Refractory acute promyelocytic leukemia successfully treated with combination therapy of arsenic trioxide and tamibarotene: A case report.

A 40-year-old male developed refractory acute promyelocytic leukemia (APL) after various treatments including all-trans retinoic acid, tamibarotene, arsenic trioxide (As2O3), conventional chemotherapy, and autologous peripheral blood stem cell transplantation. We attempted to use both tamibarotene and As2O3 as a combination therapy, and he achieved molecular complete remission. Grade 2 prolongation of the QTc interval on the electrocardiogram was observed during the therapy. The combination therapy of As2O3 and tamibarotene may be effective and tolerable for treating refractory APL cases who have no treatment options, even when they have previously been treated with tamibarotene and As2O3 as a single agent.

Bacterial Pneumonia-induced Persistent Remission of Severe Immune Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation.

A 53-year-old woman with chronic myeloid leukemia received allogeneic hematopoietic stem cell transplantation. After neutrophil engraftment, her platelet count exceeded 100,000/µL at day 64. While she was receiving corticosteroid treatment for chronic graft versus host disease (GVHD), her platelets suddenly dropped to 6,000/µL at day 210 and she was diagnosed with immune thrombocytopenia (ITP). Corticosteroids, intravenous high-dose gamma globulin (IVIg) and a splenectomy failed to increase her platelet count. She developed bacterial pneumonia at day 599 and antibiotic therapy was initiated. Soon after, her platelet count continuously increased. Her GVHD and ITP are now in remission without any ongoing treatment.

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.

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy.

Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

Phase I Clinical Trial of Intravenous L-ascorbic Acid Following Salvage Chemotherapy for Relapsed B-cell non-Hodgkin's Lymphoma.

PURPOSE: To determine the safety and the appropriate dose of intravenous l-ascorbic acid (AA) in conjunction with chemotherapy for patients with relapsed lymphoma. PATIENTS AND METHODS: Patients with relapsed CD20-positive B-cell non-Hodgkin's lymphoma, who were going to receive the CHASER regimen as salvage therapy, were enrolled and treated with escalating doses of AA administered by drip infusion after the 2nd course of the CHASER regimen. The target plasma concentration immediately after AA administration was >15 mM (264 mg/dl). RESULTS: A serum AA concentration of >15 mM was achieved in 3 sequentially registered patients, all of whom had received a 75 g whole body dose. No obvious adverse drug reaction was observed in the patients. The trial was therefore successfully completed. CONCLUSION: Intravenous AA at a whole body dose of 75 g appears to be safe and sufficient to achieve an effective serum concentration. A phase II trial to evaluate the efficacy of intravenous AA in relapsed/refractory lymphoma patients will now be initiated.

Clinical outcome of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly in the rituximab era.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein-Barr virus (EBV)-positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV-positive DLBCL is controversial. To compare the clinical outcome of EBV-positive and EBV-negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBV-encoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV-positive DLBCL patients. The median overall survival and progression-free survival times in patients with EBV-positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression-free survival could not be determined in EBV-negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV-positive DLBCL remains poor, even in the rituximab era.

ACE deletion polymorphism is associated with a high risk of non-infectious pulmonary complications after stem cell transplantation.

Non-infectious pulmonary complication (NIPC) is a serious adverse event for allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. NIPC includes both categories of lung complications: early onset idiopathic pneumonia syndrome (IPS) (onset <120 days) and late-onset non-infectious pulmonary complications (LONIPCs). Both categories have high mortality and morbidity rates, and critical treatments are not available. The renin-angiotensin system plays a critical role in pulmonary fibrosis. We, therefore, studied the relationship between angiotensin-converting enzyme gene (ACE) insertion/deletion polymorphisms and NIPC incidence in 149 consecutive allo-HSCT recipients. A total of 12.1 % (18/149) of these patients were diagnosed with NIPC (IPS, 3; LONIPCs, 15). Eight NIPC patients died from respiratory failure (mortality rate, 44.4 %). Peripheral blood stem cell transplantation was associated with a significantly higher incidence of NIPC than bone marrow transplantation and cord blood transplantation by univariate analysis (HR 3.13, P = 0.031). The serum ACE levels differed significantly according to the ACE insertion/deletion polymorphism. Patients with an ACE D/D genotype occurred at a significantly higher frequency among NIPC patients than I/D and I/I patients (HR 9.03, P < 0.0001). Multivariate analysis confirmed that NIPC is associated with ACE D/D genotypes (HR 8.8, P < 0.001). Our data support a role for the renin-angiotensin system in the pathogenesis of NIPC after allo-HSCT, and may represent a therapeutic target for complications.

Deferasirox treatment improved hematopoiesis and led to complete remission in a patient with pure red cell aplasia.

A 64-year-old woman developed pure red cell aplasia (PRCA) 4 years after thymectomy for thymoma. During anti-thymocyte globulin treatment, the patient developed cytomegalovirus pneumonia and was thus unable to continue immunosuppressive therapy and became transfusion dependent. Deferasirox was started for treatment with iron overload when serum ferritin increased to >1000 ng/mL. Seven months after initiation of deferasirox treatment, serum ferritin level decreased the normal range and the patient has remained transfusion independent thereafter. Deferasirox was discontinued when serum ferritin level decreased below 500 ng/mL, and she has maintained in complete remission over the last 15 months. Hypotheses have been raised regarding the improvement of hematopoiesis by deferasirox treatment, but the mechanism whereby this might be achieved remains unclear. Deferasirox treatment may be clinically beneficial both by reducing iron overload and by improving hematopoiesis in patients with PRCA.