Weilai Xu

Homoharringtonine in combination with cytarabine and aclarubicin resulted in high complete remission rate after the first induction therapy in patients with de novo acute myeloid leukemia.

To assess the efficacy and toxicity of HAA regimen (homoharritonine 4 mg/m2/day, days 1–3; cytarabine 150 mg/m2/day, days 1–7; aclarubicin 12 mg/m2/day, days 1–7) as an induction therapy in the treatment of de novo acute myeloid leukemia (AML), 48 patients with newly diagnosed AML, aged 35 (14–57) years, were entered into this clinical study. The median follow-up was 26 months. Eighty-three percent of patients achieved complete remission (CR), and the first single course of induction HAA regimen resulted in CR rate of 79%. The CR rate of 100, 82 and 33% were achieved in patients with favorable, intermediate and unfavorable cytogenetics, respectively. For all patients who achieved CR, the median time from the initiation of the induction therapy to the evaluation of the remission status was 32 days. For all patients, the estimated 3 years overall survival (OS) rate was 53%, whereas for patients with M5, the estimated OS rate at 3 years was 75%. The toxicities associated with HAA regimen were acceptable, and the most common toxicity was infection. This study suggested that HAA regimen might be a well-tolerable, effective induction regimen in young adult patients with AML.

FLT3 and NPM1 mutations in Chinese patients with acute myeloid leukemia and normal cytogenetics

Mutations of fms-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) exon 12 genes are the most common abnormalities in adult acute myeloid leukemia (AML) with normal cytogenetics. To assess the prognostic impact of the two gene mutations in Chinese AML patients, we used multiplex polymerase chain reaction (PCR) and capillary electrophoresis to screen 76 AML patients with normal cytogenetics for mutations in FLT3 internal tandem duplication (FLT3/ITD) and exon 12 of the NPM1 gene. FLT3/ITD mutation was detected in 15 (19.7%) of 76 subjects, and NPM1 mutation in 20 (26.3%) subjects. Seven (9.2%) cases were positive for both FLT3/ITD and NPM1 mutations. Significantly more FLT3/ITD aberration was detected in subjects with French-American-British (FAB) M1 (42.8%). NPM1 mutation was frequently detected in subjects with M5 (47.1%) and infrequently in subjects with M2 (11.1%). FLT3 and NPM1 mutations were significantly associated with a higher white blood cell count in peripheral blood and a lower CD34 antigen expression, but not age, sex, or platelet count. Statistical analysis revealed that the FLT3/ITDpositive group had a lower complete remission (CR) rate (53.3% vs. 83.6%). Survival analysis showed that the FLT3/ITD-positive/NPM1 mutation-negative group had worse overall survival (OS) and relapse-free survival (RFS). The FLT3/ITD-positive/NPM1 mutation-positive group showed a trend towards favorable survival compared with the FLT3/ITD-positive/NPM1 mutation-negative group (P=0.069). Our results indicate that the FLT3/ITD mutation might be a prognostic factor for an unfavorable outcome in Chinese AML subjects with normal cytogenetics, while NPM1 mutation may be a favorable prognostic factor for OS and RFS in the presence of FLT3/ITD.

Telomere attrition, and chromosome instability via downregulation of TRF2 contributes to arsenic trioxide-induced apoptosis of human T-cell leukemia cell line molt-4 cells

Overexpression of human telomere repeat binding factor 2 (TRF2), which may play an important role in the fate of cancer cells, has been observed in adult T-cell leukemia. Previous reports have shown that the inhibition of TRF2 results in the apoptosis of cancer cells. In this study, we demonstrated that arsenic trioxide (As2O3) induced in vitro growth inhibition and/or apoptosis of human T-cell leukemia cell line Molt-4 in a caspase-independent manner. Telomerase activity was not inhibited, although the level of the reverse transcriptase subunit of the human telomerase gene (hTERT) mRNA expression was down regulated during the early times and then recovered to the level found in untreated controls about 48 hours after treatment with As2O3. Furthermore, a remarkable telomere shortening related to exposure of As2O3 was observed in 50 population doubling. In contrast, the alteration of telomere length did not occur after exposure to higher concentration of As2O3 (10 µM) for 24 hours and 48 hours, respectively, suggesting that the shortening of telomeres induced by As2O3 is dependent of a series of cell division cycles. Chromosomal analysis showed that As2O3 exposure caused chromosomal end-to-end fusion in human T-cell leukemia cells while downregulation of TRF2 was observed. Finally, the inhibition of TRF2 protein expression and the sensitivity to As2O3 in a panel of leukemia cell lines were checked. The data revealed that inhibition of TRF2 rendered leukemia cells more susceptible to As2O3. In conclusion, the downregulation of TRF2 by As2O3 contribute to chromosomal end-to-end fusion, and apoptosis in leukemia cells, suggesting that TRF2 could be an attractive target for new therapies of leukemia.

Downregulation of hTERT: An Important As2O3 Induced Mechanism of Apoptosis in Myelodysplastic Syndrome

Two myelodysplastic syndrome (MDS) celllines, MUTZ-1 and SKM-1 cells, were used to study the effect of arsenic trioxide (As2O3) on hematological malignant cells. As2O3 induced this two cell lines apoptosis via activation of caspase-3/8 and cleavage of poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme. As2O3 reduced NF-κB activity, which was important for inducing MUTZ-1 and SKM-1 cells apoptosis. As2O3 also inhibited the activities of hTERT in MUTZ-1 and SKM-1 cells. Moreover, the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), had no effect on caspase-8 activation, although PDTC did inhibit MUTZ-1 and SKM-1 cells proliferation. Incubation of MUTZ-1 cells with a caspase-8 inhibitor failed to block As2O3-induced inhibition of NF-κB activity. Our findings suggest that As2O3 may induce apoptosis in MUTZ-1 and SKM-1 cells by two independent pathways: first, by activation of caspase-3/8 and PARP; and second, by inhibition of NF-κB activity, which results in downregulation of hTERT expression. We conclude that hTERT and NF-κB are important molecular targets in As2O3-induced apoptosis.

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.

Outcome prediction by the transcript level of BCR-ABL at 3 months in patients with chronic myeloid leukemia treated with imatinib--a single institution historical experience.

The BCR-ABL transcript level (≤ 10%) at 3 months after tyrosine kinase inhibitors can predict long term outcome in the patients with chronic myeloid leukemia in chronic phase (CML-CP). However, the significance of transcript level was still not determined in different risk groups of patients. A total of 299 patients with CML-CP were enrolled and stratified according to prior interferon-α (IFN) treatment, age, and interval time between diagnosis and imatinib treatment to investigate the prediction value of BCR-ABL transcript level for overall survival (OS), event-free survival (EFS), progression-free survival (PFS). Univariate and multivariate analysis proved that BCR-ABL transcript level at 3 months were associated with the treatment outcome. However, in the patients with prior IFN treatment, younger age, and longer interval between diagnosis and IM treatment, the predictive value of transcript value remain obscure in terms of EFS, PFS and OS, respectively, as well as cumulative incidence of PCyR, CCR, MMR and CMR. In conclusion, the transcript level of BCR-ABL at 3 months could serve as a predictive parameter, but should be used with caution.

Acquired Robertsonian translocation is not always suggestive of poor prognosis: a case of acquired Rob(13;14) in Philadelphia chromosome-negative cells of chronic myelogenous leukemia

Robertsonian translocations are the most common constitutional chromosomal changes in the general population, at about one per 1000, while only approximately 3% of these abnormalities are acquired [1]. Acquired Robertsonian translocations occur also at low frequency in hematological malignancies. There have been scattered reports about these rearrangements, in which most authors believed their cases were rare, but Welborn’s systematic study [2] indicated that acquired Robertsonian translocations are more common in hematological malignancies than originally thought, approximately one per 325 cases. Der(13;14)(q10;q10), the most common rearrangement among the Robertsonian translocations, accounted for 74% of all cases, and only 6% of acquired ones, which were mainly observed in acute lymphoblastic leukemia (ALL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL). Among myeloid neoplasms there were only three cases with acquired Rob(13;14) reported—two in acute myelogenous leukemia (AML) [3,4] and one in myelodysplastic syndromes (MDS) [5]—all of which were accompanied by other chromosome abnormalities, according to a literature review. Patients with hematological malignancies of acquired Robertsonian translocation have a very poor prognosis [2]. However, we describe a case showing that acquired Rob(13;14) in chronic myelogenous leukemia (CML) during imatinib treatment was not associated with a poor prognosis. In May 2002, a 56-year-old male patient was admitted to our hospital with fatigue, weight loss, and upper abdominal malaise. Massive splenomegaly was detected by physical examination. The blood count revealed white blood cells (WBC) 84.86 10/L, platelets (PLT) 8786 10/L, hemoglobin (Hb) 129 g/L, and hematocrit (Hct) 38.2%. Bone marrow smears showed increased cellularity with a maturation pattern of 2% blasts, 1% promyelocytes, 18.5% myelocytes, 27.5% metamyelocytes, 22.5% band cells, 13.5% segmented, 3% eosinophils, and 1.5% basophils. The myeloid:erythroid (M:E) ratio was 11.9. Cytogenetic analysis showed that the reciprocal t(9;22)(q34;q11) was found in all 10 metaphases. The patient was diagnosed with CML in chronic phase. Interferon-a usage (36 10 U, 3 days per week) resulted in a major hematological response (MHR), but no cytogenetic response was achieved after 3 months. Cytogenetic analysis still showed 100% t(9;22), without additional chromosome abnormalities. In August 2004, while still in CML chronic phase, the patient started treatment with imatinib 400 mg per day, resulting in a major cytogenetic response (MCR) after 10 months. Although complete cytogenetic response (CCR) was achieved in June 2006, Rob(13;14) was found in Philadelphia chromosome (Ph)-negative cells in five of 20 metaphases

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.

Improved long-term survival in all Sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide-based front-line therapy

Limited data was available for long‐term follow‐up in newly diagnosed acute promyelocytic leukemia (APL) patients treated with all‐trans‐retinoic acid (ATRA) plus intravenously arsenic trioxide (ATO)‐based front‐line therapy. The aim of this work was to retrospectively analyze the long‐term survival rate and frequency of therapy‐related myeloid neoplasia (t‐MN) occurring in a large cohort of APL patients. A total of 760 newly diagnosed patients with APL between January 1999 and May 2016 were evaluated. The early death rate was 9.2% (70/760). Of the remaining 690 patients with complete remission, patients were grouped according to front‐line regimens: ATRA plus ATO with or without chemotherapy (ATO group) and ATRA with chemotherapy (non‐ATO group). The median duration of follow‐up was 7.5 years (1.0‐18.3 years). ATO group showed significant superior 10‐year estimated relapse‐free survival (RFS) up to 90.3% comparing with 65.5% in the non‐ATO group (P < 0.0001). In addition, the 10‐year estimated overall survival (OS) was 93.9% for patients in the ATO group and 89.1% for those in the non‐ATO group (P = 0.03). In the subgroup analysis, the RFS rate was also higher in ATO group comparing with non‐ATO group in both low‐to‐intermediate‐risk (94.2% vs 64.6%, P < 0.0001) and high‐risk subgroup (89.6% vs 74.7%, P = 0.04). Notably, the 3‐year RFS and OS rates in the chemotherapy‐free subgroup of the low‐to‐intermediate‐risk patients (n = 88) were 100% and 100%, respectively. In the entire cohort, a total of 10 patients developed secondary malignant neoplasms, including 7 patients with therapy‐related myeloid neoplasms (t‐MN). The estimated 5‐year cumulative incidence risk of t‐MN in the ATO and non‐ATO groups was 1.0% and 0.4%, respectively (P = 0.34). Thus, our data revealed that the long‐term outcome of patients treated with ATRA plus ATO‐based regimens was associated with continuing high efficacy in all Sanz risk patients with newly diagnosed APL.