Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by impaired hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Epigenetic regulators, including TET2, DNMT3A and EZH2, are often mutated in patients with MDS. Recently, exome sequencing of blood cells from aged people without hematological malignancies have demonstrated the presence of clonal hematopoiesis with myeloid malignancies-associated mutations, such as TET2 and DNMT3A. Here, I will discuss the molecular mechanisms underlying the accumulation of epigenetic alterations and genetic mutations, including TET2, DNMT3A and EZH2, and how these promote the development of MDS and hematological malignancies in aged people with clonal hematopoiesis.

Leukemia stem cells (LSCs) are responsible for relapse of leukemia. LSCs maintain their self-renewal capacity, stemness properties, and therapeutic resistance in a manner dependent on their cell of origin and genetic alterations acquired during subsequent clonal evolution. Specific mechanisms of metabolic control and nutrient acquisition are implicated in the regulation of LSC survival. Recent advances in gene modification strategies in mice and in sophisticated metabolomics technologies are producing novel inquiries in LSC research performed in vivo. In this review, I examined our current knowledge on the roles of various metabolic pathways, including glucose metabolism, lipid oxidation, and an alternative route of amino acid and peptide supply, that support the maintenance of self-renewal capacity and therapeutic resistance in LSCs in vivo.

Recent progress in next-generation sequencing technologies allows us to discover frequent mutations throughout the coding regions of myelodysplastic syndromes (MDS), potentially providing us with virtually a complete spectrum of driver mutations in this disease. As shown by many study groups these days, such driver mutations are acquired in a gene-specific fashion. For instance, DDX41 mutations are observed in germline cells long before MDS presentation. In blood samples from healthy elderly individuals, somatic DNMT3A and TET2 mutations are detected as age-related clonal hematopoiesis and are believed to be a risk factor for hematological neoplasms. In MDS, mutations of genes such as NRAS and FLT3, designated as Type-1 genes, may be significantly associated with leukemic evolution. Another type (Type-2) of genes, including RUNX1 and GATA2, are related to progression from low-risk to high-risk MDS. Overall, various driver mutations are sequentially acquired in MDS, at a specific time, in either germline cells, normal hematopoietic cells, or clonal MDS cells.

Hematopoietic stem cells (HSCs) have the potential to self-renew and differentiate into multi-lineage mature hematopoietic cells; thus, these cells can maintain hematopoiesis. Human HSCs reside within the CD34⁺CD38^- cell fractions. Similarly, in acute myelogenous leukemia (AML), a small number of leukemic cells, called leukemic stem cells (LSCs), can be enriched within the identical CD34⁺CD38^- cell fractions. LSCs can self-renew and produce clonogenic leukemic cells, whereas non-LSCs lack the potential to self-renew or maintain leukemia; thus, AML is organized as a hierarchy that originated from LSCs. LSCs play a central role in the maintenance and progression of leukemia; therefore, these cells should be an ultimate target for the eradication of human AML. Previous studies have revealed specific molecular machineries essential for LSCs. Targeting LSC-specific molecules should be a good therapeutic approach to kill LSCs without affecting normal cells. In this review, we would like to introduce the recent progress in the LSC study.

During steady-state conditions, hematopoietic stem cells (HSCs) maintain a quiescent status in the cell cycle. Upon infection or inflammation, bone marrow HSCs begin proliferating and generating differentiated hematopoietic cells via multi-lineage differentiation and self-renewal; this effect is partially due to the alteration of their surrounding microenvironment or niche. In addition, recent studies have revealed that the bone marrow niche critically contributes to abnormal hematopoiesis, including leukemogenesis. In this review, we discuss the recent advances in our understanding of HSC/niche functions and the regulatory machineries employed during homeostasis, stress hematopoiesis, or disease conditions.

Aplastic anemia is a syndrome in which hematopoietic stem cells are decreased and bone marrow hypoplasia and pancytopenia are observed; it is considered as a T cell-mediated autoimmune disease. Recently, it has been reported that gene mutations suggestive of clonal hematopoiesis are detected in approximately one third of the patients with aplastic anemia. Among treatment approaches other than hematopoietic stem cell transplantation, immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporin is a basic approach, although it has been shown that eltrombopag, a thrombopoietin receptor agonist, is effective and that the recovery of hematopoiesis in three blood lineage is observed in some patients. Studies on the optimum dose of ATG are in progress. Regarding hematopoietic stem cell transplantation for aplastic anemia, regimens are being designed in which cyclophosphamide as a pretreatment is reduced and fludarabine is instead used in combination for the reduction of cardiotoxicity. Because HLA haploidentical transplantation has been developed and its reports are increasing for patients who cannot find appropriate donors, transplantation may be possible in patients who had previously given up on it.

Chronic kidney disease leads to dysfunction of renal erythropoietin-producing cells, resulting in a decrease in erythrocyte production. A decrease in oxygen delivery to vital organs due to anemia results in worse quality of life and is associated with poor prognosis of the patients. Treatment with human recombinant erythropoietin or its improved version of erythropoiesis-stimulating agent (ESA) with a longer half-life is effective. However, some patients show hyporesponsiveness to ESA. Hyporesponsiveness to ESA, which can be induced by factors such as inflammation and uremic toxins, is associated with poor prognosis. Production of erythropoietin in the kidney is regulated by a transcription factor, hypoxia-inducible factor (HIF). PHD regulates HIF activity, and recently developed PHD inhibitors need to be clinically used as drugs to ameliorate anemia in CKD by activating HIF.

Iron is essential for various cellular processes, but an excess of iron may cause organ damage through the production of reactive oxygen species. Therefore, the amount of iron in the body must be strictly controlled. The central regulator of systemic iron homeostasis is hepcidin, which is primarily produced in the liver. Various molecules, including HFE, transferrin receptor 2 (TFR2), and hemojuvelin (HJV), are involved in sensing systemic iron status. Hepatocytes produce hepcidin in response to excess iron and inflammatory stimuli (e.g., interleukin-6), whereas hepcidin expression is downregulated by hypoxia, anemia, and erythropoietic activity. In mice, erythroferrone, secreted from erythroblasts, suppresses hepcidin expression. Hepcidin downregulates the protein expression of ferroportin, the only iron exporter in mammalian cells, and thereby downregulates iron absorption from intestine and iron release from macrophages. Mutations in the genes HFE, TFR2, HJV, HAMP (encoding hepcidin), and SLC40A1 (encoding ferroportin) cause hereditary hemochromatosis, whereas mutations in TMPRSS6 (which encodes matriptase 2) cause iron-refractory iron deficiency anemia through the upregulation of hepcidin expression. In chronic anemias, such as β-thalassemia, myelodysplastic syndromes, and aplastic anemia, repeated red blood cell transfusion can cause systemic iron overload. Iron chelation therapy improves the prognosis of patients with such conditions.

Acute promyelocytic leukemia (APL) is defined by its characteristic morphology (AML FAB M3/M3v), specific chromosomal translocation t (15;17), and molecular correlates (PML/RARα). Treatment with all-trans retinoic acid (ATRA) combined with chemotherapy has a high cure rate. Clinical trials with arsenic trioxide (ATO) confirmed the efficacy of ATO for patients with relapsed APL. Recently, treatment with ATRA and ATO has been shown to result in high CR rates for the majority of patients with newly diagnosed APL. Many trials have been conducted to determine the optimal schedule for ATRA in combination with ATO.

The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. The study of cancer genomes has identified inherited genetic drivers that predispose cancer cells to clonal evolution. The revisions in the categories of myeloid neoplasms and acute leukemia were published as a monograph in 2016. We described familial hematological malignancies using the 2016 edition of the WHO classification.

Despite recent progress in diagnosis and leukemogenesis based on genomic landscapes in acute myelogenous leukemia (AML), advances in AML treatment lag behind. Over the past four decades, combination chemotherapy with anthracycline and cytarabine remains the standard induction therapy. Subsequent post-remission consolidation therapy stratifies patients into favorable-risk, intermediate-risk, and unfavorable-risk groups to assign post-remission therapies based on cytogenetic abnormalities and molecular mutations. Allogeneic stem-cell transplant decreases the risk of AML recurrence compared to standard chemotherapy, but it also raises the risk of serious complications. Recent large collections of matched genomic and clinical data may assist in selecting the best individualized therapy for each AML patient. Emerging evidence indicates that molecularly targeted therapies such as FLT3 and IDH inhibitors may be effective in distinct AML subtypes, providing further rationale for a personalized medicine approach. An umbrella trial, such as “BEAT AML Master Trial,” designed to offer novel targeted therapy to AML patients based on their genetic characteristics, will be launching worldwide in the near future.

Prognosis for refractory or relapsed acute myeloid leukemia (AML) patients is poor, and allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only salvage option with curative potential for these patients. As the outcome of allogeneic HSCT in patients without complete remission (CR) status is unsatisfactory, it is important to attain a second CR before HSCT. An aggressive re-induction therapy for relapsed or refractory AML patients is often accompanied with severe infectious complications due to profound myelosuppression, which makes subsequent HSCT challenging. Furthermore, in AML patients with high-risk clinical features who do not achieve CR after remission induction chemotherapy (CT), allogeneic HSCT, preemptively performed immediately after re-induction CT or without prior CT, may induce durable remission in some patients. Determining the timing of HSCT and selecting a salvage regimen as a bridging therapy to HSCT are essential for avoiding severe treatment-related complications.

Most patients diagnosed with acute myeloid leukemia (AML) are over the age of 60 years yet optimal treatment strategies for older adults remain unclear. Old age is associated with increased risk of treatment-related toxicity and worse survival compared to younger adults. It is widely recognized that chronological age does not capture the heterogeneous physiological and functional status of older adults. Thus, it is critically important to evaluate both disease-related (adverse cytogenetics, unfavorable gene mutations, secondary AML, etc.) and patient-related (age, PS, comorbidity, ADL, physical function, cognitive function, nutritional status, social situation, etc.) factors before making the treatment decision for elderly AML patients. The geriatric assessment (GA) can identify problems that may interfere with cancer treatment and predict chemotherapy toxicity and survival. Identification of the most efficient GA screening tools for detecting multiple patient-related factors is necessary to make optimal treatment decision and improve the outcomes for elderly AML patients.

Next generation sequencing (NGS) of cancer genomes is now becoming a prerequisite for accurate diagnosis and proper treatment in clinical oncology. Because the genomic regions for NGS expand from a certain set of genes to the whole exome or whole genome, the resulting sequence data becomes incredibly enormous and makes it quite laborious to translate the genomic data into medicine, so-called annotation and curation. We organized a clinical sequencing team and established a bidirectional (bed-to-bench and bench-to-bed) system to integrate clinical and genomic data for hematological malignancies. We also started a collaborative research project with IBM Japan to adopt the artificial intelligence Watson for Genomics (WfG) to the pipeline of medical informatics. Genomic DNA was prepared from malignant as well as normal tissues in each patient and subjected to NGS. Sequence data was analyzed using an in-house semi-automated pipeline in combination with WfG, which was used to identify candidate driver mutations and relevant pathways from which applicable drug information was deduced. Currently, we have analyzed more than 150 patients with hematological disorders, including AML and ALL, and obtained many informative findings. In this presentation, I will introduce some of the achievements we have made so far.

Since the development of imatinib mesylate, an ABL tyrosine kinase inhibitor (TKI), the treatment of chronic myeloid leukemia (CML) has made remarkable progress. Second and third generation TKIs have also become available for clinical use. Considering the improved treatment outcomes, chronic phase CML has become manageable, with a low mortality rate. Furthermore, clinical trials such as STIM and DADI have shown that TKI can be discontinued safely in certain CML patients. However, some CML patients, especially those in accelerated phase (AP) or blast phase (BP), require more aggressive forms of treatment such as allogenic hematopoietic stem cell transplantation. Next-generation sequencing technology and other novel technologies allow us to investigate the cause of CML and the molecular biology of progression to AP/BP in more detail. Based on these data, an increasing number of novel therapeutic agents for CML are being developed, which will improve the prognosis of CML.

Since the discovery of the activating mutation of JAK2, known as JAK2V617F, our understanding of mutation profiles, and the biological significance of this mutation in Philadelphia-negative (Ph-) MPNs has drastically changed over the last decade. Mutations of the thrombopoietin receptor MPL and chaperone protein calreticulin gene also induce aberrant activation of JAK and downstream molecules, including STAT proteins, and contribute to the development of MPNs. Mutations of the genes JAK2, MPL, and calreticulin are referred to as “driver mutations” for MPNs. Recent advances in genetic tests using next-generation sequencing have revealed that in addition to driver mutations, approximately half of Ph-MPN patients have at least one more mutation. These genes serve as components of spliceosomal machinery, DNA methylation modifiers, and regulators of histone function. Mutations of these genes are known as “non-driver mutations” and are thought to be involved in modifying the disease phenotype and progression of Ph-MPNs. In addition to its biological significance, the mutation profile also provides numerous pieces of important information for the clinical aspects of Ph-MPNs. In this study, the role of molecular profiling of Ph-MPNs for diagnosis, risk evaluation, and treatment decisions was discussed.

Myelodysplastic syndromes (MDS) are defined as hematopoietic stem cell disorders caused by various gene abnormalities. Recent analysis using next generation sequencing has provided great progress in identifying relationships between gene mutations and clinical phenotypes of MDS. It is estimated that one or more gene mutations occur in greater than 90% of MDS patients. More than 50 gene mutations affecting RNA splicing machinery, DNA methylation, histone modifications, transcription factors, signal transduction proteins, and components of the cohesion complex participate in the pathogenesis of MDS. The sequential accumulation of additional cooperating mutations drives disease evolution from clonal hematopoiesis of indeterminate potential (CHIP) to symptomatic MDS and from MDS to acute myelogenous leukemia (AML). Mutations in RNA splicing and DNA methylation occur early and are considered founding mutations, whereas others that occur later are regarded as subclonal mutations. RUNX1 mutations are more likely to be subclonal; however, they apparently play a pivotal role in familial MDS. In addition, large alterations of chromosomes are involved in the pathogenesis of MDS. 5q− syndrome, which leads to haploinsufficiency of the located genes, has consistent clinical features. Understanding gene abnormalities of MDS patients can provide clinical information, including diagnosis, prognostic score, and prediction of response to therapy.

Myelodysplastic syndrome (MDS) is a group of clonal disorders affecting hematopoietic stem cells. Thus, the only potential curative therapy is hematopoietic stem cell transplantation (HSCT). Indeed, for high-risk patients with MDS, who have a higher anticipated risk of leukemic transformation and shorter survival, HSCT is the first choice for eligible patients. DNA hypomethylating agents, the only agents proved to prolong survival, are used in non-HSCT—eligible high-risk patients with MDS. In contrast, due to high transplant-related mortality rate, treatment strategies other than HSCT are mainly applied for the low-risk group with expected long-term survival. Lately, treatment options, including the progress of supportive therapy, for low-risk patients with MDS have increased. The availability of the treatment options that enhance QOL and prolong survival is the need of the present time. This review will discuss the outline of such treatment strategies, especially for low-risk patients with MDS.

Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of mature CD5-positive, CD10-negative, CD20 weakly positive, and CD23-positive B-cells within blood, bone marrow, lymph nodes, and spleen. In proliferation centers, the survival and growth of CLL cells requires a permissive microenvironment comprising T-cells, macrophages, and stromal cells. FISH analysis has revealed that almost 80% of CLL cases carry chromosomal abnormalities including the most frequent del (13q14) and the strongest poor prognostic factor del (17p), both related to TP53 mutations. Current treatment approaches are not curative for CLL, except allogeneic hematopoietic stem cell transplantation, which is rarely offered to the majority of patients aged 70 years and older. Currently, there is no evidence that the initiation of therapy for asymptomatic early-stage disease improves the overall survival, even for patients with high-risk disease. The identification that the B-cell receptor (BCR) signaling pathway is aberrantly and constitutively activated in CLL has recently led to the development of BCR signaling inhibitors, ibrutinib and idelalisib. In addition, a novel BCL-2 antagonist, venetoclax, appears promising when used alone or in combination with anti-CD20 antibodies. The advent of novel small-molecule inhibitors has revolutionized the treatment approaches for patients with CLL.

Although Hodgkin lymphoma is a disease with a low incidence rate, there is a significant social resources perspective associated with this disease to ensure that adolescents and young adults are adequately treated and receive social reintegration. Consequently, Hodgkin lymphoma is considered an important disease in the field of oncology. Combined modality therapy, which combines chemotherapy and radiotherapy, has resulted in cure rates of more than 80% in patients with early stages of this disease, although long-term sequelae remain a problem. Response-adapted therapy using FDG-PET is being studied as a treatment strategy in an attempt to attenuate treatment to reduce toxicity in interim-PET negative cases and to enhance therapeutic intensity for interim-PET positive cases. In addition, brentuximab vedotin, which targets CD30 and anti-PD-1 antibodies, which represent immune checkpoint inhibitors, is effective even when treatment resistance develops after autologous transplantation. Both high cure rates and toxicity control are essential targets for treatment modalities of Hodgkin lymphoma. Long-term follow-up of secondary malignancy and heart and lung failure should be incorporated into such treatment strategies. In this review, I explore comprehensive treatment strategies for Hodgkin lymphoma in the early stage with both favorable and unfavorable prognosis, in the advanced stage, and relapsed or refractory disease.

The survival outcomes for children with acute lymphoblastic leukemia (ALL) have dramatically improved over recent years, and improved outcomes in adolescents and young adults patients have been achieved by applying regimens based on pediatric protocols. The treatment strategies for adult ALL are similar to those for pediatric ALL. T-cell ALL is less common than B-cell ALL. Therefore, there are only few reports of investigations in a large group of adult T-ALL patients. In Japan, nelarabine-combined chemotherapy has been tested in a phase II study in patients with newly diagnosed T-ALL. Patients with Philadelphia chromosome-positive ALL had a poor prognosis. However, the introduction of a tyrosine kinase inhibitor (TKI) has dramatically altered treatment strategies, resulting in complete remission in virtually all patients and an increased proportion of patients who undergo allogeneic stem cell transplantation. The prognosis of adults with relapsed and refractory ALL is extremely poor, and some novel agents are currently under development for relapsed and refractory ALL. This article describes the current treatment strategy and future perspectives for adult ALL.

Most patients with adult acute lymphoblastic leukemia (ALL) undergo relapse, despite the achievement of complete remission with chemotherapy. Among patients with relapsed or refractory ALL, remission rates are 18-44% with the use of standard salvage chemotherapy, but the duration of remission is short. A major goal in this population is to induce remission with a sufficient duration to prepare for stem cell transplantation. The poor outcomes and lack of durable responses seen with conventional chemotherapy have led to the development of several novel agents, including clofarabine and nelarabine. Prior to the advent of tyrosine kinase inhibitors, patients with Ph-positive ALL treated with combination chemotherapy regimens were able to achieve high rates of complete response and long survival duration along with subsequent stem cell transplantation. A potent tyrosine kinase inhibitor ponatinib that is active against the T315I mutation is available. Novel monoclonal antibodies have been developed for the treatment of patients with Ph-negative ALL. Among patients with relapsed or refractory ALL, inotuzumab ozogamicin, blinatumomab, and CAR T-cell therapy have shown promising results. Follow-up is needed to further confirm their outcomes and toxicity profiles. Several clinical trials in this field are ongoing because of the lack of an established standard therapy.

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). HTLV-1 related proteins Tax and HTLV-1 bZIP factor induce immortalization and transformation of HTLV-1-infected T-lymphocytes and eventually induce clonal proliferation. One of the apparent molecular features in ATL cells is abundant genomic abnormalities targeting characteristic pathways, including T-cell receptor signaling and the NF-κB pathway, G-protein coupled-receptor, including CCR4, and transcriptional regulation. Moreover, the overexpression of PD-L1 caused by structural variations in the 3'-UTR of the PD-L1 gene has been reported recently, which indicates possible escape of ATL cells from immune-surveillance and its therapeutic application for pharmacological intervention. The next is the downregulation of microRNAs and tumor suppressors by genome-wide epigenetic abnormalities, especially accumulation of trimethylated H3K27 induced by EZH2. Among these molecular events frequently observed in ATL cells, treatment targeting CCR4 via a monoclonal antibody has been introduced in the clinic, and immune-therapy by therapeutic vaccine with Tax peptide-pulsed dendritic cells, treatment by immune checkpoint inhibitors, and treatment targeting EZH1/2 by a small molecule inhibitor are under clinical trial. Establishment of novel treatment strategies beyond cytotoxic agents for ATL are eagerly anticipated, especially for elderly patients.

The introduction of new agents and hematopoietic stem cell transplantation into the treatment of ATL has activated its clinical research. However, the prognosis of ATL remains poor compared with those of other leukemias and lymphomas. Thus, seemingly we have to reconsider a new strategy of ATL therapy based on its unique characteristics. HTLV-1 infection of T cells results in clonal proliferation of infected cells that accumulate genetic and epigenetic abnormalities before the onset of ATL. Therefore, the treatment strategy should include the prevention of HTLV-1 infection and ATL development in addition to precision medicine based on the stratification of ATL cases by biomarkers that discriminate clinical stages of ATL. I summarize here the recent progress in ATL research focusing on the biomolecular abnormalities that lead to clonal expansion and malignant transformation of HTLV-1-infected T cells. Apparently, one of the bases for the prevention of ATL is to establish a disease entity of “chronic active HTLV-1 infection” that defines high-risk carriers for ATL development and enables preventive intervention.

Follicular lymphoma (FL) is incurable with the current standard therapeutic strategy, although the natural history of FL has improved in the last few decades. Treatment strategy for FL is considered by stage and tumor burden. For advanced-stage FL patients with low tumor burden, monitoring remains an appropriate approach. Single agent rituximab is also suggested as a good alternative. The addition of rituximab to chemotherapy has improved overall survival in advanced-stage FL patients with high tumor burden. The optimal chemotherapy to partner with rituximab might be CHOP or bendamustine. Rituximab maintenance after successful induction rituximab-based chemotherapy prolongs PFS. Recently, progression within 24 months of first-line chemotherapy has been established as a predictor of inferior outcome, with a 50% risk of death in 5 years. Addressing this high-risk group is important for optimal future treatment strategies.

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by CD5+, CCND1+, and the CCND1-IGH translocation. Although patients with MCL respond, at least temporarily, to conventional chemotherapy, they eventually have a relapse and the prognosis is generally poor. As a primary treatment option for patients with untreated MCL, a rituximab-containing chemotherapy regimen is administered according to the patient's eligibility for high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). For ASCT-eligible patients, an induction chemotherapy that includes high-dose cytarabine followed by ASCT is recommended. For ASCT-ineligible patients, a less intensive therapy, such as R-CHOP, bortezomib-containing therapy (VR-CAP), or bendamustine plus rituximab, is recommended. These induction therapies can be followed by rituximab maintenance. For those with relapsed/refractory MCL, fludarabine, bendamustine, 90Y-ibritumomab tiuxetan, and conventional cytotoxic agents can be used. Recently, ibrutinib, an inhibitor of Bruton tyrosine kinase, has been approved for relapsed/refractory MCL. Recent advances in the management of MCL will improve the prognosis of patients with MCL.

Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma, accounting for 30%-40% of all types of malignant lymphoma. Importantly, two distinct molecular subtypes, germinal center B-cell (GCB) type and activated B-cell (ABC) type, arising from B lymphocyte differentiation based on the gene expression profiling opened doors to uncover molecular pathogenesis in DLBCL. Since 2010, next-generation sequencing analyses have been revealing the landscape of genetic mutations in DLBCL. Reportedly, GCB DLBCL is characterized by the accumulation of genetic abnormalities of epigenetic modifiers. Conversely, the hallmark of ABC DLBCL is the constitutive activation of the NKκB signaling pathway due to mutations in related genes. From recent prospective trials, conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen, which is the current standard regimen for DLBCL, has been acknowledged as a well-established regimen for DLBCL. Currently, the development of a plethora of drugs targeting the activated signaling pathway and immune microenvironments is ongoing. To overcome this intractable disease with the present treatment, the breakthroughs based on molecular pathogenesis are required.

The programmed cell death-1 (PD-1) pathway serves as a checkpoint for suppressing T cell-mediated immune responses. It regulates both the physiological and pathological functions of T cells and is often involved as a mechanism of tumor immune evasion. Many clinical trials have demonstrated that blockade of PD-1 and its ligands is a promising therapeutic strategy for various kinds of malignancies. The most prominent results of PD-1 blockade therapy have been shown in clinical studies of classical Hodgkin lymphoma (cHL), and the PD-1 inhibitor nivolumab was approved for treatment of relapsed/refractory cHL in Japan at the end of 2016. There is increasing evidence that PD-1 blockade therapy is also effective in several other subtypes of lymphoid malignancies. PD-1 inhibitors demonstrate a favorable safety profile, but they can cause immune-related adverse events that affect a variety of organs, such as skin, lung, thyroid, and intestine. Although infrequent, they can develop into life-threatening conditions, and specific monitoring is recommended for the early detection and treatment of these uncommon side effects during PD-1 blockade therapy.

In Japan, the latest trends in induction therapy for patients newly diagnosed with multiple myeloma are multi-drug combinations, including bortezomib, lenalidomide, and thalidomide. Patients <65 years old and those <70 years old who have normal cardiac and lung functions without any serious complications are good candidates for high-dose L-PAM with autologous stem cell transplantation. For successful stem cell collection, anti-cancer drugs that have a negative impact on stem cell mobilization are usually excluded from induction therapies. It has been reported that bortezomib and thalidomide do not affect mobilization of stem cells; however, extended exposure to lenalidomide may have a potential risk of poor mobilization. Under these circumstances, PAD, VTD, VCD, and RVD are recommended as first induction therapies for transplant-eligible patients. On the other hand, two- or three-drug combinations are effective as induction therapies for transplant-ineligible patients >65-70 years old and <65 years old with serious complications or insufficiencies of cardiac or lung functions as well as for any patients who refuse transplantation strategy. For these patients, VMP, MPT, and Rd are usually recommended. For elderly patients >75 years old, it is important that the dosage of each drug be properly reduced according to the frailty of the patient.

The long-term outcome of multiple myeloma (MM) has been greatly improved by the advent of new agents such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), despite the disease remaining mostly incurable. Treatment design is the critical determinant for the survival period and for the quality and way of life in patients with relapsed/refractory MM (RRMM). Recently, the choice of therapeutic options for RRMM has been expanded by the introduction of second generation PIs such as carfilzomib and ixazomib, and therapeutic monoclonal antibodies such as elotuzumab and daratumumab. In the choice of treatment strategies for RRMM, including stem cell transplantation, the decision should be based on an understanding of the characteristic clinical effects of each drug and the evaluation of the cytogenetic/molecular profile, myeloma-defining events, complications, and prior MM treatment history in individual patients.

Immunomodulatory drugs (IMiDs) are a new class of anticancer compounds that are derived from thalidomide. Lenalidomide and pomalidomide are well-known IMiDs, and they have already been approved by FDA for the treatment of several diseases, including multiple myeloma. Cereblon (CRBN) is a common primary target for IMiDs. It works as a substrate receptor of CRL4. Accumulating evidence has shown that the substrate specificity of CRL4^CRBN is altered by ligands such as IMiDs. Recently, novel CRBN-binding compounds have been developed and are called “cereblon modulators”. Among these, CC-122 and CC-220 are currently under clinical development for the treatment of diffuse large B-cell lymphoma and systemic lupus erythematosus, respectively. Another new cereblon modulator CC-885 is shown to induce degradation of the translation termination factor GSPT1, resulting in an antiproliferative effect in acute myeloid leukemia. Structural analyses have revealed that CC-885 provides an interaction hotspot between CRBN and GSPT1. On the other hand, several groups have been investigating linker-based approaches for targeted protein degradation via CRBN. Several proteins, such as BRD4 and BCR-ABL, have been successfully degraded by CRL4^CRBN using these technologies. In this review, we introduce recent topics in CRBN and its binding compounds.

In the treatment of hemophilia patients, factor (F) VIII or FIX product prophylaxis results in arthropathy prevention and quality of life (QOL) improvement. Serious issues concerning hemostatic treatment of hemophilia include frequent intravenous administration of products, inhibitor development, and hemostatic treatment of patients with inhibitors. To overcome these challenges, products with extended half-life were developed. Furthermore, alternative products based on new concepts of hemostatic therapy were developed. Regarding ACE910, a bispecific antibody recognizing FIX and FX, a clinical extension 1/2 study in Japan and an international phase 3 study are ongoing. Phase 1 results demonstrated that there were few severe ACE910-related adverse events. The t_1/2 was approximately 30 days, and bleeding events were significantly reduced upon weekly subcutaneous administration in severe hemophilia A patients, independent of inhibitors. Two therapies, namely si-RNA anti-antithrombin therapy and anti-TFPI antibody therapy, aimed at rebalancing coagulation, are also under development. In addition, a gene therapy for hemophilia B has been developed by improving the vector. These new therapies could further improve the QOL of hemophilia patients.

Although thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease, appropriate diagnosis and treatment result in the higher survival rate of >80%. TTP is usually suspected with thrombocytopenia and hemolytic anemia and is confirmed by a reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) <10%. TTP is classified as acquired if a patient tests positive for anti-ADAMTS13 autoantibodies, and as congenital if ADAMTS13 gene abnormalities are identified. In patients with congenital TTP, fresh frozen plasma (FFP) transfusion for the supplementation of ADAMTS13 is performed. On the other hand, in patients with acquired TTP, plasma exchange therapy using FFP is conducted to supplement ADAMTS13 and remove anti-ADAMTS13 autoantibodies. Besides, corticosteroid therapy is often administered in conjunction with plasma exchange to suppress autoantibody production. In 2017, we aim to provide “diagnostic and treatment guidelines for TTP 2017 in Japan”. In this review, we describe new developments in diagnosis and management of TTP, which are not discussed in the guidelines.

Idiopathic thrombosis involves a group of inherited thrombophilia predisposed to severe thrombosis of early onset and associated with an adverse outcome due to recurrence, and therefore, requires long-term anticoagulation therapy. The causative factors of a predisposition to thrombosis include immobility, dehydration, infection, surgery, injury, cancer, pregnancy, and estrogen use. The inherited deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are specified as “Specific Pediatric Chronic Diseases.” However, medical expense assistance for patients terminates when they reach the age of 20 years. On April 1^st 2017, “Idiopathic Thrombosis due to Inherited Thrombophilia,” consisting of inherited AT, PC, and PS deficiencies, was specified as an “Intractable Disease,” and aid for medical expenses became available. Accordingly, progress in the research and practice of idiopathic thrombosis is expected in future to improve the medical care system and to construct a database via clinical surveys.

“Fibrin is insoluble in blood” is the most important concept to accept the coagulation system. Essentially, blood coagulation is a process to convert blood from soluble to insoluble. Fibrinolysis is another process to convert insoluble protein to soluble protein again. The blood coagulation cascade requires calcium ion and efficiently acts on platelet phospholipid membranes. On the other hand, the fibrinolysis system efficiently acts on fibrin. Unlike other vitamin K-dependent coagulation factors, thrombin can be released from the coagulation site to the systemic circulation and has multiple biological effects regulated through thrombin receptors. Thrombin is captured by thrombomodulin on endothelial cells or anti-thrombin. Low level of coagulation and fibrinolysis idling are always working even under healthy conditions because of shear stress on injured vessels. Measurement of coagulation times, such as PT and APTT, is the basic method used by numerous clinics in coagulation-related examinations. Measurement of coagulation factor activity by one method is based on the concept that excess amounts of coagulation factors circulate in the blood. Under DIC conditions, excess pathological protease activity yields a huge amount of peptides in the blood in addition to coagulation and fibrinolysis markers.

Graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplantation is associated with an increase in patient transplant-related morbidity and mortality and a decrease in quality of life. Adequate immune suppression is critical to prevent GVHD without increasing the risk of developing a severe infection or relapse of malignancy. Anti-T cell globulin (ATG) combined with other immunosuppressive drugs can reduce the risk of severe acute GVHD and extensive chronic GVHD without enhancing the rate of severe infection or relapse of malignancy. Future research is warranted to determine the optimum ATG dosage, as the pharmacokinetics of ATG substantially differs among patients and impact transplant outcomes. Therefore, further studies are required to determine the therapeutic potential of ATG for steroid refractory GVHD.

With a growing number of transplant survivors, long-term survivorship care has received more attention. In long-term survivors, mortality remains higher than that of the general population, and they are prone to a unique set of late complications. The common late effects are as follows: chronic graft-versus-host disease, organ failure, endocrine complication, secondary cancer, mental health problem, and financial burden due to factors including unemployment. Long-term follow-up (LTFU) clinic plays an important role in the screening and early intervention for late effects and in informing and supporting patients to improve their quality of life. The importance of LTFU has been recognized, and the guidelines for screening and preventive practices for long-term survivors after transplantation were first published in 2006 and updated in 2012 based on a consensus opinion of the international working group. The guidelines for LTFU have been recently published by the Japan society for hematopoietic cell transplantation; they highlight the recommended screening and intervention available in our country, utilizing the evidence on the late effects reported from our country and overseas. In this review, I would like to illustrate the background of the need for LTFU and discuss the challenges in operating an LTFU clinic to effectively provide physical, mental, and social care to transplant survivors.

Recently, post-transplant cyclophosphamide (PTCy) -based HLA-haploidentical stem cell transplantation (PTCy-haploSCT) has been increasingly performed. The mechanism of GVHD prevention by PTCy is selective depletion of proliferating alloreactive T cells, while preserving non-alloreactive T cells. Several studies have reported that the incidence of non-relapse mortality, relapse, disease-free survival, and overall survival after PTCy-haploSCT are equivalent to those after HLA-matched SCT. Furthermore, the incidence of GVHD, especially chronic GVHD, after PTCy-haploSCT was lower than that of HLA-matched SCT. In Japan, we have conducted several prospective, multicenter, phase II studies since 2013. To reduce relapse, several strategies have been developed. In the first study (Haplo13), we used peripheral blood stem cells and added busulfan (BU) to the original non-myeloablative regimen developed by a Johns Hopkins group. In the second study, we used a BU- or TBI-based myeloablative conditioning regimen (Haplo14 MAC). In the third study, we reduced the dose of PTCy (Haplo16 RIC). In the latest study (Haplo17), we reduced the dose and/or duration of MMF and tacrolimus. We hope that these studies improve the outcome of PTCy-haploSCT.

Recent developments in the field of molecular targeted therapy are certainly remarkable. However, the role of hematopoietic stem cell transplantation (HSCT) cannot be the same in this trend of targeted therapy. In the past, HSCT was the sole and ultimate treatment for refractory hematological malignancies, mainly because the conditioning regimens were strong and administering any additional therapy was impossible. In recent years, the conditioning regimens have become less intensive, thus enabling the use of additional therapies post-transplantation. In this review, we have discussed the use of each targeted therapy, such as TKIs for Philadelphia chromosome positive disease, Flt3 inhibitors, checkpoint inhibitors, monoclonal antibodies, and hypomethylating agents, in the context of using them with HSCT. Furthermore, we have discussed the importance of the intensity of chemotherapy and conditioning for HSCT and whether the depth of remission and the time of achieving deep remission are important. MRD tests can help to further delineate this point. Molecular targeted therapy will be more prevalent in the near future in the treatment of hematological malignancies where each new agent may impact the GVHD/GVL effect. Thus, clinical trials in the next decade will mostly focus on the role of HSCT and on the methods of combining it with targeted agents to provide the best therapeutic option to patients.

Restrictive transfusion is the most common and appropriate treatment for patients with bleeding disorders because it is associated with better prognosis. However, hematologists are not familiar with the indication for and effect of using fresh frozen plasma (FFP) for transfusions, which has been inappropriately used to date. FFP should not be transfused for preventing bleeding or improving coagulation test results (i.e., PT and APTT). Instead, FFP transfusion should be performed to manage hemostasis, based on the fibrinogen levels of <150 mg/dl in patients' plasmas. Severe hypofibrinogenemia can cause critical coagulopathy, which results in massive bleeding. Early and sufficient FFP transfusion can overcome this condition. In addition, in patients with severe hypofibrinogenemia and active bleeding due to hyperfibrinolytic DIC associated with acute leukemia, the administration of concentrated fibrinogen products (e.g., cryoprecipitate or fibrinogen concentrates) is effective for maintaining hemostasis.

Blood products derived from iPS cells have been pursued as a blood donor-independent and genetically manipulative measure to complement or alternate current transfusion products. Erythrocytes and platelets are anucleate blood cells that are indispensable for oxygen delivery and hemostasis, respectively. Consequently, blood transfusions have been clinically established to treat severe anemia and thrombocytopenia. However, current blood products exhibit issues with regard to supply-demand imbalance and alloimmune responses and infections, and they also face a future shortage of donors in aging societies. While the production of erythrocytes from iPS cells has challenges to overcome, such as their differentiation into an adult-type phenotype and scalable production, platelet products are qualitatively and quantitatively approaching a clinically applicable level owing to advances in expandable megakaryocyte (MK) lines, platelet-producing bioreactors, and novel reagents. Currently, the establishment of guidelines that assure the quality of iPSC-derived blood products for clinical application is in progress. Considering the minimal risk of tumorigenicity and the expected significant demand of such products, the ex vivo production of iPSC-derived blood cells can be expected to lead iPSC-based regenerative medicine to become common clinical practice.

Both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are common malignant diseases in adolescents and young adults (AYAs). Recent advances in genomic studies have helped us understand the biological nature of acute leukemia in AYAs; higher frequency of Ph-like ALL and rearrangements in DUX4, ERG, MEF2D, and ZNF384 genes in AYAs with ALL and higher frequency of FLT3-ITD, NPM1, IDH1/2, DNMT3A, ASXL1, TET2, and CEBPA mutations in AYAs with AML than that in children. The pediatric-inspired regimen has become a standard treatment approach for AYAs with ALL, but optimal treatment strategy for AYAs with AML is not yet established to date. In general, poor adherence to the pediatric-inspired regimen, whether for ALL or AML, because of toxicities is still an issue in AYAs. In addition to optimizing appropriate chemotherapies for acute leukemia in AYAs, the development of novel therapy based on genomic analyses should be explored by close cooperation between pediatric hematologists/oncologists and adult hematologists.

Both treatment and prognosis of pediatric non-Hodgkin lymphoma (NHL) have improved dramatically in the last 30 years. Currently, localized or limited-stage NHL (stage I to II) has an approximately 95%-100% 5-year event-free survival (EFS) rate. Furthermore, the prognosis for children with advanced-stage disease (stage III to IV) has doubled from approximately 40% 5-year EFS 30 years ago to more than 80%. Hodgkin lymphoma is also known to have around 80% 10-year EFS rate. These were accomplished not only by the advancement of chemotherapy drugs but also with the global development of organizational frameworks for pediatric clinical study. The Japanese Pediatric Leukemia Lymphoma Study Group is one of such frameworks that was organized in 2003, and it has been playing a great role in Japan ever since. In this study, I described some of the main steps of clinical studies for pediatric lymphoma according to each histologic entity. In the future, however, an effective treatment for refractory or recurrent diseases should be developed. In addition, a precise validation for low-risk patients who need reduced chemotherapy should be performed. Further clarifications on the conditions of patients with rare type lymphoma and an establishment of a standard therapy for them through a collaborative study on a global scale are needed.

In the 2016 revision of the World Health Organization (WHO) classification, the categories of myeloid neoplasms have not been revised significantly from the 2008 fourth edition. However, recent discovery of molecular abnormalities provides a new perspective regarding the diagnostic and prognostic markers. In myeloproliferative neoplasms, the identification of CALR gene mutation, in addition to the JAK2 and MPL mutations, has impacted the diagnostic criteria. In myelodysplastic syndromes and acute myeloid leukemia, in addition to alterations in the transcription factors and signal transduction pathways, discovery of gene mutations in the epigenetic regulators that are involved in DNA methylation, histone modification, cohesin complex, and RNA splicing, by comprehensive genetic analyses, has improved our understanding of the pathobiology of these diseases. Moreover, recent large-scale sequencing studies have revealed the acquisition of clonal somatic mutations, in the myeloid neoplasm-associated genes of the hematopoietic cells. Such mutations were detected in people with normal blood cell counts, without any apparent disease. Presence of these mutations confers an increased risk for subsequent hematological neoplasms, indicating the concept of clonal hematopoiesis of indeterminate potential. This updated WHO classification incorporates the criteria of new clinical, prognostic, morphologic, immunophenotypic, and genetic findings in myeloid neoplasms.

The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms have been published in “Blood” as a review form. A major revision is being published that will be an update of the current fourth edition and not a truly new fifth edition. Because it is considered a part of the fourth edition, while some provisional entities will be promoted to definite entities and a small number of new provisional entities added, there will be no new definite entities. As with the 2001 and 2008 classifications, an all-important Clinical Advisory Committee meeting was held to obtain the advice and consent of clinical hematologists/oncologists and other physicians critical to the revision. The classification maintains the goals of helping to identify homogeneous groups of well-defined entities and facilitating the recognition of uncommon diseases that require further clarification. Some provisional or variant entities; EBV-positive large B-cell lymphoma, elderly and Pediatric follicular lymphoma focused on the age of onset, in situ lesions, and gray zone lymphomas, recognized in the 2008 WHO classification, were revised. This will review the major areas in mature B-cell lymphoid and mature T/NK-cell lymphoid neoplasms and Hodgkin lymphoma where changes from the 2008 WHO classification.