WT1 MRNA Expression Level In Patients With Myelodysplastic Syndromes At Stable Disease After Hypomethylating Agents

BackgroundMyelodysplastic syndromes(MDS)are a heterogeneous group of clonal hematopoietic stem cell diseases,which are characterized by bone marrow failure,dysplasia and progression to acute myeloid leukemia(AML).MDS is mainly occurring in the elderly people and the majority of patients usually die from the complications of cytopenia or convert to AML.The hypomethylating agents(HMAs)azacitidine and decitabine have changed the treatment landscape of MDS since their approval by the United States Food and Drug Administration(US FDA)in 2004 and 2006,respectively.HMAs is now the standard of care in MDS.It can change the natural history of the disease.Revised International Working Group(IWG)standardized response criteria have been used to evaluate the outcome of therapy and refine treatment in MDS patients following demethylation treatment.Epigenetic therapy with hypomethylating drugs is now the standard of care in MDS.But response rates remain low and there are a significant proportion of patients with MDS who lose response or progress while on therapy.The group of patients that failed hypomethylating agents has particularly poor prognosis with an estimated survival of 4-6 months.It is a clinical challenge to decide whether or not to continue a patient when the response may not be definitive.Therefore,it is an area of active research to identify a good marker that can predict the prognosis of patients treated with HMAs.According to IWG 2006 criteria,SD was defined as no evidence of progression and without achievement of any other responses.Changes in tumor burden directly impact progression and leukemic transformation.But different patients had different SD duration and it was not well established what factors affected the outcome of patients after SD status.The outcome of patients who achieved BM CR was better,while the patients progressed to AML had worse outcome and should be offered different therapies before progression to optimize their response.By detecting the changes of WT1 level may early determine of such patients.The WT1 gene is a tumor marker of leukemic blasts.The expression level of WT1 increases in patients with acute leukemia,and it is significantly correlated with disease progression,efficacy and prognosis.WT1 mRNA expression can be used as a specific marker for detecting residual leukemia.ObjectivesThe main purpose of this study was to analyze the changes of tumor burden and the prognostic significance in patients with SD following HAMs.MethodsAdult MDS patients receiving demethylation drugs from November 2009 to November 2017 at our institution were screened.MDS patients diagnosed by World Health Organization(WHO)2008 classification.According to IWG 2006 criteria,45 MDS patients who achieve stable disease after treatment with hypomethylating agents were included.The WT1 mRNA expression levels at different time points in the bone marrow and peripheral blood samples of these patients were detected,and the relationship between the change of WT1 mRNA expression level and disease progression or acute myeloid leukemia transformation was evaluated.ResultsIn this study,we detected the level of WT1 mRNA in MDS patients following HMAs including DAC and AZA.We found that WT1 mRNA level decreased gradually following HMAs treatment in patients who achieved response and it was significantly lower at 3-5 cycles after treatment than that before treatment.This suggested that WT1 mRNA expression levels was well correlated with the efficacy of HMAs and detecting WT1 mRNA may be a useful marker for evaluation of efficacy after HMAs treatment.We also found that the levels of WT1 significantly increased after progression or leukemia evolution than that before treatment.This suggested that the WT1 mRNA expression level reflects the disease stage progression of MDS treated with HMAs.We detected the dynamic changes of WT1 mRNA expression during SD period and found that WT1 level is not constant,but showed two significant different patterns as higher than normal range or increasing change pattern,within the normal range or deceasing change pattern.The changes of WT1 mRNA expression impact the clinical outcome.95.65%patients with elevated WT1 mRNA in SD transformed to AML or progressed,only 9.09%patients with reduced WT1 mRNA progressed.In high-risk MDS,treatment goal was to prolong progression-free survival(PFS)and overall survival.Our follow-up showed that the patients with elevated WT1 level during SD status had significant worse OS and PFS rate than the patients with reduced WT1 level.Gradually increased the level of WT1 was a strong predictor of a short survival.ConclusionIn summary,WT1 mRNA expression level reflects the changes of disease condition of MDS treated with HMAs;patients with elevated WT1 mRNA expression in SD after HMAs had worse prognosis compared to patients with reduced WT1.