Acute Myeloid Leukemia With Myelodysplasia-related Changes Patients Research Articles

Survival and Prognosis of Patients with Acute Myeloid Leukemia with Myelodysplasia-Related Changes Transformed from Myelodysplastic Syndrome

To explore the risk factors affecting the survival and efficacy of patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) transformed from myelodysplastic syndrome (MDS). The clinical data of 60 patients with AML-MRC transformed from MDS who hospitalized in The Third Affiliated Hospital of Soochow University from January 2010 to December 2021 were retrospectively analyzed. The demographic data and laboratory parameters, cytogenetic karyotypes, target genes of AML detected by next generation sequence, risk stratification, treatment regimen, therapeutic efficacy and survival outcome were documented. Rank sum test and Chi-square test or Fisher exact test were used to compare the survival and efficacy. The effects of clinical parameters, risk stratification and treatment regimens on the survival and efficacy of the AML-MRC patients were analyzed by univariate and multivariate analysis. The median overall survival (OS) of the AML-MRC patients was 4.5 months, the 1-year OS rate was 28.3%, and the complete remission (CR) rate after treatment was 33.3%. The univariate analysis showed that age≥60 years, leukocytosis, severe thrombocytopenia, poor-risk group and only accepted hypomethylating agents(HMAs) or supportive therapy were the risk factors affecting OS. COX multivariate analysis showed that thrombocytopenia ( HR=4.46), HMAs therapy (compared to transplantation, HR=10.47), supportive therapy (compared to transplantation, HR=25.80) and poor-risk group (compared to medium-risk group, HR=13.86) were independent hazard factors for median OS of patients with AML-MRC. The univariate analysis showed that the risk factors affecting 1-year OS in patients with AML-MRC were age≥60 years, thrombocytopenia, time of transformation from MDS to AML (TTA)≥3 months, fibrinogen-albumin ratio index (FARI)≥0.07, CONUT score≥5, poor-risk group and supportive therapy. Binary logistic regression analysis showed that the independent risk factors for 1-year OS in AML-MRC patients were age≥60 years ( HR=11.23), thrombocytopenia ( HR=8.71), FARI≥0.07 ( HR=5.19) and poor-risk group ( HR=14.00). The risk factors affecting CR of AML-MRC patients in univariate analysis were age≥60 years, thrombocytopenia, FARI≥0.1, CONUT score≥5, poor-risk group and supportive therapy, while binary logistic regression analysis showed that age≥60 years( HR=7.35), CONUT score≥5 ( HR=9.60), thrombocytopenia ( HR=12.05) and poor-risk group ( HR=32.5) were independent risk factors affecting CR of the patients. The OS of AML-MRC patients is poor, old age(≥60 years old), supportive therapy, HMA therapy, poor-risk, thrombocytopenia, FARI≥0.07 and CONUT score≥5 may be associated with poor prognosis.

Demographic factors affecting patients with AML with myelodysplasia-related changes.

e19027 Background: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a rare and aggressive form of acute myeloid leukemia (AML) that makes up about 25-34% of its annual cases. The subtype includes a varied group of tumors with clinical, genetic, and morphological characteristics that confer poor outcomes. AML-MRC is commonly treated with intensive chemotherapy, but the median survival is only 9-12 months. Given the poor outcomes, gaining a better understanding of epidemiologic factors could reveal opportunities for earlier diagnosis and improved treatment planning. Demographic characteristics of AML-MRC patients were identified and examined using the National Cancer Database (NCDB). Methods: Individuals with a confirmed diagnosis of AML-MRC (N = 14,536) were identified using the NCDB for a retrospective analysis from 2004 to 2020. Patient sex, age at diagnosis, race, household income, insurance status, urban/rural residence, and Charlson-Deyo score were examined by descriptive statistics, and diagnostic trends by year were identified and calculated with regression analysis. Results: A total of 14,536 patients diagnosed with AML-MRC between 2004 – 2020 were identified in the NCDB. Within this timeframe, there was an increasing incidence of diagnosis per year (R2 = 0.9). AML-MRC was more common in males (61.1%) than females (38.9%), and the average age at diagnosis was 68.9 years (SD = 13.0, range = 0 – 90 years). The majority of patients (87.3%) were White. Patients were most likely to be a part of the highest median household income quartile (33.6%) and least likely to be a part of the bottom quartile (13.2%). A higher percentage of patients were insured by Medicare (63.0%) compared to private insurance (25.3%). Most patients lived in counties in metro areas of 1 million population or more (51.4%). Most individuals had Charlson-Deyo comorbidity scores of zero (68.1%). The most common type of treatment facility was academic/research programs (55.1%) followed by comprehensive community cancer programs (23.3%). Conclusions: AML-MRC is a common subtype of AML with a poor prognosis. Previous studies have found that most individuals with AML-MRC are older-aged, White males. Our study corroborated this finding and examined additional demographic factors. We found that these patients were more likely to hold insurance through Medicare, likely reflecting the older average age at diagnosis. Additionally, patients were most commonly in the highest household income quartile and living in a metropolitan area with the highest population density. This could suggest that better access to healthcare improves rates of diagnosis of AML-MRC. Especially given that more people are being diagnosed each year, further research should work to understand the effects of these, and other, socioeconomic factors on the diagnosis, treatment, and prognosis of patients with AML-MRC.

Molecular characterization of AML-MRC reveals TP53 mutation as an adverse prognostic factor irrespective of MRC-defining criteria, TP53 allelic state, or TP53 variant allele frequency.

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) generally confers poor prognosis, however, patient outcomes are heterogeneous. The impact of TP53 allelic state and variant allele frequency (VAF) in AML-MRC remains poorly defined. We retrospectively evaluated 266 AML-MRC patients who had NGS testing at our institution from 2014 to 2020 and analyzed their clinical outcomes based on clinicopathological features. TP53 mutations were associated with cytogenetic abnormalities in 5q, 7q, 17p, and complex karyotype. Prognostic evaluation of TP53MUT AML-MRC revealed no difference in outcome between TP53 double/multi-hit state and single-hit state. Patients with high TP53MUT variant allele frequency (VAF) had inferior outcomes compared to patients with low TP53MUT VAF. When compared to TP53WT patients, TP53MUT patients had inferior outcomes regardless of MRC-defining criteria, TP53 allelic state, or VAF. TP53 mutations and elevated serum LDH were independent predictors for inferior OS and EFS, while PHF6 mutations and transplantation were independent predictors for favorable OS and EFS. NRAS mutation was an independent predictor for favorable EFS. Our study suggests that TP53MUT AML-MRC defines a very-high-risk subentity of AML in which novel therapies should be explored.

CPX-351: An Old Scheme with a New Formulation in the Treatment of High-Risk AML.

Simple SummarySecondary AML (s-AML) including therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent approximately one quarter of all AML cases. These AML subcategories are predominantly associated with advanced age and present a specific biologic profile including adverse genetics and a multidrug resistance phenotype, which often determine dramatically poor outcomes after conventional chemotherapy. In 2017, the FDA approved CPX-351, a liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 molar ratio, for the treatment of adults with newly diagnosed t-AML and MRC-AML. Since the approval, many trials have been conducted or are still ongoing in order to assess the role of CPX-351 as frontline treatment in different AML subcategories, as a potential bridge to transplant or in combination with target therapies. In this review, we will discuss the current role of CPX-351 in treating these high-risk AML, focusing on how its use may potentially change the treatment paradigms of AML.Therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent aggressive diseases characterized by a dismal prognosis if compared with de novo acute myeloid leukemia, especially in older patients. In these AML subsets, standard chemotherapy regimens produce poor response rates and unsatisfactory outcomes. Historically, conventional approaches consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the “3+7” regimen. Several attempts have been conducted to ameliorate this combination regimen but inconsistent improvements in response rates and no significant changes in overall survival have been observed, until the recent introduction of targeted molecules. A liposomal formulation of traditional chemotherapy agents cytarabine and daunorubicin, termed CPX-351, enhances pharmacodynamics and synergistic effects through the maintenance of the optimal 5:1 molar ratio, which extends the treatment’s half-life and increases the bone marrow tropism of the drug. The use of CPX-351 in newly diagnosed AML-MRC and t-AML patients aged 60–75 years has demonstrated superior remission rates compared to conventional chemotherapy and improvements in event-free and overall survival. Recently, published data from a 5-year follow-up highlighted evidence that CPX-351 has the ability to produce and contribute to long-term remission and survival in older patients with newly diagnosed high-risk/secondary AML. Future perspectives include evaluation of dose intensification with CPX-351 in high-risk settings, combining this agent with targeted therapies, and better understanding the mechanism of improved responses in t-AML and AML-MRC. In this review, we will examine the role of CPX-351 inside the new AML therapeutic scenario and how its employment could potentially modify the treatment algorithm of high-risk and elderly patients with AML

The Genetic and Prognostic Characteristics of AML-MRC Patients

To investigate the genetic and prognostic characteristics of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) patients. There were 230 non-M3 AML patients treated in Ningbo First Hospital enrolled, among which 58 patients were newly diagnosed AML-MRC, the patients were followed up and SPSS 25.0 was used to statistically analyze. There were 49 patients performed genetic testing, 29 patients (59.2%) showed chromosomal abnormalities, including 7q- 8 cases (16.3%), 5q- 6 cases (12.2%), 5 cases (10.2%) of 17p abnormalities, 13 cases (26.5%) of highly abnormal complex karyotypes (CK) (≥5 unrelated chromosomal abnormalities), CK contained chromosomal abnormalities such as +8, 5q-, and 12 cases (24.5%) of monosomal karyotypes (MK). Genetic testing was performed in 37 patients, and 24 (64.9%) patients showed genetic mutations, among which ASXL1 mutation was the most common (8 cases, 21.6%), followed by TET2 mutation in 6 cases (16.2%). Kaplan-Meier analysis showed that AML-MRC patients with high CK (P=0.012), 5q- abnormalities (P=0.038), and TP53 mutations (P=0.008) had poor overall survival. AML-MRC has unique genetic characteristics, and high CK, 5q- and TP53 mutations are poor prognostic factors.

Clinical and Cytogenetical Characteristics in Acute Myeloid Leukemia with Myelodysplasia-Related Changes

To explore the clinical and cytogenetic characteristics of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) based on morphology define. A total of 180 newly diagnosed acute myeloid leukemia (AML) patients were enrolled and retrospectively analyzed, and marrow cell morphology of 126 patients were re-evaluated. The clinical and cytogenetic characteristics, including ages, sex, WBC count, HGB level, PLT count, blasts percentage, abnormal karyotype detection rate of the patients in AML with multilineage dysplasia (AML-MRC-1), secondary AML from myelodysplastic/ myeloproliferative neoplasms (MDS/MPN) (AML-MRC-2), and AML not otherwise specified (AML-NOS) groups were investigated. There was no significant differences between the patients in three groups in terms of sex, age and platelet count (P=0.898, P=0.365, P=0.853), but AML-MRC-2 group (73.2%) was higher than AML-MRC-1 (60.0%) and AML-NOS (56.4%) in the percentages of patients over 60 years old (P=0.228); there were statistically significant differences on WBC count, HGB level, and blasts percentage (P=0.000, P=0.022, P=0.000, AML-MRC-2<AML-MRC-1<AML-NOS). Abnormal karyotypes rate were 59.2% in AML-MRC patients, among which complex karyotypes and myelodysplasia-related cytogenetic abnormalities accounted for 49.3%, and 5q- was the most common (28.2%), followed by 7q-/-7 (19.1%), 17p-/-17 (14.1%), +8 (14.1%), and 20q- (12.7%). Cytogenetic abnormalities rate were compared between the patients in the three groups, the result showed that AML-MRC-2 group (73.2%) was higher than AML-MRC-1 group (40.0%) and AML-NOS group (25.4%) (P=0.000). Complex karyotypes and myelodysplasia-related abnormalities were the main abnormalities in AML-MRC-2 and AML-MRC-1 group, the percentages of complex karyotypes of the patients in the two groups showed statistically significant (41.5% vs 16.7%, P=0.026), while the percentages of other myelodysplasia-related abnormalities showed no statistically significant (17.1% vs 20.0%, P=0.753). Morphological reassessment of bone marrow cell dysplasia is crucial to the differential diagnoses between AML-MRC (defined only by morphological changes of multilineage dysplasia) and AML-NOS. And the detection rate of cytogenetic abnormalities that mainly consisted of complex karyotypes and myelodysplasia-related abnormalities was higher in AML-MRC patients.

The prognostic value of the Fibrinogen-Albumin Ratio Index in patients with myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes treated with azacitidine.

Inflammation is a major hallmark of several cancers. The present study evaluated the prognostic value of the Fibrinogen-Albumin Ratio Index (FARI) at the diagnosis in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) treated with azacitidine (AZA). A retrospective study was conducted in a single cohort of 99 patients with de novo MDS and AML-MRC who were treated with AZA between May 2011 and June 2019 in our hospital. Plasma fibrinogen and serum albumin levels were measured before the start of AZA treatment. A total of 99 patients were included in the analysis. The optimal cut-off value of FARI for predicting the 1-year overall survival (OS) was determined by a receiver operating characteristic (ROC) analysis to be 0.079. A total of 59 (60%) and 40 (40%) patients had an FARI ≥0.079 (high-FARI group) and < 0.079 (low-FARI group), respectively. The high-FARI patients had a significantly shorter OS than low-FARI patients (1-year OS, 35.6% vs. 77.5%, p < 0.001). In a multivariate analysis, parameters with independent adverse significance for the OS were a high FARI (≥0.079) (hazard ratio (HR) 2.41, 95% confidence interval (CI), 1.36-4.29; p = 0.006), and Revised-International Prognostic Scoring System (IPSS-R) very high (HR 1.483, 95% CI, 1.12-1.963, p = 0.006). A high FARI was found to be associated with a poor outcome in MDS and AML-MRC patients treated with AZA, and FARI was an independent prognostic factor for the OS in these patients. Further internal and external validations are needed to clarify the prognostic role of the FARI for MDS and AML-MRC patients.

High MYC Protein Expression in MDS Is Associated with Early Transformation to AML

Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is shown to be associated with dismal clinical outcomes and there remains a pressing need for new therapeutic strategies to improve survival outcomes. It is also important to identify targetable markers that could predict an earlier AML transformation from preexisting MDS. Our recent studies demonstrated that high expression level of MYC oncoprotein is associated inferior survival outcome in AML-MRC patients and that MYC plays an oncogenic role by epigenetic regulation of hydroxylation of 5-methylcytosine. However, the role of MYC in MDS to AML progression remain to be answered. Here, we investigated MYC protein expression levels in bone marrow (BM) specimens of patients with preexisting MDS and their subsequent AML-MRC specimens to determine whether increased MYC expression is associated with early AML progression. We retrospectively identified 32 patients with histologically confirmed AML-MRC evolving from MDS and evaluated MYC protein levels in BM biopsy specimens at the time of initial MDS diagnosis and at the time of disease transformation to AML-MRC, respectively. Clinical data including age at diagnosis, gender, CBC with differential count, cytogenetics, somatic mutations common in myeloid disease, blasts count, and IPSS were extracted at the time of MDS and AML-MRC diagnosis. MYC expression was assessed by immunohistochemistry on 4-5µm tissue sections. Deparaffinized slides were stained with anti-MYC antibody (clone Y69, Roche Diagnostics) using a Ventana Benchmark automated system. MYC expression was scored independently by two hematopathologists and categorized as low vs. high as previously described. The cut-off for high MYC expression is ≥5% positive cells. The MDS-to-AML progression free survival (PFS) and overall survival (OS) were calculated from the date of MDS diagnosis and outcomes were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical analyses were performed using SPSS v24.0. Among 32 patients, 69% (n=22) and 31% (n=10) patients had low and high MYC expression at MDS diagnosis (Table 1). The median age was 67.9 (33.5-78.7) and 61.1 (38.9-73.4) and the % of MYC positive blasts were 1% (range, 0-4.5) and 17.5% (range, 5-27.5) in low and high MYC groups, respectively, at the time of MDS diagnosis. There was no statistical difference in BM blast counts between low vs. high MYC groups (median 5% vs. 7.5%, p=0.4951). IPSS risk assessment in a total of 26 patients (19 in low MYC and 7 in high MYC) showed that 9% (n=2), 27% (n=6), 32% (n=7), and 18% (n=4) in low MYC group and 0% (n=0), 20% (n=2), 20% (n=2), and 30% (n=3) in high MYC groups had low, intermediate-I, intermediate-II, and high risk at the time of MDS diagnosis (Table 1). A total of 84% (86% [n=19] in low MYC and 80% [n=8] in high MYC) patients received treatments for MDS; ESA in 16% (n=5), hypomethylating agents in 81% (n=26), and Revlimid in 16% (n=5) (Table 1). Allogeneic stem cell transplant (allo-SCT) was performed in 12.5% (n=4) patients (n=3, low MYC; n=1, high MYC). Following AML progression, a total of 91% (n=29) patients received treatment for AML including induction chemotherapy (n=18), hypomethylating agents (n=7), and other therapies including trial (n=4) (Table 1). In the univariate analyses, patients with low MYC expression had significantly longer MDS-to-AML PFS (median 15.8 vs. 7.25 months, HR=0.1745, 95%CI=0.0591-0.5157, p=0.0016) (Figure 1), however, there was no OS difference between two groups (4.32 vs. 2.35 years, HR=0.5131, 95%CI=0.1064-2.475, p=0.6909). In a multivariate Cox model (adjusting for IPSS, age, front-line therapy, gender, allo-SCT, and MYC level), high MYC expression (HR=3.939, 95%CI=1.107-14.012, p=0.034) and IPSS risk (HR=1.903, 95%CI=1.139-3.181, p=0.014) were significant factor for MDS-to-AML PFS. In conclusion, high MYC expression at the MDS stage was associated with shorter time to AML progression, indicating that MYC plays an oncogenic role in MDS to AML transformation. Although our findings need further validation by prospective studies with greater sample size, our results support a combination treatment of hypomethylating agents with novel agents targeting MYC or/and its downstream pathways and warrant further study to identify underlying mechanisms of MYC-driven MDS to AML progression. Disclosures Talati: Pfizer: Honoraria; Astellas: Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; AbbVie: Honoraria. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Komrokji:JAZZ: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy.

Expression and Significance of Shh Signaling Pathway in Bone Marrow CD34+ Cells of Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

To study the expression of Shh singaling related gene, including Shh, Ptch1, Smo and Gli1 in bone marrow CD34+ cells of patients with myelodysplastic syndrome(MDS) and acute myeloid leukemia with myelodysplasia-related changes(AML-MRC), and to explore their clinical significance. The count of CD34+ cells in bone marrow was detected by flow cytometry in 53 patients with MDS and 30 patients with AML-MRC. Magnetic beads were used to separate CD34+ cells. The expression of Shh, Ptch1,Smo and Gli1 on CD34+ cells was detected by qRT-PCR, the effect of the 4 gene expression on prognosis of patients in MDS and AML-MRC group was compared, 25 patients with iron-deficiency anemia were used as controls. The expression levels of Shh, Smo and Gli1 of patients in MDS and AML-MRC group were significantly higher than those in control group (P＜0.05), moreover increased with disease progression(P<0.05). The expression of Ptch1 was not statistically significantly different between 3 groups（P＞0.05）. In comparison of prognosis, the expression of Smo and Gli1 in the patients of relatively high risk groups and AML-MRC groups were significantly increased (P<0.05). The median overall survival time of patients in MDS and AML-MRC groups was 12（7.5，16.5） and 6（3.0，9.0） months (P=0.000) respectively. The median survival time of MDS and AML-MRC patients with high expression of Smo and Gli1 was significantly shorter than that of MDS and AML-MRC patients with low expression of Smo and Gli1(P<0.05). Shh signaling pathway in the patients with MDS is activated, which is involved in the progress and prognosis of MDS.

AML with Myelodysplasia-Related Changes: Development, Challenges, and Treatment Advances.

Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a distinct biologic subtype of AML that represents 25–34% of all AML diagnoses and associates with especially inferior outcomes compared to non-MRC AML. Typically, patients with AML-MRC experience low remission rates following intensive chemotherapy and a median overall survival of merely 9–12 months. In light of these discouraging outcomes, it has become evident that more effective therapies are needed for patients with AML-MRC. Liposomal daunorubicin–cytarabine (CPX-351) was approved in 2017 for adults with newly diagnosed AML-MRC and those with therapy-related AML (t-AML), and remains the only therapy specifically approved for this patient population. Other studies have also demonstrated the efficacy of the hypomethylating agent (HMA) azacitidine as upfront therapy for AML-MRC patients, which, to date, is the most common treatment employed for patients unable to tolerate the more intensive CPX-351. HMAs and venetoclax combinations have also been evaluated, but additional studies utilizing these agents in this specific subgroup are needed before conclusions regarding their role in the therapeutic armamentarium of AML-MRC patients can be reached. Currently, many studies are ongoing in attempts to further improve outcomes in this historically ill-fated patient group.

Comparison of mutational profiles and clinical outcomes in patients with acute myeloid leukemia with mutated RUNX1 versus acute myeloid leukemia with myelodysplasia-related changes with mutated RUNX1

Studies comparing the prognostic role of RUNX1 mutations (RUNX1mut) in acute myeloid leukemia (AML) and acute myeloid leukemia-with myelodysplasia-related changes (AML-MRC) are limited. Our study examines the genetic profile of 118 RUNX1mut AML patients including 57 AML with RUNX1mut and 61 AML-MRC with RUNX1mut and 100 AML, NOS patients with wild type RUNX1 (RUNX1wt). Results revealed that AML-MRC patients with RUNX1mut had shorter median overall survival (OS) (11 ± 3.3 months) when compared to AML with RUNX1mut (19 ± 7.1 months) and AML, NOS with RUNX1wt (not reached) (p = .001). The most common concurrent mutations observed in AML-MRC with RUNX1mut patients were DNMT3A, SRSF2, ASXL1, and IDH2 while in AML with RUNX1mut patients were ASXL1, SRSF2, TET2, IDH2, and DNMT3A. ASXL1 and TET2 mutations appeared to adversely affect OS in AML-MRC, but not in AML with RUNX1mut. Concurrent RUNX1/DNMT3A mutations, in contrast had negative impact on OS in AML with RUNX1mut, but not in AML-MRC with RUNX1mut.

Determining the frequency of iron overload at diagnosis in de novo acute myeloid leukemia patients with multilineage dysplasia or myelodysplasia-related changes: a case control study

Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a new disease category, which was defined as a separate entity in the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. While pre-treatment iron overload in patients with myelodysplastic syndrome has been previously studied, its relationship with AML-MRC has not been studied. We aimed to investigate the relationship between serum iron tests compatible with iron overload and the diagnosis of multilineage dysplasia (MLD) and AML with myelodysplasia-related changes (AML-MRC) in AML patients diagnosed at Hacettepe University Adult Hospital between January 2002 and September 2017. Ninety-three patients who met the criteria were enrolled. Bone marrow aspirate of each patient was re-examined, and dysplasia was investigated; other data were examined from patient’s records. The iron overload status at diagnosis and transferrin saturation (TS) values were compared between the groups with and without MLD and those with and without AML-MRC. When iron overload was defined as TS ≥ 58% and ferritin ≥ 500 ng/mL, iron overload was observed in 10 (37%) patients with MLD and in 4 (13%) without MLD. The difference is almost statistically significant (p = 0.053). The mean TS value and frequency of iron overload were higher in AML-MRC patients than in non-AML-MRC patients (p < 0.05 for both). A mild positive significant correlation was observed between the dysplasia severity score and TS (r = 0.317, p = 0.032). In patients with AML-MLD and AML-MRC, iron overload occurred regardless of the transfusion status at the time of diagnosis. Morphologic severity of dysplasia may be correlated with higher TS values at the time of diagnosis.

Comparison of umbilical cord blood transplantation and hematopoietic stem cell transplantation from HLA-matched sibling donors in the treatment of myelodysplastic syndrome-EB or acute myeloid leukemia with myelodysplasia-related changes

目的比较非血缘脐血干细胞移植（UCBT）与同胞HLA全相合供者造血干细胞移植（MSD-HSCT）治疗骨髓增生异常综合征伴原始细胞增多（MDS-EB）和急性髓系白血病伴骨髓增生异常相关改变（AML-MRC）的临床疗效。方法回顾性分析2011年2月至2017年12月接受UCBT/MSD-HSCT的MDS-EB/AML-MRC患者64例，其中MDS-EB 38例，AML-MRC 26例。结果①与MSD-HSCT组比较，UCBT组AML-MRC患者比例较高[52.8%（19/36）对25.0%（7/28），P=0.025]，中位年龄较低[13（1.5~52）岁对32（10~57）岁，P=0.001]。②UCBT组与MSD-HSCT组+42 d粒细胞植入率均为100%，中位植入时间分别为17.5（11~31）d、11.5（10~20）d；UCBT组+100 d血小板植入率为91.4%，中位植入时间为40（15~96）d，MSD-HSCT组+100 d血小板植入率为100.0%，中位植入时间为15（11~43）d。③UCBT组和MSD-HSCT组比较，+100 dⅡ~Ⅳ度、Ⅲ/Ⅳ度急性GVHD累积发生率、180 d移植相关死亡率、3年累积复发率、3年总生存率和3年无病生存率差异均无统计学意义（P>0.05）。④UCBT组3年慢性GVHD、重度慢性GVHD的累积发生率均低于MSD-HSCT组[28.3%（95% CI 13.4%~45.3%）对67.9%（95%CI 46.1%~82.4%），P=0.002；10.3%（95%CI 2.5%~24.8%）对50.0%（95%CI 30.0%~67.1%），P<0.001]；UCBT组3年无严重急慢性GVHD及无复发生存（GRFS）率明显高于MSD-HSCT组[55.0%（95%CI 36.0%~70.6%）对28.6%（95%CI 13.5%~45.6%），P=0.038]。结论UCBT治疗MDS-EB/AML-MRC患者可获得比MSD-HSCT更好的移植后生存质量。

Relationship between Altered Gene Expression and DNA Methylation of the DLK1-DIO3 region in Azacitidine-Treated Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

INTRODUCTIONMyelodysplastic syndromes (MDS) represent a heterogeneous spectrum of hematopoietic stem cell disorders characterized by inefficient hematopoiesis, peripheral blood cytopenia, dysplasia in one or more myeloid cell lineages, and a tendency to evolve into acute myeloid leukemia (AML). Hypomethylating agent azacitidine (AZA) is a standard therapy for patients with higher-risk MDS and AML with myelodysplasia-related changes (AML-MRC).The DLK1-DIO3 region is located on chromosome 14q32 and contains one of the largest miRNA clusters in the genome. Functions of these miRNAs have been linked to apoptosis and proliferation. Their expression is under the control of a differentially methylated region (DMR) located in the promoter of MEG3 gene. Significant overexpression of these miRNAs has previously been found in MDS and acute promyelocytic leukemia (APL). In APL, this upregulation has been linked to hypermethylation of MEG3-DMR. AIMSWe examined (i) expression of the 14q32 miRNAs and mRNAs (DLK1, RTL1, DIO3, MEG3, and MEG8) and (ii) DNA methylation of MEG3-DMR in patients with higher-risk MDS and AML-MRC before and during AZA treatment with the aim to reveal whether the overexpression of these miRNAs is epigenetically regulated in myelodysplasia. METHODSThe study comprised 24 paired samples of CD34+ bone marrow cells obtained from 12 patients with higher-risk MDS and AML-MRC before and during AZA therapy. miRNA profiling was done using Agilent microarrays and mRNA levels of the genes located within the 14q32 region were assessed by Illumina microarrays. Measurement of MEG3 level by RT-qPCR confirmed the microarray results on an independent cohort (81 MDS and 14 AML-MRC patients, and 13 controls). Methylation status of MEG3 promoter was investigated by amplicon bisulfite sequencing. RESULTSWe studied levels of miRNAs and mRNAs encoded in the DLK1-DIO3 region and found that 50 % of untreated patients showed strong upregulation of expression activity within the locus. Following AZA therapy, we observed a significant reduction in the miRNA/mRNA expression to nearly normal levels, suggesting that expression activity might be affected by hypomethylation. Interestingly, expression levels of miRNAs and mRNAs positively correlated, indicating that transcriptional activity was regulated uniformly throughout the region.Evaluation of expression data with clinical features in the pretreatment samples revealed that expression activity was related to BM blast count, patient diagnosis, and outcome. High expression was significantly associated with the diagnosis of AML-MRC and poor outcome, whereas low expression with MDS and favorable outcome. No chromosomal abnormality or cytogenetic risk category was linked to the expression changes.In the patients before treatment, we revealed a significant hypermethylation of a part of the MEG3-DMR that closely preceded the MEG3 start codon. This hypermethylation was seen in 50 % of the patients and negatively correlated with expression activity. Interestingly, the hypermethylation was associated with longer progression-free survival after initiation of AZA therapy (hazard ratio = 0.220, P = 0.03).Following AZA therapy, we identified an apparent decrease of methylation in another part of MEG3-DMR. This hypomethylation might be attributed to the hypomethylating effect of AZA and could therefore influence the deregulated expression of the miRNA cluster.Finally, we investigated the potential application of the deregulation observed in this locus for prognostic purposes regarding the responsiveness to AZA treatment. Although, we identified changes in expression and methylation levels before AZA therapy, these changes were not associated with future response status. CONLUSIONSHere, we correlated changes in expression of 14q32 miRNAs and mRNAs with specific methylation changes in its regulatory sequences in higher-risk MDS and AML-MRC patients treated with AZA. We thoroughly investigated a complex regulatory mechanism within this region and based on our data, we assumed that epigenetic alterations affect expression activity in the locus. However, also other mechanisms such as influence of some transcription factors may play yet unrecognized roles in the resulting state.Supported by grants 17-31398A, 16-33617A, 16-33485A, and 00023736 (Ministry of Health of the Czech Republic). DisclosuresNo relevant conflicts of interest to declare.

Characteristics of acute myeloid leukemia with myelodysplasia‐related changes: A retrospective analysis in a cohort of Chinese patients

We retrospectively analyzed 449 patients with AML under the WHO classification of AML 2008 and probed implications of this classification in diagnosis and treatment of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) among them. The clinical presentations, biological features, treatments, and prognosis of patients diagnosed with AML-MRC were analyzed and compared with those of AML not otherwise specified (AML-NOS). In all patients, 115 (25.6%) were diagnosed as AML-MRC including 64 males and 51 females with median onset age of 48 years (range from 17 to 78). Their complete remission (CR) rate was 60.9% and relapse rate was 57.1%. The observed median overall survival (OS) and disease-free survival (DFS) were 10 and 5 months, respectively, which was significantly shorter than those of AML-NOS patients (P < 0.05). The prognosis of AML-MRC patients with myelodysplastic syndrome (MDS)-related cytogenetics sole was similar to those with history of MDS or myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Patients with MDS-related cytogenetic abnormalities and/or history of MDS or MDS/MPN predisposed significantly shortened CR, OS, and DFS than AML-MRC patients with only multilineage dysplasia (MLD) and AML-NOS patients (P < 0.05). Multivariate analysis showed that age, cytogenetics, and history of MDS or MDS/MPN were independent prognostic factors. Patient diagnosed as AML-MRC presented distinctive clinical and biological features. Presence of MLD does not change the prognosis.