Activated CD4+ T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy.

Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion. Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022. Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included. Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4+CD25+CD127+ T cells (hereafter referred to as "activated CD4+ T cells" ) among the total CD4+ T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4+ T cells among the total CD4+ T cells <0.73 (p=0.01, and p<0.01, respectively). Conclusion These results suggest that the proportion of activated CD4+ T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations.

Spontaneous regression of multiple solitary plasmacytoma harboring Epstein-Barr virus: a case report and literature review.

We report a rare case of spontaneous regression (SR) in an elderly untreated patient with multiple solitary plasmacytoma (MSP). Diagnosis of MSP was confirmed through surgical resection of the left nasal cavity mass and subsequent biopsy of the right humerus. The patient was considered ineligible for chemotherapy due to poor performance status. At 3-month post-diagnosis, the patient's condition worsened with deteriorating bone lesions and emergence of a new serum monoclonal protein. However, these clinical findings completely disappeared at 6 months, and positron emission tomography-computed tomography at 1 year confirmed complete metabolic remission. Notably, peripheral blood lymphocyte counts were inversely correlated with tumor progression and remission. Pathological re-evaluation of the initial biopsy specimens revealed programmed cell death protein 1 (PD-1) expression in tumor-infiltrating CD8+ T cells. In addition, tumor cells were infected with Epstein-Barr virus (EBV) but were negative for programmed cell death ligand 1 (PD-L1) expression, which is the most potent immune escape mechanism in tumor cells. While the mechanism underlying SR remains unclear, our findings suggest that host immune response as well as EBV infection may contribute to SR. Further studies are needed to elucidate the clinicopathologic mechanisms of tumor regression in plasma cell neoplasms.

Collection efficiency and safety of large-volume leukapheresis for the manufacturing of tisagenlecleucel.

BACKGROUND: In patients with relapsed or refractory B cell acute lymphoblastic leukemia or B cell non-Hodgkin lymphoma (r/r B-ALL/B-NHL) with low CD3+ cells in the peripheral blood (PB), sufficient CD3+ cell yield in a single day may not be obtained with normal-volume leukapheresis (NVL). Large-volume leukapheresis (LVL) refers to the processing of more than three times the total blood volume (TBV) in a single session for PB apheresis; however, the efficiency and safety of LVL for manufacturing of tisagenlecleucel (tisa-cel) remain unclear. This study aimed to investigate the tolerability of LVL. STUDY DESIGN AND METHODS: We retrospectively collected data on LVL (≥3-fold TBV) and NVL (<3-fold TBV) performed for patients with r/r B-ALL/B-NHL in our institution during November 2019 and September 2023. All procedures were performed using a continuous mononuclear cell collection (cMNC) protocol with the Spectra Optia. RESULTS: Although pre-apheresis CD3+ cells in the PB were significantly lower in LVL procedures (900 vs. 348/µL, p < .01), all patients could obtain sufficient CD3+ cell yield in a single day with a comparably successful rate of final products (including out-of-specification) between the two groups (97.2% vs. 100.0%, p = 1.00). The incidence and severity of citrate toxicity (no patients with grade ≥ 3) during procedures was not significantly different between the two groups (22.2% vs. 26.1%, p = .43) and no patient discontinued leukapheresis due to any complications. CONCLUSION: LVL procedures using Spectra Optia cMNC protocol was well tolerated and did not affect the manufacturing of tisa-cel.

Chimeric antigen receptor T-cell therapy after COVID-19 in refractory high-grade B-cell lymphoma.

Although chimeric antigen receptor T-cell (CAR-T) therapies have dramatically improved the outcomes of relapsed/refractory B-cell malignancies, recipients suffer from severe humoral immunodeficiencies. Furthermore, patients with coronavirus disease 2019 (COVID-19) have a poor prognosis, as noted in several case reports of recipients who had COVID-19 before the infusion. We report the case of a 70-year-old woman who developed COVID-19 immediately before CAR-T therapy for high-grade B-cell lymphoma. She received Tixagevimab-Cilgavimab chemotherapy and radiation therapy but never achieved remission. She was transferred to our hospital for CAR-T therapy, but developed COVID-19. Her symptoms were mild and she was treated with long-term molnupiravir. On day 28 post-infection, lymphodepleting chemotherapy was restarted after a negative polymerase chain reaction (PCR) test was confirmed. The patient did not experience recurrence of COVID-19 symptoms or severe cytokine release syndrome. Based on the analysis and comparison of the previous reports with this case, we believe that CAR-T therapy should be postponed until a negative PCR test is confirmed. In addition, Tixagevimab-Cilgavimab and long term direct-acting antiviral agent treatment can be effective prophylaxis for severe COVID-19 and shortening the duration of infection.

An Influx of Non-Native Bird Species into the Natural Environment Owing to the Accidental Release of Pet Birds in Japan.

The escape of pet birds into the wild raises concerns about the introduction of invasive avian species. This study investigated the impact of escaped pet birds on the introduction of non-native species in Japan. Data sourced from four lost-and-found pet websites between January 2018 and December 2021 revealed 12,125 recorded escapes exhibiting both daily occurrences and seasonal fluctuations. Statistical modeling identified the monthly average temperature (positively correlated) and maximum electricity demand (negatively correlated) as influential factors. Text analysis revealed "window" and "open" as frequently cited reasons for escapes. Budgerigars (Melopsittacus undulatus) and Cockatiels (Nymphicus hollandicus) accounted for 76% of the total escape, suggesting a low perceived risk of establishment in nonnative environments. Interestingly, two globally established invasive species, the Rose-ringed Parakeet (Psittacula krameri) and Monk Parakeet (Myiopsitta monachus), were among the escaped birds. While the Rose-ringed Parakeet is locally naturalized in Tokyo and its adjacent prefectures, the Monk Parakeet failed to establish itself in Japan. Despite the limited number of escaped Monk Parakeets, ongoing efforts are crucial for preventing the potential re-establishment of species with such capabilities.

Antitumor activity of α-pinene in T-cell tumors.

T-cell acute leukemia and lymphoma have a poor prognosis. Although new therapeutic agents have been developed, their therapeutic effects are suboptimal. α-Pinene, a monoterpene compound, has an antitumor effect on solid tumors; however, few comprehensive investigations have been conducted on its impact on hematologic malignancies. This report provides a comprehensive analysis of the potential benefits of using α-pinene as an antitumor agent for the treatment of T-cell tumors. We found that α-pinene inhibited the proliferation of hematologic malignancies, especially in T-cell tumor cell lines EL-4 and Molt-4, induced mitochondrial dysfunction and reactive oxygen species accumulation, and inhibited NF-κB p65 translocation into the nucleus, leading to robust apoptosis in EL-4 cells. Collectively, these findings suggest that α-pinene has potential as a therapeutic agent for T-cell malignancies, and further investigation is warranted.

Sutimlimab suppresses SARS-CoV-2 mRNA vaccine-induced hemolytic crisis in a patient with cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare form of acquired autoimmune hemolytic anemia driven mainly by antibodies that activate the classical complement pathway. Several patients with CAD experience its development or exacerbation of hemolysis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or after receiving the SARS-CoV-2 mRNA vaccine. Therefore, these patients cannot receive an additional SARS-CoV-2 mRNA vaccination and have a higher risk of severe SARS-CoV-2 infection. Sutimlimab is a monoclonal antibody that inhibits the classical complement pathway of the C1s protein and shows rapid and sustained inhibition of hemolysis in patients with CAD. However, whether sutimlimab could also inhibit hemolysis caused by SARS-CoV-2 mRNA vaccination is uncertain. Here, we present the case of a 70-year-old man with CAD who repeatedly experienced a hemolytic crisis after receiving SARS-CoV-2 mRNA vaccines. The patient eventually underwent SARS-CoV-2 mRNA vaccination safely, without hemolytic attack, under classical pathway inhibition therapy with sutimlimab. This report suggests that appropriate sutimlimab administration can suppress SARS-CoV-2 mRNA vaccination-induced CAD exacerbation, and that it could be a preventive strategy to minimize hemolytic attacks in susceptible populations.

Negative Prognostic Impact of High-Dose or Long-Term Corticosteroid Use in Patients with Relapsed or Refractory B-Cell Lymphoma Who Received Tisagenlecleucel.

The prognostic impact of corticosteroid therapy in patients receiving tisagenlecleucel (tisa-cel) treatment who are more likely to develop cytokine release syndrome (CRS) remains unclear. This study aimed to evaluate the clinical impact and lymphocyte kinetics of corticosteroid administration for CRS in 45 patients with relapsed and/or refractory B-cell lymphoma treated with tisa-cel. This was a retrospective evaluation of all consecutive patients diagnosed with relapsed and/or refractory diffuse large B-cell lymphoma, follicular lymphoma with histologic transformation to large B-cell lymphoma, or follicular lymphoma who received commercial-based tisa-cel treatment. The best overall response rate, complete response rate, median progression-free survival (PFS), and median overall survival (OS) were 72.7%, 45.5%, 6.6 months, and 15.3 months, respectively. CRS (predominantly grade 1/2) occurred in 40 patients (88.9%), and immune effector cell-associated neurotoxicity syndrome (ICANS) of all grades occurred in 3 patients (6.7%). No grade ≥3 ICANS occurred. Patients with high-dose (≥524 mg, methylprednisolone equivalent; n = 12) or long-term (≥8 days; n = 9) corticosteroid use had inferior PFS and OS to patients with low-dose or no corticosteroid use (both P < .05). The prognostic impact remained even in 23 patients with stable disease (SD) or progressive disease (PD) before tisa-cel infusion (P = .015). but not in patients with better disease status (P = .71). The timing of corticosteroid initiation did not have a prognostic impact. Multivariate analysis identified high-dose corticosteroid use and long-term corticosteroid use as independent prognostic factors for PFS and OS, respectively, after adjusting for elevated lactate dehydrogenase level before lymphodepletion chemotherapy and disease status (SD or PD). Lymphocyte kinetics analysis demonstrated that after methylprednisolone administration, the proportions of regulatory T cells (Tregs), CD4+ central memory T (TCM) cells, and natural killer (NK) cells were decreased, whereas the proportion of CD4+ effector memory T (TEM) cells was increased. Patients with a higher proportion of Tregs at day 7 had a lower incidence of CRS, but this did not affect prognosis, indicating that early elevation of Tregs may serve as a biomarker for CRS development. Furthermore, patients with higher numbers of CD4+ TCM cells and NK cells at various time points had significantly better PFS and OS, whereas the number of CD4+ TEM cells did not impact prognostic outcomes. This study suggests that high-dose or long-term corticosteroid use attenuates the efficacy of tisa-cel, especially in patients with SD or PD. Additionally, patients with high levels of CD4+ TCM cells and NK cells after tisa-cel infusion had longer PFS and OS.

Benefit of prednisolone alone in nodal peripheral T-cell lymphoma with T follicular helper phenotype.

A 71-year-old Japanese man presented with severe thrombocytopenia. A whole-body CT at presentation showed small cervical, axillary, and para-aortic lymphadenopathy, leading to suspicion of immune thrombocytopenia due to lymphoma. Biopsy was difficult to perform because of severe thrombocytopenia. Thus, he received prednisolone (PSL) therapy and his platelet count gradually recovered. Two and a half years after PSL therapy initiation, his cervical lymphadenopathy slightly progressed without other clinical symptoms. Hence, a biopsy from the left cervical lymph node was performed, and he was diagnosed with nodal peripheral T-cell lymphoma (PTCL) with T follicular helper (TFH) phenotype. Due to various complications, we continued treatment with prednisolone alone after the diagnosis of lymphoma; however, there was no further increase in lymph node enlargement and no other lymphoma-related symptoms for one and a half years after diagnosis. Although immunosuppressive therapy has been reported to produce a response in some patients with angioimmunoblastic T-cell lymphoma, our experience suggests that a similar subset may exist in patients with nodal PTCL with TFH phenotype, which has the same cellular origin. Immunosuppressive therapies may constitute an alternative treatment option even in the era of novel molecular-targeted therapies, especially for elderly patients who are ineligible for chemotherapy.

Bone marrow microenvironment disruption and sustained inflammation with prolonged haematologic toxicity after CAR T-cell therapy.

Mechanisms of prolonged cytopenia (PC) after chimeric antigen receptor (CAR) T-cell therapy, an emerging therapy for relapsed or refractory diffuse large B-cell lymphoma, remain elusive. Haematopoiesis is tightly regulated by the bone marrow (BM) microenvironment, called the 'niche'. To investigate whether alterations in the BM niche cells are associated with PC, we analysed CD271+ stromal cells in BM biopsy specimens and the cytokine profiles of the BM and serum obtained before and on day 28 after CAR T-cell infusion. Imaging analyses of the BM biopsy specimens revealed that CD271+ niche cells were severely impaired after CAR T-cell infusion in patients with PC. Cytokine analyses after CAR T-cell infusion showed that CXC chemokine ligand 12 and stem cell factor, niche factors essential for haematopoietic recovery, were significantly decreased in the BM of patients with PC, suggesting reduced niche cell function. The levels of inflammation-related cytokines on day 28 after CAR T-cell infusion were consistently high in the BM of patients with PC. Thus, we demonstrate for the first time that BM niche disruption and sustained elevation of inflammation-related cytokines in the BM following CAR T-cell infusion are associated with subsequent PC.

Analysis of Immunity against Measles, Mumps, Rubella, and Varicella Zoster in Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Experience.

Vaccine-preventable disease (VPD) infections are more severe in immunocompromised hosts. Vaccination against measles, mumps, rubella, and varicella zoster (VZV) (MMRV) is therefore recommended for hematopoietic stem cell transplantation (HCT) recipients. However, studies on adult HCT recipients with VPD infections are limited. At our institution, we have systematically conducted serological MMRV tests as a part of check-up examinations during long-term follow-up (LTFU) after HCT since 2015. This retrospective study aimed to evaluate changes in the serostatus between before and 2 years after allogeneic HCT. Among 161 patients, the pre-transplant seropositivity was 82.7% for measles, 86.8% for mumps, 84.2% for rubella, and 94.3% for VZV. Among 56 patients who underwent LTFU including serological MMRV tests at 2 years after HCT, the percentages maintaining seroprotective antibody levels for measles, mumps, rubella and VZV were 71.5% (40/56), 51.8% (29/56), 48.2% (27/56), and 60.7% (34/56), respectively. Vaccination was recommended for 22 patients, and 12 were vaccinated. Among the 12 vaccinated patients, rates of seroconversion were examined in 2-6 patients for each of the four viruses. They were 100% (3/3) for measles, 33.3% (1/3) for mumps, 50% (3/6) for rubella, and 0% (0/2) for VZV. Further studies are warranted to clarify the effect of vaccination in adult HCT recipients.

Possible prognostic impact of WT1 mRNA expression at day + 30 after haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide for patients with myeloid neoplasm: a multicenter study from the Okayama Hematological Study Group.

BACKGROUND: Previous studies have revealed that relapse of myeloid neoplasms after allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be predicted by monitoring Wilms' tumor 1 (WT1) mRNA expression. However, only a few studies have investigated patients who received human leukocyte antigen-haploidentical stem cell transplantation with posttransplant cyclophosphamide (PTCY-haplo). In this study, we investigated the relationship between WT1 mRNA levels and clinical outcomes in the PTCY-haplo group, and compared them with those in the conventional graft-versus-host disease prophylaxis group (conventional group). METHODS: We retrospectively analyzed 130 patients who received their first allo-HSCT between April 2017 and December 2020, including 26 who received PTCY-haplo. RESULTS: The WT1 mRNA expression level at day + 30 after allo-HSCT associated with increased risk of 1-year cumulative incidence of relapse (CIR) was ≥ 78 copies/µg RNA in the conventional group (p < 0.01) and ≥ 50 copies/µg RNA in the PTCY-haplo group (p = 0.03). CONCLUSIONS: The appropriate cutoff level of WT1 mRNA at day + 30 after allo-HSCT for predicting prognosis in patients treated with PTCY-haplo may be < 50 copies/µg RNA.

Chronic active Epstein-Barr virus infection presenting as refractory chronic sinusitis.

A 44-year-old Japanese man presented with fever and sore throat. He had a history of refractory chronic sinusitis that did not respond to several years of pharmacotherapy, and underwent endoscopic sinus surgery (ESS) 5 months prior to his presentation, but his symptoms persisted. A biopsy specimen was taken from the right nasal cavity, and extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) was diagnosed. Two years after complete remission was achieved by chemoradiation therapy, he developed hemophagocytic lymphohistiocytosis (HLH) without recurrence of ENKTL. Epstein-Barr virus (EBV)-DNA copy number was relatively high and EBV-infected lymphocytes (CD8 + T cells) were detected in the peripheral blood. Pathological review of the biopsy specimens taken during ESS showed that CD8 + T cells with slightly atypia infiltrating the stroma were EBV positive. These findings suggested that the patient had underlying chronic active EBV infection (CAEBV) that caused the refractory chronic sinusitis, eventually developed into ENKTL, and also caused HLH. Clinicians should consider adult-onset CAEBV in the differential diagnosis of patients with refractory chronic sinusitis.

Transformed diffuse large B-cell lymphoma from marginal zone lymphoma in the anterior mediastinum: A case report and review of the literature.

Marginal zone lymphoma (MZL) arising from the anterior mediastinum is rare. In the majority of reported cases, the tumor was incidentally discovered, reflecting its indolent clinical features. We present a 38-year-old woman who had no medical history, and presented with a bulky anterior mediastinal tumor complicated by life-threatening compression of the vasculature and bronchi. Biopsy specimens of the neoplasm suggested transformed diffuse large B-cell lymphoma (DLBCL) from MZL. To our best knowledge, this is the first case report of anterior mediastinum MZL associated with an aggressive clinical course and life-threatening complications likely due to transformation to DLBCL.

Nodal Peripheral T-cell Lymphoma with T Follicular Helper Phenotype Presenting as Chorea During Treatment: A Case Report and Literature Review.

A 72-year-old man presented with chorea while undergoing treatment for recurrence of nodal peripheral T-cell lymphoma with T follicular helper (TFH) phenotype. An examination by brain N-isopropyl-p-iodoamphetamine (123I-IMP)-single photon emission computed tomography (SPECT) revealed no abnormalities other than a decreased cerebral blood flow (CBF) in the left striatum. After four courses of salvage chemotherapy, his clinical symptoms and asymmetric cerebral perfusion improved, suggesting that the decreased CBF had caused chorea. The significance of brain SPECT has not been fully clarified in patients with chorea-associated malignant lymphoma, warranting further investigations. Brain SPECT is an alternative approach to identify abnormalities in such patients.