Therapeutic response and drug-induced toxicity have been reported to be associated with genetic variants of drug-metabolizing enzymes and transporters. Recently, new causative variants associated with drug response have been reported by genome-wide association studies (GWASs). Additionally, therapeutic response has been predicted using a model of multiple single-nucleotide polymorphisms. In acute lymphoblastic leukemia (ALL), the genetic variants of NUDT15 associated with therapeutic response to 6-mercaptopurine (6-MP) have been reported by GWASs, and the frequency of NUDT15 variants was higher in Asians. Then, several reports on NUDT15 genetic variants associated with 6-MP-induced toxicities and the tolerable doses and outcomes of 6-MP therapy for ALL have been published in Asian countries. The drugs used in treating hematological malignancies have reported new genetic variants associated with its therapeutic response. However, the association between these genetic variants has not been validated in other populations. Here, we reviewed recent reports on the association between the genetic variants and response to drugs used in treating hematological malignancies, such as 6-MP, cytarabine, methotrexate, and vincristine.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the approach to patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This study retrospectively analyzed patients treated with commercially available tisagenlecleucel at our hospital and evaluated its safety and effectiveness. Of the 21 patients evaluated, any grade and grade ≥3 cytokine release syndrome (CRS) occurred in 85.7% and 9.5% of the patients, respectively. A total of 66.7% received tocilizumab and 28.6% received glucocorticoids for the treatment of CRS. The complete response (CR) rate at 3 months was 61.9% (95% confidence interval [CI] 38.4-81.9). After a median follow-up of 6.3 months following CAR-T infusion, the progression-free survival (PFS) and overall survival rates at 6 months were 53.1% (95%CI 28.3-72.7) and 69.2% (95%CI 43.7-84.9), respectively. Severe cytopenia and hypogammaglobulinemia occurred frequently following CAR-T infusion. Eight patients (38.1%) had comorbidities that would have made them ineligible for leukapheresis in the JULIET trial. However, the presence of comorbidities at the time of leukapheresis had no significant effect on the rates of CR, PFS, and adverse events. Tisagenlecleucel for r/r DLBCL in the real-world setting showed high efficacy and manageable safety profile comparable with the pivotal trial.

We here present a 33-year-old woman who was referred to our hospital with a complaint of back pain and was found to have elevated IgG and hypercalcemia, as well as osteolytic lesions of pelvis and spines. ¹⁸F-FDG-PET/CT scan revealed numerous uptakes in the bones. An examination of the bone marrow revealed increased plasma cells (10.2%). Despite clinical similarities to multiple myeloma, any evidence of plasma cell clonal proliferation, including serum M-protein and light chain restriction, was not found. A reexamination of the bone marrow with a biopsy revealed the proliferation of abnormal cells with chromogranin A and synaptophysin expression but no expression of hematopoietic and epithelial cell markers. Based on these results together with extra-adrenal lesions, a diagnosis of malignant paraganglioma was made. Malignant paraganglioma is known to frequently cause bone metastasis and skeletal related events, whose clinical manifestations are similar to those of multiple myeloma. Since patients with osteolytic lesions, hypercalcemia, and hypergammaglobulinemia are likely to be referred to hematologists, malignant paraganglioma should be considered as a differential diagnosis.

There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient’s symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient’s serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.

Plasmablastic lymphoma (PBL) is a rare variant of diffuse large B-cell lymphoma that is frequently associated with HIV infection or other immunodeficiencies. We present a case of HIV-negative primary testicular PBL with long-term complete remission (CR) and successful treatment with bortezomib in combination with EPOCH (V-EPOCH). Because of rapidly increasing right testicular swelling, an 86-year-old man without immunodeficiencies was admitted to our hospital. Following that, a right high orchiectomy was performed. Histopathological and immunohistochemical analyses revealed diffuse infiltration of plasmablastic lymphocytes, which were positive for CD38, CD138, CD56, MUM1, lambda, EBER, and MYC respectively, but negative for CD20. The MIB-1 index was 90%. FDG abnormal uptake was discovered on PET/CT at systemic lymph nodes. There was no abnormal cell infiltration in either the bone marrow or cerebral spinal fluid. He was diagnosed with PBL, clinical-stage IIIE-A, IPI high-intermediate risk. He achieved durable CR more than 30 months after the diagnosis after six courses of V-EPOCH, followed by intrathecal prophylaxis (IT) and adjuvant radiation therapy (total 30 Gy). Although PBL shows an aggressive clinical course and poor prognosis, adequate therapeutic approaches for PBL have not been established due to the rarity of this disease. According to our findings, V-EPOCH combined with IT and adjuvant radiotherapy appeared to be feasible and effective as a frontline treatment for elderly patients with primary testicular PBL.

From a young age, a 63-year-old Japanese man had experienced difficulties with hemostasis during tooth extraction and epistaxis and swelling of bruised areas. He had previously been diagnosed with mild hemophilia (FVIII:C 8.5%) at age of 60 due to swelling of a right hip bruise and was administered FVIII concentrate for the first time. He had frequent bleeding around his shoulder joints and was given FVIII concentrates every time, but his hemostasis was poor. He was referred to our hospital because his FVIII activity decreased to<1% and a low-titer inhibitor (2.0 BU/ml) was detected. Because of a shoulder hematoma and new subcutaneous bleeding on both forearms, recombinant FVIIa was used to perform the hemostatic treatment. Following hemostasis, emicizumab was administered subcutaneously every 2 weeks at a dose of 3.0 mg/kg. Approximately 2 months after starting emicizumab, inhibitors were no longer detected, and FVIII activity increased to 8% after 9 months. We encountered a case of mild hemophilia A with an inhibitor that was first diagnosed in old age. The incidence of inhibitors in non-severe hemophilia A is about 10%, and about 70% of those resolves spontaneously. In this case, suppression of bleeding by emicizumab may have contributed to the spontaneous disappearance of the inhibitor.

NUP98::DDX10 is a rare fusion gene associated with acute myeloid leukemia (AML), for which the prognosis and indication for allogeneic hematopoietic stem cell transplantation are unknown. A 48-year-old woman was diagnosed with AML harboring NUP98::DDX10. The results of quantitative RT-PCR of the fusion mRNA as a minimal residual disease (MRD) marker guided the treatment. In August 2019, the patient achieved hematological remission following standard remission induction therapy with idarubicin and cytarabine. After four cycles of consolidation therapies, MRD was detected, and she underwent allogeneic stem cell transplantation in May 2020. As MRD persisted in June, the immunosuppressant was stopped and three cycles of azacitidine were administered. Despite this, a hematological relapse occurred in January 2021 that was resistant to high-dose cytarabine and an investigational agent. She died as a result of the disease’s progression. Thus, a second thought should be given to the timing of transplantation, the bridging, and the intervention for relapse after transplantation. The cases must be accumulated.

A 46-year-old man with myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable underwent myeloablative bone marrow transplantation from an HLA-DR-1-antigen-mismatched related donor while receiving tacrolimus and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. However, grade III acute GVHD of the gut occurred on day 20 and was treated with prednisolone (PSL) and oral beclomethasone dipropionate while continuing MMF. Subsequently, he presented with progressive epigastric pain. Endoscopy demonstrated multiple stomach and duodenal deep ulcers. The ulcers were suspected to be GVHD; thus, the PSL dose was increased and infliximab was administered; however, the ulcers exacerbated, resulting in repeated perforations and hemorrhagic shock. Furthemore, MMF was suspected as the cause of refractory ulcers and was discontinued on day 156, which resolved the ulcers after 6 months. MMF-induced gastrointestinal (GI) injury resembles anti-inflammatory drug-related ulcers and upper and lower GI tract GVHD, respectively. MMF-induced GI injury has been reportedly resolved after discontinuing or reducing the MMF dose. Several reports suggested that refractory upper GI ulcers and rectal sparing colitis were associated with MMF toxicities rather than GVHD in hematopoietic stem cell transplantations. Physicians should be aware that MMF can induce severe GI injury.

A 54-year-old male patient, who presented with multiple lymphadenopathies, bilateral leg edema, and oscheohydrocele, was diagnosed with diffuse large B-cell lymphoma (DLBCL) stage IVB. His lymphadenopathies disappeared after six courses of R-CHOP therapy, which consist of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone); however, right hypopyon and partly remaining testicular soft tissue masses with fluorodeoxyglucose accumulation were observed. Lymphoma cell infiltration was observed in the aqueous humor of the right anterior chamber and testis, which indicates DLBCL progression. Hypopyon disappeared after the first course of intrathecal chemotherapy combined with R-HDMA therapy, which consists of rituximab and high-dose methotrexate/cytarabine, but recurred in the third course. The patient then underwent busulfan and thiotepa (BuTT) therapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) after four courses of R-HDMA therapy. Hypopyon promptly disappeared after BuTT therapy and no hypopyon recurrence was observed 9 months after auto-PBSCT. Therefore, BuTT therapy is effective for hypopyon associated with refractory DLBCL.

An 82-year-old Japanese male patient was initially diagnosed with lymphocytosis. His complete blood count revealed a white blood cell count of 30.9×10⁹/l with 81% abnormal lymphocytes. The abnormal lymphocytes included monoclonal clones of CD38⁺ and CD138⁺cytoplasmic κ⁺ and IgG-κ M-protein, which led to the final diagnosis of plasma cell leukemia (PCL). Bortezomib and dexamethasone therapy was initiated, but the patient succumbed to the disease on the 8th day of hospitalization. A cytogenetic examination revealed a t (9;14)(p13;q32) translocation and the Western blotting confirmed high PAX5 expression. Similar to our present case, PCL cases with “lymphocytosis” have been widely reported, which some speculating the involvement of PAX5 overexpression in the pathogenesis. Such cases, including ours, may be classified as a unique group of disorders (PCL presenting as “lymphocytosis”), which requires accurate differential diagnosis and subsequent urgent multidisciplinary intensive treatment.

Hematopoietic stem cells (HSC) have self-renewal as well as multilineage differentiation capacity and maintain hematopoiesis throughout life. HSC transplantation (HSCT) is performed as a curative therapy for hematopoietic malignancies and nonmalignant hematopoietic disorders. Furthermore, bone marrow, mobilized peripheral blood, and cord blood are available sources for HSCT. HLA compatibility is the most critical factor for a successful HSCT. The HSC number in a graft is also invaluable for engraftment. Moreover, it is challenging to obtain an abundant number of HSC for patients with obesity, particularly, in cord blood. HSC ex vivo expansion is an appropriate solution for this problem. Extrinsic factors to expand and maintain HSCs, such as cytokines are identified from analysis of HSCs and their niche. Thus, HSC ex vivo expansion is improved by adding them in culture medium; however, it is still difficult for therapeutic applications. Recently, several small molecular compounds have been reported to facilitate ex vivo expansion of HSC. Clinical trials that transplant ex vivo expanded cord blood have been already expanded, and some trials demonstrate reduction of time to hematopoietic recovery. Thus, we anticipate that ex vivo expanded cord blood transplantation will be applied widely in the future.

The COVID-19 pandemic has cast a shadow over transfusion medicine based on the blood donation system. However, managing alloimmune platelet transfusion refractoriness (allo-PTR) has already been difficult. As a first step toward resolving this issue using induced pluripotent stem cell-derived platelet products (iPSC-PLTs), a clinical trial of autologous products (iPLAT1) was conducted in a patient with allo-PTR caused by anti-HPA-1a antibodies who had no compatible donor, and safety was confirmed. To produce iPSC-PLTs, a master cell bank (MCB) of expandable megakaryocyte lines (imMKCLs) is established from iPSCs. From this MCB, iPSC-PLTs are manufactured using a newly developed turbulent-type bioreactor and various compounds. Their quality, safety, and efficacy are confirmed by extensive preclinical studies. Based on the findings of the iPLAT1 study, a clinical trial of allo-transfusion of HLA homozygous iPSC-PLTs is currently ongoing and HLA class I-deficient O-type universal iPSC-PLTs are also being developed. iPSC-PLTs are expected to solve various problems, including allo-PTR in platelet transfusion, and greatly contribute to the advancement of transfusion medicine.

This study focused on amnion-derived mesenchymal stem cells (MSCs), which have immune- and inflammation-regulating properties, 1) a large number of stem cells, 2) high proliferative potential, and 3) are non-invasive to harvest. Based on the general research reported in many immune- and inflammation-related disease models, research on their commercial and therapeutic application was conducted. We have successfully manufactured a clinical trial product of amnion MSCs for the first time worldwide (clinical trial product name: AM01) and conducted physician-led clinical trials for acute graft versus host disease and Crohn’s disease. Furthermore, CTEX Corporation, the first certified venture from Hyogo College of Medicine, was launched to further accelerate the clinical trial progression to obtain the manufacturing and marketing approval for amnion MSC AM01 to be used as a regenerative medical product at early stage.

For over a decade, various chimeric antigen receptor (CAR)-modified T-cells targeting myeloid antigens have been researched and developed overseas for relapsed/refractory acute myeloid leukemia (AML). However, none of them is domestically and internationally nearing approval. Clinical trial results on CAR T-cells targeting LeY, CD33, NKG2D ligands, CD38, or CD123 have been reported; however, they have not shown significant clinical benefit. More recently, several promising studies in CLL1 CAR T-cells have been reported in China, which attracted attention. We started a first-in-human clinical trial of GMR CAR T-cells in patients with CD116-positive myeloid neoplasms, particularly AML and juvenile myelomonocytic leukemia, in 2021. CAR T-cells can be a promising and practical treatment option for patients with relapsed/refractory AML.

CAR-T therapy has shown excellent therapeutic efficacy in B-cell malignancy. Nevertheless, manufacturing stability, quality control, and CAR T-cell availability are still challenging because current CAR T-cell therapy is a personalized product derived from patient peripheral T-cells. However, allogeneic T-cells have emerged as a novel source to overcome this issue. Because induced pluripotent stem (iPS) cells are pluripotent stem cells derived from somatic cells and have in vitro self-renewal ability and pluripotency, they are expected to be a source of many regenerative medicinal products. Recently, it has become possible to generate CD8 killer T cells from iPS cells, and efforts have been made to generate CAR-CD8 killer T-cells from allogeneic iPS cells. This review discusses the induction of CD8 killer T-cells from iPS cells, efforts to improve the safety and certainty of the induction process for clinical use, and the utility of gene editing to reduce allogeneic antigenicity of iPS T-cells.