Damien Luque Paz

Les syndromes myéloprolifératifs non leucémie myéloïde chronique sont des hémopathies myéloïdes et regroupent principalement la polyglobulie de Vaquez, la thrombocytémie essentielle et la myélofibrose primitive. Ces pathologies sont associées à des mutations somatiques dites promotrices des gènes JAK2, CALR et MPL qui sont retrouvées chez plus de 90% des patients et qui entraînent une activation constitutive de la voie de signalisation JAK2-STAT5 à l’origine de la prolifération cellulaire observée. Avec le développement du séquençage de nouvelle génération, d’autres mutations somatiques dites additionnelles peuvent être détectées et participent à l’initiation et à la progression de ces pathologies. Certaines mutations additionnelles ont également un intérêt dans l’évaluation pronostique des patients. Ce travail avait pour objectif d’étudier l’impact pronostique des mutations additionnelles dans les syndromes myéloprolifératifs et de caractériser l’évolution mutationnelle dans ces pathologies à l’aide d’une évaluation séquentielle du profil mutationnel. Nous avons étudié 5 cohortes de patients soit un total de 813 patients avec un syndrome myéloprolifératif et 948 séquençages nouvelle génération analysés. Nous avons confirmé l’impact pronostique des mutations additionnelles dans la thrombocytémie essentielle. Toutefois, aucun impact pronostique n’était retrouvé lorsque nous avons spécifiquement étudié une série de patients avec mutations de CALR, ce qui suggère un impact pronostique des mutations additionnelles différent selon la mutation promotrice.L’étude séquentielle du profil moléculaire a montré que peu de mutations étaient nouvellement acquises lors du suivi en phase chronique. En effet les mutations nouvellement détectées étaient pour la plupart déjà présentes dès le diagnostic à une faible charge allélique. Par l’étude moléculaire séquentielle, nous avons montré l’intérêt pronostique du suivi de la charge allélique des mutations de CALR. Enfin, en étudiant les transformations leucémiques des syndromes myéloprolifératifs, nous avons identifié trois profils moléculaires associés à des délais de transformation différents. Ce travail de thèse contribue à la caractérisation du profil moléculaire des syndromes myéloprolifératifs. Le pronostic des mutations additionnelles pourrait différer selon la mutation promotrice, le type de mutation ou la charge allélique, ce qui devra être précisé dans de futurs études pour faciliter leur utilisation en pratique clinique.

Polycythemia vera (PV) and Essential thrombcythemia (ET) are myeloproliferative neoplasms (MPNs) that can progress to secondary myelofibrosis, a complication associated with increased mortality. Circulating CD34-positive cells at diagnosis can be used to distinguish primary myelofibrosis from other MPNs with a threshold of 10/µL. In this study, we evaluate the interest of serial CD34-positive cell quantifications during the follow-up of MPNs. We retrospectively include 180 patients with MPN (90 ET, 55 PV and 35 myelofibrosis) with at least two measurements of circulating CD34-positive cells. CD34-positive cell count showed an AUC of 0.901 for the diagnosis of post-ET/PV myelofibrosis, with a sensitivity of 54.8%, a specificity of 99.5%, a PPV of 89.5% and a NPV of 96.3% for the threshold of 15 cells/µL. The decreased sensibility could be explained by an impact of cytoreductive treatments. Then we focused on primary and secondary myelofibrosis (MF) and found that patients achieving partial or complete response (per IWG-MRT criteria) had lower CD34-positive cell levels. Finally, CD34-positive cell levels had a prognostic impact on overall survival in MF, a count ≥ 100/µL is predictive of a higher risk of death (HR = 2.9 [1.5–5.9]), independently of DIPSS classification. In conclusion, monitoring of circulating CD34-positive cells is valuable for evaluating both disease progression and prognosis in MPN patients.

Thrombotic risk assessment is crucial in newly diagnosed essential thrombocythemia (ET) and polycythemia vera (PV) patients to guide cytoreductive therapy. We assessed whether thromboinflammation biomarkers would be good candidates to improve thrombosis risk stratification. We prospectively enrolled 394 newly diagnosed, cytoreductive therapy–naïve, ET and PV patients. We measured seven plasma biomarkers of neutrophil, monocyte, platelet, and endothelial activation, including NET markers, and evaluated their association with thrombosis risk scores at diagnosis. Multivariable analysis in the whole MPN cohort showed elevated calprotectin and tissue factor levels in high-risk versus low-risk patients using the conventional two-tiered score. This was also observed in ET patients only, but not in PV patients. Patients with a JAK2V617F allele burden >20% showed higher levels of three markers, including calprotectin, supporting its role in immunothrombosis. In PV patients, calprotectin correlated with the Venous Thrombosis Score (VETS), and five markers were elevated in those with prior venous thrombosis. Lastly, aspirin use was associated with lower H3Cit levels in patients with normal platelet counts, confirming its beneficial effect on NET formation. This is the largest study to date linking thromboinflammation markers to thrombotic risk in MPN patients and identifying potential biomarkers for future thrombosis risk scores.

Accelerated‐phase (AP) or blast‐phase (BP) myeloproliferative neoplasms (MPNs) are associated with dismal prognosis, with non‐curative therapies such as hypomethylating agents (HMAs) considered in patients not eligible for intensive therapy, while some studies advocate for combination therapy with either ruxolitinib (RUXO) or venetoclax (VEN). To assess the relationship between treatment modalities and outcome, herein, we report a multicentric cohort of 149 patients (median age, 75 years) with AP/BP MPN not eligible for intensive therapy and/or allogeneic hematopoietic cell transplantation who received azacitidine (AZA) alone ( n = 60) or in combination ( n = 89; VEN [ n = 51], RUXO [ n = 27], or both [ n = 9], isocitrate dehydrogenase inhibitors [ n = 2]) between January 2019 and October 2023. With a median follow‐up of 15 months, the median overall survival of the full cohort was 8.04 months, with a 3‐year overall survival (OS) of 13%. Among disease characteristics, OS was lower in patients with BP (6.24 vs. 18.00 months in patients with AP disease, P = 0.03), complex karyotype (6.00 vs. 13.08 months, P = 0.005), and TP53 mutations (8.04 vs. 11.04 months, P = 0.009). OS was nonsignificantly higher in patients receiving AZA combinations (10.08 vs. 6.96 months in patients receiving AZA monotherapy, P = 0.12). When analyzing AZA combinations separately, patients who were treated with AZA–RUXO had higher OS (18.00 vs. 9.00 vs. 10.08 months in patients receiving AZA–VEN and AZA–VEN–RUXO, P = 0.015). The improved survival with AZA–RUXO in the absence of complex karyotype and/or TP53 mutations warrants further prospective validation. New therapeutic options are urgently needed, especially in patients with complex karyotype and/or TP53 mutations.