Atraumatic splenic rupture (ASR) is a rare but fatal complication of malignant lymphoma. However, only one case of intravascular large B-cell lymphoma (IVLBCL)-related ASR (IVLBCL-ASR) has previously been reported, and the mechanism of IVLBCL-ASR is unknown. We present the case of a 78-year-old man who died unexpectedly and was diagnosed with IVLBCL-ASR pathologically by autopsy. A massive intraperitoneal hemorrhage and four lacerations on the splenic surface were discovered during the autopsy. CD20-positive lymphoma cells that infiltrated into small vessels were highly concentrated in the center of the spleen and were only slightly distributed in the lacerations on the splenic surface. Therefore, increased intrasplenic pressure due to lymphoma cell proliferation was identified as the cause of ASR. The patient had undergone ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) for tongue cancer evaluation 3 months earlier, and positive uptake was found in the right adrenal gland, where lymphoma cell infiltration was confirmed by the autopsy. Our findings suggest that clinicians should be aware that the advanced stage of IVLBCL can cause fatal ASR via increased intrasplenic pressure. Therefore, early diagnosis and early treatment intervention are desirable to prevent the onset of IVLBCL-ASR, and ¹⁸F-FDG PET/CT is useful for the early diagnosis of IVLBCL.

Protein-losing enteropathy is rarely associated with malignant lymphoma. This report describes the case of a 67-year-old man with diffuse large B-cell lymphoma (DLBCL) and concomitant protein-losing enteropathy who was admitted to our hospital for evaluation of watery diarrhea, edema, and abdominal fullness. On admission, the patient reported a history of weight gain. Subsequent examination showed ascites, hepatosplenomegaly, and hypoalbuminemia. Notably, 99mTc-labeled human serum albumin scintigraphy revealed protein loss from the intestine, and the patient was diagnosed with protein-losing enteropathy. Endoscopy revealed erosive and edematous hyperplasia of the gastric-colonic mucosa, and histopathological evaluation of a biopsy specimen showed proliferation of CD20⁺ and CD5⁺ tumor cells. Thus, the diagnosis of DLBCL was histopathologically confirmed. Lymphomatous infiltration of the bone marrow was observed; however, no lymphadenopathy was detected. Based on these findings, the patient was diagnosed with protein-losing enteropathy associated with gastrointestinal infiltration of CD5⁺ DLBCL. Hypoalbuminemia and diarrhea improved following the initiation of R-CHOP regimen. The DLBCL showed a favorable response to treatment, and gastrointestinal lesions and hepatosplenomegaly improved, along with the resolution of protein-losing enteropathy.

The standard therapies for primary cutaneous anaplastic large cell lymphoma (pcALCL) in an advanced stage remain undefined. A 71-year-old man presented with multiple erythema and nodules. He was diagnosed with lymphomatoid papulosis (LyP) through a skin biopsy from the left postauricular area. All skin lesions achieved complete response by electron beam irradiation. However, nodular lesions appeared in both inner canthi 5 months later. Histopathological evaluation of the lesional biopsy revealed dominant infiltration of CD30-positive large cells. Positron emission tomography/computed tomography revealed fluorodeoxyglucose-positive cervical and inguinal lymph node swelling and right tonsillitis, followed by the diagnosis of pcALCL and TNM classification T3bN3M0. Since the patient had severe chronic obstructive pulmonary disease and recurrent pneumonia, he received low-dose methotrexate (MTX) (15 mg/week) therapy. Low-dose MTX effectively debulked the lymphadenopathies over time without particular adverse effects. Although the standard therapies for pcALCL are not established, low-dose MTX was effective and considered safe for patients with frailty and compromised respiratory function. Further study is warranted on the pathophysiology of pcALCL after the development of LyP and mechanisms of action of low-dose MTX against LyP and pcALCL.

A 44-year-old female was diagnosed with follicular lymphoma (FL), grade 3A stage III, by right cervical lymph node biopsy at the age of 43 years. The patient chose to not receive the treatment despite the high tumor burden. The patient came back after 18 months with respiratory distress and had systemic infiltration and pleural effusion. Positron emission tomography (PET)/computed tomography (CT) showed fluorine-18 deoxyglucose accumulation with maximum standardized uptake value ranging from 10 to 18 in bone marrow, liver, spleen, lung, and systemic lymph nodes (cervical, supraclavicular, infraclavicular, axillary, mediastinal, hilar, para-aortic, iliac, and inguinal). Left inguinal lymph node biopsy revealed mixed cellularity classical Hodgkin lymphoma (CHL), which was thought to be an FL transformation or a composite condition. The patient was treated with A + AVD and achieved lymph node shrinkage as well as improvement of tumor fever and pleural effusion. Interim PET/CT showed improvement in most parts after two courses; however, it revealed some new or progressive lesions in the bone marrow and left cervical lymph nodes. Left cervical lymph node biopsy revealed nodular sclerosis CHL. The patient was treated with ESHAP, which resulted in stable disease; following this, the patient was treated with nivolumab, which was highly effective. FL transformation to CHL is rare, and this is the first report of such transformation without treatment.

A 66-year-old man with fever was diagnosed with B-cell acute lymphoblastic leukemia. He failed to achieve complete remission after initial hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) therapy and was referred to our hospital to undergo allogeneic stem cell transplantation. Bone marrow aspiration showed 97.5% lymphoblasts positive for CD19. Blood tests revealed the presence of broad antihuman leukocyte antigen (HLA) antibodies. After blinatumomab therapy, bone marrow aspiration showed 19.6% blasts. Furthermore, after additional mini-mitoxantrone, etoposide, and cytarabine (mini MEC) therapy, the patient achieved complete remission. Interestingly, after blinatumomab therapy, the blood tests revealed that the titers of anti-HLA antibodies had decreased, and cord blood transplantation was performed in complete remission. This case report revealed that chemotherapy including blinatumomab, which targets CD19-positive cells, has the potential to decrease antibody-producing cells, thus leading to a dramatic reduction of anti-HLA antibodies.

Hematopoietic stem cells’ (HSCs) metabolic dynamics regulate cell fate and differentiation. To maintain the stemness of HSCs, it is necessary to maintain an appropriate balance of adenosine triphosphate (ATP) production by the glycolytic system and mitochondria. In conventional intracellular ATP measurement, snapshot analysis is performed after the lysis of a large number of cells, resulting in the loss of single-cell level and spatiotemporal information. To overcome this technical limitation, we recently developed a methodology for measuring ATP concentration in living HSCs using knock-in mice of an intracellular ATP concentration biosensor called GO-ATeam2, which employs the principle of Förster resonance energy transfer. The current understanding of metabolism in HSCs, the metabolic dependence of HSCs revealed by the GO-ATeam2 system, and the prospects for novel metabolic measurement techniques in the future are reviewed in this paper.

Somatic mutations in the epigenetic regulator ASXL1 are considered a poor prognostic factor in myeloid malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). ASXL1 mutations coexist with other mutations in majority of patients, suggesting that its mutation alone is insufficient to cause cancer. ASXL1 mutations have been detected in age-related clonal hematopoiesis (CH), which has been linked to an increased risk of hematological malignancies. Therefore, ASXL1 mutations are likely to be one of the first events in the tumorigenesis process. With our most recent findings, we summarize the mechanisms by which ASXL1 mutations cause CH and hematological malignancies in this review.

Thalidomide was developed as a sedative drug during the 1950s. Unfortunately, it has serious teratogenic properties. When pregnant women ingested thalidomide, their infants developed serious malformations such as short limbs. However, thalidomide is now recognized as a clinically useful drug, with several countries approving it as an anti-myeloma treatment. Although the direct target of thalidomide was largely debated until recently, our groups discovered cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase as a primary target of thalidomide in 2010. CRBN binds not only to thalidomide, but also to various thalidomide derivatives such as lenalidomide and pomalidomide, as well as compounds containing a thalidomide moiety. These compounds are known as cereblon modulators, which induced specific neosubstrates of CRBN E3 ubiquitin ligase such as Ikaros and Aiolos. Several groups have now joined the CRBN research and have reported the basic mechanism of CRBN and its binding compounds. In this review, we present our findings as well as recent advances in this subject area.

With the advent of new drugs, the treatment outcome of multiple myeloma (MM) has dramatically improved. However, cure for MM has been difficult to attain, and the prognosis of cases resistant to various treatments remains extremely poor. In March 2021, the United States Food and Drug Administration approved idecabtagene vicleucel (Ide-cel) —a B-cell maturation antigen-targeted chimeric antigen receptor (CAR) T-cell therapy —for the treatment of patients with relapsed/refractory MM. The Japanese Ministry of Health, Labor and Welfare approved Ide-cel in December 2021, and CAR T-cell therapy for MM will soon be available for clinical use. This review highlights the latest evidence regarding CAR T-cell therapy for MM.

Diamond-Blackfan anemia (DBA), congenital dyserythropoietic anemia (CDA), and inherited sideroblastic anemia (ISA) are representative diseases of inherited bone marrow failure syndromes in erythrocyte diseases. DBA is primarily caused due to ribosomal dysfunctions. Furthermore, reticulocytes and erythroid progenitor cells decrease considerably within the peripheral blood and bone marrow, respectively. CDA is caused by a disturbance in red blood cell maturation and ineffective erythropoiesis due to hemolysis in the bone marrow. CDA is mainly classified into types I to III, and multinucleated erythroblasts observed in the bone marrow, typically in the internuclear bridge in type I. ISA is caused by iron metabolism dysfunction in the mitochondria due to defective heme synthesis. Sideroblasts appear ringed due to iron accumulation in the mitochondria of erythroid precursors. Gene mutation analysis is indispensable for the confirmatory diagnosis of these diseases; however, narrowing down the diagnosis, by examining the erythrocytes in the peripheral blood and the erythroblast morphology in the bone marrow, is also important.

Sideroblastic anemias (SAs) are a group of heterogeneous congenital and acquired disorders characterized by anemia and presence of ring sideroblasts in the bone marrow. Congenital SA is a rare condition caused by mutations of genes involved in heme biosynthesis, iron-sulfur cluster biosynthesis, and mitochondrial protein synthesis. SAs can also occur following exposure to certain drugs or alcohol or caused by copper deficiency (secondary SA). SAs have been found to be associated with myelodysplastic syndrome (idiopathic SA), which strongly correlates with specific somatic mutations in SF3B1 (splicing factor 3b subunit 1), involved in the RNA splicing machinery. The recent widespread use of genome-editing technology and next-generation sequencing has led to a better understanding of the molecular pathophysiology of SAs. This review discusses the current understanding of the pathophysiology of SAs.

Autoimmune hemolytic anemia (AIHA) is a type of anemia caused by the destruction of red blood cells due to autoantibodies targeting membrane proteins. AIHA is divided into two types based on the thermal amplitude: warm AIHA (at 37°C) and cold AIHA (at <37°C). Anemia and jaundice are the major symptoms of AIHA, and in cold agglutinin disease the peripheral circulation disturbance deteriorates patients’ quality of life. Cumulative evidence has revealed that both types of AIHA increase the risk of thrombosis and intravascular hemolysis appears to be the most critical factor in the pathogenesis. Complement activation plays an important role in the intravascular hemolysis of AIHA, though the coagulation and hemostatic systems and the crosstalk between these systems also contributes significantly to the pathogenesis of thrombosis. Future treatment of AIHA should be targeted at not only alleviating anemia but also reducing thrombotic risk.

B-cell lymphoma accounts for approximately 70% of malignant lymphomas, and its treatment outcomes have drastically improved after the introduction of rituximab. Most patients with diffuse large B-cell lymphoma (DLBCL) are successfully treated with the current standard chemotherapeutic regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, 30-40% of patients with DLBCL have unsatisfactory treatment outcomes. Molecular genetic research has greatly contributed to the identification of pathogenic mechanisms of lymphoma and factors leading to poor prognosis. Thus, novel agents for targeting factors in key signaling pathways, relevant targeted antigens, and epigenetic enzymes have been developed. Additionally, development of immunotherapies such as anti-CD19-chimeric antigen receptor (CAR) T cell and bispecific antibody therapy have led to a paradigm shift for relapsed or refractory DLBCL treatments. Herein, we discuss the results of clinically impactful studies on the treatment strategies of B-cell lymphoma, including DLBCL, follicular lymphoma, and lymphoplasmacytic lymphoma.

According to the recently revised WHO classification, peripheral T-cell lymphomas (PTCL) can be classified into up to 30 subtypes. Because the majority of these subtypes were rare cancers, their pathophysiology was not well understood. However, technological advancements including multi-omics approaches such as genomic and gene expression analyses have made significant progress in understanding the pathophysiology of PTCL. Based on the results of these basic studies, the classification of T-cell lymphomas has been changed. Furthermore, new markers discovered through genomic analysis and gene expression analysis are being incorporated into the diagnostic processes of PTCL. Furthermore, multiple new drugs were approved to treat patients of PTCL. Clinical trials are also being carried out as first-line treatments to test the efficacy to combine these new drugs with conventional treatments.

Multiple myeloma (MM) is still one of the most difficult hematological diseases. It is distinguished by recurrent relapses despite successful treatment. Proteasome inhibitors, immunomodulatory imide drugs, and monoclonal antibodies have all been developed in the last 10 years as treatment options for MM. However, obtaining a long-term treatment-free period for relapsed and refractory multiple myeloma (RRMM) remains difficult. The most recent and intriguing research is on new BCMA-targeting therapies. CAR-T cell therapy, in particular, has shown promising results in the treatment for triple class refractory MM patients. BCMA CAR-T cell therapy is gaining attention as a potentially game-changing treatment for multiple myeloma. Fortunately, CAR-T cell therapy will be available in Japan in January 2022. However, numerous issues must be addressed. Many RRMM patients receive CAR-T cell therapy, for example, relapse, and progression-free survival are short. This section provides an overview of clinical study results for CAR-T cell therapy targeting BCMA, and the antibody-drug conjugate, bispecific antibodies, selinexor, and venetoclax.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made the management of coronavirus disease-2019 (COVID-19) in patients with hematological disorders a new and important theme for hematologists. Patients with myeloproliferative neoplasms (MPNs) are susceptible to SARS-CoV-2 and are at an increased risk of death after the onset of COVID-19. Thus, infection prevention measures, including vaccination for all patients, are important. Patients with MPNs who have COVID-19 have a poor prognosis, as do patients with other hematological malignancies. The thrombogenic characteristics of MPNs increase the risk of venous thrombosis due to COVID-19. Anticoagulant therapy is adjusted according to the risk of each case after COVID-19 onset. However, thrombosis occurs at a high rate, especially in patients with essential thrombocythemia. Additionally, patients with myelofibrosis have an increased risk of death and bleeding. Ruxolitinib treatment poses a risk of SARAS-CoV-2 infection, and its abrupt discontinuation after infection is associated with an increased risk of death. The emerging evidence of COVID-19 has been quickly reflected in the available treatment recommendations and guidelines.

Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of chronic myeloid leukemia (CML). Five types of TKIs, including the third-generation TKI, ponatinib, are available in Japan, and TKI resistance has almost been overcome. However, TKI-related adverse events, such as vascular occlusive diseases that are frequently associated with ponatinib use, have become a critical concern. A recent dose optimization study of ponatinib demonstrated a dosing regimen that balances its risks and benefits in CML therapy. Furthermore, asciminib, a CML therapeutic drug with a new mechanism of action, has become available and is being applied clinically in Europe and the USA. This article outlines the latest treatments developed for CML in the chronic phase with prior therapy.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell neoplasms, which are characterized as bone marrow failure with a propensity to develop acute myeloid leukemia (AML). Patients with MDS tend to be of higher age, with usually poor antineoplastic chemotherapy response. The life prognosis of MDS is poor, and its curative treatment is limited to allogeneic hematopoietic cell transplantation. Recent advances in hematopoietic cell transplantation, including alternative donors or reduced-intensity conditioning regimens, resulted in an expanded treatment indication for patients of higher age. Moreover, several novel therapeutic agents are implemented after the elucidation of pathological processes in MDS. Therapeutic agents that can alter the disease course, including azacitidine and lenalidomide, are approved and available in Japan. Additionally, other therapeutic agents for MDS, such as erythropoiesis-stimulating agents and oral iron chelators, are also available, and clinical trials for novel agents are also underway. This study discussed the updated risk-stratified treatment strategies for MDS and the development of novel agents.

Acute myelogenous leukemia (AML) is a hematopoietic malignancy that is characterized by clonal autonomous proliferation of myeloid cells with impaired differentiation and maturation. Recent advances in next-generation sequencing technology have elucidated the pathogenesis of AML at the genetic level. Furthermore, the molecular targeted therapy to efficiently eradicate leukemic cells has been rapidly expanding since 2017. In Japan, gilteritinib and quizartinib, which target FMS-like tyrosine kinase 3, and venetoclax, which targets B-cell lymphoma 2, have finally become available after resolving the drug launch lag between Japan and the United States. The combination of venetoclax and azacitidine, which was simultaneously approved with venetoclax for AML, is expected to be more effective than conventional therapy in patients who are ineligible for transplantation. Herein, we review the National Comprehensive Cancer Network guidelines for intensive chemotherapy in Japan and the United States and discuss the future of AML treatment, including the development of novel agents.