An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment.
Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells (HSCs) that is often treated with DNA methyltransferase 1 (DNMT1) inhibitors (5-azacytidine [AZA], 5-aza-29-deoxycytidine), suggesting a role for DNA methylation in disease progression. How DNMT inhibition retards disease progression and how DNA methylation contributes to MDS remain unclear. We analyzed global DNA methylation in purified CD34+ hematopoietic progenitors from MDS patients undergoing multiple rounds of AZA treatment. Differential methylation between MDS phenotypes was observed primarily at developmental regulators not expressed within the hematopoietic compartment and was distinct from that observed between healthy hematopoietic cell types. After AZA treatment, we observed only limited DNA demethylation at sites that varied between patients. This suggests that a subset of the stem cell population is resistant to AZA and provides a basis for disease relapse. Using gene expression data from patient samples and an in vitro AZA treatment study, we identified differentially methylated genes that can be activated following treatment and that remain silent in the CD34+ stem cell compartment of high-risk MDS patients. Haploinsufficiency in mice of one of these genes (NR4A2) has been shown to lead to excessive HSC proliferation, and our data suggest that suppression of NR4A2 by DNA methylation may be involved in MDS progression. STEM CELLS TRANSLATIONAL
The efficacy of azacitidine (AZA) on survival of lower risk (LR) ‐ myelodysplastic syndromes (MDS) is controversial. To address this issue, we retrospectively evaluated the long‐term survival benefit of AZA for patients with LR‐MDS defined by International Prognostic Scoring System (IPSS). Using data from 489 patients with LR‐MDS in Nagasaki, hematologic responses according to International Working Group 2006 and overall survival (OS) were compared among patients that received best supportive care (BSC), immunosuppressive therapy (IST), erythropoiesis‐stimulating agents (ESA), and AZA. Patients treated with AZA showed complete remission (CR) rate at 11.3%, marrow CR at 1.9%, and any hematologic improvement at 34.0%, with transfusion independence (TI) of red blood cells in 27.3% of patients. and platelet in 20% of patients, respectively. Median OS for patients received IST, ESA, BSC, and AZA (not reached, 91 months, 58 months, and 29 months, respectively) differed significantly (P < .001). Infection‐related severe adverse events were observed in more than 20% of patients treated with AZA. Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR‐MDS patients.
Azacitidine is a mainstay of therapy for MDS-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their post-treatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pre- (n=449) and post- (n=289) treatment bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their post-treatment clone size on treatment outcomes. In Cox proportional hazard modeling, multi-hit TP53 mutation (HR, 2.03; 95% CI, 1.42-2.91; P<.001), EZH2 mutation (HR, 1.71; 95% CI, 1.14-2.54; P=.009), and DDX41 mutations (HR, 0.33; 95% CI, 0.17-0.62; P<.001), together with age, high-risk karyotypes, low platelet, and high blast counts, independently predicted OS. Post-treatment clone size accounting for all drivers significantly correlated with International Working Group (IWG)-response (P<.001, trend test), except for that of DDX41-mutated clones, which did not predict IWG-response. Combined, IWG-response and post-treatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, IPSS-M (c-index, 0.653 vs 0.688; P<.001, likelihood ratio test). In conclusion, evaluation of post-treatment clone size, together with pre-treatment mutational profile as well as IWG-response have a role in better prognostication of azacitidine-treated myelodysplasia patients.
In murine and zebrafish preclinical models of Diamond-Blackfan anemia (DBA), supplementation with the essential amino acid L-leucine ameliorates defective erythropoiesis and alleviates anemia, probably via upregulation of the mammalian target of rapamycin signaling pathway. [1][2][3] In addition, at least a single European patient with DBA experienced improved hemoglobin levels during L-leucine supplementation. 4 Because dysregulated ribosome biogenesis similar to that underlying DBA is present in cells from patients with myelodysplastic syndromes (MDSs) associated with deletion of chromosome 5q, it has been proposed that L-leucine might also improve MDS-associated anemia, especially in patients with the so-called 5q-syndrome, a lower-risk form of MDS associated with haploinsufficiency of ribosomal component ribosomal protein S14. 1,5 To date, no clinical experience with L-leucine in MDS has been reported, although the low cost, widespread availability, and excellent tolerability of this dietary supplement suggest that clinical trials should be undertaken.Three consenting patients with World Health Organization-defined MDS with isolated del(5q) (a 71-year-old man, a 65-year-old woman, and a 58-year-old woman; 2 of whom were red cell transfusiondependent and 1 of whom had no response to erythropoiesisstimulating agent therapy) who were reluctant to initiate treatment with lenalidomide took L-leucine capsules obtained from a nutritional supplement store at a dose of 1500 mg orally 3 times daily for 2 to 3 months, approximating the 700 mg/m 2 dose chosen for a planned trial of L-leucine in transfusion-dependent patients with DBA. The DBA trial is registered at www.clinicaltrials.gov as #NCT01362595.Although no adverse events were observed during L-leucine therapy, none of the patients experienced any improvement in their cytopenias or transfusion needs. Two of the 3 patients subsequently agreed to take lenalidomide, and both became transfusion-independent during that therapy.DBA is a congenital disorder with germline associated with mutations in ribosomal genes. The goal of therapy is to improve red blood cell production from erythroid progenitor cells with dysfunctional ribosomes. In MDS with del(5q), patients have somatically acquired ribosomal protein S14 haploinsufficiency, as well as haploinsufficiency for multiple additional genes on chromosome 5q and additional somatic mutations. The goal of therapy in MDS is to eliminate the del(5q) clone or, potentially, to improve red blood cell production from the neoplastic clone or residual normal hematopoietic clones. Of note, an improvement in ribosome function could potentially improve the clonal advantage of the del(5q) MDS clone. An absence of response could be a result of an insufficient dose of L-leucine, a more general lack of response in patients with ribosomal dysfunction, or that L-leucine does not improve erythropoiesis more specifically in del(5q) MDS. We eagerly await results of the formal DBA clinical trial and additional clinical experience with L-leuci...
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