CALR mutation

This study highlights a case of MPN with a more clinically aggressive Type 1 calreticulin (CALR) mutation, where a combination of low-dose IL-2 immunotherapy and targeted therapy with oral tretinoin (all-trans retinoic acid, ATRA, a vitamin A derivative) improved immune cells, particularly NK-cell-mediated destruction of malignant cells, reduced CALR mutation levels to undetectable, and alleviated disease symptoms. The aim is to offer a new, low-toxicity personalized treatment strategy that eradicates cancer-initiating stem cells, reduces side effects, and provides an option for patients with limited conventional therapy alternatives.

Ongoing treatment with hydroxyurea was substituted with ropeg (week 0: 250 mcg; week 2: 350 mcg; week 4 onwards: 500 mcg every 2 weeks). In conclusion, ropeg was safe and induced CHCR associated with significant molecular responses in patients with early MF. ClinicalTrials.gov Identifier: NCT04988815.

Early studies have demonstrated mutant CALR can elicit T-cell responses, laying the foundation for efforts to exploit this vulnerability through vaccines, antibody-based strategies, and T-cell-based therapies. Here, we summarize the current understanding of normal and mutant CALR biology, discuss progress in developing CALR-directed immunotherapies, and highlight the challenges and opportunities for translating these approaches into the clinic.

P=N/A, N=260, Recruiting, University Hospital, Angers | Trial completion date: Apr 2026 --> Apr 2030 | Trial primary completion date: Apr 2023 --> Apr 2027

A platelet count ≥238,000/mm³ was an independent factor correlated with the JAK2V617F mutation and a strong predictor of latent MPN (OR=17.3; 95% CI [2.8-105.1]; p=0.002). Screening for JAK2V617F is useful for diagnosing latent MPNs revealed by SVT, while MPL and CALR mutations are rare and not recommended.

Both in vitro and in vivo experiments confirmed that targeted inhibition of CALR effectively suppresses BLCA growth. This study not only elucidates the mechanism by which CALR maintains high expression through the CALR/HIF-1α positive feedback loop and promotes malignant progression in BLCA but also provides a theoretical foundation for its potential use as a prognostic biomarker and therapeutic target.

Therapies that eradicate cancer stem cells enable cure, but their feasibility is unknown. We establish an approach to potentially cure MPNs by proving mutant calreticulin to be a MPN stem cell marker that can be targeted by CAR-T cells to selectively wipe out disease in preclinical models of human MPNs.

Diagnostically, MRI/MRV is the first choice, with the primary challenge being the differentiation of venous sinus hypoplasia from thrombosis in ET patients, combined with the detection of the JAK2 mutation for confirmation. This review summarizes the genetic and cellular mechanisms linking ET to CVST, discusses tailored diagnostic strategies and therapies (JAK inhibitors, anticoagulants), and highlights the need for further research to clarify the interplay between molecular abnormalities and vascular factors, aiming to optimize clinical management.

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.