Kosuke Tsuboi

Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia

The optimal treatments for relapsed acute promyelocytic leukemia (APL) remain equivocal. We conducted a phase 2 study to evaluate the efficacy and feasibility of a sequential treatment consisting of induction and consolidation with arsenic trioxide (ATO), peripheral blood stem cell (PBSC) harvest after high-dose cytarabine chemotherapy, and autologous hematopoietic cell transplantation (HCT). Between 2005 and 2009, 35 patients (26 with hematologic and 9 with molecular relapse) were enrolled. Induction therapy resulted in complete remission in 81% of those with hematologic relapse, and most patients became negative for PML-RARα after the first ATO consolidation course, but 4 remained positive. Administration of the second ATO consolidation course further decreased the transcript levels in 3 patients. In total, 25 patients proceeded to PBSC harvest, all of whom successfully achieved the target CD34+ cell doses, and 23 underwent autologous HCT with PML-RARα-negative PBSC graft. Posttransplant relapse occurred in 3 patients, and there was no transplant-related mortality. With a median follow-up of 4.9 years, the 5-year event-free and overall survival rates were 65% and 77%, respectively. These findings demonstrate the outstanding efficacy and feasibility of the sequential treatment featuring ATO and autologous HCT for relapsed APL. This study was registered at http://www.umin.ac.jp/ctr/ as #C000000302.

A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia.

Barasertib (AZD1152) is a highly potent and selective Aurora B kinase inhibitor. The safety, efficacy and pharmacokinetic (PK) profile of barasertib were investigated in Japanese patients with advanced acute myeloid leukemia. Barasertib (50-1200mg) was administered as a continuous 7-day intravenous infusion every 21 days. No dose-limiting toxicities were reported and barasertib 1200mg was chosen for further evaluation in Japanese patients. Neutropenia and febrile neutropenia were the most commonly reported adverse events. The PK profile was similar to Western patients. A promising overall hematologic response rate of 19% was achieved, which warrants further investigation in these patients.

Preferential hypermethylation of the Dickkopf-1 promoter in core-binding factor leukaemia.

The Dickkopf‐1 (DKK1) gene product is an extracellular Wnt inhibitor. Hypermethylation of the DKK1 promoter results in transcriptional silencing and may play an important role in cancer development. Here, we investigated hypermethylation of the DKK1 promoter in patients with acute myeloid leukaemia (AML), especially core‐binding factor (CBF) leukaemia. The methylation status of DKK1 was analysed using methylation‐specific polymerase chain reaction in 47 patients with AML. DKK1 methylation was found in 14 (29·8%) patients, and more frequently in those with CBF leukaemia (6 of 12 patients), than in those with acute promyelocytic leukaemia (APL) (0 of 6 patients) (P = 0·03). In contrast, Wnt inhibitory factor‐1 methylation was found in APL (4 of 6 patients) but not in CBF leukaemia (0 of 12 patients) (P = 0·001). Multivariate analyses suggested that DKK1 methylation was a risk factor for poorer overall survival. Sequential analysis using four paired samples obtained at diagnosis and relapse suggested that DKK1 methylation was involved in the progression of leukaemia. Therefore, DKK1 methylation may be involved in leukaemogenesis, especially in CBF leukaemia, and may be a useful prognostic marker in AML.

Prognostic Significance of FLT3 Internal Tandem Duplication and NPM1 Mutations in Acute Myeloid Leukemia in an Unselected Patient Population

Mutations in the fms-like tyrosine kinase 3(FLT3) gene containing an internal tandem duplication(@#@ FLT3/ITD@#@) or mutations in the nucleophosmin 1 gene(NPM1) are thought to be prognostic indicators in acute myeloid leukemia (AML). Previous studies suggested that FLT3/ITD mutation indicates a poor prognosis and thatNPM1 mutation indicates a more favorable one, but these studies were often performed with selected patient populations. We investigated the clinical significance of these mutations at our institution with an unselected group of patients with newly diagnosed AML. This group included patients ≥60 years old and those with a poor performance status. Using polymerase chain reaction and sequencing analyses, we detected FLT3/ITD mutations in 12 patients (20.0%) andNPM1 mutations in 7 patients (11.7%) among a group of 60 patients. There was a nonsignificant trend for FLT3/ITD mutation to be associated with a poorer predicted overall survival (OS) probability in this population. In contrast, OS was significantly higher in patients with wild-typeNPM1 than in patients withNPM1 mutation, both for all AML patients and for AML patients with a normal karyotype. In this general and unselected AML patient population,NPM1 mutation was not a prognostic indicator of a favorable outcome.

Identification of a novel SEPT9-ABL1 fusion gene in a patient with T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL), a rare type of peripheral T-cell leukemia, is characterized by marked splenomegaly with rapidly progressive lymphocytosis and a poor prognosis. Nine kinds of ABL1 chimeric genes have been identified in various kinds of hematological malignancies, such as chronic myeloid leukemia and B- or T-lymphoblastic leukemia. However, there have been no reports describing T-PLL cases with ABL1 rearrangements. We herein report a case of T-PLL with a novel SEPT9-ABL1 fusion gene which induced strong resistance to tyrosine kinase inhibitors such as imatinib and dasatinib.

A novel aberrant form of e13a2 BCR-ABL1 transcript in chronic myelogenous leukemia undetectable with the standardized real-time quantitative polymerase chain reaction from the Europe Against Cancer Program.

The detection and monitoring of BCR-ABL1 transcripts using real-time quantitative polymerase chain reaction (RQ-PCR) is indispensable for the management of patients with chronic myelogenous leukemia (CML) (1). The Europe Against Cancer (EAC) Program has established a standardized RQ-PCR protocol for BCR-ABL1 assay reproducibility and data comparison among laboratories (2, 3). The RQ-PCR primer set, ENF501 and ENR561 (Figure 1A), is designed to amplify the two major types of BCR-ABL1 transcripts, e13a2 and e14a2, where either BCR exon 13 (e13) or 14 (e14) is fused to ABL exon 2 (a2), respectively. We recently experienced a CML patient who harbored a novel form of aberrant e13a2 transcript, which was undetectable with the EAC protocol. A 62-year-old Japanese woman was diagnosed with CML based on the detection of t(9;22)(q34;q11.2). Fluorescent in situ hybridization (FISH) analysis revealed that 92.8% of bone marrow cells were positive for BCR-ABL1. SYBR Green I RQ-PCR with the EAC primer set, however, could not detect the BCR-

Erratum to: Successful bypass surgery for esophageal carcinoma under adequate factor XIII/13 replacement therapy in a case of intractable autoimmune hemorrhaphilia due to anti-Factor XIII/13 antibodies

Autoimmune hemorrhaphilia due to anti-factor XIII (FXIII) antibodies (AH13) is a life-threatening disease associated with high risk of surgical bleeding. Since AH13 occurs mainly in the elderly, patients of AH13 tend to be complicated with other life-threatening diseases that may require surgical procedures. During our nation-wide survey on AH13, supported by the Japanese Ministry of Health, Labor, and Welfare, patients with unexplained bleeding were examined for FXIII-related parameters and anti-FXIII autoantibodies. A 64-year-old man had previously been tentatively diagnosed with AH13 and received immunosuppressive therapies, as FXIII inhibitor was detected by functional cross-mixing studies. About 2 years later, he was definitively diagnosed with AH13, because our immuno-chromatographic test and enzyme-linked immuno-sorbent assay detected FXIII-bound anti-FXIII-A subunit autoantibodies. Since routine endoscopic examination revealed suspected esophageal carcinoma, a preparatory FXIII pharmacokinetic (PK) analysis was performed by infusing FXIII concentrates prior to biopsy. Consequently, biopsy of this lesion was done without bleeding complications. One month later, a second PK study was carried out before surgery, and esophageal bypass surgery was completed successfully under FXIII replacement therapy. Our experience with this case suggests that operations can be performed safely and with confidence even in patients with such life-threatening hemorrhagic diseases.

An Acceptable Incidence of Infusion Site Reactions after Subcutaneous Bortezomib Administration in the Upper Arm in Japanese Patients with Multiple Myeloma

(e.g. warmth, erythema or itching) without a grade 1 or higher ISR were recorded as grade 0 ISR. A total of 197 scBor injections were administered to the 22 patients, and no ISRs of grade 2 or higher were observed. Grade 1 ISRs occurred after 6 of the 197 total injections (3.0%) in 3 patients (13.6%). In our study, none of the patients who developed grade 1 ISRs required treatment. Associated reactions recorded as grade 0 ISRs occurred after 49 injections (24.9%) in 7 patients (31.8%; table 1 ). The most common symptom was redness (46 injections; 23.4%). Three patients (Nos. 9, 18 and 21) who had developed redness after every scBor injection in the abdomen never exhibited any reactions after the injection site was shifted to the upper arm. Kamimura et al. [5] reported that in 158 subcutaneous injections administered to 15 patients, grades 2 and 1, and associated reactions recorded as grade 0 ISRs occurred in 7 (4.4%; abdomen: 1 and thigh: 6), 40 (25.3%; abdomen: 22 and thigh: 18) and 111 patients (70.3%; abdomen: 70 and thigh: 41), respectively. As the two studies are different, their results cannot be compared; however, our data demonstrated an acceptable incidence of ISRs after scBor administration in the upper arm. The adipose tissue volBortezomib (Bor) provides survival benefits to patients with multiple myeloma [1] . Subcutaneous (sc) administration is a more common route of Bor administration than intravenous injection due to its lower incidence and severity of peripheral neuropathy and equivalent efficacy [2, 3] . It is currently recommended that scBor injections should be rotated among eight different sites on the abdomen and thigh. However, the safety of scBor injections in the upper arm remains unclear. We herein analyzed the incidence and severity of injection site reactions (ISRs) in 22 Japanese patients with multiple myeloma who were treated with scBor at a concentration of 2.5 mg/ml at two facilities in Kanagawa, Japan (Ebina General Hospital and Ozawa Hospital). The Bor dosage was 1.3 mg/m 2 in all patients. scBor was administered at a nearly 30° angle to avoid epidermal infiltration; all injections were performed by nurses who understood the safe Bor administration protocol. The upper arm injection sites were selected alternately from side to side in the upper arms and at a region at least 2 cm distant from a prior injection site. ISRs were graded according to the National Cancer Institute Common Toxicity Criteria version 4.0 [4] . Additionally, any associated symptoms Received: February 5, 2014 Accepted after revision: April 1, 2014 Published online: July 1, 2014