CALR mutation

P=N/A, N=90, Active, not recruiting, University Health Network, Toronto | Recruiting --> Active, not recruiting

Patients with JAK2V617F- and CALR-unmutated ET tend to present at a younger age and exhibit a lower incidence of thrombosis compared to those with JAK2V617F-mutated ET. The application of WES enabled the detection of uncommon and potential driver mutations in JAK2V617F- and CALR-unmutated ET.

AYA MPN patients have unique clinico-pathological characteristics that alter their disease presentation, thrombo-haemorrhagic risks and kinetics of progression. Further research should focus on developing AYA-specific risk stratification models, the impact of nondriver somatic mutations, and therapies with potential for disease modification.

In the disseminated NSG model, DX1-2C11 delivered immediate tumor burden reduction and significantly prolonged the overall survival of mice compared to the control group. Taken together, these data suggest that bispecific T cell engaging antibody targeting mutCALR represents a curative strategy that efficiently eliminates mutant MPN stem cells in vivo.

This study demonstrates, for the first time, the successful targeting of mCALR with CAR-T cells as a therapeutic strategy for MPNs. The chosen construct shows strong preclinical efficacy against established cell lines and patient-derived cells. Additionally, transcriptomic profiling uncovered apoptosis resistance mechanisms and supports a combination strategy with BH3 mimetics, such as venetoclax. These findings provide a compelling rationale for ongoing preclinical development and future clinical application of anti-mCALR CAR-T cells for the treatment of MPNs.

The Cal26B11-based DAS-ELISA provides a reliable, non-invasive tool for detecting CALR mutations and shows promise for monitoring disease dynamics and treatment response, supporting its potential as a complementary biomarker. These preliminary findings warrant validation in larger prospective studies.

In contrast, Type 2 mutations showed increased CALR dimerization and were partially resistant to antibody targeting but could be impacted by ruxolitinib triple combination. Together, our data demonstrate an ultra-precision medicine approach tailored to either Type 1 OR Type 2 mutation classes will be required for maximal efficacy and complete blockade of JAK/STAT signalling, with far-reaching implications for patient management.

The velocity of neutrophil chemotaxis was significantly increased in all patients, in particular for those with mutations in CALR. These data reveal a major shift in the neutrophil activity in ET and suggest that the immunomorphological techniques presented here may allow reproducible and widely available characterization of neutrophil status.

Molecular responses were striking, but largely confined to JAK2-mutated patients. To our knowledge, this is the largest retrospective cohort of strictly WHO-defined pre-PMF patients treated with interferon and observed for a reasonable duration of time.

P=N/A, N=90, Recruiting, University Health Network, Toronto | Trial completion date: Feb 2026 --> Dec 2026 | Trial primary completion date: Aug 2025 --> Dec 2026

To investigate this question, we used a knock-in mouse that constitutively expresses a Calr frameshift allele and introduced conditional Ezh2 deletion triggered by tamoxifen...Short-term colony assays showed that inhibition of PPARγ modestly increased the anti-proliferative effect of cytarabine on AML-derived stem and progenitor cells, suggesting a possible reliance on FAO...At a non-critical stage, peripheral counts remain near-normal while bone marrow HSPC compartments are already distorted. AML-like, but not sMF-like, Flk2- CD48+ LSK cells transmit leukemia and display enhanced fatty-acid-oxidation signatures, suggesting a distinct, potentially targetable metabolic bias.

Equally, there is a major focus on next generation JAK inhibitors and mutant calreticulin antibodies. There is also increasing conversation around the need for novel endpoints, as the limitations of symptom assessment, in particular, become apparent and candidate biomarkers of disease modification emerge.