Nosocomial coronavirus disease 2019 (COVID-19) had occurred at our hospital. We retrospectively analyzed the differences between patients with nosocomial COVID-19 and either hematological disease (n=40) or other diseases (n=57). The analysis was completed within 60 days for surviving patients. Among the patients with hematological disease and those with other diseases, there were 21 (52.5%) and 20 (35.1%) deaths, respectively. Although the patients with hematological disease received favipiravir more frequently than patients with other diseases (21 [52.5%] vs. 15 [35.3%], respectively; P<0.05), their median overall survival was poor (29 days; P=0.078). Furthermore, the median duration from oxygen therapy initiation to death or intubation was significantly shorter in the patients with hematological disease (5 days [range, 1-17 days] vs. 10 days [1-24 days], respectively; P<0.05). Furthermore, the patients with hematological disease and nosocomial COVID-19 exhibited more marked respiratory failure and poorer outcomes leading to death in a shorter time period than the patients with other diseases and nosocomial COVID-19.

Acute leukemia (AL) during pregnancy poses a substantial risk to both mothers and fetuses. Treatment for leukemia should be initiated promptly; however, the management of AL in pregnant women and fetuses is usually challenging, especially during the second trimester. Here, we report two cases of AL that developed during the second trimester of pregnancy. In one case, chemotherapy was initiated while continuing the pregnancy; in the second case, a cesarean section was performed prior to chemotherapy initiation. As per current medical records, both infants are thriving without any medical problems. The optimal strategy for the treatment of AL during pregnancy typically includes chemotherapy after delivery. However, if fetal development is not sufficient for ex utero survival, the only alternatives available are the initiation of treatment while continuing the pregnancy or treatment after therapeutic abortion (if it is legally allowed). According to previous studies and as per the results from our first case, the initiation of chemotherapy while sustaining the pregnancy may be an acceptable option if it is conducted with appropriate informed consent. The treatment of AL in the second trimester of pregnancy should be carefully decided, while taking into account the medical, legal, and social aspects, such as gestational weeks, maternal and fetal status, and wishes of the patients and their families.

A 58-year-old man received high-dose melphalan with autologous peripheral blood stem cell transplantation for multiple myeloma in stringent complete response (sCR). Relapse occurred 4 years after the transplantation, and he was placed on ixazomib, lenalidomide, and dexamethasone (IRd) and achieved sCR. On the 10th day of the 10th course of IRd, he developed fever followed by generalized skin eruption with vesicles, headache, and dizziness. Varicella-zoster virus (VZV) antigen from the vesicle and VZV-DNA from the cerebrospinal fluid were detected, and he was diagnosed with systemic VZV infection. He was placed on intravenous acyclovir (ACV), and the infection resolved completely. VZV infection has been recognized as an important complication associated with the use of proteasome inhibitors; however, to our knowledge, there have been no reported cases of serious systemic VZV infection associated with ixazomib. The clinical course of this case strongly suggests the importance of prophylaxis for VZV infection during treatment with ixazomib.

A 74-year-old man was admitted to hospital due to suspected acute leukemia. He had a history of thymic carcinoma, which had been treated with carboplatin in combination with either paclitaxel or amrubicin. However, the tumor remained unresponsive to these treatments. Administration of tegafur/gimeracil/oteracil (TS-1) was initiated, which resulted in tumor size reduction and a partial response. However, leukopenia persisted after the last TS-1 treatment, and four years after the initial treatment, increased blast cell counts were found in a blood film . Bone marrow analysis showed blasts with Auer rods, faggot cells, and dysplastic promyelocytes. Flow cytometry was positive for CD13, CD33, CD34, CD117, and myeloperoxidase, but negative for HLA-DR. PML-RARA fluorescence in situ hybridization was positive. Cytogenetic analysis revealed 47,XY,t (15;17) (q22;q21),+21. Thus, therapy-related acute promyelocytic leukemia (tAPL) was diagnosed. The patient achieved and maintained complete remission for more than 20 months by a de novo APL-treatment regimen including all-trans retinoic acid, arsenic trioxide and tamibarotene. Moreover, the thymic carcinoma has remained stable. Although secondary malignancies of thymic carcinoma have been previously reported, therapy-related leukemia, especially tAPL, is very rare.

A 50-year-old woman diagnosed with surgically resected plasmacytoma of the ovaries and uterus presented with another plasmacytoma in the pancreas with positive uptake on positron emission tomography (PET) and massive right pleural effusion with plasma cell infiltration (myelomatous pleural effusion). After four courses of the bortezomib, lenalidomide, and dexamethasone regimen as induction therapy, partial response was achieved with reduced myelomatous pleural effusion and negative uptake on PET in the pancreatic plasmacytoma. However, soon after she received bortezomib and high-dose cyclophosphamide for peripheral blood stem cell harvesting, right myelomatous pleural effusion increased without signs of heart failure or infection. Because of the progressive nature of the disease, daratumumab was introduced as 2 courses of daratumumab, lenalidomide, and dexamethasone (DLd) regimen, after which she achieved complete response with disappearance of the pleural effusion. After autologous peripheral blood stem cell transplantation, she received an additional four courses of the DLd regimen as consolidation therapy. She maintained relapse-free survival for two years with maintenance therapy containing daratumumab and dose-reduced lenalidomide. Our case may suggest the usefulness of daratumumab before autologous peripheral stem cell transplantation for relapsed/refractory myelomatous pleural effusion.

Dimethyl sulfoxide (DMSO) is used as a cryoprotectant for peripheral blood stem cells (PBSC) preservation. Dimethyl sulfide (DMS) is a metabolite of DMSO secreted through patients' breath after PBSC infusion. It possesses malodor causing an unpleasant environment. We evaluated the efficacy of a photocatalyst environment purifier, which has the potential to lyse toxic substances, in reducing DMS malodor. High DMS concentration in the air after PBSC infusion rapidly decreased after operating the device. Our results suggest that photocatalytic reaction has the potential to reduce the DMS odor associated with PBSC infusion.

Although Hodgkin lymphoma is now among the most curable of the lymphomas, the relapse rate after the first-line treatment remains at 20-30%. Brentuximab vedotin (BV) has been developed for the treatment of newly diagnosed classical Hodgkin lymphoma (cHL), relapsed/refractory cHL, or consolidation after autologous stem cell transplantation. Notably, BV treatment combined with doxorubicin, vinblastine, and dacarbazine treatment has been established as standard treatment for newly diagnosed advanced-stage cHL. Immune-checkpoint inhibitors represent another class of promising cancer immunotherapies that may be used to treat advanced cancers, including cHL. Anti-programmed death-1-blocking antibodies have been used to enhance immunity in cases of several malignancies and obtain durable responses, most notably in patients who have been administered heavy treatment for relapsed/refractory cHL. Several clinical trials, including single agents or combination therapies for cHL, have been developed or are currently under investigation. The results of the ongoing and future clinical trials may establish new paradigms for the treatment of cHL.

Almost 20 years have passed after rituximab, an anti-CD20 mouse-human chimeric monoclonal antibody therapeutic, was introduced in the clinical setting for the treatment of CD20-positive B cell malignancies. Although the prognosis has significantly improved in most B cell malignancies, resistance to rituximab with/without chemotherapies is also widely recognized. With this background, newer generation antibody therapeutics and other molecular targeting drugs that show more effectiveness especially to refractory patients are critically required. In this review, molecular mechanisms of the second/third generation anti-CD20 antibodies (ofatumumab and obinutuzumab), anti-CD19 chimeric antigen-receptor T-cells (CAR-T-CD19; tisagenlecleucel, axicabtagene ciloleucel), and the anti-PD-1 antibodies (nivolumab and pembrolizumab) are presented. The therapeutic effectiveness of those drugs as monotherapy and/or combined therapy with conventional chemotherapy (immunochemotherapy) and another molecular targeting therapeutics (so-called “chemo-free” regimens) are also reviewed.

Although multiple myeloma has been defined as incurable, and the treatment outcome has recently improved rapidly. Antibodies against multiple myeloma, elotuzumab, and daratumumab can safely enhance their effects even when added to the combination therapy of proteasome inhibitors and immunomodulators that have been used till date. Initially, triplet therapy combining antibody therapy with doublet therapy was approved in Japan for relapsed or refractory multiple myeloma. In 2019, daratumumab combination therapies were approved for newly diagnosed multiple myeloma patients, and these therapies are the new standard of care. Recently, the results of clinical trials that added daratumumab to the triplet therapies of proteasome inhibitors, immunomodulators, and dexamethasone have been reported. These trials report greater therapeutic effects, with a significant improvement in the MRD negative rate. We hope that quadruplet therapy including these antibodies will be available in clinical practice, leading to further improvements in the treatment outcomes.

In 2018, two novel antibody therapies, inotuzumab ozogamicin (InO) and blinatumomab, against relapsed or refractory acute lymphoblastic leukemia were approved in Japan. In InO, the antitumor drug ozogamicin is conjugated to the anti-CD22 antibody. Blinatumomab is a bispecific T cell engager antibody comprising the variable regions of the anti-CD19 and the anti-CD3 antibodies. The remission rate of InO is about 75%; however, the frequency of sinusoidal obstruction syndrome is increased when allogeneic hematopoietic cell transplantation is performed after InO treatment. Blinatumomab has a remission rate of 45-70%. The management of cytokine release syndrome during blinatumomab treatment is required in certain cases. Although both the treatments have higher remission and negativity of minimal residual disease rates compared to those in conventional chemotherapy, it is difficult to maintain remission in the long term. Allogeneic hematopoietic stem cell transplantation should be performed as commonly as possible.

Treatment with eculizumab (Soliris^®), a humanized anti-C5 monoclonal antibody improves the quality of life of patients with paroxysmal nocturnal hemoglobinuria (PNH), remarkably reduces hemolysis, improves symptoms associated with hemolysis, and prevents thrombosis. Because eculizumab therapy is not a curative treatment, it is necessary to continue infusion every two weeks, which has been an issue from the viewpoint of convenience. In recent years, an improved version of eculizumab, ravulizumab (Ultomiris^®), which relies on the technology of recycling antibodies has been developed and can be administered every 8 weeks. Crovalimab (SKY59), which can be administered subcutaneously every four weeks, is also under development, and therefore, the convenience for patients with PNH is improving. However, many issues still persist, and several new anti-complement drugs are currently under development. Hopefully, a better drug will be developed by thorough examination of what drug is best for the patient by considering not only its efficacy and safety but also its convenience.

This review aimed to evaluate the molecular mechanism underlying the development of myeloproliferative neoplasms (MPN) caused by mutant calreticulin (CALR). This mutation is found in a subset of patients with Philadelphia chromosome-negative MPNs, and it encodes a molecular chaperone. However, it is essentially impossible to elucidate the oncogenic property of mutant CALR from the wild-type CALR function. Studies have reported that mutant CALR forms a homomultimeric complex via intermolecular interaction between novel domains acquired due to a frameshift mutation, gains a high binding affinity for myeloproliferative leukemia protein (MPL), the thrombopoietin receptor, through a presumptive structural change, and acts as an agonist for MPL. In this review, I would like to describe the course of the discovery of this unique molecular mechanism and discuss future scope of research on mutant CALR.

Human herpesvirus (HHV)-6B encephalitis has been increasingly recognized as an important central nervous system (CNS) complication after allogeneic hematopoietic stem cell transplantation. In this review, the best way to diagnose and treat this devastating complication is described. Diagnostic pitfalls: HHV-6B encephalitis should be diagnosed based on the presence of CNS symptoms, positive results for HHV-6 DNA in the cerebrospinal fluid (CSF), and exclusion of other causes of CNS symptoms. There are potential pitfalls when diagnosing HHV-6B encephalitis. Moreover, false-positive detection of HHV-6 DNA in the CSF can occur. Pleocytosis is observed in few patients, and CSF protein levels are often normal. Limbic encephalitis findings are not commonly detected through a brain MRI at the time of development. Prevention: Neither routine monitoring nor routine prophylactic antiviral therapy is recommended to prevent the development of HHV-6B encephalitis. Treatment: Empiric therapy should be started immediately after HHV-6B encephalitis is suspected. The Guideline Committee of the JSHCT recommends full-dose foscarnet (180 mg/kg/day) for the treatment of HHV-6B encephalitis. Therapeutic effect of anti-HHV6 therapy is assessed based on CNS symptoms and HHV-6 DNA in the CSF, which should be evaluated 1-2 weeks after initiating treatment. Even in patients exhibiting good therapeutic effects, antiviral treatment should be continued for at least 3 weeks.

Expanded human bone marrow-derived mesenchymal stromal/stem cells (MSC) have been used in the treatment of acute graft-versus-host disease (GVHD). It is currently accepted that the use of allogeneic off-the-shelf MSC has therapeutic efficacy with no apparent serious early-onset adverse effects; however, further development would be needed to overcome the current situation of MSC therapy for intractable GVHD. In the emerging recognition of the importance of extracellular vesicles (EV) as modulators of cell-cell communication physiologically and pathologically, we recently revealed that human bone marrow MSC-derived EV ameliorate GVHD clinically and pathologically through the preservation of peripheral naïve T-cell populations in a murine model. In this article, we summarize future perspectives on MSC-based therapy for GVHD.

Graft-versus-host disease (GVHD) is a potentially life-threatening complication associated with allogeneic hematopoietic stem cell transplantation (allo-SCT). Although prophylaxis and GVHD treatment using immunosuppressants are essential for a successful allo-SCT, profound immunosuppression could lead to an infection and/or the recurrence of malignant diseases. Recently, the concept of tissue tolerance has emerged. This concept has been identified as a means to suppress GVHD by relying on tissue-intrinsic mechanisms that are independent from those underlying immune tolerance. Thus, GVHD prophylaxis and treatments targeting the mechanisms that promote tissue tolerance could help suppress GVHD and maintain leukocyte-mediated immune responses against tumors and infectious pathogens. Epithelial regeneration from LGR5-positive intestinal stem cells and epithelial maintenance mediated by metabolites from the intestinal microbiota are representative mechanisms that promote tissue tolerance in the gut. However, these protective mechanisms are weakened by GVHD and conditioning regimens. This review focuses on the pathophysiology of acute GVHD and tissue-intrinsic mechanisms that promote tissue tolerance.

Owing to recent advances in genome analysis technology, many chromosomal abnormalities and gene mutations involved in leukemia onset or recurrence have been discovered in acute myeloid leukemia. These findings contribute to not only the clinical usage, such as prognostic factors or minimal/measurable residual disease (MRD) markers, but also to the development of novel molecular-targeted drugs. In this study, the utility of MRD analysis using the NPM1 mutation and prognosis analysis using a highly sensitive KIT mutation detection method will be outlined.

The event-free survival rate for childhood acute myeloid leukemia (AML) is approaching 60%, owing to the use of intensive chemotherapy, optimal indication of hematopoietic stem cell transplantation, and advances in supportive care. For further improvement, the development of more definitive risk stratification system and introduction of more effective treatment options are necessary. Recently, much attention has been drawn on minimal residual disease (MRD) that is considered a strong prognostic factor for children with AML. Recent studies from the United States and Europe have shown the prognostic impact of FCM-based MRD detection and it is already used for risk stratification in modern AML protocols. Myeloid leukemia in Down's syndrome (ML-DS) has unique characteristics, and ML-DS children are recently being treated separately from non-DS AML children with less intensive treatment. It has been shown that relapsed and refractory cases of ML-DS are difficult to treat; however, no universal prognostic factor has been found yet. In order to determine accurate methods for identifying a subgroup with poor prognosis, an attempt to analyze the role of MRD had been examined in the JPLSG AML-D11 study. In this study, the MRD by FCM and targeted deep sequencing for GATA1 after initial induction therapy were significant prognosis factors for predicting relapse.