Almost all genetic abnormalities involved in the occurrence and progression of myelodysplastic syndromes (MDS) and acute myeloid leukemia have been reported within the last decade. The molecular mechanisms of these genetic changes involved in causing dysfunctions in hematopoietic cells have also been clarified in recent years. For MDS, gene mutations of RNA splicing factors and cohesin complex have been shown to trigger not only aberrant RNA splicing or decreased chromatin insulation but also DNA damage response and transcriptional dysregulation through inefficient interaction between promoters and enhancers. Consequently, these newly identified disease-causing mechanisms may be considered potential therapeutic targets.

Clonal hematopoiesis (CH) harboring a leukemia-related mutation has been recently found in about 10% of healthy elderly individuals, which has been attracting attention. Although most people with CH do not develop hematological malignancies, some may develop hematological malignancies 10 times more frequently than age-matched controls. On the other hand, compared to age-matched controls, the probability of developing cardiovascular diseases in people with CH is 2-fold, which is thought to shorten the life expectancy. Moreover, one out of four patients with solid cancer and one out of two patients with aplastic anemia, whose mutation profiles overlap with but are distinct from common mutations identified with CH of elderly people, harbor CH. The study of CH has just begun, and there are many unknowns. In an aging society of unprecedented proportions, which is also attracting attention from the society, the establishment of a new research field that investigates CH in the near future is likely.

A huge number of indigenous commensal bacteria reside in the intestines of humans and animals. However, the host animals do not unconditionally accept gut microbiota. In order to contain gut microbiota by secreting immunoglobulin A, the intestine is equipped with the intestinal immune system, literally the largest peripheral lymphoid tissue in the body where 60 to 70% of peripheral immune cells are accumulated. On the other hand, the gut microbiota greatly impact the host physiology and pathology. Normal development of the host immune system relies on interaction with the gut microbiota. In addition, abnormal gut microbiota, or dysbiosis, is known to be associated with various disease statuses including autoimmune diseases. Understanding of the causal relationship between the pathophysiology of these diseases and dysbiosis is still limited, but verification experiments using animal models have been clarifying that gut microbiota is an important regulatory factor the pathogenesis and progression of these diseases.

Various factors have led to anemia, including a deficiency or excess of trace metals. Copper deficiency, zinc deficiency and lead poisoning are of particular clinical importance. Among them, it should be noted that copper deficiency is increasing due to the use of zinc preparations and the generalization of gastric and intestinal nutrition.

Thalassemia is caused by a reduced production of one globin chain due to a quantitative imbalance between the α-globin and non-α-globin chains that make up the hemoglobin. It is classified into α- and β-thalassemia and characterized by microcytosis with polycythemia, and a Mentzer index of ≤13 aids in the diagnosis. In the genetic analysis of α-thalassemia, the Southeast Asian type was found to be the most common genetic subtype among Japanese and non-Japanese without a substantial difference. Conversely, the genetic analysis of β-thalassemia revealed differences in the types and frequencies of mutations between Japanese individuals and foreigners living in Japan, with Japanese-specific mutations such as −31 A→G (TATA box). Acquired α-thalassemia exists in exceptional cases, and cases of myelodysplastic syndrome with acquired Hemoglobin H disease have been reported as α-thalassemia myelodysplastic syndrome. Recent trials using a novel therapeutic agent, luspatercept, for transfusion-dependent β-thalassemia revealed that luspatercept safely and significantly reduces the transfusion volume.

Treatments of aplastic anemia comprise supportive therapy and aplastic anemia-specific therapy to recover from hematopoiesis. Supportive therapy includes transfusion, granulocyte colony-stimulating factor, and iron chelation therapy in addition to symptomatic treatment. Aplastic anemia-specific treatments that aim to achieve hematopoietic recovery are immunosuppressive therapy, thrombopoietin receptor agonist (TPO-RA) treatment, allogeneic hematopoietic stem cell transplantation, and anabolic hormone therapy. Although the transplantation achieves complete recovery of hematopoiesis (healing), there is a risk of death from transplant-related complications. The most effective drug therapy is the combination of TPO-RA and the immunotherapy combined with anti-thymocyte globulin and cyclosporine. This treatment is also effective against secondary, drug-induced, or hepatitis-associated aplastic anemia. In the treatment of aplastic anemia, the treatment choice is made based on the disease severity and patient ages.

Pure red cell aplasia (PRCA) is characterized by normocytic anemia with reticulocytopenia and marked reduction of the bone marrow erythroid precursors. PRCA may be congenital (Diamond-Blackfan anemia) or acquired. Acquired PRCA may present in the context of various backgrounds, the most common type in Japan being idiopathic, thymoma-associated, and large granular lymphocyte leukemia. Idiopathic and secondary PRCA that do not respond to the treatment of the underlying disease are generally treated using immunosuppressive agents. A retrospective study PRCA2004/2006 suggests that maintenance therapy and management of infectious complications is crucial for improving the prognosis in patients with PRCA. Recently, allogeneic stem cell transplantation has been considered as a potential option for the treatment of patients with PRCA who are refractory to immunosuppressive therapy. Sirolimus and roxadustat may be effective for relapsed/refractory PRCA with renal insufficiency and anti-erythropoietin antibody-mediated PRCA, respectively. Some gene mutations were detected in certain patients who had acquired PRCA, and the identification of STAT3 mutations may be useful in PRCA management. A prospective cohort study PRCA2016 has been ongoing in Japan, and novel discoveries provide hope for improving the outcome in patients with PRCA.

Oxygen biology is currently a focus of intensive scientific research. Three scientists received the Nobel prize in physiology or medicine for their outstanding scientific efforts in revealing the mechanisms of oxygen sensing and defense against hypoxia. Hypoxia is a final common pathway to end-stage kidney disease and plays a crucial role in the pathogenesis of cardiovascular complications. Hypoxia-inducible factors (HIFs) are master regulators of defensive mechanisms against hypoxia. Erythropoietin is one of the main targets of HIFs that enhances oxygen delivery by increasing the production of red blood cells. HIF levels are regulated by HIF-prolyl hydroxylase (HIF-PH) inhibitors, which are now available as a new therapeutic modality against anemia in chronic kidney disease. HIF-PH inhibitors raise some theoretical concerns, but should be noted for their potential organ-protective effects.

Paroxysmal Nocturnal hemoglobinuria, PNH is usually caused by the somatic mutation of X-linked PIGA gene followed by the clonal expansion of the GPI (glycosylphosphatidylinositol) anchor defective hematopoietic stem cell clone. There are two hypotheses for the mechanism of clonal expansion, one is selection theory, in which GPI deficient cells escape from attacks of cytotoxic cells, and another is benign tumor theory in which GPI deficient cells get the additional mutations and acquire proliferative nature. Recently, we identified two types of PNH patients caused by the biallelic mutation of PIGT on chromosome 20 and PIGB on chromosome 15. Both PNH clones had the germ-line mutation in one allele and another allele was somatically mutated in a hematopoietic stem cell. Both somatic mutations were loss of heterozygosity (LOH), deletion in PIGT-PNH and copy neutral LOH (CN-LOH) in PIGB-PNH. These PNH patients had typical PNH symptoms, but they have in addition auto-inflammatory features. Unlike in PIGA-PNH cells, GPI is synthesized in PIGT-PNH cells and, since its attachment to proteins is blocked, free GPI is expressed on the cell surface. Similarly, in PIGB-PNH cells, GPI intermediates are accumulated and expressed on the cell surface. Those GPIs together with complement activation cause the inflammasome activation.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene represent the most common genetic alteration in acute myeloid leukemia (AML), identified in approximately one third of patients newly diagnosed with AML. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple inhibitors of FLT3 signaling have been developed in the last few years with variable kinase-inhibitory properties, pharmacokinetics, and toxicity profiles. At present, two FLT3 inhibitors (gilteritinib and quizartinib) have been approved as monotherapies for relapsed/refractory FLT3-mutated AML in Japan, and many more drugs are currently being researched in clinical trials as monotherapies or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front line, relapsed/refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. Despite significant advances, some issues need to be overcome, including the resistance to FLT3 inhibitors and controversies regarding the role of FLT3 inhibitors in maintenance therapies and the role of allogeneic stem cell transplantation in FLT3-mutated AML.

The etiology and pathogenesis of acute myeloid leukemia (AML) have been elucidated at chromosomal and genetic levels. The classification and prognosis for its treatment has clearly involved specific chromosomal aberrations and genetic mutations. The recent comprehensive genomic analysis represented by next-generation sequencers has led to discovering new genetic mutations in AML. These findings have not only been applied clinically as prognostic factors and MRD markers but also contributed to the development of new molecular-targeting drugs. Many new drugs have already been approved in the USA and Europe, and new stratified treatments have tried to incorporate them. With the advent of venetoclax, treatment strategies, especially for patients with poor prognosis and who are unfit, have been substantially revised, and the maintenance therapy for AML is also being reevaluated in accordance to the National Comprehensive Cancer Network guidelines. This article will review the current status of AML treatment in Japan and according to Western guidelines.

Recurrence in acute myeloid leukemia (AML) is a major barrier in patients who achieve complete remission after induction of remission and consolidation therapy and desire long-term survival. Allogeneic hematopoietic stem cell transplantation lowers recurrence risk in patients; however, recurrence is common even after transplantation. Many maintenance therapies for AML aim to lower recurrence risk; therefore, research has focused on identifying drugs with a tolerable adverse-effect profile. Thus far, many trials of cytotoxic anticancer drugs used in maintenance therapy have showed no improvement in survival rates. In contrast, recent studies on immunomodulation, epigenetics, molecular-targeted drugs, etc. have demonstrated promising results. Therefore, we plan to review various maintenance therapies, such as immunotherapy, demethylating agents, and targeted therapies (including fms-like tyrosine kinase 3 inhibitors in particular) based on the current evidence. Moreover, we describe a new strategy that incorporates the assessment of measurable minimal residual disease.

Leukemia is caused by uncontrolled proliferation of immature hematopoietic progenitors. MLL fusion proteins, generated by chromosomal translocations, activate a broad range of previously transcribed genes to achieve the same expression profile as that of the parent cell in the daughter cells, thereby promoting self-renewal. Normally, replication of the expression profile only occurs in the hematopoietic stem cells (HSCs). A transactivation system comprised of MLL and AF4/ENL/P-TEFb (AEP) complexes promotes it by reactivating CpG-rich promoters. In the normal hematopoietic development, this system is tightly regulated and progressively suppressed during the course of hematopoietic differentiation so that non-HSC hematopoietic cells would not self-renew. Genetic mutations such as fusions of MLL and AEP components generate a constitutively active form of the MLL transcriptional machinery, which aberrantly promotes self-renewal even in non-HSC hematopoietic cells. In this review, I depict a molecular mechanism of MLL fusion-mediated leukemogenesis from a standpoint that leukemogenesis is driven by aberrant self-renewal that is mediated by hyper-active transcriptional machinery, and introduce several molecularly targeted therapies in the making which specifically perturb this transactivation system.

The coronavirus disease 2019 (COVID-19) pandemic has exerted a considerable impact in our region; thus, we have been performing only emergency transplants in March 2020. At present, all inpatients and surgical patients are being tested and screened for COVID-19. If they are found to be positive, they are transferred to the COVID-19 ward, where a specialized team manages them. Team-based care allows the hematology/oncology teams to perform their regular duties. In particular, for post-transplant patients, treatment decisions are made through discussion with infectious disease specialists, and in principle, the patients are treated using the same protocol as that used for the general COVID-19 infected patients. Currently, vaccination is being promoted at a rapid pace based on the Centers for Disease Control and Prevention Guidelines (CDC) guidelines. At our institution, when a situation of suspected nosocomial COVID-19 infection occurred, all healthcare workers were tested. Thereafter, all hospitalized patients were tested every week for COVID-19, and we were able to overcome the situation. Although definitive measures for COVID-19 are yet to be established, signs of an end to the infection are beginning to appear with a wider availability of vaccines.

Precision medicine refers to a medical model wherein treatments are customized for the patients according to their lifestyles, genetic background, and other molecular and physiological test results. Herein, I discuss the utility of comprehensive genomic profiling of hematologic malignancies and provide a perspective on the future of genomics-based precision medicine in the field of hematology/oncology.

The chronic myeloid leukemia (CML) therapeutic landscape has dramatically changed with the development of tyrosine kinase inhibitors (TKIs), which allows for a near-normal life expectancy. Five TKIs have been currently approved for CML treatment in Japan, of which four have been indicated as first-line therapy (i.e., imatinib, nilotinib, dasatinib, and bosutinib). Nowadays, the long-term prognosis of patients with CML is determined not by the primary disease but rather by the comorbidities and treatment-related adverse events (AEs), including cardiovascular events. Assessment of risk profile and comorbidities at diagnosis is essential for the appropriate choice of TKI and long-term survival management. The ability of some patients who achieve deep molecular responses to discontinue therapy successfully is well documented. Long-term treatment-free remission with continued response to TKI therapy is now recognized as the most optimal treatment benefit for some patients.This article discusses treatment strategies, AE management, and future perspectives based on the latest CML treatment guidelines.

BCR-ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML). Currently, five BCR-ABL TKIs are approved for use in patients with CML, but the long-term use of these TKIs is associated with various cardiovascular events. Typical cardiovascular adverse events include pulmonary hypertension caused by dasatinib and arterial occlusive diseases caused by nilotinib and ponatinib. Although mechanisms of cardiovascular adverse events of BCR-ABL TKIs in the treatment of CML have not been clarified, differences in their inhibitory activities on off-target kinases, including those involved in vascular function, may be related to individual safety profiles. Arterial occlusive diseases are common in patients with a history of cardiovascular disease and risk of atherosclerosis. Arterial occlusive diseases, such as ischemic heart disease, ischemic cerebral disease, and peripheral arterial occlusive disease, worsen the prognosis and quality of life of patients with CML. Therefore, appropriate management strategies are required. This paper outlines cardiovascular adverse events associated with TKI treatment, including arterial obstructive diseases, pulmonary arterial hypertension, and QT interval prolongation.

The development of gene analysis in cancer is remarkable, and understanding of molecular pathology has been elucidated. Somatic mutations, that is, genetic analysis in cancer cells, have contributed to the accurate diagnosis of tumors, prognostic prediction, and detection of therapeutic targets. In contrast, germline mutations have been identified as the cause of hereditary diseases. In the past, symptom diagnosis was the main focus for hereditary diseases. However, genetic information has greatly contributed to its definitive diagnosis. For hematopoietic malignancies, the 2016 revision of the World Health Organization classification newly proposed a section on myeloid neoplasms with germline predisposition. Genetic predispositions characterized by the development of lymphoid neoplasms and solid tumors have also been reported. Since 2016, new findings such as SAMD9/9L mutation have been discovered. This chapter outlines the typical genetic predisposition to myelodysplastic syndrome/leukemia.

Myelodysplastic syndrome (MDS) is a group of clonal diseases caused by the accumulation of genetic mutations. The outcome of MDS extremely varies, with an overall survival ranging from just a few months to years. Therefore, accurate classification and prognostic scoring are essential. Patients with MDS are generally divided into two risk groups. For low-risk patients, the treatment goal is to improve ineffective hematopoiesis and quality of life. Meanwhile, in high-risk patients, treatment aims to extend survival and prevent progression to leukemia. To date, different guidelines recommend azacytidine, which is a hypomethylating agent, as the initial treatment. This is the only therapy associated with a significant survival in high-risk patients who are not eligible for hematopoietic stem cell transplantation. However, the response rate is only about 40%, and responses are mostly transient. Recent advancements in sequencing technologies have improved our understanding of the molecular pathogenesis of MDS by identifying somatic mutations in almost each patient with MDS. The high phenotypic and clinical heterogeneity of patients with MDS is primarily based on genetics. Due to a high degree of heterogeneity, the treatment policy for patients with MDS is still challenging. In this review, we will discuss the current treatment strategies for MDS in Japan, including future perspectives.

Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN), wherein JAK2 V617F mutation exists as a common driver mutation, and the JAK-STAT pathway is constitutively activated. The treatment goal for ET and PV is the prevention of thrombosis and bleeding. The treatment strategy for ET is careful observation or antiplatelet therapy with or without cytoreductive therapy based on the thrombotic risk. The treatment strategy for all PV patients is phlebotomy with a target hematocrit of <45% in addition to antiplatelet therapy. Moreover, for patients at a high risk of thrombosis, additional cytoreductive therapy is considered beneficial. In this session, we discuss important points for ET diagnosis, thrombotic risk stratification, and the details of treatment strategy and current practice with evidence from clinical trials in ET. Furthermore, current topics in the treatment of ET and PV will be introduced with a focus on clinical data about interferon-α, which is reported to induce not only hematologic response but also molecular and histopathologic response in MPN.

Myeloproliferative neoplasms (MPN) are caused by somatic mutations in hematopoietic stem/progenitor cells and result in excessive increase in the blood cell mass in the peripheral blood and/or fibrosis in the bone marrow. JAK2, CALR, and MPL mutations are well-known driver mutations of MPN and are widely applied as diagnostic markers of MPN. Moreover, several studies using massive parallel sequencing technologies have shown that mutations in ASXL1, EZH2, SRSF2, and IDH1/2 affect the prognosis of overt primary myelofibrosis and have further clarified that the mutation order may influence the MPN phenotype. More recently, our group identified that CREB3L1 mRNA was overexpressed in a platelet- and megakaryocyte-specific manner in driver mutation positive MPN and that the quantitation of this gene expression can be used as a diagnostic marker for MPN. In this educational lecture, we discuss the clinical impacts of the mutations frequently identified in MPN patients.

The prognosis of patients with follicular lymphoma (FL) has improved over the last decades. However, most patients with FL will eventually relapse. The management of FL is mainly determined by clinical stage and tumor burden. For localized-stage patients, an involved-field radiation therapy is recommended. For advanced-stage low tumor burden patients, watchful waiting remains the standard treatment, whereas rituximab monotherapy may be an alternative option. Immuno-chemotherapy combined with rituximab maintenance has been the standard care for patients with high tumor burden. Recently, the novel anti-CD20 monoclonal antibody obinutuzumab was approved for the treatment of FL. Obinutuzumab with chemotherapy followed by obinutuzumab maintenance is considered one of the standard therapeutic options. After relapse or progression, it is necessary to consider a treatment strategy based on several disease-related, treatment-related, and patient-related factors. During the last decade, the development of biological knowledge and use of molecularly targeted agents offer new therapeutic perspectives with chemo-free strategies. This review highlights the current standards for the treatment of FL.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma affecting about 14,000 patients per year in Japan. Recent progress in molecular genetic investigation has clarified the underlying mechanism of this heterogeneous disease applied to therapeutic developments. R-CHOP therapy was established as a standard regimen for DLBCL and provides a cure in many patients. However, about 30-40% of patients still develop relapsed/refractory (R/R) disease. The development of effective treatments for R/R DLBCL patients is thus an urgent issue. The development of immunotherapy for intractable DLBCL patients such as anti-CD19 chimeric antigen receptor (CAR)-T therapy and bispecific T-cell engager (BiTE) has recently progressed. This new modality demonstrates efficacy in patients with resistance to conventional anticancer drugs. The advent of emerging immunotherapy is a paradigm shift in lymphoma treatment and is important for clinicians to catch up with these changes.

Chronic lymphocytic leukemia (CLL) is a rare type of lymphoid malignancy among Japanese. Its clinical course is indolent, and the prognosis is good. The two types of CLL based on the mutation status of the IgH gene V segment have been documented in the literature. Then, the del (17p)/TP53 subtype is emphasized, and the treatment strategy for the three subtypes differs. Recent knowledge on molecular pathogenesis facilitated the usage of Bruton’s tyrosine kinase (BTK) and BCL2 inhibitors for the treatment of CLL. A better response can be obtained with the use of these novel agents, resulting in a higher rate of negativity for measurable residual disease (MRD). The treatment strategy based on MRD negativity and the treatment outcomes of CLL will improve in future.

It is over two decades since the first retrospective analysis indicated the superiority of pediatric-like therapy for adolescent and young adult (AYA) patients in 2000. To date, many prospective studies confirmed the efficacy and safety of pediatric-like therapy for AYA and older adult ALL, while therapy for pediatric ALL also made progress by innovating a new technology such as stratification of therapy by minimal residual disease (MRD). Furthermore, it is expected that further improvements will be achieved by applying newly approved anti-cancer drugs such as inotuzumab ozogamicin and blinatumomab. In this review, I will introduce these front line studies and discuss about the perspective of adult B-ALL treatment.

Four cycles of ABVD followed by 30 Gy IFRT (ISRT) is a standard regimen, as an initial treatment, for patients with early-stage classical Hodgkin lymphoma (cHL), whereas 2 cycles of ABVD followed by 20 Gy IFRT (ISRT) is an alternative regimen for those with favorable early-stage cHL. For patients with unfavorable early-stage cHL including bulky disease, local radiotherapy can be safely omitted if negative findings on interim PET are obtained after 2 cycles of escalated BEACOPP plus 2 cycles of ABVD. ABVD (6/8 cycles) or brentuximab vedotin (BV) with concurrent AVD (6 cycles) is a standard regimen for patients with advanced-stage cHL. For elderly cHL patients (60 years of age or older) and multiple comorbidities, the risk of treatment-related adverse events is higher, which can potentially lead to poor outcomes. BV with sequential AVD therapy, which is a unique combination strategy, has been developed for elderly cHL patients. The combination of anti-PD-1 antibodies with AVD therapies is currently being evaluated in some clinical trials. This review includes current evidence that primarily focuses on randomized clinical trials for newly diagnosed adult cHL patients and management points in clinical practice for those patients.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non-Hodgkin lymphomas (NHLs) with poor prognoses as compared with those of B-cell NHLs. CHOP or CHOP-like regimen has been considered to be the standard treatment for almost all pathological subtypes of PTCL; however, these regimens result in low complete response rate and short progression-free survival (PFS). Due to these insufficient results with CHOP-based chemotherapy, there is an urgent need for more effective and newer therapeutic strategies. The positive results of the ECHELON-2 study, which demonstrated significantly longer PFS with brentuximab vedotin plus CHP therapy in the frontline treatment for CD30-positive PTCLs, have a great impact on our clinical practice. At present, translational research is being actively conducted to elucidate molecular biology in PTCLs, and deep understanding of the underlying molecular mechanism of PTCLs would produce changes in disease classification. Until now, clinical development of novel agents based on the clinical classification has been carried out for all PTCL subtypes, but from now, treatment development based on molecular biology will be strongly required.

Lymphoma comprises a group of diseases characterized by neoplastic proliferation of mature B, T, and NK cells. This disease entity is widely recognized to be clinically, pathologically, molecularly, and genetically heterogeneous. The classification of lymphomas was classically based on morphology and immunology, but recent dramatic advances in next-generation sequencing technology have revealed various genetic alterations in lymphomas, which influenced the revision of the WHO classification in 2017. Accumulating evidence on genetic alterations has enabled the development of more accurate diagnostic strategies and prognostic markers. Moreover, these findings provide opportunities to exploit new therapeutics that target genetic alterations, which would facilitate the use of precision medicine in lymphomas. Here, we briefly review the fundamental methods of genetic analysis using next-generation sequencing technology and describe the entire scenario of genetic alterations, focusing on the recent major studies that have revealed various genetic alterations in each lymphoma subtype and present a detailed discussion of the results and methods.

Ph-like acute lymphocytic leukemia (ALL) is a subtype of Ph-negative B precursor ALL, and its gene expression profile is similar to that of Ph+ALL. In recent decades, comprehensive genomic analyses have revealed that Ph-like ALL has two types. The first type is associated with the ABL-class tyrosine kinase fusion gene, and the second type with fusion genes involving cytokine receptors or molecules, including CRLF2, which are correlated with the activation of the JAK/STAT pathway. Based on these findings, tyrosine kinase or JAK inhibitors were found to be effective for Ph-like ALL. Genetic abnormalities identified in Ph-like ALL, except for CRLF2 rearrangement, are quite rare. Thus, functional studies regarding each genomic abnormality are relevant for establishing targeted therapies for Ph-like ALL. To develop a targeted molecular therapy, a functional study of NCOR1-LYN, which is a novel ABL-class fusion gene, was conducted on pediatric patients with Ph-like ALL.

Waldenström’s macroglobulinemia or lymphoplasmacytic lymphoma (WM/LPL) is a rare subtype of indolent B-cell lymphoma with plasmacytic differentiation. Owing to its rarity, the pathogenesis, biology, and standard of care have not been established. In 2012 the MYD88 L265P mutation is proven as the major oncogenesis in WM/LPL; therefore, the pathogenesis and underlying biology of WM/LPL have been drastically explored. Furthermore, treatment options have also been developed, and Bruton’s tyrosine kinase (BTK) inhibitor has been recently approved for untreated and relapsed/refractory WM/LPL in August 2020 in Japan. In this article, after a brief review of the clinical and biological characteristics of WM/LPL, we discuss the ideal therapeutic algorithm, including novel BTK inhibitor.

Multiple myeloma has been known as an incurable disease; however, since the approval of bortezomib in Japan in 2006 as the treatment for relapsed and refractory multiple myeloma, novel agents such as immunomodulatory drugs (IMIDs) and antibodies have been introduced one after another. Hence, progression-free survival and overall survival rates have markedly improved, regardless of the transplantation indication, and we have entered an era of a possible cure. Now that long-term survival can be expected, some clinical issues exist: 1) when to start treatment, 2) what regimen to choose for initial treatment, 3) how to continue treatment including maintenance therapy, 4) what to do for supportive care, and 5) what to choose for relapse treatment. The answers to these questions should be revised year-by-year according to the evidence from new clinical trials. This paper will discuss the current state of knowledge based on the latest evidence on treatment strategies for patients with myeloma who are ineligible for transplantation.

Systemic AL amyloidosis is a disease wherein amyloid proteins derived from monoclonal immunoglobulin light chains produced by abnormal plasma cells are deposited in the tissues through the whole body and cause organ failure. The treatment aims to minimize treatment-related toxicity and mortality to achieve a deeper and more persistent hematologic response as early as possible. Stem cell transplantation is preferred; however, only 20% of patients are eligible. Patients are selected as per strict transplant indication criteria. Transplant-ineligible patients receive chemotherapy with high efficacy, such as melphalan/dexamethasone, bortezomib/cyclophosphamide/dexamethasone, and daratumumab/bortezomib/cyclophosphamide/dexamethasone. The prognosis of advanced cardiac amyloidosis remains poor, and delays in diagnosis are fatal. Early diagnosis and early treatment are important to prevent and minimize organ damage.

Over the past two decades, there have been many advances in the treatment of multiple myeloma (MM), and the median survival continues to increase. The driving force behind this progress has been the development of novel therapeutic agents, such as proteasome inhibitors and immunomodulators. Antibody drugs have a different mechanism of action in comparison with these drugs and can be combined with existing drugs to enhance the therapeutic efficacy. To date, elotuzumab, an anti-SLAMF7 antibody; daratumumab, an anti-CD38 antibody; and isatuximab have been introduced. D-MPB and DLd have become the standard first-line treatment for untreated, newly diagnosed MM; whereas DBd, DLd, DCd, Isa-Pd, ELd, and EPd have become the standard of care for relapsed and refractory MM. New antibody drugs, such as bi-specific antibodies and antibody-drug conjugates, targeting various antigens, including BCMA, are now under development. In this educational lecture, I will review the status on development and clinical trials of these antibody drugs.

During the nosocomial coronavirus disease 2019 (COVID-19) outbreak, patients with hematological disorders showed poorer survival and aggressive course of respiratory failure than patients with other disorders. Two patients with immune thrombocytopenia who were being treated with prednisolone experienced severe respiratory failure related to COVID-19 and finally died. Patients who were yet to achieve remission and those receiving chemotherapy with steroids had a higher risk of death, and the mortality rate was higher in patients with lymphoid malignancies, including lymphoma and myeloma, than in those with myeloid malignancies. We describe the case of a myeloma patient in whom high-dose steroid administration was able to achieve considerable resolution of respiratory failure. In patients with unsuccessful seroconversion of anti-SARS-CoV-2 IgG antibodies, recurrence or re-infection of COVID-19 should be closely monitored.

The cancer immunoediting theory states that selective pressure by the immune system can sculpt tumor phenotypes and genotypes during all stages of tumor development. Multiple myeloma development has been recognized as a multistage process that includes premalignant expansion of plasma cells, symptomatic progression, and recurrent relapses. We discuss the dynamic crosstalk between the immune system and malignant plasma cells in light of the cancer immunoediting theory. Myeloma progression triggers dramatic alterations in the bone marrow, including bone destruction, inflammation, and angiogenesis, thereby generating an immunosuppressive milieu. We also present an overview of the immune microenvironment in multiple myeloma.

Many patients who require consultations for thrombocytopenia and coagulation test abnormalities are referred to hematology outpatient clinics. In this article, we provide information that would guide you through the differential diagnosis of these relatively common abnormalities that physicians encounter in their daily clinical practice.

Von Willebrand disease (VWD) is a congenital bleeding disorder caused by quantitative and qualitative abnormalities in von Willebrand factor (VWF). VWD was first reported in 1926 by Dr. Erik von Willebrand, a Swedish physician, who reported a bleeding disorder in a family. VWD manifests as bleeding from the skin and mucous membranes (abnormal primary hemostasis). The symptoms are less severe than those of hemophilia and may be undiagnosed in many cases. Evidence-based guidelines are required for selection and patient management. Since ristocetin cofactor activity (vWF:RCo) and VWF antigen levels (vWF:Ag) are not routinely measured in clinical laboratories, the actual diagnosis is often determined by a mild prolongation of the activated partial thromboplastic time (APTT) associated with a relative decrease in factor VIII activity. Particularly, it is desirable to provide standard treatment measures on how to introduce the recently proposed bleeding score (BS; clinically scored for various bleeding symptoms of VWD) and how to deal with gynecological symptoms, such as excessive menstruation and irregular vaginal bleeding. In terms of treatment options, recombinant vWF concentrates were introduced in 2020, which has led to the expansion in the range of treatment options for patients.

The supplementation of factor (F-) VIII or F-IX products for hemophilia treatment has helped in preventing arthropathy and considerably improving the quality of life (QOL) of patients. However, serious issues related to hemostatic treatment of hemophilia include the need for repeated intravenous infusion of products, inhibitor development, and hemostatic treatment for patients with inhibitors. To overcome these issues, some extended half-life products and nonclotting factor products were developed. An anti-F-IX/F-X bispecific antibody, emicizumab, which has a longer half life and can be administered subcutaneously, has achieved significant reduction in bleeding in patients with severe hemophilia, irrespective of the inhibitor. Furthermore, clinical trials of si-RNA anti-antithrombin therapy and antitissue factor pathway inhibitor antibody therapy, based on the concept of rebalancing coagulation, have been ongoing. Moreover, gene therapy has been currently developed by the improvement of vector. These newly developed therapies for hemophilia, as a paradigm shift in hemophilia treatment, could provide further improvement in the QOL of patients.

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially life-threatening disease that is characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and ischemic organ damage resulting from the formation of platelet-rich thrombi in the microvasculature. It is especially related to a severe deficiency of ADAMTS13, the specific von Willebrand factor-cleaving protease. Thus, <10% of the normal activity of ADAMTS13 is an essential diagnostic marker for establishing a diagnosis of TTP. TTP can be of congenital form that is termed the Upshaw-Schulman syndrome (USS) that is caused by genetic abnormality of ADAMTS13 and acquired form that is caused by autoantibodies against ADAMTS13. The congenital form is treated with the infusion of fresh frozen plasma, and the treatment of the acquired form involves plasma exchange combined with immunosuppressive therapy that uses corticosteroids and rituximab. Recently, the efficacy and safety of new drugs caplacizumab, single-domain antibody against ADAMTS13, and recombinant ADAMTS13 products have been reported in large-scale clinical trials conducted in other countries. These results suggested the better outcome in the treatment for the patients with TTP in the near future.

Helicobacter eradication therapy is the first-line therapy for patients with Helicobacter positive idiopathic thrombocytopenic purpura (ITP) in Japan. Indications for treatement in patients with Helicobacter negative, or post-Helicobacter eradicated ITP are platelet counts less than 20×10⁶/l or severe bleeding. The first-line treatment for these patients is corticosteroids. Thrombopoietin receptor agonists (TPO-RAs), rituximab, and splenectomy are second-line treatments for patients with corticosteroid refractory ITP. The choice of a second-line treatment should be determined in consideration of the advantages and disadvantages of each treatment. TPO-RAs are effective in over 80% of patients; however, long-term administration is usually needed. Rituximab treatment ends in four weeks, but its durable response rate is relatively low. The durable response rate of splenectomy is relatively high; however, it causes long-term complications. Effective treatments for patients with ITP who are refractory to second-line treatments have not been established. Some novel drugs are under clinical trials, and a treatment strategy for these patients is expected to be established.

In 2020, infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) rapidly spread across the world to become a global pandemic. Coronavirus disease-2019 (COVID-19) is associated with a high rate of coagulopathy and thrombotic complications. The underlying mechanisms involved in these processes are complex. In addition to the low physical activity, blood coagulation activation accompanied by excessive immune/inflammatory reactions and vascular endothelialitis associated with the presence of intracellular SARS-CoV-2 and disrupted cell membranes contribute substantially to the complexity of the mechanisms. The types of thrombosis that occur include arterial thrombosis and venous thromboembolism. Microthrombi in alveolar capillaries are observed in COVID-19 patients. Considering the possible involvement of thrombosis in the worsening of COVID-19, prophylactic anticoagulant therapy, such as low-molecular-weight heparin or unfractionated heparin, is essential for patients with moderate and severe infections. Even with prophylactic anticoagulant therapy, the incidence of thrombosis remains high. Consequently, control of the underlying inflammation and vascular endothelial protection may be required in combination with anticoagulant therapy.

Blood transfusion, which has been conducted as a basic medical procedure since 17th century, is a supportive therapy to compensate loss of each blood component. All blood materials are donated, and alive and subject to decay, type-dependent for transfusion, vary in quality, may induce severe adverse reactions, such as anaphylaxis, and may transmit infectious agents. Therefore, not only the scientific and clinical decisions but also ethical considerations should be focused on for their use. All blood products are determined as “Products Derived from Specific Organism” by the Pharmaceutical and Medical Devices Law in Japan. Of note, blood management systems are different among countries; the Japanese Red Cross Society is a unique organization that collects and manufactures blood products under supervision of the Japanese Government. It establishes a hemovigilant system by which it collects all the information concerning transfusion-related adverse events and provides them to the responsible transfusion service staff of each hospital. Physicians should check all the information from the Japanese Red Cross and refer both the “Guidelines for Blood Transfusion” and “Guidelines for the Usage of Blood Products” by the Ministry of Health, Labor and Welfare for transfusion practice.

Sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD) of the liver, is one of the most relevant complications of hepatic sinusoidal endothelial origin that appears early after hematopoietic cell transplantation (HCT). Despite its relatively low incidence and the spontaneous resolution of most SOS/VOD cases, severe SOS/VOD evolved to multi-organ failure with an >80% mortality rate and represents one of the major clinical problems after HCT. The sinusoidal endothelial cells and hepatocytes are damaged by toxic metabolites generated by the conditioning regimen in these patients. Several risk factors have been identified for SOS/VOD development. Although defibrotide is recommended for both prevention and treatment, no satisfactory therapy exists for managing severe SOS/VOD. Thus, this review describes the new definition of SOS/VOD diagnosis and the severity grading of suspected SOS/VOD from the European Society for Blood and Marrow Transplantation. Furthermore, it describes the results of current treatment including the Japanese therapeutic use program, defibrotide treatment protocol.

Graft versus host disease (GVHD) prophylaxis using antithymocyte globulin (ATG) has been shown for chronic GVHD inhibition effect by a series of randomized control trials in unrelated hematopoietic or peripheral blood stem cell transplantation (PBSCT). Lower doses of ATG have been used in recent studies, although the optimal dose of ATG remains undefined. Consequently, a multicenter phase II study of low-dose ATG (2 mg/kg Thymoglobulin^®) was conducted in patients undergoing human leukocyte antigen-matched PBSCT, showing the safety and efficacy for the prevention of both acute and chronic GVHD. In a nationwide retrospective study for ATG in unrelated PBSCT, the ATG group had a significantly lower incidence of chronic GVHD and a higher probability of GVHD- and relapse-free survival compared with the non-ATG group, although the dose of ATG used was low (1.0-3.0 mg/kg of Thymoglobulin^®). Regarding absolute lymphocyte count (ALC) before the administration of ATG, the incidences of grades III-IV acute GVHD and moderate-to-severe chronic GVHD were significantly higher in patients with high ALC before ATG. Conversely, the relapse rate was significantly higher in patients with low ALC before ATG, suggesting a strategy to individualize ATG dosing by modulating ATG doses according to ALC before ATG.

Allogeneic hematopoietic cell transplantation (allo-HCT) plays an important role as the most potent therapeutic option for refractory acute lymphoblastic leukemia (ALL). However, advances of supporting therapy have enabled more intensive chemotherapy, and severe late complication of allo-HCT has been recognized, thus, indication of allo-HCT is now limited to carefully selected population with highest risk for relapse, based on assessment by minimal residual disease status. Furthermore, especially for B-cell precursor ALL, we should re-establish a role of allo-HCT in the entire of therapeutic strategy, including novel options, such as small molecular agents and immunotherapy. We are now required to maximize safety and efficacy of allo-HCT for selected high-risk ALL.

Graft-versus-host disease (GVHD) is a major complication that occurs after allogeneic hematopoietic stem cell transplantation (HSCT). While the allogeneic immune response may cause GVHD, it also plays essential roles in the resultant antitumor effects and in engraftment facilitation. Therefore, the application of necessary and sufficient immune control at an appropriate time according to the condition of each individual patient is the key to successful HSCT. Recently, the landscape of HSCT has changed drastically due to the diversification of transplanted grafts and the emergence of novel immunosuppressive methods and immune-modulatory agents. In this review, we first describe the current understanding of the immune pathogenesis of acute and chronic GVHD, and then, we discuss the characterization and therapeutic intervention for GVHD after diversified HSCT.

Respiratory viral infection is a common disease even among immunocompetent individuals. Moreover, approximately 40% of the hematopoietic cell transplantation (HCT) recipients suffer from a respiratory infection within 100 days after HCT. New respiratory viruses have been continuously identified in the past 20 years, such as new strains of coronaviruses (CoV), human metapneumovirus (HMPV), and human bocavirus (BoV). In 2019, severe acute respiratory syndrome coronavirus (SARS-CoV)-2 that caused the coronavirus disease (COVID)-19 pandemic was identified. The 30-day overall survival after lower respiratory tract disease (LRTD) due to CoV, including SARS-CoV-2 or HMPV, was 60-70%, which is similar to that after LRTD due to influenza or respiratory syncytial virus. However, whether BoV is a pathogen of LRTD remains unclear. Moreover, corticosteroid has been reported as an efficient drug for LRTD due to SARS-CoV-2. Antiviral drug (remdesivir), anti-IL-6 receptor antibody (tocilizumab), and JAK inhibitor (ruxolitinib) are also expected to be efficient for the treatment of COVID-19. Thus, managing respiratory viruses in HCT recipients needs to be learned based on experiences from the COVID-19 pandemic.

Hepatitis B, hepatitis C and HIV infections are well-known infectious diseases caused by blood products, but recently there have been almost no reports. In 2011, hepatitis E virus (HEV) antibody test was covered by insurance in Japan, and certain numbers of transfusion-transmitted HEV were reported, and five cases were recognized in 2019. As the Japanese Red Cross has started to examine individual NAT of HEV for all blood donors since August 2020, and the number of transfusion-transmitted HEV will decrease. In addition, Trypanosoma cruzi antibody test for selective blood donors has been examined since August 2016, and the risk of Chagas disease infection by blood transfusion will be decreased. In the future, it is important for protecting against the transfusion-transmitted infection to inspect bacterial tests and know the information of emerging infectious disease occurring overseas. When the emerging infectious diseases such as DENV (dengue virus), WNV (West Nile virus), Zika (Zika virus) and CHIKV (chikungunya virus) occur in Japan, it is necessary to stimulate countermeasures and prepare what kind of tests should be performed for blood donors or criteria for blood donation.

The tumor microenvironment (TME) acquires immune resistance during the process of tumor formation. Recently, cancer immunotherapy has been attracting attention as a treatment modality, following the three major standard cancer treatments (surgical therapy, radiation therapy, and chemotherapy), for its potential to overcome such an immunosuppressive TME. Particularly, blocking antibodies against immune checkpoint molecules, such as PD-1 and CTLA-4 have caused a paradigm shift in cancer treatment. However, several patients do not respond to existing cancer immunotherapy; therefore, the establishment of a novel therapeutic target is essential. Macrophages are the most abundant cells in various tumors and are biased toward immunosuppressive forms. Therefore, research is ongoing globally to determine whether macrophages could be therapeutic targets. Interleukin-34 (IL-34) has been reported as a factor that biases macrophages to immunosuppressive forms. It is expressed in various types of cancer cells and plays important roles in multiple aspects of the TME. In this review, we comprehensively introduce the roles of IL-34 in the TME.

Leukemias diagnosed in <1-year-old infants generally have an aggressive clinical nature and unique biological characteristics. Acute lymphoblastic leukemia (ALL) in infants is still intractable and difficult to treat as compared with other pediatric ALLs, for which considerable progress in treatment outcomes has been recently achieved. Infant leukemia cells frequently carry chromosome translocations involving the 11q23 locus, resulting in the rearrangement and fusion of the KMT2A (MLL) gene. Among several KMT2A fusion genes, KMT2A-AFF1 (MLL-AF4) fusion is characteristically observed in neonatal and infant ALL, representing a hallmark of poor prognosis. The cytogenetic/molecular abnormalities t (1;22)(p13.3;q13.1)/RBM15-MKL1 and t (8;16)(p11.2;p13.3)/KAT6A-CREBBP (MOZ-CBP) are also well-known in acute myeloblastic leukemia in this population. Although many neonatal leukemias occurring within the first 28 days of birth are refractory, spontaneous remissions are occasionally observed, especially in the case of t (8;16). Therefore, international collaborative studies are necessary to improve understanding and facilitate the development of better treatment for this rare disease. Thus, this study summarizes the recently reported clinical, cytogenetic, and molecular biology aspects of neonatal and infant leukemias.