Distinct mutational pattern of myelodysplastic syndromes with and without 5q- treated with lenalidomide.
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ABSTRACT:
SUBMITTER: Adema V
PROVIDER: S-EPMC8370477 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Publications
Distinct mutational pattern of myelodysplastic syndromes with and without 5q- treated with lenalidomide.
Adema Vera V Palomo Laura L Toma Andrea A Kosmider Olivier O Fuster-Tormo Francisco F Benito Rocío R Salgado Rocío R Such Esperanza E Larrayoz María José MJ Xicoy Blanca B Hernandez-Sanchez Jesus Maria JM Maietta Paolo P Neef Alexander A Fontenay Michaela M Ibañez Mariam M Diez-Campelo Maria M Alvarez Sara S Maciejewski Jaroslaw P JP Fenaux Pierre P Sole Francesc F
British journal of haematology 20200309 4
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Project description:Anemia is a key survival prognostic factor in lower-risk myelodysplastic syndromes (MDS). Lenalidomide (LEN) can correct anemia in 25% of MDS patients without deletion 5q (del5q). As this therapy will inevitably fail, understanding the outcome of these patients will facilitate development of subsequent treatment strategies. To answer this question, an international retrospective study focused on LEN-treated lower-risk, non-del5q, MDS patients was performed. We analyzed the overall survival after LEN failure, its prognostic factors and the impact of post LEN treatment options. We included a total of 384 patients. The median overall survival after failure of LEN was 43 months. In multivariate analysis, adverse cytogenetics, excess of blasts at the initiation of LEN, and the type of failure (classified as stable disease, relapse, intolerance, or progression) were the main determinants of outcome. Subsequent therapy with hypomethylating agents was associated with a prolonged survival compared to BSC (median OS= 51m vs. 36m, p=0.01). In conclusion, the survival for non-del5q MDS patients after failure of LEN remains relatively prolonged, though with a wide range. Clinical trial participation remains the recommendation for these patients even if options such as hypomethylating agents may be considered.
| S-EPMC5514957 | biostudies-literature
Project description:Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin β. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379.
| S-EPMC4937206 | biostudies-literature
Project description:While lenalidomide (LEN) is the standard of care for the lower-risk myelodysplastic syndromes (MDS) patients with deletion 5q, 35% will not respond to or do not tolerate the drug. Moreover, most of the patients will lose their response after a few years. Defining the outcome of patients with LEN failure and determining the impact of subsequent therapies is therefore important to develop alternative strategies. Based on an international collaboration, we were able to compile a total of 392 patient cases of lower-risk MDS patients with 5q deletion and to analyze their outcome after failure of lenalidomide. The median survival following LEN failure was 23 months. We observed a negative impact on survival of advanced age, higher bone marrow blast count at LEN initiation, progression after LEN failure, and unfavorable cytogenetics. Among the treatment strategies, we observed a relatively prolonged survival of patients treated subsequently with hypomethylating agents and only a limited impact on survival of allogeneic transplantation. In conclusion, our work stresses the relatively short survival of this group of patient and defines the expected baseline for the needed future investigations in this group of patients.
| S-EPMC5669859 | biostudies-literature
Project description:Whereas lenalidomide is an effective therapy for del(5q) MDS patients, a minority of non-del(5q) MDS patients achieve hematologic improvement with lenalidomide. We used computational biology modeling and digital drug simulation to examine genomic data from 56 non-del(5q) MDS patients treated with lenalidomide, and then matched treatment response with molecular pathways. The computer inferred genomic abnormalities associating with lenalidomide treatment response in non-del(5q) MDS to include trisomy 8, del(20q), or RUNX1 loss of function mutations. Genomic abnormalities associating with lenalidomide resistance in non-del(5q) MDS patients included mutations in SF3B1, TET2, WNT3A amplification, MCL1 amplification, and/or PSEN2 amplification. These results may inform protocols for determining appropriateness of lenalidomide in non-del(5q) MDS.
| S-EPMC7246771 | biostudies-literature
Project description:Lenalidomide was approved in Japan for the treatment of patients with myelodysplastic syndromes associated with a 5q deletion (del 5q-MDS) in August 2010. A post-marketing surveillance (PMS) study enrolled 173 patients with del 5q-MDS who started lenalidomide treatment between August 2010 and September 2011 (mean ± standard deviation [SD] age 72.4 ± 9.0 years) and observed for up to 6 cycles or 6 months. Adverse drug reactions (ADRs) and serious ADRs were reported in 78.0% and 50.9% of patients. The most commonly observed ADRs were thrombocytopenia or platelet count decreased (46.2%), neutropenia or neutrophil count decreased (42.2%), and rash (23.1%). Of 114 patients who were red blood cell transfusion-dependent at baseline, 39 (34.2%) achieved transfusion independence during lenalidomide treatment. Of 173 patients, 19 (11.0%) had confirmed acute myeloid leukemia (AML) progression during the study. Moreover, long-term follow-up (3 years) was available for 68 of the 173 patients, of whom 12 (17.6%) progressed to AML during the additional period. This PMS study investigated the safety and effectiveness of lenalidomide in patients with del 5q-MDS. No new safety concerns were noted in routine clinical use in Japan and no evidence was found for an increased risk of AML progression following lenalidomide treatment.
| S-EPMC10522743 | biostudies-literature
Project description: Not available
| S-EPMC7932918 | biostudies-literature
Project description:BackgroundLenalidomide could effectively induce red blood cell (RBC) transfusion independence (TI) in patients with lower-risk (Low/Intermediate-1) myelodysplastic syndrome (MDS) with or without 5q deletion. However whether lenalidomide ultimately improves the overall survival (OS) of lower-risk MDS patients and reduces the progression to AML remains controversial.MethodA meta-analysis was conducted to examine the efficacy and safety of lenalidomide in the treatment of lower-risk MDS. Efficacy was assessed according to erythroid hematologic response (HI-E), cytogenetic response (CyR), OS and AML progression. Safety was evaluated based on the occurrence rates of grades 3-4 adverse events (AEs).ResultsSeventeen studies were included consisting of a total of 2160 patients. The analysis indicated that the overall rate of HI-E was 58% with 95% confidence interval (CI) of 43-74%. The pooled estimates for the rates of CyR, complete CyR, and partial CyR were 44% (95% CI 19-68%), 21% (95% CI 13-30%) and 23% (95% CI 15-32%), respectively. The patients with 5q deletion had significantly higher rate of HI-E and CyR than those without 5q deletion (P = 0.002 and 0.001, respectively). The incidences of grades 3-4 neutropenia, thrombocytopenia, leukopenia, anemia, deep vein thrombosis, diarrhea, fatigue and rash were 51% (95% CI 30-73%), 31% (95% CI 20-42%), 9% (95% CI 5-13%), 7% (95% CI 2-12%), 3% (95% CI 2-5%), 3% (95% CI 1-5%), 2% (95% CI 1-4%) and 2% (95% CI 1-3%), respectively. Lenalidomide significantly improved OS (HR: 0.62, 95% CI 0.47-0.83, P = 0.001) and lowered the risk of AML progression in del(5q) patients (RR: 0.61, 95% CI 0.41-0.91, P = 0.014).ConclusionsIn spite of the AEs, lenalidomide could be effectively and safely used for the treatment of lower-risk MDS patients with or without 5q deletion.
| S-EPMC5100926 | biostudies-literature
Project description: Not available
| S-EPMC6173782 | biostudies-literature
Project description: Not available
| S-EPMC9452671 | biostudies-literature
Project description:Lenalidome is a drug especially effective in low risk myelodysplastic syndromes (MDS) with isolated 5q deletion. However, 25% of the patients did not respond. TP53 mutations have been described to play a role in the disease progression, and karyotypic complexity also has an important impact in the outcome. We selected 53 MDS patients with 5q deletion and treated with lenalidomide and we studied by the following techniques: conventional G-banding cytogenetics (CC), single nucleotide polymorphism arrays (SNP-A) and sequencing, in order to assess their impact on treatment response and disease progression. Low karyotypic complexity (by CC), a high baseline platelet count (>280x103/L) and TP53 unmutated gene status are associated with the achievement of hematological response (P=0.005, P=0.008 and P=0.057, respectively). In a multivariate model, the most important predictors for lenalidomide failure are karyotypic complexity (P=0.014) and a platelet count below 280x103/L (P=0.042). Additionally, none of the TP53 mutated cases achieved complete cytogenetics response. Nevertheless, inclusion of defects by SNP-A did not allow for a better separation of responders and non responders. These findings constitute a useful reference data to be considered before lenalidomide treatment enrollment.
2013-07-01 | GSE35656 | GEO