CALR mutation

Preclinical and early clinical advances - including monoclonal antibodies, bispecific T-cell engagers, CAR-T therapies, antibody-drug conjugates, and peptide/viral vector vaccines - have demonstrated selective activity against CALR-mutant clones while sparing normal hematopoiesis, with encouraging evidence of molecular remissions and disease modification. Although challenges such as immune tolerance remain, mutant CALR-directed therapies represent a potential transformative shift in essential thrombocythemia, and primary myelofibrosis treatment.

In multivariable analysis, TP53 mutations and higher peripheral blast burden adversely affected OS, while CALR mutations appeared to be associated with improved OS, peripheral blasts also independently predicted relapse. These data underscore the cure rate of approximately one-third of MPN-BP and highlight peripheral blasts and TP53 as actionable risk markers for transplant strategies.

In contrast, gDNA is more informative in confirming treatment response. The lymphocyte percentage predicts cfDNA utility, enabling rational test selection and a practical framework for optimizing MPN management.

Furthermore, the HMR profile was also associated with a higher risk of progression to acute leukemia, while it did not influence the probability of CHR or progression to MF. In conclusion, CALR VAF and HMR profile appear to be more important than CALR mutation type regarding treatment response and major clinical outcomes in ET.

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.