Dose of Deferasirox Correlates with Effects but Is Different in Low-Risk Myelodysplastic Syndrome and Aplastic Anemia

Abstract Backgrou n d : Patients with low-risk myelodysplastic syndrome (MDS) and aplastic anemia (AA) often need transfusions, which may accelerate the iron overload. The aim of this study was to evaluate the efficacy, safety and dose-effect relation of deferasirox (DFX) for patients with low-risk MDS and AA who were refractory to regular treatment in the real-world setting. M ethods: This was a retrospective study. Patients with low-risk MDS or AA who failed to standard treatments and were transfusion-dependent were enrolled. DFX was given as the only treatment apart from transfusion. Patients were recorded for their medical history, laboratory tests, nuclear magnetic resonance (MRI), echocardiography and calculated for their overall survival (OS). Dose-effect relations of DFX were evaluated after the first 6 months. Total annual exposure of DFX was calculated after 12 months, expressed as accumulated exposure time at dose of 20mg/kg/d. R esults: Of the 112 patients finally enrolled, 61 (54.5%) were low-risk MDS and 51 (45.5%) were AA. The median age was 56 (10, 89) years and 52.7% patients were males. The minimum dose of DFX for significant SF decrease was 20 mg/kg/d at 6 months; and the minimum accumulation of DFX had to reach 9 months at 20 mg/kg/d to maintain the efficacy at the time of 12 months for patients with low-risk MDS (p＜0.050). Different from MDS, the minimum dose for significant SF decrease was 10 mg/kg/d at 6 months; and the minimum accumulation had to reach 3 months at 20 mg/kg/d to maintain the efficacy at the time of 12 months for patients with AA (p＜0.050). Meanwhile, with same dose of exposure, significant improvements in hematological parameters were also observed in AA, but no dose-effect relations were found in MDS. 62.3% MDS and 51.0% AA patients stopped transfusion in the next 6 months. Erythroid responders had lower SF than non-responders after 12 months of DFX, both for MDS and AA (p＜0.05). Lower alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with baseline after 12 months of DFX were observed and longer exposure time correlated with lower ALT (p＜0.050). No significant changes in cardiac function, however. Similar side effects were found in MDS and AA, with gastrointestinal disorders and elevated serum creatinine the most common. Higher dose and longer exposure time of DFX correlated with longer overall survival, both for patients with MDS and AA (p＜0.050). Conclusion: Although dose of DFX varies greatly in different individuals, a significant decrease in SF and an improvement of hematologic parameters, organ functions, or even overall survival can be achieved if the accumulate dose reaches a certain level. In that case, patients with low-risk MDS need higher dose than those with AA. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Korszakváltás a gyermekkori szerzett csontvelő-elégtelenséggel járó kórképek kezelésében Magyarországon

Orvosi Hetilap ◽

10.1556/650.2018.31171 ◽

2018 ◽

Vol 159 (42) ◽

pp. 1710-1719

Author(s):

Krisztián Kállay ◽

Judit Csomor ◽

Emma Ádám ◽

Csaba Bödör ◽

Csaba Kassa ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Survival Rate ◽

Myelodysplastic Syndrome ◽

Aplastic Anemia ◽

Severe Aplastic Anemia ◽

Juvenile Myelomonocytic Leukemia ◽

Reduced Intensity Conditioning ◽

Myelomonocytic Leukemia ◽

Reduced Intensity

Abstract: Introduction: Acquired bone marrow failures are rare but fatal diseases in childhood. Since 2013, Hungary has been participating as a full member in the work of the European Working Group on uniform diagnostics and therapy in patients with acquired bone marrow failure syndromes. Hypocellular refractory cytopenia of childhood has been emphasized as a frequent entity, transplanted by reduced intensity conditioning with excellent outcomes. Aim: To analyse and compare the results of treatment before and after our joining. Method: A total of 55 patients have been treated in the 8 centres of the Hungarian Pediatric Oncology Network during 5 years between 2013 and 2017 (severe aplastic anemia: 9, myelodysplastic syndrome: 41, juvenile myelomonocytic leukemia: 5 patients). Allogeneic hematopoietic stem cell transplantation was performed in severe aplastic anemia in 7 cases, while antithymocyte globulin was administered in one case and one patient died before diagnosis. In patients with myelodysplastic syndromes, watch and wait strategy was applied in 4, while transplantation in 37 cases. Reduced intensity conditioning was used in 54 percent of these cases. Transplantation was the treatment of choice in all 5 patients with juvenile myelomonocytic leukemia. Results: In the whole patient cohort, the time from diagnosis to treatment was median 92 (3–393) days, while in severe aplastic anemia median 28 (3–327) days only. Grade II–IV acute graft versus host disease occurred in 22.6%, grade III–IV in 6.8% and chronic in 11.2%. All the patients treated with severe aplastic anemia are alive and in complete remission (100%). The overall estimated survival rate is 85.1% in myelodysplastic syndrome, while 75% in juvenile myelomonocytic leukemia. The median follow-up was 30.4 (1.1–62.5) months. There was a remarkable increase in overall survival comparing the data before (1992–2012) and after (2013) joining the international group, 70% vs. 100% (p = 0.133) in severe aplastic anemia and 31.3% vs. 85.1% (p = 0.000026) in myelodysplastic syndrome. Conclusion: Due to a change in the paradigm of the conditioning regimen in hypocellular refractory cytopenia of childhood, the overall survival rate has significantly increased. Orv Hetil. 2018; 159(42): 1710–1719.

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Mutational Characteristics and Changing Pattern from Idiopathic Cytopenia of Undetermined Significance to High-Risk Myelodysplastic Syndrome Stratified By IPSS-R

Blood ◽

10.1182/blood-2019-125236 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3009-3009

Author(s):

Eun-Ji Choi ◽

Young-Uk Cho ◽

Seongsoo Jang ◽

Chan-jeoung Park ◽

Han-Seung Park ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Rna Splicing ◽

Conflicts Of Interest ◽

Low Risk ◽

International Prognostic Scoring System ◽

Intermediate Risk ◽

Sequencing Data ◽

Undetermined Significance

Background: Unexplained cytopenia comprises a spectrum of hematological diseases from idiopathic cytopenia of undetermined significance (ICUS) to myelodysplastic syndrome (MDS). Revised International Prognostic Scoring System (IPSS-R) is the standard tool to assess risk in MDS. Here, we investigated the occurrence, characteristics, and changing pattern of mutations in patients with ICUS and MDS stratified by IPSS-R score. Methods: A total of 211 patients were enrolled: 73 with ICUS and 138 with MDS. We analyzed the sequencing data of a targeted gene panel assay covering 141 genes using the MiSeqDx platform (Illumina). The lower limit of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. Bone marrow components were assessed for the revised diagnosis according to the 2016 WHO classification. Lower-risk (LR) MDS was defined as those cases with very low- or low-risk MDS according to the IPSS-R. Higher-risk (HR) MDS was defined as those cases with high- or very high-risk MDS according to the IPSS-R. Results: Patients with ICUS were classified as very low-risk (39.7%), low-risk (54.8%), and intermediate-risk (5.5%) according to the IPSS-R. Patients with MDS were classified as LR (35.5%), intermediate-risk (30.4%), and HR (34.1%). In the ICUS, 28 (38.4%) patients carried at least one mutation in the recurrently mutated genes in MDS (MDS mutation). The most commonly mutated genes were DNMT3A (11.0%), followed by TET2 (9.6%), BCOR (4.1%), and U2AF1, SRSF2, IDH1 and ETV6 (2.7% for each). IPSS-R classification was not associated with mutational VAF and the number of mutations in ICUS. In the 49 LR MDS, 28 (57.1%) patients carried at least one MDS mutation. The most commonly mutated genes were SF3B1 (20.4%), followed by TET2 (12.2%), U2AF1 (10.2%), DNMT3A (10.2%), ASXL1 (10.2%), and BCOR (6.1%). Higher VAF and number of mutations were observed in LR MDS compared to ICUS patients. In the 42 intermediate-risk MDS, 27 (64.3%) patients carried at least one MDS mutation. The most commonly mutated genes were ASXL1 (23.8%), followed by TET2 (21.4%), RUNX1 (16.7%), U2AF1 (14.3%), DNMT3A (14.3%), SF3B1 (9.5%), and SRSF2, BCOR, STAG2 and CBL (7.1% for each). In the 47 HR MDS, 36 (76.6%) patients carried at least one MDS mutation. The most commonly mutated genes were TET2 (25.5%), followed by DNMT3A (14.9%), TP53 (14.9%), RUNX1 (12.8%), U2AF1 (10.6%), ASXL1 (10.6%), and SRSF2 and KRAS (6.4% for each). As the disease progressed, VAF and number of the MDS mutations gradually increased, and mutations involving RNA splicing, histone modification, transcription factor or p53 pathway had a trend for increasing frequency. Specifically, ASXL1, TP53, and RUNX1 mutations were the most striking features in patients with advanced stage of the disease. Cohesin mutations were not detected in ICUS, whereas these mutations were detected at a relatively high frequency in HR MDS. Our data were summarized in Table 1. Conclusions: We demonstrate that on disease progression, MDS mutations are increased in number as well as are expanded in size. Furthermore, a subset of mutations tends to be enriched for intermediate- to HR MDS. The results of this study can aid both diagnostic and prognostic stratification in patients with unexpected cytopenia. In particular, characterization of MDS mutations can be useful in refining bone marrow diagnosis in challenging situations such as distinguishing LR MDS from ICUS. Disclosures No relevant conflicts of interest to declare.

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GPX3 methylation is associated with hematologic improvement in low-risk myelodysplastic syndrome patients treated with Pai-Neng-Da

Journal of International Medical Research ◽

10.1177/0300060520956894 ◽

2020 ◽

Vol 48 (9) ◽

pp. 030006052095689

Author(s):

Shujun Yang ◽

Tong Gao ◽

Zhonghua Zheng ◽

Binbin Lai ◽

Lixia Sheng ◽

...

Keyword(s):

Clinical Trial ◽

Myelodysplastic Syndrome ◽

Methylation Level ◽

Hematological Parameters ◽

Low Risk ◽

Controlled Clinical Trial ◽

Platelet Response ◽

Female Patients ◽

Platelet Counts ◽

Male Patients

Objective The aim of this prospective randomized controlled clinical trial was to explore the relationship between GPX3 methylation and Pai-Neng-Da (PND) in the treatment of patients with low-risk myelodysplastic syndrome (MDS). Methods There were 82 low-risk MDS patients who were randomly divided into the following two groups: androl, thalidomide, and PND capsule (ATP group, n = 41); or androl and thalidomide (AT group, n = 41). Hemoglobin and neutrophil and platelet counts and changes in GPX3 methylation level were assessed. Results The plasma hemoglobin level increased in both groups after treatment. However, the platelet count increased only in the ATP group. Patients in the ATP group had a better platelet response than the AT group, and GPX3 methylation markedly decreased after treatment with ATP but not after treatment with AT. Moreover, male patients had a significantly lower GPX3 methylation level than female patients, while platelet counts from male patients increased dramatically after the ATP regimens compared with female patients. GPX3 methylation changes were negatively correlated with platelet changes in ATP group. Conclusion PND can improve hematological parameters and decrease the GPX3 methylation level. Decreasing GPX3 methylation is associated with the hematologic response that includes platelet in GPX3 methylation. China Clinical Trial Bureau (ChiCTR; http://www.chictr.org.cn/ ) registration number: ChiCTR-IOR-15006635.

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MDM2 SNP309 and TP53 SNPArg72Pro Polymorphisms in Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v114.22.1745.1745 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1745-1745

Author(s):

João Agostinho Machado Neto ◽

Fabiola Traina ◽

Paula Melo Campos ◽

Marilisia Andreoli ◽

Irene Lorand Metze ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Disease Progression ◽

Low Risk ◽

Healthy Controls ◽

Mdm2 Snp309 ◽

P53 Pathway ◽

Hematopoietic Stem ◽

High Risk Disease

Abstract Abstract 1745 Poster Board I-771 Introduction Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress towards acute myeloid leukemia (AML). The progression of the disease may be associated with genetic or epigenetic alterations and a possible change in protein function. MDM2/P53 pathway plays an important role in the control of apoptotic and proliferation mechanisms. Single nucleotide polymorphisms (SNPs) were identified in the TP53 and MDM2 genes. MDM2 SNP309 results in higher levels of MDM2 and attenuates p53 pathway. The SNP in codon 72 of the TP53 gene results in either a C or G nucleotide and leads to either Proline (Pro) or Arginine (Arg), respectively. The Arg variant has been shown to be more potent in apoptosis induction and the Pro variant has been shown to be better in inducing cell-cycle arrest and to have a greater ability to repair damaged-DNA. The aim of the present study was to investigate the incidence of MDM2 and TP53 polymorphisms in MDS patients and to correlate the frequency of these SNPs with age, neutrophis and platelets at diagnosis, low risk versus high risk disease according to FAB (RA and RARS versus AREB and AREBt) and IPSS (Low and Int-1 versus Int-2 and high), cytogenetic risk (low versus intermediate and high risk), disease progression and overall survival. Patients and Methods We studied 103 healthy controls and 63 patients with MDS. According to FAB, patients were distributed as follows: 43 RA, 10 RARS, 7 RAEB, 1 RAEBt and 2 CMML. The median follow-up time was 40 months (range 2 – 159 months). Samples were obtained from peripheral blood or bone marrow and were screened for the presence of polymorphisms MDM2 SNP309 and TP53 SNPArg72Pro, by PCR analysis with specific primers and appropriate restriction enzyme. Appropriate statistical analyses were used for each test. Results The frequencies of genotypes for MDM2 SNP309 and TP53Pro7Arg were similar between MDS and healthy controls; MDM2 SNP309: 51% vs 53%, for TT, 38% vs 32% for TG, and 11% vs 15% for GG, TP53Pro7Arg: 47.5% vs 44%, for Arg/Arg, 47,5% vs 42% for Pro/Arg, and 5% vs 14% for Pro/Pro. No differences were observed between MDS patients with presence or absence of the polymorphisms in relation to age, neutrophis and platelets at diagnosis, low risk versus high risk disease according to FAB, IPSS and cytogenetic risk, disease progression and overall survival. Conclusions MDM2 and TP53 polymorphisms have been described to affect the risk for cancer, onset age and overall survival in solid tumors and leukemias. This was the first study to report these SNPs in MDS and leads to believe that these polymorphisms are not associated with risk for the disease and with clinical data. Keywords: MDM2, p53, myelodysplasia, polymorphisms Disclosures No relevant conflicts of interest to declare.

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GDF11 Increased in Patients with Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v126.23.5224.5224 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5224-5224

Author(s):

Yu Han ◽

Huaquan Wang ◽

Zonghong Shao

Keyword(s):

Bone Marrow ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Peripheral Blood ◽

Conflicts Of Interest ◽

Risk Group ◽

Low Risk ◽

Mean Corpuscular Hemoglobin ◽

Corpuscular Hemoglobin ◽

Normal Controls

Abstract Objective To analyze the concentration of growth differentiation factor 11(GDF11) in peripheral blood of patients with myelodysplastic syndrome (MDS), so as to evaluate the relationships between these changes and erythropoiesis functions and to explore the role of GDF11 in the pathogenesis of MDS. Methods The concentration of GDF 11 in peripheral blood was detected by enzyme-linked immuno sorbent assay in 44 MDS patients and 10 normal controls from September 2014 to June 2015 at our hospital. The percentage of nucleated erythrocyte (CD235a) in bone marrow was detected by flow cytometry. The correlation between these changes and erythropoiesis functions, including red blood cell count, hemoglobin, reticulocyte (RET%), hematokrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular-hemoglobin concentration (MCHC) and late erythroblast in bone marrow were evaluated. Results (1)The concentration of GDF11(128.67±47.62)in high-risk MDS patients was significantly higher than that of low-risk MDS patients (65.96±36.55,p<0.01)and higher than that of normal controls (29.76±10.10,p<0.01); The concentration of GDF11 in low-risk MDS patients was significantly higher than that of normal controls (p<0.05). (2) The expression of CD235a in high-risk group(38.49±5.42)was not different with that in low-risk group(42.64±7.36, p>0.05). (3)In high-risk MDS patients, the expression of GDF11 was negatively correlated with Hb, RET%, RBC, MCHC, Hct in peripheral blood and late erythroblast, CD235a+ cells in bone marrow(r=-0.437,r=-0.428,r=-0.444,r=-0.553,r=-0.661,r=-0.436,r=-0.52,all p<0.05),and the expression of GDF11 was positively correlated with MCV(r=0.52, p <0.05),but it was not correlated with MCH (p >0.05).(4) In low-risk MDS patients, the expression of GDF11 was negatively correlated with Hb, RET% (r=-0.491Ar=-0.606,both p<0.05),it was not correlated with RBC, MCHC, MCV, MCH, Hct, late erythroblast and CD235a+ cells (all p>0.05). Conclusion GDF11 increased in patients with MDS and it was negatively correlated with late erythropoiesis. Disclosures No relevant conflicts of interest to declare.

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Genetic Mutation in Cytopenic Patients: Distinctive Genomic Profile between Preclinical Vs. Clinical Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2019-128037 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5429-5429

Author(s):

Kritanan Songserm ◽

Amornchai Suksusut ◽

Sunisa Kongkiatkamon ◽

Kitsada Wudhikarn ◽

Chinnachote Teerapakpinyo ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Somatic Mutations ◽

Conflicts Of Interest ◽

Gene Mutations ◽

Genetic Alterations ◽

Genetic Mutation ◽

Low Risk ◽

Genomic Profile

Genetic mutation in cytopenic patients: Distinctive genomic profile between preclinical vs. clinical myelodysplastic syndrome. Introduction Myelodysplastic syndromes (MDS) are heterogeneous groups of clonal hematopoietic disorders. The current diagnosis of MDS is based on morphologic assessments of dysplasia which are subjected to inter-observer variability and cytogenetic abnormalities which are frequently absent. Somatic mutations in myeloid-related genes have been identified in MDS. However, they are also found in idiopathic cytopenia of unknown significance (ICUS) that shows no significant dysplasia. Therefore, we aimed to explore the clinical implications of genetic mutations in ICUS and compared with MDS. The secondary objective was to find association between degree of dysplasia and somatic mutations. Materials and Methods The patients with peripheral cytopenia ≥1 lineage (ANC < 1,800/mm3, hemoglobin < 10 gm/dL, platelet < 100x109/mL) without explainable causes were enrolled. Bone marrow aspirates were evaluated independently by 2 hematologists. Of note, dysplasia are defined by WHO 2008 classification (eg. Erythroid lineage: ring sideroblasts, megaloblastoid change; granulocytic lineage: hypogranularity, pseudopelger-huet anomaly; megakaryocytic lineage: hypolobate, micro-megakaryocyte). The significant dysplasia cut off was 10% in single lineage or more. If there was a discrepancy, the third hematologist would help to reach the final consensus. We extracted DNA from bone marrow and performed next generation sequencing (NGS) that targeted 143 myeloid-related genes. Results Forty-eight patients were enrolled in this study. The median age at diagnosis was 70 years (71-96). Results of bone marrow examinations were categorized by morphology into 3 groups; non-significant dysplasia (dysplasia < 10%) 27%, low risk MDS (IPSS-R ≤3.5) 42% and high-risk MDS/sAML (IPSS-R >3.5/Blast≥20% in BM or peripheral blood) 31%. Most of cases (77%) carried normal cytogenetics while other genetic alterations were complex chromosome (6%), -Y (6%), del(5q) (4%), trisomy 8 (2%), del(20q) (2%), i(17q) (2%). Thirty from 48 cases (62%) harbored more than 1 somatic mutation. Twenty-eight gene mutations were identified. Mutations were detected 1.6 mutation per 1 patient in average. Most frequent somatic mutations were ASXL1:10/80 (12%), TET2:9/80 (11%), MFDS11: 6/80 (7%), TP53:6/80 (7%), and RUNX1:5/80 (6.25%). The proportions of cases with somatic mutations were not different across the groups (no dysplasia 50%, non-significant dysplasia 80% and significant dysplasia 62%). According to mutation types in each group, mutations in epigenetic pathways were the most frequent mutations across all patient subgroups (ICUS 64.7%, low-risk MDS 51.8 %, and high-risk MDS 52.5%). Mutations in transcription factor were predominated in MDS (18.5% and 25.0% in low-risk and high-risk MDS, respectively) compared to ICUS (11.7%). Individual average frequency of gene mutations was significantly different between disease subtype (high risk MDS 2.7 gene/person, low risk MDS 1.1 gene/person, ICUS 1.3 gene/person (P=.038). Higher variant allele frequency (VAF) of mutated genes was significantly observed in high risk MDS (38.3%) compared to low risk MDS (30.8%) and preclinical MDS (29.0%) (P=.03). Conclusion In conclusion, molecular profiling was significantly different between preclinical MDS and MDS groups in terms of types of somatic mutations and VAF. This unique contrast could be used to distinguish between preclinical MDS and clinically significant MDS. In contrast, degree of marrow dysplasia was not associated with number of gene mutations in this study. Prediction for clinical consequent of somatic mutations in CCUS requires long term follow up. Disclosures No relevant conflicts of interest to declare.

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Detection of CD55- and CD59-Negative Immature Reticulocytes May Improves Sensitivity/Specificity to Identify a Minor Population of PNH-Type Cells in Patients with Myelodysplastic Syndrome/Aplastic Anemia

Blood ◽

10.1182/blood.v118.21.4373.4373 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4373-4373

Author(s):

Naoshi Obara ◽

Shoko Satoh ◽

Yasushi Okoshi ◽

Shigeru Chiba ◽

Haruhiko Ninomiya

Keyword(s):

Myelodysplastic Syndrome ◽

Red Blood Cells ◽

Aplastic Anemia ◽

Peripheral Blood ◽

Blood Cells ◽

Mononuclear Cells ◽

Conflicts Of Interest ◽

Normal Subjects ◽

Good Alternative ◽

Minor Population

Abstract Abstract 4373 [Background] Paroxysmal nocturnal hemogloblinuria (PNH) is a hemolytic disease characterized by complement-sensitive red blood cells (RBC). Sometimes, a tiny amount of PNH-type, i.e., CD55- or CD59-negative, red blood cells as well as neutrophils can be detected in peripheral blood from patients with myelodysplastic syndrome (MDS)/ aplastic anemia (AA). It has been reported that the presence of PNH-type cells is correlated with a good response to immunosuppressive therapy foe these disease. However, the ratio of PNH-type RBCs to normal RBCs is always underestimated because PNH-type red blood cells have a shortened life span in the circulation, and there are some patients who have very low number of circulating granulocytes. [Metods] Peripheral blood was obtained from 37 patients with MDS or AA and 30 normal subjects. Mononuclear cells were then stained with antibodies against CD55, CD59, and CD71, and analyzed by a flowcytometer. Subsequently, CD55 and CD59-negative and CD71-positive reticulocytes, representing an immature fraction of reticulocytes, were identified. Sensitivity and specificity were compared for the detection of PNH-type immature reticulocytes with those evaluated by a PNH-type RBC- and granulocyte-detecting method. [Results and discussion] All 30 normal subjects were negative when the cut-off value for CD55 and CD59-negative and CD71-positive reticulocytes was set at 0.008%. With this cut-off value, PNH-type immature reticulocytes were detected in 18 out of 37 MSA/AA patients. When the cut-off values for PNH-type RBCs and granulocytes were set at 0.005% and 0.01%, respectively, in accordance with the original report by Sugimori, et al, 16 and 18 cases among 37 MDS/AA patients were positive for PNH-type RBCs and granulocytes, respectively. All the 16 cases positive for PNH-type RBCs were also positive for PNH-type granulocytes and immature reticulocytes, while 2 cases negative for PNH-type RBCs were evaluated to be positive for both PNH-type granulocytes and immature reticulocytes. All the cases positive for granulocytes were also positive for immature reticulocytes, and vice versa. These observations indicate that the method to detect minor population of PNH-type immature reticulocytes is feasible and comparable with that to detect PNH-type granulocytes, and could be superior to the PNH-type RBC-detection method in terms of sensitivity, without reducing specificity. If the evaluation of PNH-type granulocytes is difficult, PNH-type immature reticulocytes may be a good alternative to be evaluated. Disclosures: No relevant conflicts of interest to declare.

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Efficacy and Toxicity Of Decitabine Versus CHG Priming Regimen In Patients With Higher Risk Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v122.21.2789.2789 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2789-2789 ◽

Cited By ~ 1

Author(s):

Lingyun Wu ◽

Xiao Li ◽

Feng Xu ◽

Chunkang Chang ◽

Qi He ◽

...

Keyword(s):

Overall Survival ◽

Myelodysplastic Syndrome ◽

Low Dose ◽

Conflicts Of Interest ◽

International Prognostic Scoring System ◽

Overall Response ◽

Clinical Responses ◽

Myelomonocytic Leukemia ◽

Low Dose Cytarabine ◽

Count Recovery

Abstract Objectives Decitabine has been approved for the treatment of myelodysplastic syndrome (MDS). CHG regimen (low-dose cytarabine and homoharringtonine in combination with granulocyte colony-stimulating factor (G-CSF)) has been reported to be effective in higher risk MDS patients. The comparative efficacy of these 2 forms of treatment in MDS is unknown. The objective of the current study was to compare the efficacy and toxicity of decitabine and CHG regimen in higher risk MDS. Methods We compared lower intensity decitabine with CHG regimen in higher risk MDS (International Prognostic Scoring System (IPSS) intermediate- or high-risk or chronic myelomonocytic leukemia (CMML)). Decitabine was given 20 mg/m2 intravenously over 1 hour daily for 5 days. CHG chemotherapy consisted of an intravenous continuous infusion of low-dose cytarabine (25 mg/d) (days 1–14) and homoharringtonine (1 mg/d) (days 1–14) in combination with G-CSF (300 μg/d) by subcutaneous injection from day 0 until peripheral neutrophil count recovery to 2.0× 109/L. The complete remission (CR), overall response (OR), overall survival and toxicity was compared between the two groups. Results A total of 132 patients with higher risk MDS were enrolled in this study, 70 cases in decitabine group and 62 cases in CHG group. The CR rate was 25.7% with decitabine, compared to 32.3% with CHG regimen (p=0.538). The overall response rate (including CR, partial remission (PR), marrow CR and hematological improvement (HI)) between the two groups was also not significantly different (68.6% with decitabine and 58.1% with CHG regimen) (p = 0.209). Overall survival was not significantly different between the two groups (median survival: 18.2 months in decitabine group vs 15.3 months in CHG group; p=0.176). Grade 4 neutropenia occurred more frequently with decitabine (58.3 %) than with CHG regimen (32.3 %) (p = 0.004). Grade 4 thrombocytopenia was also more frequently with decitabine (61.4 %) than with CHG regimen (38.7 %) (p = 0.009). Conclusions Both decitabine and CHG regimens were effective in treating patients with higher risk MDS. The two regimens did not differ in terms of clinical responses. However, decitabine showed severer hematological toxicities than CHG regimen. This trial was registered at www.clinicaltrials.gov as ChiCTR-ONC-11001501. Disclosures: No relevant conflicts of interest to declare.

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Decitabine Induces Ferroptosis in Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2019-122000 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2995-2995 ◽

Cited By ~ 1

Author(s):

Qi Lv ◽

Huaquan Wang ◽

Zonghong Shao ◽

Limin Xing ◽

Lanzhu Yue ◽

...

Keyword(s):

High Risk ◽

Myelodysplastic Syndrome ◽

Iron Overload ◽

Cell Viability ◽

Cell Lines ◽

Conflicts Of Interest ◽

Inhibitory Effect ◽

Low Risk ◽

Ferritin Concentration ◽

The Difference

Decitabine is one of the classical demethylation drugs in the treatment of myelodysplastic syndrome (MDS); however, the exact mechanism of decitabine has not been fully understood. Such knowledge is essential to develop mechanism-based, targeted approaches in the treatment of MDS. Here, we show that decitabine-induced ROS raise leads to ferroptosis in myelodysplastic syndrome cells. To investigate whether decitabine could induce ferroptosis in MDS cells and its mechanism, cell lines SKM-1 and MUTZ-1 were co-cultured with decitabine and ferroptosis inhibitor (ferrostatin-1), respectively. CCK-8 assay was used to detect the effects of drugs on cell viability. At the same time, we observed whether necroptosis inhibitor (necrostatin-1), apoptosis inhibitor (z-vad-fmk) and iron chelating agent (DFO) could reverse the inhibitory effect of decitabine on MDS cells. The results showed that, necrostatin-1 could increase the cell viability significantly. The growth-inhibitory effect of decitabine on SKM-1 and MUTZ-1 could be partially reversed by ferrostatin-1, DFO and necrostatin-1. The effect of ferrostatin-1 is the most significant. Ferroptosis inducer (erastin) could increase the cytotoxicity of decitabine at different concentrations. Flow cytometry was used to detect the ROS level. Biochemical method was used to detect the intracellular glutathione (GSH) level and glutathione peroxidase (GPXs) activity. The results showed that, the level of GSH and the activity of GPXs decreased while the ROS level increased in SKM-1 and MUTZ-1 cell lines when treated with decitabine, which could all be inhibited by ferrostatin-1. The iron overload model of C57BL/6 mice was next constructed to observe whether iron overload could induce ferroptosis. The results showed that, the concentration of hemoglobin in peripheral blood of mice was negatively correlated with intracellular Fe2+level and ferritin concentration. Iron overload led to decreased viability of bone marrow mononuclear cells (BMMNCs), which was negatively correlated with intracellular Fe2+level. Ferrostatin-1 and necrostatin-1 partially reversed the decline of cell viability in iron overload groups, and erastin promoted the proliferation of BMMNCs in iron overload mice. The level of GSH and the activity of GPXs decreased while the ROS level increased in BMMNCs of iron overload mice compared with the control. DFO could increase the level of GSH in iron overload mice. Ferrostatin-1, z-vad-fmk and DFO could increase the GPXs activity of BMMNCs in iron overload mice. Finally, to explore the role of ferroptosis in the pathogenesis of low-risk and high-risk MDS patients respectively, the BMMNCs were obtained from low-risk MDS, high-risk MDS and lymphoma patients respectively and co-cultured with decitabine and above-mentioned inhibitors. The results showed that, ferrostatin-1, necrostatin-1, z-vad-fmk could significantly reverse the inhibitory effect of decitabine of low-risk MDS patients. Necrostatin-1 and Fer-1 could also reverse the inhibitory effect of decitabine of high-risk MDS patients, although the difference was not significant. Decitabine could significantly increase the ROS level in both MDS groups, which could both be inhibited by ferrostatin-1 or promoted by erastin. Ferrostatin-1, necrostatin-1 and z-vad-fmk could significantly reverse the inhibitory effect of decitabine on GSH level in low-risk MDS patients. Ferrostatin-1 and necrostatin-1 could significantly reverse the inhibitory effect of decitabine on GSH level in high-risk MDS patients. Erastin combined with decitabine could further reduce the GSH level, and the difference was significant in high-risk MDS group. For low-risk MDS group, GPXs activity of ferrostatin-1 combined with decitabine and z-vad-fmk combined with decitabine groups were significantly higher than that of decitabine group. For high-risk MDS group, the activity of GPXs of ferrostatin-1 combined with decitabine and necrostatin-1 combined with decitabine groups were significantly higher than that of decitabine group. Erastin could further decrease the activity of GPXs when compared with decitabine group. Our findings reveal a novel therapeutic mechanism of decitabine and may open a new window for therapeutic targeting in the treatment of MDS. Figure Disclosures No relevant conflicts of interest to declare.

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Myelodysplastic Syndrome Patients Younger Than 50 Years: Epidemiological Data and Clinical Features

Blood ◽

10.1182/blood.v116.21.4976.4976 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4976-4976

Author(s):

Massimo Breccia ◽

Paola Finsinger ◽

Roberto Latagliata ◽

Laura Cannella ◽

Giuseppina Loglisci ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Clinical Features ◽

Who Classification ◽

Conflicts Of Interest ◽

Low Risk ◽

Refractory Anemia ◽

Monosomy 7 ◽

Younger Patients ◽

Male Predominance

Abstract Abstract 4976 Less than 10% of patients with myelodysplastic syndromes (MDS) are younger than 50 years. It is yet unknown the exact role of prognostic scoring systems in this subset, because clinical relevant data were derived from large series of elderly patients. Undefined are also the clinical features of younger patients exposed to potential mutagens due to occupational reasons. Aim of our study was to report and analyze one of the largest series of young MDS, in terms of prognosis and overall survival. Ninety-one patients with MDS aged less than 50 years consecutively diagnosed and conservatively treated form July 1983 and December 2009 are reported and compared with the whole population of elderly MDS patients. Median age at diagnosis was 44 years (range 21–50). Sex M/F ratio was 0.68. According to FAB criteria there were 56 patients with refractory anemia (RA), 3 with refractory anemia with ringed sideroblasts (RARS), 22 with refractory anemia with excess of blasts (RAEB), 5 with refractory anemia with excess of blasts in transformation (RAEB-t) and 5 with chronic myelomonocytic leukemia (CMML). Revised 2008 WHO classification reclassified low risk patients as pure RA (only 8 patients), refractory unilineage cytopenia (RCUD, refractory thrombocytopenia, 2 patients) and refractory cytopenia with multilineage dysplasia (RCMD, 45 patients). RAEB patients were classified as RAEB-1 (11 patients) and RAEB-2 (11 patients). Eighty-five patients had evaluable cytogenetic analysis: the most frequent karyotypic change was trisomy 8 (10.5%), followed by monosomy 7 (5%). Among this cohort, 23 patients had occupational exposure to potential mutagens (more frequently benzene and its derivates and solvents): in the exposed group there was a male predominance (16/7), a higher frequency of RCMD (52%) and a higher frequency of monosomy 7 (13%). At a median follow-up of 72 months, 22 patients (24 %) evolved to acute leukemia: among the exposed cohort, a higher frequency of AML evolution was observed (39% vs 19% of non-exposed). IPSS categorization showed 30 patients as low risk, 35 patients as intermediate-1, 14 patients as intermediate-2 and 4 patients as high risk, with intermediate-1 risk being the more commonly detected. Both the intermediate-2 and high risk according to IPSS, together with age cut-off above 40 years, male sex, FAB and WHO high-risk definition and exposure to carcinogens during lifetime, were found to be predictive of a shorter overall survival. Comparison of younger patients with elderly MDS population followed in the same Institute over the same period of time, showed statistical differences in survival (88 months for younger vs 24 months for elderly MDS, p<0.0001), sex ratio (p=0.002), FAB and WHO classification (both p=0.03). These results suggest that MDS in patients aged less than 50 years could be identified as a distinct category and that aggressive approaches should rarely be recommended for younger patients belonging to the low and intermediate-I risk groups. Disclosures: No relevant conflicts of interest to declare.

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