[Relationship between clinical characteristics and myelodysplastic syndrome patients with isocitrate dehydrogenase gene mutations].

OBJECTIVE: To assess the prevalence and clinical characteristics of isocitrate dehydrogenase 1 and 2 (IDH 1 and IDH2) gene mutations in myelodysplastic syndrome (MDS) patients. METHODS: Pretreatment bone marrow specimens were enriched for mononuclear cells in 108 adult patients with de novo MDS from January 2006 to August 2012. Genomic DNA was extracted from mononuclear cells. And PCR and direct sequencing were performed to sequence exon 4 of IDH gene. RESULTS: IDH mutations were discovered in 11 MDS patients (10.19%, 11/108) and all were heterozygous. The frequencies of IDH1 and IDH2 mutations were 5.56% (6/108) and 4.63% (5/108) respectively. Only one type of IDH1 mutation (c.394C→, p.R132C) was identified in our cohort. All IDH2 mutations caused the changes of R140 (c.419G→A, p.R140Q). However IDH2 R172 mutation was not detected. The combined mutations of IDH1 and IDH2 were not simultaneously observed in the same patient. The prevalence of IDH mutation was higher in advanced-stage MDS than those early-stage MDS patients. Mutated and wild-type groups had significantly difference in bone marrow blast percentage (median 12.5% vs 6.0%, P = 0.013) at diagnosis, but not in white blood cell count, hemoglobin level and platelet count, etc. In the normal karyotype group, the frequencies of IDH mutations were as similar as those in the abnormal karyotype group (10.61% (7/66) vs 10.00% (4/40), P > 0.05). The median follow-up time was 472 d, our data indicated that IDH mutations were correlated with poor overall survival (median time 512 vs 740 d, P = 0.017). IDH mutations were also an inferiorly predictive factor in the intermediate-1 group patients of International Prognostic Scoring System (IPSS) (median survival time 512 d vs not reached, P = 0.038). There was also better efficacies than other treatments in IDH mutation positive patients (median survival time 623 vs 165 d, P = 0.049). CONCLUSIONS: IDH mutation is a vital biomarker for better risk stratification of MDS patients with and improving IPSS. Hypomethylation agents may be effective for treating IDH mutation positive patients.

Oral arsenic and retinoic acid for high-risk acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has become curable over 95% patients under a complete chemo-free treatment with all-trans retinoic acid (ATRA) and arsenic trioxide in low-risk patients. Minimizing chemotherapy has proven feasible in high-risk patients. We evaluated oral arsenic and ATRA without chemotherapy as an outpatient consolidation therapy and no maintenance for high-risk APL. We conducted a multicenter, single-arm, phase 2 study with consolidation phases. The consolidation therapy included Realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary end point was the disease-free survival (DFS). Secondary end points included measurable resident disease, overall survival (OS), and safety. A total of 54 participants were enrolled at seven centers from May 2019. The median age was 40 years. At the median follow-up of 13.8 months (through April 2022), estimated 2-year DFS and OS were 94% and 100% in an intention-to-treat analysis. All the patients achieved complete molecular remission at the end of consolidation phase. Two patients relapsed after consolidation with a cumulative incidence of relapse of 6.2%. The majority of adverse events were grade 1-2, and only three grade 3 adverse events were observed. Oral arsenic plus ATRA without chemotherapy was active as a first-line consolidation therapy for high-risk APL.Trial registration: chictr.org.cn number, ChiCTR1900023309.

Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms.

Decitabine (DAC) is commonly used for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Previous studies have indicated DAC sequentially combined with idarubicin was an effective treatment for myeloid neoplasms. Therefore, a clinical study was conducted of the sequential combination of DAC followed by low-dose idarubicin/cytarabine in high-risk myeloid neoplasms. A total of 30 patients with a diagnosis of high-risk MDS, AML evolving from MDS or relapsed/refractory AML were enrolled in the study. DAC was administered 20 mg/m(2) daily for 3 consecutive days. Idarubicin (3 mg/m(2)/day) was administered 24 h after the last administration of DAC for 5-7 consecutive days, combined with cytarabine (30 mg/m(2)/day) for 7-14 days. The overall complete remission rate was 66.67%. The results demonstrate that epigenetic priming with decitabine followed by low-dose idarubicin/ytarabine has an increased anti-leukemia effect compared to traditional chemotherapy in high-risk myeloid neoplasms.

Impact of Chemotherapy Delay on Overall Survival for AML with IDH1/2 Mutations: A Study in Adult Chinese Patients.

The effect of time from diagnosis to treatment (TDT) on overall survival of patients with acute myeloid leukemia (AML) remains obscure. Furthermore, whether chemotherapy delay impacts overall survival (OS) of patients with a special molecular subtype has not been investigated. Here, we enrolled 364 cases of AML to assess the effect of TDT on OS by fractional polynomial regression in the context of clinical parameters and genes of FLT3ITD, NPM1, CEBPA, DNMT3a, and IDH1/2 mutations. Results of the current study show IDH1/2 mutations are associated with older age, M0 morphology, an intermediate cytogenetic risk group, and NPM1 mutations. TDT associates with OS for AML patients in a nonlinear pattern with a J shape. Moreover, adverse effect of delayed treatment on OS was observed in patients with IDH1/2 mutations, but not in those with IDH1/2 wildtype. Therefore, initiating chemotherapy as soon as possible after diagnosis might be a potential strategy to improve OS in AML patients with IDH1/2 mutations.

Antitumor activity of CDA-â ¡, a urinary preparation, on human multiple myeloma cell lines via the mitochondrial pathway.

Cell differentiation agent II (CDA­II) is a DNA methyltransferase inhibitor isolated from healthy human urine. In the present study, the antitumor activity of CDA­II on human multiple myeloma (MM) cell lines via the mitochondrial pathway was first revealed. The human MM cell lines were exposed to CDA­II. Cytotoxicity, caspase activation, apoptosis and the effects on the mitochondrial pathway were assessed. CDA­â…¡ was capable of decreasing the depolarized mitochondrial membranes and activating caspase­3 and ­9 and poly (ADP­ribose) polymerase in MM cells treated with CDA­II. CDA­II induced caspase­dependent cell death accompanied by a significant decrease in X-linked inhibitor of apoptosis protein (XIAP), survivin and Mcl­1 levels. The caspase­3 inhibitor, Z­DEVD­FMK, inhibited CDA­II­induced apoptosis. CDA­II potently increased the Bax levels, decreased the Bcl­2/Bax ratio and decreased the expression of the downstream targets of NF­κB. In conclusion, the results of the present study demonstrated that CDA­II treatment leads to the inhibition of p65 nuclear localization and potently induces caspase­dependent apoptosis in MM cells mediated through the mitochondrial pathway at low nanomolar concentrations. These results indicate that CDA­II is a novel inhibitor of NF­κB activity, with notable antimyeloma efficacy. This study provides a rationale for the clinical investigation of CDA­â…¡ in human MM.

Novel influenza A (H1N1) in patients with hematologic disease.

Patients with hematologic disease are likely to be at increased risk for infection with influenza. We retrospectively analyzed 11 cases of patients with hematologic disease who were infected with pandemic H1N1 virus in our department, including their clinical manifestations, laboratory and imaging findings, outcomes of antiviral therapy, and factors associated with mortality. Notably, nine patients had lower respiratory tract disease. Five patients progressed to respiratory failure and eventually died, despite treatment with antivirals and/or corticosteroids and/or mechanical ventilation. We concluded that H1N1 2009 infection was associated with a severe course and high rate of mortality in patients with hematologic disease, and early diagnosis and antiviral treatment were important to reduce the rate of severe complications and mortality.