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BIOMARKER:

CRLF2 rearrangement

i
Other names: CRLF2, Cytokine Receptor Like Factor 2, Thymic Stromal Lymphopoietin Protein Receptor, Cytokine Receptor-Like Factor 2, TSLP Receptor, IL-XR, TSLPR, CRL2, Thymic Stromal-Derived Lymphopoietin Receptor, Cytokine Receptor CRL2 Precusor, Cytokine Receptor-Like 2, CRLF2Y, ILXR
Entrez ID:
4d
Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia. (PubMed, Res Sq)
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.
Journal
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ABL1 (ABL proto-oncogene 1) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1)
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IKZF1 deletion • CRLF2 rearrangement
27d
Improved Outcomes of Adult Patients with Philadelphia-like Acute Lymphoblastic Leukemia (Ph-Like ALL) Treated within an Integrated Leukemia/Transplant Program with Incorporation of Pediatric Inspired Regimens and Early Allogeneic Transplant (ASH 2024)
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.
Clinical
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • JAK2 (Janus kinase 2) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CRLF2 (Cytokine Receptor Like Factor 2) • CSF1R (Colony stimulating factor 1 receptor)
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CRLF2 rearrangement • JAK2 rearrangement
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clonoSEQ
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Blincyto (blinatumomab)
27d
Enhanced Flow Cytometry and Next Generation Sequencing Assays for Residual B Lymphoblastic Leukemia (B-ALL) Reveal a Subset with Discordant Results Due to Leukemic Changes Post-Therapy (ASH 2024)
There is an excellent overall concordance between the NGS and enhanced MFC assays to a limit of detection of 0.001% using routine clinical samples from a pediatric oncology service where anti-CD19 immunotherapy is frequently administered. MFC is able to identify a subset of discordant cases with clear residual disease that is not identifiable by NGS due to changes in clonal sequence (NGS false negatives). Conversely, NGS identifies a subset of discordant cases that likely represent persistent clonal sequences in myelomonocytic populations whose relationship to relapse risk remains to be determined (potentially NGS false positives).
Next-generation sequencing • IO biomarker • Discordant
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KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2) • CD73 (5'-Nucleotidase Ecto) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD22 (CD22 Molecule) • CD24 (CD24 Molecule) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • NRP1 (Neuropilin 1) • CD81 (CD81 Molecule)
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CRLF2 rearrangement
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clonoSEQ
1m
CRLF2-rearranged B-cell ALL with extramedullary lineage switch to AML following CD19-targeted therapy. (PubMed, J Immunother Cancer)
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.
Journal
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KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2)
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KMT2A rearrangement • MLL rearrangement • CRLF2 rearrangement
2ms
Judicious use of precise fluorescence in situ hybridisation panels guided by population prevalence may assist pragmatic detection of clinically targetable Philadelphia chromosome-like acute lymphoblastic leukaemia fusions: a systematic review. (PubMed, Pathology)
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.
Review • Journal
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CRLF2 (Cytokine Receptor Like Factor 2)
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CRLF2 rearrangement
6ms
An integrated classification of tumor suppressor IKZF1 inactivation and oncogenic activation in Philadelphia chromosome-like acute lymphoblastic leukemia. (PubMed, Hemasphere)
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.
Journal
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • CRKL (CRK Like Proto-Oncogene, Adaptor Protein) • STAT5A (Signal Transducer And Activator Of Transcription 5A)
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CRLF2 rearrangement • JAK2 rearrangement
7ms
MOLECULAR PROFILING OF ALL IN PEDIATRIC PATIENTS TREATED AT SOLCA, GUAYAQUIL. EVALUATION OF PROGNOSTIC VALUE. PRELIMINARY REPORT. (EHA 2024)
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.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • NOTCH1 (Notch 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • WT1 (WT1 Transcription Factor) • TCF3 (Transcription Factor 3) • PBX1 (PBX Homeobox 1) • CSF1R (Colony stimulating factor 1 receptor) • FOXP1 (Forkhead Box P1) • CALR (Calreticulin) • BCL11B (BAF Chromatin Remodeling Complex Subunit BCL11B) • LZTS1 (Leucine Zipper Tumor Suppressor 1) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor) • PDGFC (Platelet Derived Growth Factor C)
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CRLF2 rearrangement • BCL11B mutation
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FusionPlex™ Pan-Heme panel
8ms
IKZF1PLUS alterations contribute to outcome disparities in Hispanic/Latino children with B-lymphoblastic leukemia. (PubMed, Pediatr Blood Cancer)
Our study shows enrichment of high-risk genetic variants in H/L B-ALL and raises consideration for novel therapeutic targets.
Journal
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ABL1 (ABL proto-oncogene 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • P2RY8 (P2Y Receptor Family Member 8) • DUX4 (Double Homeobox 4)
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CDKN2A deletion • IKZF1 deletion • CRLF2 rearrangement
1year
Outcome Disparities Among Hispanic and Non-Hispanic Patients with Acute Lymphoblastic Leukemia (ASH 2023)
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.
Clinical
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • TCF3 (Transcription Factor 3) • PBX1 (PBX Homeobox 1)
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CRLF2 rearrangement
1year
Ruxolitinib and Chemotherapy in Adolescents and Young Adults With Ph-like Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P1, N=15, Recruiting, University of Chicago | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2023 --> Sep 2026
Trial completion date • Trial primary completion date
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IL7R (Interleukin 7 Receptor) • SH2B3 (SH2B Adaptor Protein 3)
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CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 rearrangement • SH2B3 deletion
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Rituxan (rituximab) • cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • cyclophosphamide • vincristine • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine
1year
Association of Latino Ethnicity with Cytogenetic Subtype in Pediatric Acute Lymphoblastic Leukemia: A Report from the Reducing Ethnic Disparities in Acute Leukemia Consortium (ASH 2023)
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.
Clinical
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RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • TCF3 (Transcription Factor 3) • PBX1 (PBX Homeobox 1)
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MLL rearrangement • MLL rearrangement • CRLF2 rearrangement
1year
Philadelphia-like B-Cell Acute Lymphoblastic Leukemia in a Largely Hispanic Population: Disease Features and Outcomes in the Era of Immunotherapy a Single Institutional Study (ASH 2023)
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.
Clinical • IO biomarker
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ABL1 (ABL proto-oncogene 1) • JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • PAX5 (Paired Box 5) • P2RY8 (P2Y Receptor Family Member 8)
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CRLF2 rearrangement • ABL1 fusion • CRLF2 mutation • EPOR rearrangement
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Blincyto (blinatumomab)
1year
The Impact of Age and Genomics on Drug Sensitivity in 1,076 Children and Adults with B-Cell Acute Lymphoblastic Leukemia (ASH 2023)
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.
Clinical
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ABL1 (ABL proto-oncogene 1) • KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2) • AFF1 (AF4/FMR2 Family Member 1) • DUX4 (Double Homeobox 4)
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CRLF2 rearrangement
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dasatinib • cytarabine • Besponsa (inotuzumab ozogamicin) • vincristine • daunorubicin • nelarabine • mercaptopurine
1year
Venetoclax and Blinatumomab for Adult Patients with Relapsed/Refractory or MRD Positive Ph-Negative B-Precursor ALL: First Results of the GMALL-Bliven Trial (ASH 2023)
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..
Clinical • Minimal residual disease
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ABL1 (ABL proto-oncogene 1) • KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2) • ZNF384 (Zinc Finger Protein 384)
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CD19 positive • MLL rearrangement • CRLF2 rearrangement
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Venclexta (venetoclax) • Blincyto (blinatumomab)
1year
Use of Ponatinib Alone or Combined with Other Therapies in Relapsed/Refractory Ph-like Acute Lymphoblastic Leukemia. a Campus ALL Real-Life Study (ASH 2023)
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.
Clinical • IO biomarker
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ABL1 (ABL proto-oncogene 1) • RB1 (RB Transcriptional Corepressor 1) • JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • P2RY8 (P2Y Receptor Family Member 8)
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CRLF2 rearrangement • JAK2 mutation • JAK2 fusion • JAK2 rearrangement
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Iclusig (ponatinib) • Blincyto (blinatumomab)
1year
Secondary Lesions and Sensitivity to Signaling Inhibitors of Pediatric iAMP21 B-Cell Precursor Acute Lymphoblastic Leukemia (ASH 2023)
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.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • CRLF2 (Cytokine Receptor Like Factor 2) • IL7R (Interleukin 7 Receptor) • SH2B3 (SH2B Adaptor Protein 3)
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CRLF2 rearrangement • JAK2 mutation • JAK1 mutation
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Mekinist (trametinib) • Xospata (gilteritinib) • Jakafi (ruxolitinib)
1year
Role of Allogeneic Stem Cell Transplantation in Preventing Relapse in Adult BCR::ABL1-like Acute Lymphoblastic Leukemia (ASH 2023)
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.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • JAK2 (Janus kinase 2) • KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • NUP214 (Nucleoporin 214) • BLNK (B Cell Linker)
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KRAS mutation • CDKN2A deletion • KMT2A rearrangement • MLL rearrangement • CRLF2 rearrangement • JAK2 mutation • IKZF1 deletion + CDKN2A deletion • CRLF2 mutation • ABL1 deletion
1year
A surrogate molecular approach for the detection of Philadelphia chromosome-like B-acute lymphoblastic leukemia. (PubMed, Cancer)
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.
Journal
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ABL1 (ABL proto-oncogene 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • AFF1 (AF4/FMR2 Family Member 1) • TCF3 (Transcription Factor 3) • P2RY8 (P2Y Receptor Family Member 8) • PBX1 (PBX Homeobox 1) • MUC4 (Mucin 4, Cell Surface Associated) • CEACAM6 (CEA Cell Adhesion Molecule 6) • SPATS2L (Spermatogenesis Associated Serine Rich 2 Like)
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CRLF2 rearrangement • MUC4 expression
over1year
Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL. (PubMed, Leukemia)
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.
Preclinical • Journal
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CRLF2 (Cytokine Receptor Like Factor 2) • TSLP (Thymic Stromal Lymphopoietin)
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CRLF2 rearrangement
over1year
BCR::ABL1-like acute lymphoblastic leukaemia: a single institution experience on identification of potentially therapeutic targetable cases. (PubMed, Mol Cytogenet)
An algorithm implementing widely available techniques enables the identification of BCR::ABL1-like ALL cases in settings with limited resources.
Journal
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ABL1 (ABL proto-oncogene 1) • CRLF2 (Cytokine Receptor Like Factor 2)
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CRLF2 rearrangement
over1year
Approach to Ph-Like ALL (SOHO 2023)
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.
IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • IGH (Immunoglobulin Heavy Locus) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • PAX5 (Paired Box 5) • JAK3 (Janus Kinase 3) • P2RY8 (P2Y Receptor Family Member 8) • ABL2 (ABL Proto-Oncogene 2, Non-Receptor Tyrosine Kinase) • CSF1R (Colony stimulating factor 1 receptor) • EBF1 (EBF Transcription Factor 1) • GSPT1 (G1 To S Phase Transition 1) • IL7 (Interleukin 7) • TSLP (Thymic Stromal Lymphopoietin)
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NTRK3 fusion • CDKN2A deletion • CRLF2 rearrangement • CRLF2 overexpression • CRLF2 mutation • EPOR rearrangement • JAK2 fusion
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Blincyto (blinatumomab)
over1year
Mucin 4 (MUC4) Protein is Expressed in B-Acute Lymphoblastic Leukemia (B-ALL) and is restricted to BCR::ABL1 Positive and BCR::ABL-like Subtypes. (PubMed, Hum Pathol)
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.
Journal
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ABL1 (ABL proto-oncogene 1) • CRLF2 (Cytokine Receptor Like Factor 2) • MUC4 (Mucin 4, Cell Surface Associated)
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CRLF2 rearrangement • MUC4 expression
over1year
Emerging molecular subtypes and therapies in acute lymphoblastic leukemia. (PubMed, Semin Diagn Pathol)
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.
Review • Journal
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ABL1 (ABL proto-oncogene 1) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • PAX5 (Paired Box 5) • TCF3 (Transcription Factor 3) • PBX1 (PBX Homeobox 1) • CDX2 (Caudal Type Homeobox 2) • BCL11B (BAF Chromatin Remodeling Complex Subunit BCL11B) • MEF2D (Myocyte Enhancer Factor 2D) • NUTM1 (NUT Midline Carcinoma Family Member 1) • ZEB2 (Zinc Finger E-Box Binding Homeobox 2) • DUX4 (Double Homeobox 4) • ZNF384 (Zinc Finger Protein 384)
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KMT2A rearrangement • MLL rearrangement • MYC rearrangement • CRLF2 rearrangement • IKZF1 mutation • PAX5 mutation • ABL1 fusion
over1year
Journal
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CRLF2 (Cytokine Receptor Like Factor 2) • P2RY8 (P2Y Receptor Family Member 8)
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CRLF2 rearrangement
over1year
Philadelphia-like acute lymphoblastic leukemia: the journey from molecular background to the role of bone marrow transplant-review article. (PubMed, Ann Hematol)
Precision medicine should be implemented in the treatment of such cases. Here in this review, we summarize the available data on Ph-like ALL.
Review • Journal
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • CRLF2 (Cytokine Receptor Like Factor 2)
|
CRLF2 rearrangement • BCR expression
over1year
Journal
|
CRLF2 (Cytokine Receptor Like Factor 2)
|
CRLF2 rearrangement
over1year
Ruxolitinib and Chemotherapy in Adolescents and Young Adults With Ph-like Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P1, N=15, Recruiting, University of Chicago | Trial primary completion date: Sep 2022 --> Sep 2023
Trial primary completion date • Combination therapy
|
JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IL7R (Interleukin 7 Receptor) • SH2B3 (SH2B Adaptor Protein 3)
|
CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 rearrangement • SH2B3 deletion
|
Rituxan (rituximab) • cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • cyclophosphamide • vincristine • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine
over1year
LINEAGE SWITCH POST IMMUNOTHERAPY: CURRENT STATUS AND FUTURE DIRECTIONS (ASPHO 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.
IO biomarker
|
CD19 (CD19 Molecule) • KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2)
|
KMT2A rearrangement • MLL rearrangement • CRLF2 rearrangement • IGH-CRLF2 fusion
|
Blincyto (blinatumomab) • Besponsa (inotuzumab ozogamicin)
over1year
Genomic landscape of Down syndrome-associated acute lymphoblastic leukemia. (PubMed, Blood)
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.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • CRLF2 (Cytokine Receptor Like Factor 2) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • IGF2BP1 (Insulin Like Growth Factor 2 MRNA Binding Protein 1) • CEBPD (CCAAT Enhancer Binding Protein Delta)
|
CRLF2 rearrangement
over1year
preclinical development of a novel anti-tslpr bispecific antibody 1b7/cd3 targeting crlf2-rearranged ph-like b-all (AACR 2023)
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.
Preclinical
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IFNG (Interferon, gamma) • IL6 (Interleukin 6) • CRLF2 (Cytokine Receptor Like Factor 2) • TNFA (Tumor Necrosis Factor-Alpha) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • CD69 (CD69 Molecule) • IL10 (Interleukin 10) • TSLP (Thymic Stromal Lymphopoietin)
|
CRLF2 rearrangement
|
Blincyto (blinatumomab) • Besponsa (inotuzumab ozogamicin)
almost2years
Classification and genetics of pediatric B-other Acute Lymphoblastic Leukemia by targeted RNA-sequencing. (PubMed, Blood Adv)
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.
Journal
|
ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • PAX5 (Paired Box 5) • TCF3 (Transcription Factor 3) • P2RY8 (P2Y Receptor Family Member 8) • PBX1 (PBX Homeobox 1) • EPOR (Erythropoietin Receptor) • GATA3 (GATA binding protein 3) • MEF2D (Myocyte Enhancer Factor 2D) • NUTM1 (NUT Midline Carcinoma Family Member 1) • DUX4 (Double Homeobox 4) • ZNF384 (Zinc Finger Protein 384)
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MLL rearrangement • IKZF1 deletion • CRLF2 rearrangement • IGH-CRLF2 fusion
almost2years
New P1/2 trial
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • P2RY8 (P2Y Receptor Family Member 8) • EPOR (Erythropoietin Receptor) • PTPN2 (Protein Tyrosine Phosphatase Non-Receptor Type 2) • SH2B3 (SH2B Adaptor Protein 3) • DDX3X (DEAD-Box Helicase 3 X-Linked) • USP9X (Ubiquitin Specific Peptidase 9 X-Linked)
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CRLF2 rearrangement • CRLF2 overexpression • IL7R mutation • IGH-CRLF2 fusion • PTPN2 mutation
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Venclexta (venetoclax) • cytarabine • Jakafi (ruxolitinib) • cyclophosphamide
almost2years
AALL1521: A Phase 2 Study of Ruxolitinib With Chemotherapy in Children With Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P2, N=171, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting
Enrollment closed
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • EPOR (Erythropoietin Receptor) • SH2B3 (SH2B Adaptor Protein 3)
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CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 fusion • SH2B3 deletion
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cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • cyclophosphamide • vincristine • prednisone • leucovorin calcium • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine • Erwinase (erwinia L-asparaginase)
almost2years
Correlation of the surface expression of thymic stromal lymphopoietin receptor with the presence of CRLF2 gene rearrangements in children with B-lineage acute lymphoblastic leukemia. (PubMed, Int J Lab Hematol)
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.
Journal • Stroma
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CRLF2 (Cytokine Receptor Like Factor 2) • TSLP (Thymic Stromal Lymphopoietin)
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CRLF2 rearrangement
almost2years
Enrollment open
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CD19 (CD19 Molecule) • KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2) • CD22 (CD22 Molecule) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)
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KMT2A rearrangement • MLL rearrangement • CD19 expression • CRLF2 rearrangement
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Orca-T
almost2years
Leukemogenesis in infants and young children with trisomy 21. (PubMed, Hematology Am Soc Hematol Educ Program)
While treatment of ML-DS achieves long-term survival in approximately 90% of children, the outcome of DS-ALL is inferior to ALL in children without DS. Ongoing studies in primary cells and model systems indicate that the role of trisomy 21 in DS leukemogenesis is complex and cell context dependent but show promise in improving management and the treatment of relapse, in which the outcome of both ML-DS and DS-ALL remains poor.
Journal
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • GATA1 (GATA Binding Protein 1)
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CRLF2 rearrangement