BACKGROUND:Schnitzler syndrome is an adult-onset autoinflammatory disease characterized by an urticaria-like rash and monoclonal gammopathy with fever and fatigue. Although some treatments have shown efficacy in clinical trials, no approved treatment exists. We aimed to assess canakinumab, an anti-IL-1β monoclonal antibody, in Japanese patients. METHODS:This phase II, multicenter, single-arm, open-label study enrolled five patients with active disease from four hospitals. Patients received a single subcutaneous dose of canakinumab 150 mg. The primary endpoint was the proportion of patients achieving a complete clinical response (CR), based on physician global assessment on Day 7. If a CR was not achieved on Day 7 or by 8 weeks post-treatment, the dose was increased to 300 mg. Dosing continued every 8 weeks until 24 weeks. The study also evaluated patient-reported disease activity and changes in acute inflammatory markers, including white blood cell count, neutrophil count, C-reactive protein concentration, and serum amyloid A level. Quality of life was assessed using the Dermatology Life Quality Index and the 36-item Short Form health survey. Safety was also evaluated. RESULTS:Sixty percent (3/5) of patients had a CR on Day 7. One of the remaining two patients had a CR 7 days after the dose was increased to 300 mg. All five patients, including those who did not achieve a CR, showed improvement in inflammatory markers and quality of life scores, and no new adverse events were detected. CONCLUSIONS:In this trial, canakinumab showed a potential for usefulness in Japanese patients with Schnitzler syndrome.

Craniocervical edema appears soon after chimeric antigen receptor T-cell (CAR-T) therapy in some cases. This phenomenon is often observed right after systemic cytokine release syndrome (CRS), and it is called local CRS (L-CRS). In severe cases, L-CRS causes airway obstruction and asphyxia, but it is not yet well known among hematologists. In this report, we present mild and severe cases of L-CRS. Tocilizumab might have limited efficacy against L-CRS, and early administration of corticosteroids can be important. We hope that this case report raises awareness of L-CRS as an acute-onset adverse event after CAR-T therapy.

BACKGROUND:The advantage of intensified myeloablative conditioning (MAC) over standard MAC has not been determined in haematopoietic stem cell transplantation (HSCT) for adult acute lymphoblastic leukemia (ALL) patients. METHODS:To evaluate heterogeneous effects of intensified MAC among individuals, we analyzed the registry database of adult ALL patients between 2000 and 2021. After propensity score matching, we applied a machine-learning Bayesian causal forest algorithm to develop a prediction model of individualized treatment effect (ITE) of intensified MAC on reduction in overall mortality at 1 year after HSCT. RESULTS:Among 2440 propensity score-matched patients, our model shows heterogeneity in the association between intensified MAC and 1-year overall mortality. Individuals in the high-benefit group (n = 1220), defined as those with ITEs greater than the median, are more likely to be younger, male, and to have higher refined Disease Risk Index (rDRI), T-cell phenotype, and grafts from related donors than those in the low-benefit group (n = 1220). The high-benefit approach (applying intensified MAC to individuals in the high-benefit group) shows the largest reduction in overall mortality at 1 year (risk difference [95% confidence interval], +5.94 percentage points [0.88 to 10.51], p = 0.011). In contrast, the high-risk approach (targeting patients with high or very high rDRI) does not achieve statistical significance (risk difference [95% confidence interval], +3.85 percentage points [-1.11 to 7.90], p = 0.063). CONCLUSIONS:These findings suggest that the high-benefit approach, targeting patients expected to benefit from intensified MAC, has the capacity to maximize HSCT effectiveness using intensified MAC.

Prolonged hematotoxicity is the most common long-term adverse event in chimeric antigen receptor T cell therapy (CAR-T). To evaluate the impact on prolonged cytopenia of inflammatory status after CAR T infusion, we performed a single-center retrospective study and analyzed patients with B cell lymphomas after CAR-T. Among 90 patients analyzed at 90 days after infusion, the cumulative incidence was 57.5% for prolonged neutropenia, 36.7% for anemia, and 49.8% for thrombocytopenia. Patients who experienced cytokine release syndrome (CRS) had significantly higher incidence and longer duration of prolonged cytopenia. In addition, we found that among patients with grade 1 CRS, those with a longer duration of CRS-related symptoms (>5 days; grade 1b in modified CRS grading [m-CRS]) had a significantly higher incidence and longer duration of prolonged cytopenia than those whose CRS-related symptoms resolved within 5 days (grade 1a m-CRS). Multivariate analysis revealed that a higher m-CRS grade (grade 1b or 2; hazard ratio [HR], 2.42), higher peak CRP (≥10 mg/dL; HR, 1.66), longer duration of elevated CRP (≥10 days; HR, 1.83), and a decrease in serum inorganic phosphorus concentration (≥30% from baseline; HR, 1.95) were associated with significantly higher cumulative incidence of prolonged neutropenia, as well as anemia and thrombocytopenia. Using these factors, we developed a new predictive scoring model for prolonged hematotoxicity, the KyoTox a-score, which can successfully stratify the incidence and duration of cytopenia independent of the existing model, CAR-HEMATOTOX, which is based on laboratory data at lymphodepletion. Thus, this newly developed post-CAR-T inflammation-dependent score is accurate and useful for predicting prolonged hematotoxicity.

Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for B cell malignancies. A certain fraction of patients, however, experience post-CAR-T relapse, and due to the difficulty of precise relapse prediction, biomarkers that can predict the strength and duration of CAR-T efficacy are needed before CAR-T infusion. Therefore, we performed a single-center cohort study including 91 diffuse large B cell lymphoma (DLBCL) patients treated with CAR-T in order to identify such a new prognostic biomarker. After confirming that each of the already reported prognostic parameters (disease status at leukapheresis, primary refractoriness, number of treatment lines, CD3+ cell counts at leukapheresis) has only limited predictive performance, we established a new composite parameter by integrating these four variables, and found that it predicts progression-free survival (PFS) after CAR-T infusion with statistical significance. Moreover, after comprehensive correlation analyses of this new composite parameter with all individual laboratory variables, we determined that the standard deviation of red blood cell distribution width (RDW-SD) at leukapheresis shows significant correlation with the composite parameter and may be a prognostic biomarker (R2 = 0.76, p = 0.02). Validation analysis indicated that a higher RDW-SD is significantly associated with poorer PFS after CAR-T cell therapy (HR, 3.46, P = 0.03). Thus, this study suggests that a single parameter, RDW-SD at leukapheresis, is a novel, useful biomarker that can be obtained early to predict therapeutic effects of CAR-T cell therapy. Post-CAR-T maintenance or re-induction therapies should be adopted for higher risk patients, who may relapse after CAR-T therapy.

Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved management of relapsed or refractory multiple myeloma. However, manufacturing failure due to poor cell growth necessitates revised treatment strategies that negatively impact patients. To identify risk factors for CAR-T cell manufacturing failure in myeloma patients, a nationwide cohort study was performed, analyzing patients who underwent apheresis for idecabtagene vicleucel in Japan. Of the 154 patients analyzed, 13 cases (8.4%) experienced manufacturing failure. We compared clinical factors between patients with manufacturing failure (failed group) and those who met specifications (successful group). Patients in the failed group had a higher prevalence of deletion 17p at diagnosis (38.5% vs. 14.9%), were more likely to have been treated with alkylating agents within 6 months before apheresis (53.8% vs. 23.4%), and had undergone more chemotherapy lines prior to apheresis (median, 6 vs. 5). Additionally, failed patients exhibited significantly lower hemoglobin levels (8.6 vs. 10.0g/dL), platelet counts (5.9 vs. 13.8 × 104/μL), and CD4/CD8 ratios (0.169 vs. 0.474) than successful cases. Multivariate analysis revealed that low platelet counts (odds ratio [OR] 0.130 for every increase of 105/μL; p=0.041), or low CD4/CD8 ratios (OR 0.100 for each doubling; p=0.003) at apheresis increased the risk of manufacturing failure. Alkylating agents within 6 months before apheresis were associated with decreased platelet counts and CD4/CD8 ratios. Manufacturing failure remains an obstacle to CAR-T cell therapy for myeloma patients. Avoiding risk factors, such as alkylating agents, and adopting risk-adapted strategies may optimize CAR-T cell therapy for myeloma patients.

AbstractIntroductionPatients undergoing chimeric antigen receptor (CAR) T‐cell therapy face prolonged treatment timelines and are prone to cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) after infusion. Disabilities in physical function and the importance of rehabilitation during CAR‐T‐cell therapy to maintain physical function have been poorly documented.MethodWe performed a retrospective cohort study to assess changes in exercise tolerance via differences in a 6‐min‐walking distance (Δ6MWD) and factors influencing it.ResultsA total of 77 patients who underwent rehabilitation during CAR‐T‐cell therapy were enrolled, and their 6MWD was 450 m (median, range 180–705 m) before and 450.5 m (107.0–735.0 m) 30 days after CAR‐T treatment. No significant alteration in Δ6MWD was observed overall (11.0 m, 95% confidence interval, −56.1 to 88.2 m). Multiple regression analyses indicated that age (over vs. under 65 years) revealed no notable differences in Δ6MWD (20 vs. 10 m), while ΔHb (β = 0.24, p = 0.03), moderate/severe CRS (grade 1 with continuous fever or grade ≥2; β = −0.25, p = 0.03), and ICANS (any grade; β = −0.22, p = 0.04) were significantly associated with lower Δ6MWD.ConclusionThis real‐world study indicated that CAR‐T‐cell therapy is less likely to reduce physical function even in older patients if rehabilitation is properly performed, whereas CRS and ICANS can be risk factors to deprive exercise tolerance.

To assess the benefits of HLA-haploidentical haematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) relative to those of umbilical cord blood (UCB) transplantation in acute lymphoblastic leukaemia (ALL), we analysed 1999 patients (PTCy-haplo, 330; UCB, 1669), using the nationwide Japanese registry. PTCy-haplo was associated with a significantly higher relapse rate, but lower non-relapse mortality, which results in overall survival and disease-free survival, comparable to those of UCB. Among patients in CR1, PTCy-haplo showed a significantly higher survival than UCB regardless of the CD34+ cell dose. Our findings provide valuable insights into the donor selection algorithm in allogeneic HSCT for adult patients with ALL.

Advances in understanding of the pathogenesis of B-cell lymphoma have led to development of various novel targeted therapies. Among them, CD19-targeted chimeric antigen receptor (CAR) T-cell therapies for relapsed and refractory B-cell lymphomas have shown remarkable efficacy in clinical trials, and three CAR T-cell products are now available in Japan. Real-world evidence (RWE) has shown that these products can provide comparable efficacy to clinical trials in clinical practice, where CAR T-cells were administered in patients with wider range of backgrounds. This finding will certainly broaden the role of CAR T-cell therapies in the treatment of B-cell lymphoma. However, since about half of the patients treated with CAR T-cell therapy progress thereafter, there is an urgent need for risk stratification and optimized management of refractory cases. Here, we review the results of clinical trials and RWE of CAR T-cell therapy in B-cell lymphoma.

[Introduction] HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCB) are alternative to HLA-matched hematopoietic stem cell transplantation (HSCT). However, advantage of PTCy-haplo versus UCB has not been determined in patients with acute lymphoblastic leukemia (ALL). Thus, we compared post-HSCT outcomes of PTCy-haplo and UCB in adult patients with ALL to determine patient subgroups who benefit from PTCy-haplo. [Methods] We analyzed data on adult patients (≥16 years) with ALL who underwent HSCT with PTCy-haplo or single-unit UCB between January 2013 and December 2021, using the Japanese nationwide registry database. Endpoints of the analysis included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse, non-relapse mortality (NRM), engraftments, acute and chronic graft-versus-host disease (GVHD), and infections. In addition to multivariate analysis, propensity score matching was performed as a sensitivity analysis. [Results] We analyzed 1999 patients (PTCy-haplo, 330; UCB, 1669). Median age at HSCT was 44.5 years (range, 16-73) in PTCy-haplo and 45 years (range, 16-74) in UCB group. The proportion of patients who underwent HSCT in the first complete remission (CR1) (PTCy-haplo, 50.3%; UCB, 48.8%) and median time from diagnosis to HSCT (PTCy-haplo, 7.8 months; UCB, 7.7 months) were comparable between the groups. Regarding conditioning, the proportion of those who received myeloablative conditioning (PTCy-haplo, 50.6%; UCB, 54.8%), or conditioning with total body irradiation (PTCy-haplo, 82.4%; UCB, 79.3%) were comparable between the groups. Multivariate analyses showed that PTCy-haplo recipients had comparable 3-year OS (54.1% vs. 52.3%; adjusted hazard ratio [aHR], 0.93; p = 0.51) and DFS (49.7% vs. 47.1%; aHR, 1.06; p = 0.60) with UCB recipients. PTCy-haplo recipients had a significantly higher 3-year relapse rate (32.2% vs. 26.4%; aHR, 1.47; p = 0.01), but had a significantly lower 3 -year NRM (18.1% vs. 26.5%; aHR, 0.70; p = 0.03) as compared to UCB along with significantly faster neutrophil (median, 16 days vs. 20 days) and platelet (median, 30 days vs. 42 days) engraftments, and lower incidence of viral, fungal and bacterial infections. There was no significant difference in cumulative incidence of acute GVHD (30.9% vs. 36.4%, grade II-IV at 100 days; p = 0.15), or chronic GVHD (22.5% vs. 20.9% at 3 years; p = 0.85) between the two groups. These comparable OS and DFS between the two groups were confirmed after minimizing differences in patient characteristics with propensity score matching analysis (Figure 1A). Then, to identify patient subgroups who benefit from PTCy-haplo rather than UCB transplant, we performed subgroup analyses of OS. Significantly favorable effects of PTCy-haplo over UCB were observed in patients with CR1 at HSCT (HR, 0.66; p = 0.03). Indeed, propensity score matching analysis showed that PTCy-haplo recipients had a significantly higher 3-year OS (76.4% vs. 67.6%; HR, 0.57; p = 0.01) and DFS (70.5% vs. 60.6%; HR, 0.66; p = 0.03) than UCB recipients, along with a significantly lower NRM (12.9% vs. 26.3%; HR, 0.39; p < 0.01), and a comparable relapse rate (16.6% vs. 13.1%; HR, 1.41; p = 0.25) with UCB. These results suggest that the low NRM in PTCy-haplo transplant outweighs potential concerns of relapse among patients transplanted in CR1 (Figure 1B). By contrast, in patients with ≥ 2 nd CR or non-CR at HSCT, survival benefits of PTCy-haplo were not observed. [Conclusions] Our results suggest that while both PTCy-haplo and UCB are suitable alternative donor sources for adult ALL patients without HLA-matched donors, in patients with CR1, selection of PTCy-haplo rather than UCB improves post-transplant prognosis.

The frequency of the manufacturing failure of chimeric antigen receptor (CAR)-T cell therapy in clinical practice is unknown. To clarify the current state of how likely CAR-T cell production is to succeed or fail for B-cell acute lymphoblastic leukemia (B-ALL), we analyzed cases in which the production of tisagenlecleucel was performed for patients with B-ALL at 15 facilities in Japan from October 2019 to March 2022. Total 81 patients (47 males and 34 females) were analyzed. The median age at apheresis was 13 years (1-25) with a median number of prior treatments of 4 (1-9). The numbers of patients with histories of allogeneic transplantation, inotuzumab ozogamicin, or blinatumomab treatments were 51 (63.0%), 26 (32.1%), and 37 (45.7%), respectively. The median blast percentage and CD3+ cell counts in peripheral blood were 0% (0-91.5), and 611/µl (35-4,210) at apheresis, and the median number of CD3+ cells shipped was 2.2×109 (0.5-8.3). While cases with a history of heavy prior treatment before apheresis were included, no manufacturing failures were observed. Continuing to monitor the status of manufacturing failures is necessary as the number of B-ALL cases treated with CAR-T cell therapy increases.

To evaluate the prognostic impact of complex karyotype (CK) and/or monosomal karyotype (MK) in combination with various clinical factors on allogeneic stem cell transplantation (HSCT) outcomes of patients with acute myeloid leukaemia (AML), we analysed the registry database of adult AML patients who underwent allogeneic HSCT between 2000 and 2019 in Japan. Among 16 094 patients, those with poor cytogenetic risk (N = 3345) showed poor overall survival (OS) after HSCT (25.3% at 5 years). Multivariate analyses revealed that CK and/or MK (hazard ratio [HR], 1.31 for CK without MK; 1.27 for MK without CK; and 1.73 for both), age at HSCT ≥50 years (HR, 1.58), male sex (HR, 1.40), performance status ≥2 (HR, 1.89), HCT-CI score ≥3 (HR, 1.23), non-remission status at HSCT (HR, 2.49), and time from diagnosis to HSCT ≥3 months (HR, 1.24) independently reduced post-HSCT OS among patients with poor cytogenetic risk AML. A risk scoring system based on the multivariate analysis successfully stratified patients into five distinct groups for OS. This study confirms the negative effects of CK and MK on post-HSCT outcomes, and offers a powerful risk scoring system for predicting prognoses after HSCT among AML patients with unfavourable cytogenetics.

Background aims: Before autologous stem cell transplantation (ASCT), hematopoietic stem cells must be stim-ulated to move from the bone marrow to the peripheral blood for harvesting. Plerixafor, a C-X-C chemokine receptor type 4 antagonist, is used to increase stem cell harvests. However, the effects of plerixafor on post-ASCT outcomes remain unclear.Methods: In a dual-center retrospective cohort study of 43 Japanese patients who received ASCT, the authors compared transplantation outcomes in patients who underwent stem cell mobilization with granulocyte col-ony-stimulating factor with (n = 25) or without (n = 18) plerixafor.Results: The number of days to neutrophil and platelet engraftment was significantly shorter with plerixafor than without plerixafor, as assessed by univariate (neutrophil, P = 0.004, platelet, P = 0.002), subgroup, pro-pensity score matching and inverse probability weighting analyses. Although the cumulative incidence of fever was comparable with or without plerixafor (P = 0.31), that of sepsis was significantly lower with plerix-afor than without (P < 0.01). Thus, the present data indicate that plerixafor leads to earlier neutrophil and platelet engraftment and a reduction of infectious risk.Conclusions: The authors conclude that plerixafor may be safe to use and that it reduces the risk of infection in patients with a low CD34+ cell count the day before apheresis.& COPY; 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.

Abstract Background Forecasting acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) is highly challenging with conventional statistical techniques due to complex parameters and their interactions. The primary object of this study was to establish a convolutional neural network (CNN)-based prediction model for aGVHD. Method We analyzed adult patients who underwent allogeneic HSCT between 2008 and 2018, using the Japanese nationwide registry database. The CNN algorithm, equipped with a natural language processing technique and an interpretable explanation algorithm, was applied to develop and validate prediction models. Results Here, we evaluate 18,763 patients between 16 and 80 years of age (median, 50 years). In total, grade II–IV and grade III–IV aGVHD is observed among 42.0% and 15.6%. The CNN-based model eventually allows us to calculate a prediction score of aGVHD for an individual case, which is validated to distinguish the high-risk group of aGVHD in the test cohort: cumulative incidence of grade III–IV aGVHD at Day 100 after HSCT is 28.8% for patients assigned to a high-risk group by the CNN model, compared to 8.4% among low-risk patients (hazard ratio, 4.02; 95% confidence interval, 2.70–5.97; p < 0.01), suggesting high generalizability. Furthermore, our CNN-based model succeeds in visualizing the learning process. Moreover, contributions of pre-transplant parameters other than HLA information to the risk of aGVHD are determined. Conclusions Our results suggest that CNN-based prediction provides a faithful prediction model for aGVHD, and can serve as a valuable tool for decision-making in clinical practice.

Optimized management of citrate-induced hypocalcemia is required to provide safe leukapheresis. We prospectively analyzed subjects who underwent leukapheresis for cytotherapy, and evaluated serum ionized (iCa) concentrations before, at the end of, and 1 h after leukapheresis. During leukapheresis, calcium gluconate solution was continuously supplemented intravenously with hourly measurement of iCa. 76 patients including 49 lymphapheresis for chimeric antigen receptor T-cell therapy and 27 stem cell collections were enrolled. Median processing blood volume was 10 L (range, 6–15 L). Fluctuating hypercalcemia, in which the iCa concentration rose above its upper limit 1 h after leukapheresis, was observed in 58 subjects (76.3%). Multivariate analysis revealed that higher ratios of processing blood volume to body weight, more rapid calcium supplementation, and lower iCa concentration at the end of leukapheresis significantly increased elevation of serum iCa concentration by 1 h after leukapheresis. Based on multivariate analyses, we developed a formula and a diagram that accurately estimates serum iCa concentration 1 h post-leukapheresis. This suggests optimal targets for iCa concentration and calcium supplementation rates. In cases with high ratios of processing blood volume to body weight, slowing the rate of blood processing, rather than increasing calcium supplementation should safely alleviate hypocalcemia during leukapheresis without inducing hypercalcemia thereafter.

BACKGROUND:Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan.METHODS:A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information.RESULTS:Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma.CONCLUSIONS:Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

Background aims: While donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) in the recipient before transplantation are associated with graft failure in cord-blood transplantation (CBT), effects of DSAs other than against HLA-A, -B or -DRB1 on transplantation outcomes remained poorly understood. Methods: We retrospectively analyzed 567 single-unit CBT recipients to evaluate impact of DSAs against HLADP and -DQ on CBT outcomes. Results: Among 143 recipients (25.2%) who had anti-HLA antibodies, nine harbored DSAs against HLA-DP or -DQ. DSAs against HLA-DP or -DQ were associated with a significantly lower neutrophil engraftment rate (55.6% versus 91.8%, P = 0.032) and with a marginally lower platelet engraftment rate (46.7% versus 75.3%, P = 0.128) at day 100 after transplantation, compared with patients without anti-HLA antibodies. Time to neutrophil and platelet engraftment in patients with DSAs for HLA-DP or -DQ was significantly longer than that in patients without anti-HLA antibodies (median, 25 versus 21 days, P = 0.002 in neutrophil; median 61 versus 46 days, P = 0.014 in platelet). Cumulative incidence of bacterial infection at day 100 was significantly greater (88.9% versus 57.1%, P = 0.024), and re-transplant-free survival was marginally lower (55.6% versus 76.8%, P = 0.132) in patients with DSAs against HLA-DP or -DQ, compared with those without anti-HLA antibodies. These findings suggest that DSAs against HLA-DP or -DQ lead to unfavorable engraftment, which may increase risk of bacterial infection, and reduce survival soon after CBT. Conclusions: Our results suggest the importance of evaluating DSAs against HLA-DP and -DQ in recipients before selecting CB units. (c) 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc.