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

Advances in replacement therapy with clotting factor (F) VIII or FIX product have contributed greatly to reducing the incidence of hemophilic arthropathy and improving quality of life (QOL) in patients with hemophilia. However, frequent intravenous administration of clotting factor products, blood access, and development of alloantibodies (inhibitors) have been important issues. Clinical studies aimed at addressing these issues have been conducted in Japan as well, including a multicenter study to determine factors involved in inhibitor development. Drug development has also progressed: several clotting factor products with extended half-life and non-clotting factor therapies have been introduced in quick succession. Anti-FIX/FX bispecific antibody in particular has a long half-life when administered subcutaneously and controls bleeding in patients with hemophilia A. Anti-antithrombin therapy and anti-TFPI monoclonal antibody products that work by rebalancing coagulation have also been developed. In addition, gene therapy has been approved for adults in U.S. and Europe, where improved vectors and codon optimization have enabled protein expression up to the near-therapeutic hemostatic range. Recent significant developments in hemophilia treatment are expected to overcome long-standing problems and further improve QOL.

Chimeric antigen receptor (CAR) T-cell therapy is an innovative treatment for B-cell malignancies and multiple myeloma. CAR T-cell therapy is now approved in Japan and has become one of the essential therapeutic options for chemotherapy-resistant disease. It has many unique features that distinguish it from conventional chemotherapies, including the limitations imposed by the production of CAR-T cells from autologous T cells, and the limited availability and mandatory waiting period for treatment. Importantly, each patient has only one opportunity to receive CAR T-cell therapy. To achieve the maximum therapeutic benefit from CAR T-cell therapy, it is necessary to understand all aspects of CAR T-cell therapy, including factors that influence its efficacy. The design of the entire treatment sequence, including before and after CAR T-cell therapy, is also important to optimize clinical outcomes. In addition, since this treatment is only available at a limited number of facilities, effective coordination between local hospitals and treatment centers is also important. This educational session will focus on the practical aspects of CAR T-cell therapy in adults and will provide indispensable knowledge for providing CAR T-cell therapy to patients with B-cell lymphoma and multiple myeloma.

Immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 antibodies have been the three mainstays of myeloma treatment. B-cell maturation antigen (BCMA)-targeted immunotherapy, including chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies (BsAbs), is emerging as another important class of treatment. Two BCMA-targeting CAR-T products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel, are approved in Japan, but only ide-cel is available for clinical use. Recently, a randomized phase III study comparing ide-cel with standard therapy in patients with refractory myeloma who had received 2 to 4 prior lines of therapy showed that ide-cel was superior in terms of both response rate and PFS. Based on these results, ide-cel was approved as a third-line therapy. The new availability of bispecific antibodies has also raised new clinical questions regarding how to use CAR-T and BsAbs for each patient, and in what order. Limited data have suggested that favorable responses can be achieved when BsAbs are administered after CAR-T, but responses are suboptimal when CAR-T is administered after BsAbs. Finally, it is important to note that coordination between referring centers and treating centers, including aspects such as timing of patient referral, bridging therapy, and long-term follow-up after CAR-T, is critical to optimization of CAR-T.

Recent advances in sequencing technologies have clarified the driver gene landscape in Philadelphia chromosomenegative (Ph-) myeloproliferative neoplasms (MPNs) and progressed understanding of MPN pathogenesis. Beyond mutations in the main three drivers of MPN, namely JAK2, MPL and CALR, somatic mutations in the epigenetic regulators and RNA splicing factors have been identified and their association with transformation to myelofibrosis and acute myeloid leukemia have been determined. Clonal expansion of hematopoietic cells with driver mutations (clonal hematopoiesis) has been detected in healthy individuals, especially in elderly people. In MPN patients, however, initial driver mutations such as those in JAK2 and DNMT3A have been shown to be acquired in utero or during childhood. In this review, I will summarize the recent findings about clonal evolution in MPN and the role of driver mutations.

A 72-year-old woman presented with generalized lymphadenopathies and plasmacytosis accompanied by polyclonal hypergammopathy. ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed FDG accumulation in the systemic lymph nodes, spleen, and multiple bones. Human immunodeficiency virus antibody was negative. Lymph node histologic findings showed a monotonous population of plasma cells with a starry-sky appearance. The cells were positive for CD19, λ, and Epstein-Barr virus-encoded RNA, and negative for CD20 and CD56. The MIB-1 index was 80%. A diagnosis of plasmablastic lymphoma with plasmacytosis and polyclonal hypergammopathy was made, and complete metabolic response was achieved after six cycles of dose-adjusted-EPOCH therapy (etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin).

There is growing recognition of post-transplant cyclophosphamide (PTCy) as the new standard prophylaxis for graft-versus-host disease (GVHD) in HLA-matched peripheral blood stem cell transplants with reduced intensity conditioning, based on recent results of randomized phase III trials of PTCy. Allogeneic hematopoietic cell transplantation (HCT) with PTCy is thought to have GVHD-dependent and -independent graft-versus-tumor (GVT) effects. Its GVHD-dependent effects may be attenuated by PTCy-induced alloreactive T cell dysfunction and preferential recovery of regulatory T cells after HCT, but its GVT effects do not appear to be significantly impaired in patients in remission or with indolent disease. As patients not in remission are often also candidates for transplantation in Japan, it will be necessary to use PTCy as a platform to establish a strategy that could also be effective in patients not in remission and to revise the donor selection algorithm.

Cold agglutinin disease (CAD), an immune hemolytic disease mediated by the classical complement-dependent pathway, accounts for approximately 8% of autoimmune hemolytic anemia (AIHA) cases. Primary CAD is a clonal B-cell lymphoproliferative disease of the bone marrow that produces IgM type-M protein, while conventional secondary CAD is cold agglutinin syndrome (CAS). Clinical findings are broadly classified into chronic anemia due to hemolysis and symptoms associated with peripheral circulatory failure due to erythrocyte aggregation under cold exposure. Not all patients require drug therapy, but monoclonal antibody therapy against complement C1s is preferred for the former presentation and B-cell suppressors for the latter. As cold AIHA is treated differently than warm AIHA, misdiagnosis can significantly impact the outcome of treatment. The most important aspect of blood testing is temperature control of specimens. Cold agglutinin titer, IgM quantification, electrophoresis, and immunofixation methods may produce false-negative results if the serum is not temperature-controlled at 37-38°C until serum separation. Correct handling of specimens, along with knowledge of the various clinical features of CAD, will lead to correct diagnosis and appropriate treatment.

A 62-year-old woman with adult T-cell leukemia/lymphoma (ATL) received umbilical cord blood transplantation (CBT) in first complete remission. However, relapse of ATL was detected on day 74 post-transplantation, as evidenced by the rapid growth of lymphoma cells in peripheral blood and an increase in soluble interleukin-2 receptor (sIL2R) levels. Discontinuation of immunosuppressant therapy alone did not improve ATL findings, but treatment with lenalidomide caused lymphoma cells to disappear from the peripheral blood and sIL2R levels to return to normal. Pancytopenia was observed as a lenalidomide-associated adverse effect, but lymphocyte counts were not reduced. The patient was judged to be in complete remission based on results of Southern blot analysis and human T-cell leukemia virus 1 (HTLV-1)-infected cell analysis using flow cytometry (HAS-Flow). Flow cytometric analysis of peripheral blood and FISH analysis of X and Y chromosomes revealed that the therapeutic effect of lenalidomide was associated with an increase in the number of donor-derived peripheral natural killer cells. ATL relapse was not observed at 13 months into lenalidomide treatment. Our results suggest that lenalidomide is an effective option for the treatment of post-transplant relapsed ATL.