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The discovery of driver genes such as JAK2 in myeloproliferative neoplasms (MPN) led to a better understanding of MPN pathogenesis as a constitutive activation of the JAK/STAT signal. Following these findings, several types of JAK inhibitors have been developed. Ruxolitinib, a JAK1/2 inhibitor licensed for polycythemia vera and myelofibrosis, demonstrated efficacy in regulating hematocrit levels, lowering spleen volume, and relieving MPN-related symptoms. However, some patients with myelofibrosis are refractory to JAK inhibitors, and some are intolerant due to cytopenia. Furthermore, JAK inhibitors did not slow the progression of acute leukemia, indicating the need for new therapeutic methods for myelofibrosis. Novel medicines, including BCL inhibitor, MDM2 inhibitor, LSD1 inhibitor, PI3K inhibitor, BET inhibitor and telomerase inhibitor, are presently being evaluated in clinical studies for myelofibrosis with the potential to enhance clinical outcomes.

Multiple myeloma (MM) is a hematological malignancy characterized by aberrant clonal plasma cells in the bone marrow. Despite significant advances in the treatment of MM, infection remains a main cause of death. MM patients have an increased risk of infection compared to their healthy counterparts due to several factors related to underlying disease, advanced age, comorbidities, and MM treatment. MM patients are at high risk of infection during the first 3 months after diagnosis and during relapse. Anti-myeloma drugs frequently result in severe immunosuppression and increased risk of infection. Proteasome inhibitors deplete T cells, lenalidomide and pomalidomide induce neutropenia, and CD38 antibodies reduce B cell function. To prevent infection in MM patients, we should take appropriate action by medical prophylaxis and vaccination.

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

Chronic graft-versus-host disease (GVHD) affects various organs and causes significant morbidity and mortality after allogeneic hematopoietic cell transplantation. The 2005 National Institutes of Health consensus criteria for chronic GVHD have set international standards for endpoints and designing and reporting of clinical trials; these criteria were revised in 2014 to incorporate accumulated evidence and controversies. In addition, preclinical studies of chronic GVHD have identified treatment targets such as regulatory T cells, B-cell signaling, Th17 cells, Tc17 cells, follicular helper T cells, follicular regulatory T cells, and fibrosis-promoting factors. These efforts led to the approval of ibrutinib, belumosudil, and ruxolitinib by the U.S. Food and Drug Administration for treating chronic GVHD after failure of one or more lines of systemic therapy, and an increasing number of investigational agents that target different biological pathways of chronic GVHD are under development in clinical trials. To address challenges in a rapidly evolving field, a third National Institutes of Health consensus project was held in 2020, in which investigators, patient advocacy organizations, and pharmaceutical companies aimed to define basic and clinical research roadmaps that may lead to significant change in chronic GVHD management over the next 5 years.

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.

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.

The introduction of proteasome inhibitors and immunomodulatory and antibody drugs has dramatically improved the prognosis of multiple myeloma (MM) in the 21st century. Despite the development of such highly effective MM therapeutics, however, patients may develop drug resistance and become refractory to standard therapies, and thus cannot be cured. New molecular targeted (venetoclax, selinexor), immunomodulatory (iberdomide), and antibody drugs (isatuximab, belantamab mafodotin), as well as bispecific T-cell engagers (BiTE) and chimeric antigen receptor T-cell (CAR T-cell) therapy, have been developed in the past 1-2 years, and promising results have been reported. In this article, we mainly review these drugs currently under development.

Myelodysplastic syndromes (MDS) are malignant clonal stem cell disorders. There are two main treatment options for higher-risk MDS, i.e., eligible and ineligible hematopoietic stem cell transplantation (HSCT). Transplantation-eligible patients should receive HSCT immediately, with or without prior therapy. In contrast, for patients who are ineligible for HSCT, azacitidine (AZA) may now be the first choice of treatment, which significantly prolongs overall survival in responder patients when compared with conventional care regimens. However, there are major problems regarding the management of patients with disease relapse after HSCT and those with loss of response to AZA. In this review, treatment strategies and future perspectives, including the use of novel agents, are presented with the aim of improving the outcome of higher-risk MDS.

POEMS syndrome is a rare paraneoplastic disorder characterized by polyneuropathy, organomegaly, endocrinopathy, λ-type monoclonal protein derived from only two germlines (IGLV1-40 or IGLV1-44), skin changes, extravascular volume overload, and serum vascular endothelial growth factor elevation. To understand the molecular pathophysiology of the disease, comprehensive genetic analyses of bone marrow plasma cells was performed in 20 patients with the syndrome. Although a median of 14.5 mutated genes were identified per patient, none of the driver gene mutations frequently found in multiple myeloma were detected. RNA sequencing revealed a transcription profile specific to POEMS syndrome, which suggested that the genetic and transcriptional profiles of plasma cells in POEMS syndrome are distinct from multiple myeloma and monoclonal gammopathy of undetermined significance. Treatment strategies for the devastating disease have been developed by targeting monoclonal plasma cells with novel agents, mainly thalidomide, followed by autologous stem cell transplantation (ASCT). Moreover, the 5-year overall survival after ASCT has improved to as high as 90% with dramatic improvement in symptoms and activities of daily living. However, the 5-year progression-free survival during long-term follow-up has dropped to 60%. Therefore, identifying novel therapeutic targets are imperative for further improvement of disease outcomes.

Recent advances in drug treatment for higher-risk myelodysplastic syndromes (MDS) have focused on DNA hypomethylating agents (HMAs). Azacitidine (AZA), a representative HMA available in Japan, has demonstrated a survival benefit over conventional treatment. However, unsatisfactory treatment profiles of AZA exemplified by a low response rate of <20% complete remission (CR), a short duration of response (usually <1 year), and dismal outcomes after the failure to fulfil unmet needs in AZA treatments have highlighted the urgent need for the development of novel therapeutic modalities. In this manuscript, an array of novel agents under clinical investigation for higher-risk MDS is introduced. The drugs in the most advanced phase of development include SGI-110, a next-generation DNA hypomethylating agent that is designed to prolong cellular exposure time, and the multi-kinase inhibitor rigosertib, which is specifically active against patients with higher-risk MDS who fail to respond to conventional HMAs. Other lines of agents under investigation include a combination of histone deacetylase inhibitors and hypomethylating agents, immune checkpoint inhibitors, spliceosome inhibitors, BCL2 inhibitors, and IDH1/2 inhibitors, all of which have been developed by exploiting the recent understanding of the molecular pathogenesis of MDS, including the tumorigenic role of common mutations and disturbance of tumor immunity.

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.

IgE multiple myeloma (MM) is a rare subtype of MM characterized by an aggressive and poor prognosis. Although novel agents have improved the prognosis of MM, there are few case reports of IgE MM treated with these agents. A 53-year-old male patient presented with pain in the right rib and was diagnosed with IgE-κ MM. He was treated with multidrug chemotherapy, including bortezomib and lenalidomide, and underwent autologous stem-cell transplantation (ASCT). Finally, he achieved a complete response after the initiation of pomalidomide. In previous reports, majority of patients with refractory IgE MM treated with novel agents had a poor prognosis. In contrast, patients who were treated with novel agents from the beginning and underwent ASCT had a long-term survival. Overall, the use of novel agents as the first-line therapy is expected to improve IgE MM prognosis.