Summary
For successful chimeric antigen receptor T (CAR‐T) cell therapy, CAR‐T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR‐T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B‐cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 104/μL; p = 0.01) and CD4/CD8 T‐cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3–24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105/μL; p = 0.022) or low CD4/CD8 ratios (
I N TRODUC TIONAdvances in the use of bortezomib as a proteasome inhibitor (PI) and lenalidomide as an immunomodulatory drug (IMID) in early-stage multiple myeloma (MM) therapy have improved both the progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed MM. 1,2 However, all patients eventually relapse and require further treatments. Thus, relapsed/refractory MM (RRMM) is the main challenge of recent clinical research. Specifically, pomalidomide as an IMID, ixazomib or carfilzomib as second-generation PIs, and anti-CD38 (daratumumab and isatuximab) or anti-SLAMF-7 (elotuzumab) monoclonal antibodies are being used in addition to the above drugs, and many combinations of two or three of these agents have been investigated for the treatment of RRMM. Under such circumstances, understanding which regimens are better than others is not easy. The evolving field of treatment options, such as the recently approved agents selinexor (a first-in-class selective inhibitor of nuclear export), melflufen (a peptide-drug conjugate), and venetoclax (a BCL2 inhibitor),
Background
Transfusion‐associated circulatory overload (TACO) is an adverse reaction associated with a high risk of mortality. The actual incidence of TACO and hypertension associated with transfusion in Japan is unknown.
Methods
A multicentre retrospective observational study was conducted across 23 institutions during the 1‐year period of 2016. Patients were included if they developed TACO or their blood pressure (either systolic or diastolic) increased by at least 30 mmHg during the transfusion. TACO was confirmed by the primary physicians and transfusion medicine teams and recorded in the data on passive surveillance, and additional data were extracted from electronic medical records.
Results
In our patient cohort of 31 384 patients who underwent transfusion, the incidence of TACO and hypertension was 0·03% and 0·2%, respectively. However, 43% of the participating institutions didn't report any cases. When comparing risk factors between the TACO and hypertension groups, there were significant differences in comorbidities, such as abnormal findings on chest x‐ray. Significant differences between the two groups were observed post‐transfusion pulse rate, body temperature and oxygen saturation (P < 0·01). In the group of patients with hypertension, the level of BNP increased significantly after transfusion in 45% (5/11) of the patients. We identified 4 patients in the hypertension group who met the new ISBT’s TACO criteria.
Conclusion
Our study suggests that more attention should be given to TACO in Japan, particularly in terms of improving surveillance systems. For the early diagnosis of TACO, it is crucial to carefully monitor vital signs including blood pressure.
Background
The standard cryoprotectant for human cellular products is dimethyl sulfoxide (DMSO), which is associated with hematopoietic cell infusion‐related adverse events (HCI‐AEs) in hematopoietic stem cell transplantation including peripheral blood stem cell (PBSC) transplantation (PBSCT). DMSO is often used with hydroxyethyl starch (HES), which reduces DMSO concentration while maintaining the postthaw cell recovery. The cryoprotectant medium CP‐1 (Kyokuto Pharmaceutical Industrial) is widely used in Japan. After mixture of a product with CP‐1, DMSO and HES concentrations are 5% and 6%, respectively. However, the safety profile of CP‐1 in association with HCI‐AEs has not been investigated.
Study Design and Methods
To compare CP‐1 with other cryoprotectants, we conducted a subgroup analysis of PBSCT recipients in a prospective surveillance study for HCI‐AEs. Moreover, we validated the toxicity of CP‐1 in 90 rats following various dose administration.
Results
The PBSC products cryopreserved with CP‐1 (CP‐1 group) and those with other cryoprotectants, mainly 10% DMSO (non‐CP‐1 group), were infused into 418 and 58 recipients, respectively. The rate of ≥grade 2 HCI‐AEs was higher in the CP‐1 group, but that of overall or ≥grade 3 HCI‐AEs was not significantly different, compared to the non‐CP‐1 group. Similarly, after propensity score matching, ≥grade 2 HCI‐AEs were more frequent in the CP‐1 group, but the ≥grade 3 HCI‐AE rate did not differ significantly between the groups. No significant toxicity was detected regardless of the CP‐1 dose in the 90 rats.
Conclusions
Infusion of a CP‐1‐containing PBSC product is feasible with the respect of HCI‐AEs.
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