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

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma in Japan. Approximately half of all patients can be cured with frontline rituximab-containing chemoimmunotherapy. However, patients with relapsed or refractory disease after standard chemotherapy often have a poor prognosis. Various novel therapies have been developed to improve outcomes in this population. In particular, immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibody therapies have significantly transformed the treatment landscape for relapsed or refractory DLBCL. Several ongoing clinical trials are also investigating incorporation of these novel agents into frontline treatment regimens. This review outlines current treatment strategies for DLBCL and highlights recent advances in clinical development, with a focus on emerging immunotherapies.

Drug interactions occur when the concomitant use of multiple drugs enhances or reduces their pharmacological effects, or causes unexpectedly strong adverse reactions. Major mechanisms include alterations in cytochrome P450 (CYP) enzyme activity, chelation within the gastrointestinal tract, and inhibition of renal transporters. In the treatment of hematologic malignancies, combination of molecular targeted therapies with immunosuppressants often increases the risk of infections due to drug-induced cytopenia and immunosuppression. Azole antifungal agents, frequently used for the prevention and treatment of fungal infections, are known to inhibit CYP enzymes. This inhibition can increase the plasma concentrations of targeted therapies, thereby enhancing their toxicity and increasing the risk of severe adverse effects. The degree of interaction is influenced not only by specific drug combinations but also by interindividual variability. Advanced pharmacokinetic approaches such as concentration ratio-interaction risk methods, physiologically based pharmacokinetic modeling, and population pharmacokinetic analysis allow for the prediction and evaluation of such interactions. These tools enable more precise drug selection and dosage adjustments tailored to individual patients, supporting treatment personalization and promoting safer, more effective drug therapy in clinical practice.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) experience a significant decline in quality of life (QOL) due to various symptoms and organ damage associated with intravascular hemolysis. Red blood cell transfusions and other traditional supportive therapies offer only limited symptomatic relief and fail to prevent critical complications such as thrombosis and chronic kidney disease. Eculizumab, a C5 inhibitor introduced in 2010, directly inhibits intravascular hemolysis, and thus not only resolves hemolysis-related symptoms but also prevents organ damage and improves survival. This has resulted in a paradigm shift in the treatment of PNH. In this era of anti-complement therapy, the goal of PNH therapy can now be elevated to preventing intravascular hemolysis. However, the emergence of new issues, such as primary resistance due to C5 gene polymorphisms, breakthrough hemolysis, and extravascular hemolysis have hindered improvement of QOL. Various drugs have been developed to address these issues, including long-acting C5 inhibitors (ravulizumab and crovalimab) and proximal complement inhibitors capable of blocking extravascular hemolysis, such as a C3 inhibitor (pegcetacoplan), a factor B inhibitor (iptacopan), and a factor D inhibitor (danicopan). In particular, proximal complement inhibitors further enhance QOL because they inhibit both intravascular and extravascular hemolysis, resulting in greater improvement of hemoglobin levels and transfusion independence, and thereby further enhancing of QOL. Today, it is possible to achieve optimal improvement in QOL by appropriately selecting one of the three C5 inhibitors as first-line therapy or one of the three proximal complement inhibitors as second-line therapy, based on the patient's clinical condition and lifestyle.

Objective: The objective of this study was to evaluate the efficacy and safety of glucarpidase in eight Japanese patients with delayed methotrexate (MTX) elimination following high-dose methotrexate therapy (HD-MTX) under near-clinical conditions.

Methods: This was a multicenter, single-arm, open-label, phase II clinical study. Glucarpidase was administered in accordance with the criteria for delayed MTX elimination described in the package insert, and supportive care for HD-MTX was continued after glucarpidase dosing.

Results: The plasma MTX concentration 48 hours after the first dose of glucarpidase decreased by at least 90% from baseline in all patients. Moreover, 87.5% of patients had plasma MTX concentrations below 1 µmol/l. Grade ≥3 adverse events were reported in 25.0% of patients, but no adverse events were found to be causally related to glucarpidase.

Conclusion: The results of this study are similar to those of previous clinical studies, and indicate that glucarpidase should be effective and safe in clinical practice.

Patient 1 was a 65-year-old woman diagnosed with chronic myeloid leukemia (CML) in 2016. She was treated with dasatinib at a dose of 100 mg. After achievement of deep molecular remission (DMR) in 2018, the dasatinib dose was decreased to 50 mg a day. In April 2021, the patient suddenly developed high fever, skin swelling and redness, muscle swelling, and pain in bilateral lower extremities. Detection of G type hemolytic streptococcus in blood culture led to a diagnosis of streptococcal toxic shock syndrome (STSS). The patient recovered from disseminated intravascular coagulation and multiple organ failure by treatment with several antibiotics, fresh frozen plasma (FFP), and plasma exchange over a period of 2 months. Patient 2 was a 53-year-old man who developed CML in 2011. He was prescribed nilotinib, but efficacy could not be evaluated due to poor treatment adherence. Treatment with dasatinib was started instead within a year. DMR was achieved, but the patient developed STSS in July 2021. Both of these cases of STSS occurred in patients treated with dasatinib, which suggests that STSS may be related to dasatinib treatment in CML patients. We conducted a literature review to determine whether CML treatment selection was appropriate in these patients.

T-cell acute lymphocytic leukemia (T-ALL) with SPI1 fusion, a leukemia subtype first identified in Japan, has a very poor prognosis. A 7-year-old boy was admitted to our hospital with fever, cervical lymphadenopathy, eyelid edema, and purpura. White blood cell count was markedly increased (551,000/µl). Flow cytometric analysis revealed cyCD3, CD1a, CD8, and HLA-DR positive T-ALL, and fusion gene screening identified TCF7::SPI1 fusion. The patient was treated according to the JPLSG ALL-T11 protocol. He responded poorly to prednisolone, but favorably to L-asparaginase. After completion of early intensification therapy, molecular remission was confirmed. However, due to the patient's poor response to prednisolone, and the presence of the SPI1 fusion gene, hematopoietic stem cell transplantation from an HLA-matched unrelated donor was performed in first remission. So far, the patient has been in remission for 36 months from the time of onset. Hematopoietic stem cell transplantation in first remission may be effective treatment for patients with T-ALL and SPI1 fusion.

The advent of anti-CD19 chimeric antigen receptor-T cell therapy has dramatically changed the treatment strategy for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Three products are recently available in Japan, but to the best of our knowledge, real-world data are only available for tisagenlecleucel. This study was a retrospective analysis of 27 patients who received axicabtagene ciloleucel (axi-cel) for R/R DLBCL at our institution. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 24 (88.9%) and 8 patients (29.6%), respectively, and corticosteroids were used in 19 patients (70.4%). The median follow-up period was 8.1 months (range, 1.0-23.2), and the 6-month progression-free survival and overall survival rates were 80.2% (95% confidence interval [CI], 58.8-91.3) and 92.0% (95%CI, 71.6-97.9), respectively. Although our study was limited by its small sample size and short follow-up period, it demonstrated that axi-cel was highly effective and safe at our institution.