NCT03280888

Relevance of Peripheral Cells in the Pathophysiology of Chronic Myelomonocytic Leukemia (CMML)

Status unknown Last updated 19 March 2018

What this trial tests

trial in Chronic Myelomonocytic Leukemia in 50 participants. Status unknown.

Timeline

5 November 2014

Primary endpoint
5 November 2018

5 November 2018

Quick facts

Lead sponsor	Centre Hospitalier Universitaire de Nice
Status	Status unknown
Study type	OBSERVATIONAL
Enrollment	50
Start date	5 November 2014
Primary completion	5 November 2018
Estimated completion	5 November 2018
Sites	1 location across France

Conditions studied

• Chronic Myelomonocytic Leukemia — all drugs for Chronic Myelomonocytic Leukemia →

Sponsor

Centre Hospitalier Universitaire de Nice

Who can join

18 and older, any sex, with Chronic Myelomonocytic Leukemia. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

Chronic Myelomonocytic Leukemia (CMML) is the most frequent of myelodysplastic/myeloproliferative syndromes, as defined by the WHO classification of myeloid malignancies. The median age at diagnosis is around 70 years with a strong male predominance. CMML is a clonal disease of the bone marrow hematopoietic stem cell mainly characterized by persistent monocytosis (\>1x109/L) and the presence of immature dysplastic granulocytes in the peripheral blood of CMML patients. Allogeneic stem cell transplantation (ASCT) remains the only curative option in CMML. However, CMML patients are rarely eligible for this kind of therapy, mainly due to their advanced age. The gold standard treatment of CMML thus remains hydroxyurea, which is usually initiated when the disease becomes proliferative, and demethylating agents, which could be efficient in the most aggressive forms of CMML. Nevertheless, the pathogenesis of CMML remains poorly understood and new therapies are urgently needed for patients in treatment failure.

In recent years, a large numbers of gene mutations have been discovered in CMML, none of which are specific of this entity, as they can be encountered with different frequencies in other myeloid neoplasms. These mutated genes encode signaling molecules (NRAS, KRAS, CBL, JAK2, FLT3 and several members of the Notch pathway), epigenetic regulators (TET2, ASXL1, EZH2, IDH1, IDH2,.) and splicing factors (SF3B1, SRSF2, ZRSF2). Mutations in the transcription regulators RUNX1, NPM1 and TP53 have also been reported in CMML. However, the role of these mutations in leukemogenesis is still unclear. CMML is also characterized by defects in monocyte to macrophage differentiation. These defects in monocyte differentiation can be attributed to the presence of immature dysplastic granulocytes that secrete high levels of alpha-defensins HNP1-3 that antagonize the purinergic receptor P2RY6 in CMML patients. These CD14-/CD15+/CD24+ immature granulocytes that belong to the same clone than the leukemic monocytes seem to have immunosuppressive properties ressembling those of the myeloid-derived suppressor cells (MDCS) described in solid tumours. Whether these immature granulocytes contribute to autoimmune manifestations or immunoescape and progression of CMML is a conendrum and remains to be determined.

In this context, the proposed project aims at identifying news insights into the pathophysiology of CMML through a better definition of the phenotype and function of monocytes and immature granulocytes that characterize this pathology.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression.
   Fleming V, Hu X, Weber R, Nagibin V, et al · · 2018 · cited 354× · PMID 29552012 · DOI 10.3389/fimmu.2018.00398