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

Acute myelogenous leukemia (AML) has a poor prognosis in patients who are ineligible for intensive chemotherapy. The combination of azacitidine and venetoclax has been shown to have high overall efficiency and remission rates, even in patients ineligible for aggressive chemotherapy. However, myelosuppression is often prolonged after treatment, and infection can also occur. Severe myelosuppression is often addressed by dose titration, but specific dose titration methods have not been clarified. We used the standard induction therapy with azacitidine plus venetoclax, and if blasts decreased to 20% or less, switched to 7+7 therapy to shorten venetoclax to 7 days starting from the next cycle. In the 19 patients we treated (median age 80 years), response rate above MLFS was 100%, CR 57.9%, CRc (CR+CRi) 78.8%, median OS 693 days, median PFS 458 days, and median OS was not reached in previously untreated patients. This indicates that 7+7 is a highly effective and well-tolerated treatment.

There are two main types of clinical trials: industry-sponsored trials and investigator-initiated trials. Both of these, like the two sets of wheels on a car, are essential to development of treatments. Numerous clinical trials have been conducted in multiple myeloma, contributing to the development of new drugs and the current treatment landscape. Highly effective novel immunotherapies, such as bispecific antibodies and chimeric antigen receptor T-cell therapy, have emerged, and could be incorporated into the treatment landscape in the near future. However, given the improved performance of current standard therapies, the drawbacks (e.g., toxicity) of immunotherapy can be expected to outweigh the benefits (efficacy) in some patients. Therefore, clinical trials are designed to evaluate treatments stratified based on factors such as post-treatment efficacy and disease risk, and stratified treatment approaches are increasingly being considered as well as one-size-fits-all approaches to treatment development. In addition, the use of real-world data is being explored to make clinical trials more efficient. These approaches are expected to further improve the individualization and efficiency of multiple myeloma treatment.

T cell malignancies pose several unique issues for CAR-T cell therapy that were not significant concerns with CAR-T cells for B-cell malignancies. A general problem to consider in the production of CAR-T cells is "on target-off tumor toxicity." This occurs when the antigen targeted by the CAR-T cells is also expressed on normal cells, not just tumor cells, which causes CAR-T cells to damage these normal cells. In CAR-T cell therapy for T cell tumors, antigens expressed on T cells (such as CD5, CD7, etc.) are the targets, which leads to a problem known as "fratricide," where CAR-T cells kill each other. Other issues include T cell aplasia and contamination of CAR-T cell products with tumor cells. However, several recent clinical trials have shown excellent outcomes for CAR-T cell therapy when genome editing technology is used to overcome these issues by knocking out target antigens or T cell receptors. This review article outlines these challenges and their solutions and discusses the results of recent clinical trials.

Acquired hemophilia A (AHA) is a bleeding disorder caused by autoantibody (inhibitor) production targeting blood coagulation factor VIII (FVIII). It is characterized by sudden onset, and often causes extensive and severe bleeding in soft tissue. Acquired hemophilia A is diagnosed when coagulation tests show normal PT, prolonged APTT, decreased FVIII activity, normal VWF activity, and positive FVIII inhibitor. Hemostatic therapy mainly consists of bypass therapy, which activates the extrinsic coagulation pathway, bypassing the need for FVIII or factor IX. Emicizumab, a bispecific antibody that substitutes for FVIII function, can be used to prevent bleeding. Immunosuppressive therapy is necessary to suppress or eradicate inhibitors. The majority of patients go into remission with treatment, but some die from bleeding symptoms or infections associated with immunosuppressive therapy.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for refractory/relapsed (R/R) hematologic malignancies, with six products approved for B-cell tumors and multiple myeloma as of the end of 2023. However, adoptive cell therapy (ACT) for solid tumors is hindered by critical challenges in multiple areas, including (1) lack of appropriate tumor-specific antigens, (2) inefficient T-cell trafficking and infiltration into the tumor microenvironment, and (3) immunosuppressive signals within the tumor milieu that induce T-cell dysfunction. This review examines the existing clinical trial data on ACT for solid tumors to elucidate the current landscape of ACT development for solid tumors. It also outlines the trajectory of ACT for solid tumors and integrative approaches to overcoming the complex tumor microenvironment.

Immune checkpoint inhibitor (ICI)-induced thrombocytopenias are rare immune-related adverse events (irAE), but ICI-related thrombotic thrombocytopenic purpura (TTP) is extremely rare. A 79-year-old woman with non-small cell lung cancer received maintenance therapy with the anti-human PD-L1 monoclonal antibody durvalumab. Four weeks after the last infusion, she developed overt TTP. Remission was achieved by plasma exchange and prednisolone, and the patient has now been recurrence-free for over 12 months. To our knowledge, this is the first report of TTP occurring as an irAE of durvalumab.

A 66-year-old man was diagnosed with symptomatic IgG-λ multiple myeloma based on the presence of anemia, thrombocytopenia, renal dysfunction, and a tumor on the right sixth rib. Bone marrow aspiration yielded a dry tap and biopsy revealed myelofibrosis grade 2. Partial response was achieved with Bd (bortezomib and dexamethasone) and VRd (bortezomib, lenalidomide, and dexamethasone). The patient received autologous stem cell transplantation, but the myeloma relapsed 3 months later, and liver tumors developed as well. DKd (daratumumab, carfilzomib, and dexamethasone) was administered, but the patient died due to disease progression. Autopsy revealed multiple extramedullary lesions in the liver, spleen, gallbladder, adrenal glands, kidneys, and multiple lymph nodes, as well as ascites.