Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations.
Myeloproliferative neoplasms are clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis. Few therapeutic options are available, among which interferon α (IFNα) presents interesting properties like the ability to induce hematologic responses (HRs) and molecular responses (MRs) in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). HR was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and 2 patients even achieved complete MR. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next-generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2, and TP53 genes). The presence of additional mutations was associated with poorer MR on CALR mutant clones, with only minor or no MRs in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient, but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of HRs and MRs in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy.
Service de Biologie Cellulaire, Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France;
Emmanuelle
E
Verger
Service de Biologie Cellulaire, Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France;
Bruno
http://orcid.org/0000-0002-6514-3905
B
Cassinat
Laboratoire d'Hematologie, Centre Hospitalier Régional Universitaire de Brest, Brest, France; Université de Brest, Unité de Formation et de Recherche de medecine, Brest, France;
Aurélie
A
Chauveau
Service de Biologie Cellulaire, Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France;
Christine
C
Dosquet
Laboratoire d'Hematologie, Hopital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Creteil, France; Université Paris 12, Creteil, France;
Stephane
S
Giraudier
Service de Biologie Cellulaire, Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France;
Marie-Hélène
MH
Schlageter
Service d'Hematologie Clinique, Institut de Cancérologie, Centre Hospitalier Régional Universitaire de Brest, Brest, France;
Jean-Christophe
JC
Ianotto
Department of Hematology and Bone Marrow Transplant, National Center for Cancer Care and Research, and.
Mohammed A
MA
Yassin
Qatar Medical Genetic Center, Hamad Medical Corporation, Doha, Qatar;
Nader
N
Al-Dewik
Département de Cytologie Clinique, Centre Hospitalier Universitaire de Nimes, Nimes, France;
Serge
S
Carillo
Oncogard, Institut de Cancerologie du Gard, Nimes, France;
Eric
E
Legouffe
Hematologie Biologique, Centre Hospitalier Universitaire Angers, Angers, France; Université d'Angers, Unité de Formation et de Recherche de Medecine, Angers, France;
Valerie
V
Ugo
Service de Biologie Cellulaire, Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Diderot, Paris, France; and.
Christine
C
Chomienne
Université Paris Diderot, Paris, France; and Centre d'Investigations Cliniques, Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.
Jean-Jacques
http://orcid.org/0000-0002-8121-438X
JJ
Kiladjian
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001241:Aspirin / Q000627:therapeutic use; D037282:Calreticulin / Q000235:genetics*; D060965:Clonal Evolution / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D005260:Female; D005500:Follow-Up Studies; D016158:Genes, p53; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D056687:Off-Label Use; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012074:Remission Induction; D012097:Repressor Proteins / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D055815:Young Adult
C473949:ASXL1 protein, human; C576483:CALR protein, human; D037282:Calreticulin; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D011092:Polyethylene Glycols; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human; D001241:Aspirin; D006918:Hydroxyurea