Mechanism of Action of Interferon in the Treatment of Myeloproliferative Neoplasms

Sponsor
Institut National de la Santé Et de la Recherche Médicale, France
Study ID
NCT05850273
Status
Recruiting
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Conditions

  • Myeloproliferative Neoplasm

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Study Details

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include: Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are myeloid malignancies resulting from the transformation of a multipotent hematopoietic stem cell (HSC) caused by mutations activating the JAK2/STAT pathway. The most prevalent mutation is JAK2V617F. Type 1 and Type 2 calreticulin (CALR) and thrombopoietin receptor (MPL) mutations are also observed in ET and PMF. Additional non-MPN mutations affecting different pathways are also found, particularly in PMF, and are involved in disease initiation and/or in phenotypic changes and /or disease progression and/or response to therapy. There is an obvious and urgent need for an efficient therapy for MPN. In particular, PMF remain without curative treatment, except allogeneic HSC transplantation and JAK inhibitors have limited effects on the disease outcome. Among novel therapeutic approaches, Peg-IFNα2a (IFN) is the most efficient harboring both high rates of hematological responses in JAK2V617F and CALRmut MPN patients and some molecular responses mainly in JAK2V617F patients including deep molecular response (DMR). Nevertheless, several studies, including our own, have demonstrated that the IFN molecular response in CALRmut patients is heterogeneous and overall much lower than in JAK2V617F patients. Moreover, some JAK2V617F MPN patients do not respond to IFN, and DMR is only observed in around 20% of JAK2V617F patients. Finally, long-term treatments are needed (2-5 years) to obtain a DMR, jeopardizing its success due to possible long-term toxicity. The underlying reasons for failure, drug resistance, heterogeneous molecular response in CALRmut patients and the long delays for DMR in JAK2V617F patients remain unclear, largely because the mechanisms by which IFNα targets MPN malignant clones remain elusive. Significant improvement of IFN efficacy cannot be achieved without basic and clinical research. Hence our two lines of research are to * Understand how IFNα specifically targets neoplastic HSCs * Predicting and improving patient response during IFNα therapy

Key Dates

First listed
May 9, 2023
Start date
Mar 16, 2023
Status verified
Apr 2026
Primary completion
Mar 16, 2028
Completion
Mar 16, 2033

Study Design

Enrollment
80 participants (estimated)

Primary Outcome Measure

Clonal architecture of hematopoietic progenitors of patients [ Time Frame: During 5 years from day 0 of IFN treatment, 3 to 4 times per year ]

Central Contacts

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