Yanling Ren

Clinical characteristics of T-cell lymphoma associated with hemophagocytic syndrome: Comparison of T-cell lymphoma with and without hemophagocytic syndrome

T-cell lymphoma-associated hemophagocytic syndrome (T-LAHS) has been frequently reported in Asian countries and is considered with extremely poor prognosis. To summarize its clinical characteristics and explore its early diagnosis and treatment, we retrospectively analyzed the records of 113 patients with aggressive T cell lymphoma, of which 28 were associated with LAHS. According to WHO classification (2001), 22 cases were classified into peripheral T-cell lymphoma (unspecified), 2 into extranodal NK/T-cell lymphoma, and 4 into systemic anaplastic large cell lymphoma. The median survivals of the LAHS and no-LAHS groups were 40 days and 8 months, respectively. The elevating rates of serum lactate dehydrogenase (LDH) (100% vs. 55%), ferritin (100% vs. 64%), fasting triglycerides (79% vs. 43%), and hypofibrinogen (43% vs. 14%)levels were higher in the LAHS group than in the no-LAHS group (P < 0.05), so were bone marrow involvement (57% vs. 32%, P < 0.05)and liver dysfunction (40% vs. 13%, P < 0.05). Eleven of the 28 LAHS patients did not receive any chemotherapy, and 14 received CHOP regimen as initial chemotherapy. Three patients in critical conditions were given plasma exchange and gained the chance of initial chemotherapy. We suggest that in patients presenting with fever, hepatosplenomegaly, cytopenia, and constantly increasing levels of serum LDH, CA125, ferritin, transglutaminase, and β2-microglobulin, T-LAHS should be taken into account. Repeating biopsies of multiple parts of bone marrow may help diagnosis. The therapeutic result of chemotherapy alone or combined for T-LAHS was discouraging and the survival time of most cases was no more than 1 year. Plasmapheresis as initial therapy is worth considering in critical cases.

Homoharringtonine affects the JAK2-STAT5 signal pathway through alteration of protein tyrosine kinase phosphorylation in acute myeloid leukemia cells.

Objectives:  Homoharringtonine (HHT) was efficient in therapying patients with acute myeloid leukemia (AML) in China, but little is known about the mechanism of its action. As the abnormal activation of JAK2 associated pathway is important to AML, we try to explore the effect of HHT on JAK2‐STAT pathway in AML cells, thus supplying theoretical basis for wider use of HHT.

Clinicopathological study on peripheral T-cell non-Hodgkin lymphoma with bone marrow involvement: a retrospective analysis from China

We reviewed 173 patients with an initial diagnosis of peripheral T-cell non-Hodgkin lymphoma (PTCL) and compared the patients with bone marrow involvement (BMI) to those without to have a better understanding of the clinical characteristics, treatments, survival and prognosis of PTCLs with BMI. We found that 40% (70/173) of the patients had BMI, and its frequency was 64% in angioimmunoblastic T-cell lymphoma (TCL), 46% in PTCL unspecified, 29% in anaplastic large T-cell lymphoma, 23% in extranodal NK/T-cell lymphoma and 13% in enteropathy-type TCL. In the BMI group, 36% of patients had lymphoma-associated hemophagocytic syndrome (LAHS), compared with 8% of the patients without BMI (8/103, P < 0.001). The estimated 1-year overall survival (OS) rates of patients with LAHS in the BMI and non-BMI groups were 5 and 49%, respectively. The increased levels of lactate dehydrogenase, fasting triglycerides and β2-microglobulin between the BMI and non-BMI groups were not significantly different, but ferritin increased significantly and liver dysfunction-related diseases were seen more in the BMI group. As much as 51% of patients of the BMI group had anemia, compared with 27% of the patients without BMI (P = 0.001). The estimated 2-year OS rates in the two groups were 10 and 34%. The estimated 2-year OS rate of the 67 patients with BMI, who did not lose to follow-up, was 22%, compared with 38% in the non-BMI group. The median survival times of the 2 groups were 120 and 356 days. The estimated 2-year OS rate of patients treated by CHOP regimen was 9%, compared with 51% of those with intensive chemotherapy, with a significant difference (log rank P = 0.0008). The median survival time of the 14 patients subjected to chemotherapy combined with l-asparaginase was 365 days and that of the 7 patients undergoing hemopoietic stem cell transplantation (HSCT) was 575 days. A total of 3 patients in a critical condition underwent plasmapheresis as initial therapy and achieved stable condition. We conclude that patients with PTCLs with BMI on initial diagnosis usually have hemaphagocytic syndrome and poor prognosis. BMI without lymphadenopathy is a patent clinical feature in most PTCLs. Patients with anemia on initial diagnosis in the BMI group usually have poor prognosis than those without. Intense chemotherapy, addition of l-asparaginase in chemotherapy and HSCT are comparatively efficient treatments of PTCLs. For patients in critical conditions, plasmapheresis before chemotherapy would lower the risk and improve the tolerance to chemotherapy.

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

Abstract 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/m2 daily for 3 consecutive days. Idarubicin (3 mg/m2/day) was administered 24 h after the last administration of DAC for 5–7 consecutive days, combined with cytarabine (30 mg/m2/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.

PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation

Patients with secondary acute myeloid leukemia (sAML) arising from myelodysplastic syndromes have a poor prognosis marked by an increased resistance to chemotherapy. An urgent need exists for adjuvant treatments that can enhance or replace current therapeutic options. Here we show the potential of LB100, a small-molecule protein phosphatase 2 A (PP2A) inhibitor, as a monotherapy and chemosensitizing agent for sAML using an in-vitro and in-vivo approach. We demonstrate that LB100 decreases cell viability through caspase activation and G2/M cell-cycle arrest. LB100 enhances daunorubicin (DNR) cytotoxicity resulting in decreased xenograft volumes and improved overall survival. LB100 profoundly upregulates miR-181b-1, which we show directly binds to the 3′ untranslated region of Bcl-2 mRNA leading to its translational inhibition. MiR-181b-1 ectopic overexpression further diminishes Bcl-2 expression leading to suppression of sAML cell growth, and enhancement of DNR cytotoxicity. Our research highlights the therapeutic potential of LB100, and provides new insights into the mechanism of LB100 chemosensitization.

Diagnosis and management of acquired thrombotic thrombocytopenic purpura in southeast China: a single center experience of 60 cases

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening thrombotic microangiopathy. This study aimed to provide a profile of the diagnosis and management of patients with acquired TTP collected in 10 years in a single center in southeast China. A total of 60 patients diagnosed with acute acquired TTP from March 2005 to August 2015 were enrolled. Among the 60 patients, 52 patients presented with their first episodes, and eight patients had two or more episodes. The median age at presentation was 49 (range, 17 to 78) years with a female predominance (male:female ratio, 1:1.60). ADAMTS 13 activity were analyzed in 43 patients, among whom 33 (76.7%) patients had a baseline level of < 5%. Mortality was 30%. Plasma exchange (PEX) was performed in 62 of 69 (89.9%) episodes. Corticosteroids were administered in 54 of 69 (78.3%) episodes. Other immunosuppressants (e.g., vincristine, cyclosporine, and cyclosporin) were used in 7 of 69 (10.1%) episodes. Rituximab was documented in 4 patients with refractory/relapsed TTP for 5 episodes, showing encouraging results. In conclusion, the diagnosis of TTP depended on a comprehensive analysis of clinical data. Plasma ADAMTS13 activity assay helped confirm a diagnosis. PEX was the mainstay of the therapy, and rituximab can be used in relapsed/refractory disease.

Successful treatment of Candida tropicalis osteomyelitis with Micafungin in a leukemia patient

The incidence of invasive candidal infection is increasing. The widespread use of central intravascular catheters, invasive procedures, immunosuppression, diabetes mellitus, total parenteral nutrition, broad-spectrum antibiotics and drugs abuse predispose patients to the infection. Eye, kidney, liver, skin, cardiac and brain infections are the most common site of invasive candidiasis while vertebral osteomyelitis is rare. Most Candida vertebral osteomyelitis is caused by Candida albicans. Less common organisms include C. tropicalis, C. glabrata and C. parapsilosis [1]. Both amphotericin B and the azoles have a role in the treatment, but treatment failure with either agent had been reported [2], [3]. Micafungin belongs to echinocandins, and interferes with the synthesis of fungal cell wall. We report a Candida tropicalis infection manifested with osteomyelitis following a previous candidemia in a leukemia patient who was successfully treated by Micafungin.

Clinical and biological characteristics of acute myeloid leukemia with 20–29% blasts: a retrospective single-center study

Abstract It is controversial whether acute myeloid leukemia (AML) patients with 20–29% bone marrow (BM) blasts should be considered AML or myelodysplastic syndromes (MDS). We retrospectively studied 382 patients, including 108 AML with 20–29% BM blasts (AML20–29), 210 AML with ≥30% BM blasts (AML ≥ 30), and 64 MDS with 10–19% BM blasts (MDS-EB2). We found that AML20–29 were more similar to MDS-EB2 in terms of advanced age, less blood count, the increased presence of poor-risk cytogenetics. The frequency of mutated genes in AML20–29 had both the characters of AML and MDS. Median overall survival of AML20–29 and MDS-EB2 were similar and shorter than those of AML ≥ 30 (p = .045). Multivariate analysis showed inferior survival with increased age, low platelet count and FLT3 mutations. Our findings suggest that AML20–29 have clinical features more similar to MDS than AML.

Isocitrate dehydrogenase 2 mutations correlate with leukemic transformation and are predicted by 2-hydroxyglutarate in myelodysplastic syndromes

PurposeThe myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by the presence of somatically mutated hematopoietic stem cells (HSCs) that increase the risk of progression to secondary acute myeloid leukemia (sAML). Mutations in isocitrate dehydrogenase (IDHmut) are thought to correlate with the increased production of the oncogenic protein 2-hydroxyglutarate (2-HG) in AML. The aim of this study was to examine whether serum 2-HG has utility as a prognostic biomarker, and whether elevated 2-HG levels are predictive of IDH mutations in patients with MDS.MethodsGenetic profiling was utilized to determine the genetic composition of a large cohort of MDS patients, including the presence or absence of IDH1 or IDH2 mutations (n = 281). Serum 2-HG levels were detected by liquid chromatography–tandem mass spectrometry.ResultsIn the current study of MDS patients, elevated serum 2-HG levels were predictive of inferior overall- and leukemia-free survival irrespective of IPSS risk grouping. Higher serum 2-HG levels predicted the presence of IDH mutations. IDH2mut patients had a higher risk of leukemic transformation. The co-occurrence of DNMT3A or SRSF2 mutations was found to be increased in IDH2mut patients. IDH2 mutations were associated with significantly worse OS and LFS amongst patients with low-risk MDS by IPSS grouping.ConclusionsThe noted predictive value of serum 2-HG levels and IDH2 mutations on OS and LFS support the use of biomarkers and/or underlying cytogenetics in novel prognostic scoring systems for MDS.

The high NRF2 expression confers chemotherapy resistance partly through up-regulated DUSP1 in myelodysplastic syndromes

Although cytarabine has been widely considered as one of the chemotherapy drugs for high-risk myelodysplastic syndromes (MDS), the overall response rate is only approximately 20-30%. Nuclear factor erythroid 2-related factor 2 (NRF2, also called NFE2L2) has been shown to play a pivotal role in preventing cancer cells from being affected by chemotherapy. However, it is not yet known whether NRF2 can be used as a prognostic biomarker in MDS, or whether elevated NRF2 levels are associated with cytarabine resistance. Here, we found that NRF2 expression levels in bone marrow from high-risk patients exceeded that of low-risk MDS patients. Importantly, high NRF2 levels are correlated with inferior outcomes in MDS patients (n=137). Downregulation of NRF2 by the inhibitor Luteolin, or lentiviral shRNA knockdown, enhanced the chemotherapeutic efficacy of cytarabine, while MDS cells treated by NRF2 agonist Sulforaphane showed increased resistance to cytarabine. More importantly, pharmacological inhibition of NRF2 could sensitize primary high-risk MDS cells to cytarabine treatment. Mechanistically, downregulation of dual specificity protein phosphatase 1, an NRF2 direct target gene, could abrogate cytarabine resistance in NRF2 elevated MDS cells. Silencing NRF2 or dual specificity protein phosphatase 1 also significantly sensitized cytarabine treatment and inhibited tumors in MDS cells transplanted mouse models in vivo. Our study suggests that targeting NRF2 in combination with conventional chemotherapy could pave the way for future therapy for high-risk MDS.