[Rinsho ketsueki] The Japanese journal of clinical hematology最新文献

The success of immune checkpoint inhibitors and CAR-T cell therapies has established immunotherapy as the "fourth pillar" of cancer treatment, alongside surgery, radiation, and chemotherapy. However, the therapeutic efficacy of immunotherapy for myeloid malignancies remains limited. While tumor immunology research has traditionally focused on T cells, attention has recently shifted to the roles of innate immune cells in the tumor microenvironment. These cells, which include macrophages, myeloid-derived suppressor cells, dendritic cells, and natural killer cells, have been found to play significant roles in the development and progression of myeloid malignancies. To develop effective immunotherapies for myeloid malignancies, it is essential to deepen our understanding of the roles of innate immunity within the bone marrow microenvironment and explore strategies to harness these mechanisms. This paper reviews the latest findings on innate immunity in myeloid malignancies and discusses the potential of immunotherapies that leverage innate immune responses.

Relapsed or refractory acute myeloid leukemia (AML) continues to have a poor prognosis, highlighting the urgent need for novel therapeutic approaches. Immunotherapy, with its distinct mechanisms of action from chemotherapy or molecularly targeted therapies, offers a promising option for treatment-resistant cases. To date, numerous chimeric antigen receptor (CAR) T cell products targeting surface antigens such as CD33, CD123, and CLL-1 have been developed and evaluated in clinical trials. T cell receptor (TCR)-T therapies targeting intracellular antigens such as WT1 are also in development, with some clinical studies reporting encouraging results. However, the development of cell therapies for AML presents unique challenges, including the identification of suitable surface target antigens and overcoming the immunosuppressive tumor microenvironment. Consequently, no cellular product has yet achieved regulatory approval. This article provides an overview of the current landscape and key challenges in the development of cell therapies for AML.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytic disease with no established therapeutic approach. Here we report a case of ECD treated with molecular targeted therapy. A 61-year-old woman diagnosed with ECD with BRAF^V600E mutation received combination therapy with a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Grade 1 fever and liver injury were detected early in the course of treatment, leading to temporary interruption. However, treatment was successfully resumed with concomitant administration of prednisolone. The BRAF^V600E allele frequency in plasma cell-free DNA became negative at 8 weeks of treatment, and PET/CT confirmed a partial metabolic response at 24 weeks. Recent studies have demonstrated the benefit of molecular targeted therapy for ECD. However, due to the rarity of ECD, treatment guidelines remain poorly defined, with limited guidance on indicators of treatment efficacy, optimal treatment duration, and criteria for treatment cessation. In the case of our patient as well, it will be necessary to consider the duration of treatment while carefully monitoring the clinical course.

A 62-year-old man presented with anemia and neutropenia, and was diagnosed with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC). His disease was refractory to treatment, but went into remission after a third regimen, venetoclax plus azacitidine (Ven+Aza). However, the disease relapsed during treatment for an infection, and he underwent allogeneic peripheral blood stem cell transplant while not in remission. He did not achieve remission after transplantation, but treatment with azacitidine and early discontinuation of immunosuppressants led to remission. However, relapse occurred on day250 in the form of pericardial effusion. After drainage, Ven+Aza therapy was started again, and the pericardial effusion disappeared rapidly. The patient has been continuing the same treatment, and has remained in remission for more than 15 months. Isolated extramedullary relapse caused by pericardial effusion is rare, and this case illustrates that Ven+Aza therapy may be effective.

An 80-year-old woman presented with fatigue. Routine blood tests at her previous medical institution revealed a decreased white blood cell count, leading to a diagnosis of low-risk myelodysplastic syndrome. During observation, the disease progressed to acute myeloid leukemia (AML), and she was subsequently referred to our hospital. At the time of AML diagnosis, bone marrow examination detected minor BCR-ABL mRNA. Fluorescence in situ hybridization showed a positive BCR-ABL fusion signal in 7.5% of bone marrow cells. Treatment with venetoclax and azacitidine was initiated, and led to hematological remission after one cycle. A bone marrow examination after two cycles confirmed the maintenance of hematological remission, and RT-PCR showed reduced minor BCR-ABL mRNA levels. AML with BCR-ABL1 fusion generally has a poor prognosis and has no established treatment, but in this case, treatment with venetoclax and azacitidine successfully induced remission and demonstrated potential efficacy against BCR-ABL fusion-positive clones.

Primary bone marrow lymphoma (PBML) is a malignant lymphoma characterized by proliferation of lymphoma cells exclusively in the bone marrow without lymphadenopathy. Despite the dismal prognosis of PBML, it is a very rare lymphoma with limited evidence concerning its pathophysiology, making accumulation of cases important. We herein report three cases of PBML at our institution. The first patient was an 80-year-old man who presented with hemophagocytic syndrome and pancytopenia at admission, and died of septic shock during initial chemotherapy. The second patient was a 64-year-old man who achieved complete remission with intensive chemotherapies, but relapsed shortly after completing the final chemotherapy course. The third patient was a 66-year-old woman who underwent chemotherapies and allogeneic hematopoietic stem cell transplantation, only to relapse shortly after transplantation. Although early intervention with chemotherapy is essential for PBML treatment, diagnosis of PBML is very challenging due to the absence of lymph node involvement. Moreover, treatment outcomes of existing chemotherapy and transplantation therapies for PBML are still poor. Further accumulation of cases and development of new treatment strategies are desirable.

The goal of treatment for lower-risk myelodysplastic neoplasms (MDS) is to improve cytopenia, and therapeutic options should include agents with few adverse events. Since anemia is the main symptom of this disease, red blood cell transfusions, darbepoetin, anabolic steroids, and immunosuppressive agents are considered when the disease is symptomatic, but with the advent of the novel anti-anemic agent luspatercept, there is growing debate regarding the timing of therapeutic intervention and the hemoglobin (Hb) levels at which red blood cell transfusion should be considered in this disease. As a result, there is a growing debate among institutions regarding these issues. It has become clear that there are slight differences in the criteria for initiation of transfusion and the timing of therapeutic intervention with anti-anemic agents at different centers. In this review, we will discuss the extent to which therapeutic intervention for lower-risk MDS improves the quality of life (QOL) of patients and how to improve the efficiency of limited healthcare resources, including an overview of ongoing clinical trials.

Aggressive adult T-cell leukemia-lymphoma (ATL) is a rare T-cell malignancy with a poor prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy, but the long-term survival rate is approximately 40%, which is poor compared to other hematopoietic tumors. The most common cause of death after allo-HCT is ATL relapse. Approximately 40% of patients experience a relapse following allo-HCT, and the prognosis after relapse remains poor. In recent years, various strategies have been attempted to prevent and treat post-transplant ATL relapse. Cord blood and HLA haplo-identical related donors are widely used as alternative donors to Japan Marrow Donor Program donors for transplantation in remission soon after diagnosis, and novel drugs for ATL are used as salvage therapy before or after allo-HCT. Monitoring of measurable residual disease with flow cytometry has also been attempted for early detection of post-transplant relapse. Nevertheless, there is still insufficient evidence for the prevention and treatment of post-transplant relapse of ATL. Given the limited experience at individual hospitals and the increasing population of HTLV-1 carriers throughout the country, it is desirable to build evidence based on treatment experience and analysis of clinical specimens from hospitals throughout Japan.