Identification of a Polymorphic Gene, BCL2A1, Encoding Two Novel Hematopoietic Lineage-specific Minor Histocompatibility Antigens

We report the identification of two novel minor histocompatibility antigens (mHAgs), encoded by two separate single nucleotide polymorphisms on a single gene, BCL2A1, and restricted by human histocompatibility leukocyte antigen (HLA)-A*2402 (the most common HLA-A allele in Japanese) and B*4403, respectively. Two cytotoxic T lymphocyte (CTL) clones specific for these mHAgs were first isolated from two distinct recipients after hematopoietic cell transplantation. Both clones lyse only normal and malignant cells within the hematopoietic lineage. To localize the gene encoding the mHAgs, two-point linkage analysis was performed on the CTL lytic patterns of restricting HLA-transfected B lymphoblastoid cell lines obtained from Centre d'Etude du Polymorphisme Humain. Both CTL clones showed a completely identical lytic pattern for 4 pedigrees and the gene was localized within a 3.6-cM interval of 15q24.3–25.1 region that encodes at least 46 genes. Of those, only BCL2A1 has been reported to be expressed in hematopoietic cells and possess three nonsynonymous nucleotide changes. Minigene transfection and epitope reconstitution assays with synthetic peptides identified both HLA-A*2402– and B*4403-restricted mHAg epitopes to be encoded by distinct polymorphisms within BCL2A1

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan

Background: In a Phase 3 international clinical trial (VIALE-C), venetoclax plus low-dose cytarabine improved the response rate and overall survival versus placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy. After the enrollment period of VIALE-C ended, we conducted an expanded access study to provide preapproval access to venetoclax in combination with low-dose cytarabine in Japan. Methods: Previously, untreated patients with acute myeloid leukemia who were ineligible for intensive chemotherapy were enrolled according to the VIALE-C criteria. Patients received venetoclax (600 mg, Days 1–28, 4-day ramp-up in Cycle 1) in 28-day cycles and low-dose cytarabine (20 mg/m2, Days 1–10). All patients took tumor lysis syndrome prophylactic agents and hydration. Safety endpoints were assessed. Results: Fourteen patients were enrolled in this study. The median age was 77.5 years (range = 61–84), with 78.6% over 75 years old. The most common grade ≥ 3 treatment-emergent adverse event was neutropenia (57.1%). Febrile neutropenia was the most frequent serious adverse event (21.4%). One patient developed treatment-related acute kidney injury, leading to discontinuation of treatment. Two patients died because of cardiac failure and disease progression that were judged not related to study treatment. No patients developed tumor lysis syndrome. Conclusions: The safety outcomes were similar to those in VIALE-C without new safety signals and were well managed with standard medical care. In clinical practice, more patients with severe background disease are expected, in comparison with in VIALE-C, suggesting that it is important to carefully manage and prevent adverse events

High-dose Dexamethasone Therapy as the Initial Treatment for Idiopathic Thrombocytopenic Purpura: Protocol for a Multicenter, Open-label, Single Arm Trial

Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of <20, 000 /μL, or with <50, 000/ μL and bleeding symptoms. The primary endpoints of this trial are the proportion of responses (complete plus partial response) on day 180 (day 46+180) after the completion of the 46-day high-dose dexamethasone therapy. The results of this investigation of the effectiveness and safety of this regimen will be essential for the establishment of standard therapy for ITP

An open-label trial of the prophylactic administration of voriconazole in patients who undergo allogeneic hematopoietic stem cell transplantation: study protocol

Invasive fungal infections, especially those caused by Aspergillus, can be fatal in patients who have undergone allogeneic hematopoietic stem cell transplantation. Fluconazole, itraconazole and micafungin can be used to prevent fungal infections in patients undergoing allogeneic hematopoietic stem cell transplantation, but fluconazole is not effective against Aspergillus, and itraconazole has less tolerability from gastrointestinal toxicity. Micafungin is approved for prophylaxis at a dose of 50 mg/day, less than a therapeutic dose. Voriconazole, the current preferred agent for invasive Aspergillus infection, is available in both oral and intravenous preparations, and has recently been approved for prophylaxis in Japan. Some US and European studies have reported on the prophylactic use of voriconazole, but the efficacy and safety of this has not been confirmed in Japan. Hence, this prospective study of voriconazole as prophylaxis against invasive fungal infections in patients who have received allogeneic hematopoietic stem cell transplantation is being performed to evaluate its efficacy and safety, including incidence rate of proven/probable invasive aspergillosis and other fungal infections, and adverse event(s) due to voriconazole administration. We are also investigating potential interactions between voriconazole and immunosuppressive drugs by monitoring the blood concentration of a calcineurin inhibitor in Japanese patients. Further, this study aims to improve the clinical outcomes of allogeneic hematopoietic stem cell transplantation recipients