Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.
Josquin Moraly
(1, 2)
,
Julien Rossignol
(2, 3)
,
Claire Rouzaud
(1)
,
Thomas Gabas
(4)
,
Hassiba Bouktit
(2)
,
Ludovic Lhermitte
(2, 4)
,
Danielle Canioni
(2, 4)
,
Sylvie Fraitag
(2, 4)
,
Julie Bruneau
(4, 5)
,
Stephane Barete
(6)
,
Felipe Suarez
(4)
,
Thomas Ballul
(2, 3)
,
Cécile Meni
(2, 4)
,
Laura Polivka
(2, 3, 4)
,
Louis Terriou
(7)
,
David Launay
(7)
,
Laurence Bouillet
(8, 9)
,
Caroline Gaudy-Marqueste
(10)
,
Marie Gousseff
(11)
,
Edwige Le Mouel
(12)
,
Antoine Neel
(13)
,
Dana Ranta
(14)
,
Roland Jaussaud
(14)
,
Philippe Guilpain
(15, 16)
,
Laurent Frenzel
(2, 3, 4)
,
Julie Agopian
(17, 18)
,
Patrice Dubreuil
(17, 18)
,
Céline Greco
(2, 4)
,
Sophie Dimicoli-Salazar
(19)
,
Mael Heiblig
(20, 21)
,
Clément Gourguechon
(22)
,
Olivier Tournilhac
(23, 24)
,
Rose-Marie Javier
(25)
,
Florence Castelain
(26)
,
Quentin Cabrera
(27)
,
Marie Pierre Gourin
(28)
,
Ewa Wierzbicka-Hainaut
(29)
,
Jose Miguel Torregrosa-Diaz
(29)
,
Cristina Bulai
(30)
,
Christian Lavigne
(31)
,
Cyrille Hoarau
(32)
,
Michel Arock
(6)
,
Gandhi Damaj
(33)
,
Olivier Lortholary
(1, 2)
,
Olivier Hermine
(2, 3, 4)
1
Centre d'infectiologie Necker-Pasteur [CHU Necker]
2 CEREMAST - Centre de référence des mastocytoses
3 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
4 Hôpital Necker - Enfants Malades [AP-HP]
5 UPCité - Université Paris Cité
6 CHU Pitié-Salpêtrière [AP-HP]
7 Hôpital Claude Huriez [Lille]
8 CREAK - Centre de référence national des angiœdèmes
9 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
10 TIMONE - Hôpital de la Timone [CHU - APHM]
11 CHBA - Centre hospitalier Bretagne Atlantique (Morbihan)
12 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
13 Hôtel-Dieu de Nantes
14 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
15 Hôpital Saint Eloi [CHU Montpellier]
16 UM - Université de Montpellier
17 CRCM - Centre de Recherche en Cancérologie de Marseille
18 IPC - Institut Paoli-Calmettes
19 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
20 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
21 CIRI-LIB - Immuno-Biologie des Lymphomes [CIRI]
22 CHU Amiens-Picardie
23 CIC 1405 - Centre d'Investigation Clinique [CHU Clermont-Ferrand]
24 CHELTER - Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias
25 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
26 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
27 CHU Sud Saint Pierre [Ile de la Réunion]
28 Hôpital Dupuytren [CHU Limoges]
29 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
30 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
31 CHU Angers - Centre Hospitalier Universitaire d'Angers
32 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
33 IHBN - Institut d'Hématologie de Basse-Normandie
2 CEREMAST - Centre de référence des mastocytoses
3 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
4 Hôpital Necker - Enfants Malades [AP-HP]
5 UPCité - Université Paris Cité
6 CHU Pitié-Salpêtrière [AP-HP]
7 Hôpital Claude Huriez [Lille]
8 CREAK - Centre de référence national des angiœdèmes
9 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
10 TIMONE - Hôpital de la Timone [CHU - APHM]
11 CHBA - Centre hospitalier Bretagne Atlantique (Morbihan)
12 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
13 Hôtel-Dieu de Nantes
14 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
15 Hôpital Saint Eloi [CHU Montpellier]
16 UM - Université de Montpellier
17 CRCM - Centre de Recherche en Cancérologie de Marseille
18 IPC - Institut Paoli-Calmettes
19 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
20 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
21 CIRI-LIB - Immuno-Biologie des Lymphomes [CIRI]
22 CHU Amiens-Picardie
23 CIC 1405 - Centre d'Investigation Clinique [CHU Clermont-Ferrand]
24 CHELTER - Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias
25 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
26 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
27 CHU Sud Saint Pierre [Ile de la Réunion]
28 Hôpital Dupuytren [CHU Limoges]
29 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
30 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
31 CHU Angers - Centre Hospitalier Universitaire d'Angers
32 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
33 IHBN - Institut d'Hématologie de Basse-Normandie
Julien Rossignol
- Fonction : Auteur correspondant
Antoine Neel
- Fonction : Auteur
- PersonId : 1409124
- ORCID : 0000-0002-7707-5794
- IdRef : 139574247
Mael Heiblig
- Fonction : Auteur
- PersonId : 1495108
- IdHAL : mael-heiblig
- ORCID : 0000-0003-1682-8657
Olivier Hermine
- Fonction : Auteur
- PersonId : 1308844
- ORCID : 0000-0003-2574-3874
- IdRef : 069884927
Résumé
Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.
Domaines
Sciences du Vivant [q-bio]
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American J Hematol - 2024 - Moraly - Efficacy and safety of mammalian target of rapamycin inhibitors in systemic.pdf (1.37 Mo)
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