A New Diagnostic Algorithm to Non-invasively Track Fibrotic Changes in Myeloproliferative Neoplasms Based on C-C Chemokine Receptor 2 Detection. From Flow Cytometry to the Development of Targeted Positron Emission Tomography Molecular Imaging. Pre-clinical Studies and First In-human Proof of Concept

Обзор

Chronic "Philadelphia-negative" myeloproliferative syndromes are chronic blood disorders. They include essential thrombocythemia, polycythemia vera, and myelofibrosis. Myelofibrosis may arise de novo ("primary myelofibrosis") or represent the evolution of essential thrombocythemia or polycythemia vera ("secondary myelofibrosis"). The myelofibrotic stage-characterized, as the name implies, by the presence of bone marrow fibrosis (deposition of scar-like tissue)-is generally associated with a more severe and symptomatic disease. To date, the only way to assess fibrotic progression in these disorders is bone marrow biopsy. The aim of this project is to evaluate whether the identification, tracking, and quantification of cells expressing a specific receptor (CCR2), a selective biomarker of fibrosis, may allow early and non-invasive identification of the fibrotic stage of the disease through: * laboratory analysis on a blood sample (using flow cytometry) * use in PET-CT (positron emission tomography combined with computed tomography) of a tracer specific for the CCR2 receptor, capable of selectively binding to CCR2-expressing cells (⁶⁸Ga-DOTA-ECL1i).

Подробное описание

It is well established that the presence of bone marrow fibrosis in Philadelphia-negative myeloproliferative neoplasms (MPNs) defines a more severe disease stage, with a worse prognosis and a high risk of leukemic transformation. Therefore, accurate allocation of each patient to the correct diagnostic category is essential for subsequent therapeutic planning, which may also include bone marrow transplantation for selected patients.

To date, the only method available to assess bone marrow fibrosis is histopathological analysis of the bone marrow, which inevitably requires an invasive procedure such as bone marrow biopsy.

The aim of this project is to evaluate whether tracking and quantification of CD34⁺CCR2⁺ cells through flow cytometry (FCM) on peripheral blood and functional imaging may represent a valid non-invasive tool for identifying the fibrotic stage of the disease, thus supporting clinicians at key diagnostic time points, such as:

At disease onset, in support of histopathology for differential diagnosis when morphological features alone may be ambiguous (e.g., ET vs prePMF, unclassifiable MPNs); During follow-up, in cases of suspected progression of ET/PV to secondary myelofibrosis (SMF), as a screening tool prior to bone marrow biopsy; As an alternative to bone marrow biopsy, when clinical conditions do not allow the procedure.

To this end, the project is structured around the following AIMS:

AIM 1 - Tracking of CD34⁺CCR2⁺ cells by flow cytometry as a diagnostic tool supporting histopathology in the differential diagnosis of MPN subtypes.

AIM 2 - Functional imaging of CCR2⁺ cells using the radioligand ⁶⁸Ga-DOTA-ECL1i in a murine model of myelofibrosis.

AIM 3 - Functional imaging of CCR2⁺ cells using the radioligand ⁶⁸Ga-DOTA-ECL1i in patients affected by MPNs.

Вмешательства

• Диагностический тест Diagnosis of MPN subtypes
  Non-invasive imaging method (PET/CT) and flow-cytometry

Первичные конечные точки

• Percentage of circulating CD34+/CCR2+ cells [Срок оценки: At study enrollment]

Вторичные конечные точки (3)

• Bone marrow SUVmax on 68Ga-DOTA-ECL1i PET/CT [Срок оценки: At imaging session]
• Volume of active bone marrow on 68Ga-DOTA-ECL1i PET/CT [Срок оценки: At imaging session]
• Tracer uptake in extramedullary sites [Срок оценки: At imaging session]

Критерии участия

Критерии включения

• Diagnosis of ET/PV/prePMF/overtPMF according to the WHO 2016 criteria and of SMF according to the IWG-MRT criteria (with histopathological data).
• Age >= 18 yrs
• ECOG performance status <=3

Критерии исключения

• Pregnancy/breastfeeding
• Ongoing therapy with immunomodulatory drugs (JAK-inhibitors, interferon).
• For PET imaging, patients should be off any cytoreductive treatment for at least 3 months.
• Antiplatelet agents are allowed

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Скрининг

Центры проведения

Италия · 1 центр

• Dipartimento di Medicina e Chirurgia — Parma

Идентификаторы

NCT: NCT07419178 · 66/2023/SPER/AOUPR · GR-2021-12373308

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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