Comparison of the Molecular Spectrum of Lenalidomide-Treated Myelodysplastic Syndrome with and without Del(5q)

Autor: Blanca Xicoy, Beatriz Arrizabalaga Amunchastegui, Paula Gomez-Marzo, Francisco Fuster-Tormo, Jesús María Hernández-Rivas, Nuri de Haro, Francesc Solé, Pierre Fenaux, Valeria Visconte, Esperanza Such, Juan C. Cigudosa, María José Larrayoz, Mar Mallo, Lurdes Zamora, Michaela Fontenay, Alexander Neef, Laura Palomo, Kamila Janusz, Paolo Maietta, Mónica del Rey, Jaroslaw P. Maciejewski, Rocío Benito, Olivier Kosmider, José Cervera, María José Calasanz, Rocío Salgado, Mariam Ibáñez, Vera Adema
Rok vydání: 2016
Předmět:
Zdroj: Blood. 128:3172-3172
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v128.22.3172.3172
Popis: Background: Lenalidomide (LEN) is an immunomodulatory drug which binds cereblon through a glutarimide ring modulating the substrate specificity of CRL4CRBNE3 ubiquitin ligase complex, resulting in the proteosomal degradation of specific disease-related proteins. LEN is approved for the treatment of RBC transfusion-dependent (TD) low and int-1 risk MDS patients with del(5q), 70% of whom reach RBC transfusion-independence (TI) and 50% complete cytogenetic remission. It is also under investigation in RBC -TD low and int-1 risk MDS without del(5q) resistant to erythropoietin stimulating agents and with 20-30% of patients reaching RBC-TI. Herein we aimed to study whether molecular mutations in MDS patients with and without del(5q) influenced the response to LEN treatment. Methods: We collected 95 MDS patients treated with LEN, 72 with del(5q) and 23 without del(5q) (23/23: normal karyotype, presence of ringed sideroblasts and SF3B1MUT). Retrospective clinical information was available for 65 patients. To characterize the mutational spectrum of patients with del(5q) and non del(5q), we combined results from multi amplicon targeted sequencing Ion Torrent (44 cases) and from captured-based targeted deep sequencing (51 cases). The Ion Torrent panel included 39 of the most frequently mutated genes in MDS (ASXL1, BCOR, BRAF, CBL, CDKN2A, CEBPA, DNMT3A, ETV6, EZH2, FLT3, GNAS, IDH1, IDH2, JAK2, KIT, KRAS, LUC7L2, MPL, NF1, NPM1, NRAS, PHF6, PTPN11, RAD21, RPS14, RUNX1, SETBP1, SF1, SF3A1, SF3B1, SMC3, SPARC, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, ZRSR2). The Ion Torrent panel was then extended for the captured-base sequencing and updated with the addition of 43 genes including BCORL1, CALR, CSNK1A1 and KDM6A. The average depth per gene was 780x per sample. Results: Patients with del(5q) vs. non del(5q) had an equal risk distribution (LR: 46/55 vs. 21/22; HR: 9/55 vs. 1/22). We restricted our analyses to LR patients. Median age was 69 yrs (34-90) and M:F ratio was 15:50. A significantly higher median of hemoglobin (Hb) levels were found in del(5q) in comparison to non del(5q) patients (9 g/dL (6-13) vs. 8 g/dL (7-9); P=.001). Molecularly we found that a slightly lower number of mutations occurred in del(5q) [2 mutations (0-6)] compared to the number of mutations in non del(5q) [3 mutations (1-7); P=.001]. WHO 2008 distribution was significantly (P We then compared responders vs. non-responders. LEN median treatment was 10 mo. (3-48 mo.), with an overall follow-up of 4 years (4mo.-10 yrs). As expected, LEN response rate was significantly (P We then selected mutated genes present in at least 3 patients. CSNK1A1 (2), BCOR (3), CTCF (3) CUX1 (3), JAK2 (9) KIT (3) and TP53 (11) were restricted to the del(5q) patients. No genes were restricted to non del(5q) group. However, those genes in both groups [del(5q) vs. non del(5q)] were significantly more mutated in non del(5q) group rather than in del(5q) group: ASXL1 (N=6/23 vs. N=4/72; P=.005) and TET2 (N=9/23 vs. N=8/72; P=.002). CSNK1A1 (2) and MECOM (2) genes were restricted to the responders group. CTCF (3), SRSF2 (3), GNAS (2) and IDH2 (2) were only represented in the non-responders group. Genes significantly mutated in non-responders vs. responders were TET2 (N=11/33 vs. N=2/29; P=.011) and TP53 (N=6/33 vs. N=1/29; P=.069). Conclusion: In conclusion, this multicenter study describes that del(5q) and non del(5q) have a different mutational profile although no unifying somatic defect was found. Moreover, non-responders patients had a higher number of mutations and a higher percentage of TET2 and TP53 mutations while responders showed some unique mutations. Disclosures Maciejewski: Celgene: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Sole:Celgene: Membership on an entity's Board of Directors or advisory committees.
Databáze: OpenAIRE