and fluorescence in situ hybridization. Furthermore, Ph-like ALL cases were characterized according to CRLF2 expression and kinase-activating genomic alterations. Minimal residual disease of Ph-like ALL cases were quantified using flow cytometry-minimal residual disease assay. A surrogate molecular approach was established to detect Ph-like ALL cases from low- and middle-income countries.

Finally, toxicology studies using cynomolgus monkeys found that the maximum tolerated dose of 1B7/CD3 was ≤1 mg/kg. Overall, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 in patients with CRLF2-rearranged B-ALL.

An algorithm implementing widely available techniques enables the identification of BCR::ABL1-like ALL cases in settings with limited resources.

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.

In conclusion, MUC4 is a specific, albeit insensitive, marker for these high-risk subtypes of B-ALL. We propose that MUC4 IHC may be employed diagnostically to rapidly identify these B-ALL subtypes particularly in resource limited settings or when an aspirate sample is not available for ancillary genetic studies.

It was classified as early T-precursor lymphoblastic leukemia/lymphoma and T-ALL, NOS in the WHO revised 4th edition and WHO 5th edition. The ICC added an entity into early T-cell precursor ALL, BCL11B-activated, and also added provisional entities subclassified based on transcription factor families that are aberrantly activated.

No abstract available

Precision medicine should be implemented in the treatment of such cases. Here in this review, we summarize the available data on Ph-like ALL.

No abstract available

P1, N=15, Recruiting, University of Chicago | Trial primary completion date: Sep 2022 --> Sep 2023

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.

Unsupervised hierarchical clustering analyses of CRLF2-rearranged DS-ALL identified substantial heterogeneity within this group, with the BCR::ABL1-like subset linked to an inferior event-free survival (hazard ratio=5.27, P=9.3×10-8), even after adjusting for known clinical risk factors (hazard ratio=4.32; P=0.0020). These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.

Although targeted therapies such as blinatumomab, inotuzumab ozogamicin, and CD19 CAR T cell therapy are a significant treatment advance for patients with B-ALL, there is still an unmet medical need for novel therapies for B-ALL. Consistent with clinical observation, we observed a transient increase of six major cytokines (IFNγ, IL-6, IL-8, IL-10, MCP-1 and TNFα) 4hr post the initial dosing, but no notable induction of cytokine levels after the second dosing (except for IL-8). Thus, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 BsAb in patients with CRLF2-rearranged B-ALL.

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

P2, N=171, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting

When surface TSLPR is detected at the diagnosis of BCP-ALL, close attention should be given to the search for chromosomal aberrations involving CRLF2 at any level of expression.

P1, N=18, Recruiting, Crystal Mackall, MD | Not yet recruiting --> Recruiting