Yin Tong

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.

Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial

BACKGROUND Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukaemia. However, their efficacy has not been tested in a multicentre randomised controlled trial in a large population. We assessed the efficacy and safety of homoharringtonine-based induction treatment for management of newly diagnosed acute myeloid leukaemia. METHODS This open-label, randomised, controlled, phase 3 study was done in 17 institutions in China between September, 2007, and July, 2011. Untreated patients aged 14-59 years with acute myeloid leukaemia were randomly assigned (by a computer-generated allocation schedule without stratification) to receive one of three induction regimens in a 1:1:1 ratio: homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and aclarubicin 20 mg/day on days 1-7 (HAA); homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and daunorubicin 40 mg/m(2) per day on days 1-3 (HAD); or daunorubicin 40-45 mg/m(2) per day on days 1-3 and cytarabine 100 mg/m(2) per day on days 1-7 (DA). Patients in complete remission were offered two cycles of intermediate-dose cytarabine (2 g/m(2) every 12 h on days 1-3). The primary endpoints were the proportion of patients who achieved complete remission after two cycles of induction treatment and event-free survival in the intention-to-treat population. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-06000054. FINDINGS We enrolled 620 patients, of whom 609 were included in the intention-to-treat analysis. 150 of 206 patients (73%) in the HAA group achieved complete remission versus 125 of 205 (61%) in the DA group (p=0.0108); 3-year event-free survival was 35.4% (95% CI 28.6-42.2) versus 23.1% (95% CI 17.4-29.3; p=0.0023). 133 of 198 patients (67%) in the HAD group had complete remission (vs DA, p=0·20) and 3-year event-free survival was 32.7% (95% CI 26.1-39.5; vs DA, p=0.08). Adverse events were much the same in all groups, except that more patients in the HAA (12 of 206 [5.8%]) and HAD (13 of 198 [6.6%]) groups died within 30 days than in the DA group (two of 205 [1%]; p=0.0067 vs HAA; p=0.0030 vs HAD). INTERPRETATION A regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia. FUNDING Chinese National High Tech Programme, Key Special Research Foundation of the Ministry of Science and Technology of China, National Nature Science Foundation of China, National Clinical Key Specialty Construction Project.

High efficacy of arsenic trioxide plus all-trans retinoic acid based induction and maintenance therapy in newly diagnosed acute promyelocytic leukemia.

We conducted a retrospective study to evaluate the efficacy of combining arsenic trioxide (ATO) with all-trans-retinoic acid (ATRA) based induction therapy, followed by 3 courses of consolidation chemotherapy and 2-year sequential ATO/ATRA maintenance therapy in acute promyelocytic leukemia (APL). 137 patients were enrolled in the study. The complete remission (CR) rate was 93.4%. All the 9 (6.6%) induction failures were due to early death. With a median follow-up of 35 months, 5 relapses (4%) in CR patients were recorded, including 3 isolated CNS relapses. By using the Kaplan-Meier analysis, the 5-year overall survival and relapse-free survival of the low/intermediate risk group and high-risk group was 98.9% versus 97.4% and 98.7% versus 87.9%, respectively. The results indicated that ATO based first-line protocol is highly effective for treatment of newly diagnosed APL.

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.

Long-term efficacy of low-dose all-trans retinoic acid plus minimal chemotherapy induction followed by the addition of intravenous arsenic trioxide post-remission therapy in newly diagnosed acute promyelocytic leukaemia.

We evaluated the efficacy of low‐dose all‐trans retinoic acid (ATRA) plus minimal chemotherapy for induction in newly diagnosed acute promyelocytic leukaemia (APL). Furthermore, we compared its long‐term outcome with or without the addition of intravenous arsenic trioxide (ATO) in post‐remission therapy. From January 2004 to September 2011, a total of 109 patients with a median age of 41 years (range 14–73) were enrolled in the study. Two arms were assigned according to post‐remission protocols: ATO group cases were subsequently treated with intravenous ATO, standard chemotherapy, and ATRA. No‐ATO group cases were subsequently treated with chemotherapy and ATRA only. Patients were monitored of minimal residual disease (MRD) by reverse‐transcriptase polymerase chain reaction. The haematologic complete remission (CR) rate was 96.3%. The early death rate was 0.9%. At a median follow‐up of 49 months (range 8–102 months), the Kaplan–Meier estimates of 5‐year relapse‐free survival were significantly better for patients in the ATO group than in the no‐ATO group, 94.4% vs 54.8% (p = 0.0001), and the 5‐year overall survival rate was 95.7% vs 64.1%, in the two groups (p = 0.003). Our data show that low‐dose ATRA plus minimal chemotherapy exhibits efficacy in induction therapy for untreated APL and suggest that the addition of ATO to post‐remission therapy significantly improves the long‐term outcome. Copyright

Characteristics and prognosis analysis of additional chromosome abnormalities in newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide as the front-line therapy

Currently, there are few studies that address the prognostic significance of baseline additional chromosomal abnormalities (ACAs) in newly diagnosed acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO) as the front-line therapy. A series of 271 consecutive APL patients has been cytogenetically investigated between 2004 and 2011 in our institution. The incidence of ACAs was 27% (46/172) in APL cases with t(15;17). Trisomy 8 was the most recurrent abnormality, accounting for 30% (14/46) of patients with ACAs, followed by +21 (7%, 3/46) and -7/7q (7%, 3/46). Nine cases (14.1%) were found to have additional balanced translocation aberrations, most of them are new and non-recurrent. Treatment protocols consisted of all-trans retinoic acid (ATRA) and chemotherapy with or without the ATO therapy. Overall, patients with and without ACAs had similar complete remission (CR) rates (94% and 98%, respectively, P=0.344). With a median follow-up of 41 months, univariate analysis showed that ACAs did not show any prognostic significance in relapse-free survival (RFS) and overall survival (OS). In addition, ATO treatment was an independent favorable predictor for RFS. Thus, this data provides insights into cytogenetic features of APL, and suggests that ATO-based combination therapy improved RFS in de novo APL patients, while ACAs had no impact on prognosis.

β-Catenin and AKT are promising targets for combination therapy in acute myeloid leukemia

In this study, we confirmed that combining HHT with ACR can result in synergistic cytotoxicity to AML cells in vitro and in vivo. Combining HHT and ACR simultaneously inhibited PI3K/AKT and WNT/β-catenin signaling in AML cells. Significant increases in growth inhibition and apoptosis were induced by an AKT inhibitor when the WNT3A gene of THP-1 cells was silenced. HHT+ACR could synergistically induce the apoptosis of CD34(+)/CD38(-) primary AML cells. These results highlight β-catenin and AKT are promising targets for combination therapy for AML.

Automated analysis of acute myeloid leukemia minimal residual disease using a support vector machine

We investigated the ability of support vector machines (SVM) to analyze minimal residual disease (MRD) in flow cytometry data from patients with acute myeloid leukemia (AML) automatically, objectively and standardly. The initial disease data and MRD review data in the form of 159 flow cytometry standard 3.0 files from 36 CD7-positive AML patients in whom MRD was detected more than once were exported. SVM was used for training with setting the initial disease data to 1 as the flag and setting 15 healthy persons to set 0 as the flag. Based on the two training groups, parameters were optimized, and a predictive model was built to analyze MRD data from each patient. The automated analysis results from the SVM model were compared to those obtained through conventional analysis to determine reliability. Automated analysis results based on the model did not differ from and were correlated with results obtained through conventional analysis (correlation coefficient c = 0.986, P > 0.05). Thus the SVM model could potentially be used to analyze flow cytometry-based AML MRD data automatically, objectively, and in a standardized manner.

Anaplastic large-cell lymphoma with atypical chromosomal translocation t(2;5) and hypophyseal tumor.

Abstract Anaplastic large T-cell lymphoma (ALCL) is frequently associated with the t(2;5)(p23;q35). Here, we report a case of ALCL with an atypical translocation of t(2;5)(p24;q13) and other complex translocations. This complex abnormal karyotype may result in chemotherapy resistance and a poor outcome. Interestingly, a hypophyseal tumor was detected simultaneously by magnetic resonance imaging in this case. We think it is probable that the tumor in the hypophysis might be associated with the ALCL.