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.

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.

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.

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.

[A survey of fertility preservation in patients with hematologic malignancies in the Chugoku and Shikoku regions].

We interviewed the adult and pediatric hematologists in the Chugoku and Shikoku regions in order to determine their opinions and attitudes about fertility preservation in 2020. A questionnaire on fertility preservation practices was sent to 59 doctors in 46 adult and pediatric hematology-oncology hospitals, out of which 52 doctors (88.1%) responded. Forty doctors (76.9%) had no rules about the explanation and 37 doctors (71.2%) answered that the attending physicians provided the explanation alone in their hospitals. Many doctors had no rules about the target age group of patients. Only few hospitals were able to complete the treatment of hematological malignancies and fertility preservation within their own infrastructure. Several doctors referred to neighboring hospitals for fertility preservation; however, five hospitals were unable to provide fertility preservation and had no relationship with other hospitals. Doctors should give fertility preservation options to all patients at risk of infertility because of their cancer treatment. It is suggested that the local networks should be utilized and relationships with neighboring hospitals strengthened.

[Successful treatment with enzyme replacement therapy for pelvic fragile fracture in an elderly case of type I Gaucher's disease].

A 76-year-old male with lower-limb weakness was admitted to our hospital where thrombocytopenia and anemia were noticed. CT showed massive splenomegaly and multiple nodules inside the spleen. Bone marrow examination showed an increase of macrophages with large cytoplasm. Suspected of splenic lymphoma, the patient underwent splenectomy. Spleen specimens were histologically analyzed and suggested the probability of Gaucher's disease (GD). Leukocyte glucocerebrosidase (GBA) enzyme activity had decreased to 1.25 nmol/mg, and mutation analysis of GBA revealed two missense variants, p.D448H (D409H), p.L483P (L444P), which confirmed the diagnosis of type I GD. Fourteen months after splenectomy, he developed right buttock pain, and pelvic magnetic resonance imaging showed a fragile right pubic and pelvic fracture. We initiated injection of imiglucerase as enzyme replacement therapy (ERT) and administered bisphosphonate. His symptoms gradually improved without surgical treatment. In addition, thrombocytopenia and anemia also improved, and angiotensin-converting enzyme levels decreased. Type I GD should be considered a differential diagnosis of giant splenomegaly and thrombocytopenia, even in the elderly. ERT or substrate reduction therapy should be administrated to GD patients, while paying attention to the development of bone lesions.

[Hyper-IL-6 syndrome mimicking IgG4-related disease].

Distinguishing between IgG4-related disease (IgG4-RD) and hyper-interleukin (IL) -6 syndrome, such as immune mediated conditions, autoimmune diseases, and idiopathic multicentric Castleman disease (iMCD) is challenging. Here, we report the case of a 69-year-old man with cervical lymphadenopathy who was admitted to our hospital and histologically diagnosed with hyper-IL-6 syndrome mimicking IgG4-RD phenotypically. Laboratory data detected polyclonal hypergammaglobulinemia comprising IgG, including IgG4 (2,350 mg/dl). Computed tomography revealed presence of systemic lymphadenopathy, enlarged bilateral submandibular glands, and infiltrative shadow in the right lower lung. Magnetic resonance imaging revealed diffusely enlarged pancreas the size of a sausage and hypointense rim on T2, suggesting autoimmune pancreatitis as part of IgG4-RD. Biopsy of the cervical lymph node revealed proliferation of IL-6-positive mature plasma cells in the expanded interfollicular area with an elevated IgG4+/IgG+ cell ratio (approximately 70%). These histological findings were consistent with hyper-IL-6 syndrome rather than IgG4-RD; however, the serum IL-6 level was slightly elevated. Bone marrow aspiration detected both IgG4- and IL-6-positive mature plasma cells. Although this case cannot be diagnosed as IgG4-RD because it failed to meet its diagnostic criteria, administration of oral prednisolone (0.5 mg/kg) resulted in rapidly improved lymphadenopathy, enlarged pancreas, and serological findings. This report can be helpful for the diagnostic assessment of polyclonal hypergammaglobulinemia conditions.

[Early relapse after autologous peripheral blood stem cell transplantation in an elderly patient with enteropathy-associated T-cell lymphoma].

A 73-year-old male with melena was admitted to our hospital. Computed tomography (CT) scan revealed the thickening of the jejunal and ileal walls and swelling of the mesenteric lymph nodes. Type II enteropathy-associated T-cell lymphoma (EATL) was diagnosed based on the pathological analysis of the resected specimen. Positron emission tomography and CT scan showed complete remission (CR) after surgery, and he further received CHOP therapy. However, 2 months after the completion of the therapy, the patient's disease relapsed, and he presented with abdominal pain. Ifosfamide, dexamethasone, etoposide, and cytarabine therapy was administered, and the second CR was observed in the patient. Subsequently, the patient was administered high-dose chemotherapy (MCEC) with autologous peripheral blood stem cell transplantation (auto-PBSCT). The treatment was well tolerated. Engraftment was performed on day9, and he was discharged on day17 after auto-PBSCT. However, at 6 months after auto-PBSCT, the second relapse of the disease was observed in the patient. He received salvage therapy; however, the patient died because of disease progression. Because of the dismal prognosis of EATL treated with conventional chemotherapy, the feasibility and efficacy of auto-PBSCT have been investigated. To the best of our knowledge, there is no report on an elderly patient (age >70 years) with EATL who underwent auto-PBSCT. Thus, more data should be collected and analyzed to confirm that this therapy could be a promising treatment option for elderly patients with EATL.

Citrobacter braakii bacteremia-induced septic shock after colonoscopy preparation with polyethylene glycol in a critically ill patient: a case report.

BACKGROUND: Polyethylene glycol (PEG) is widely used for bowel cleaning in preparation for colonoscopy because of its safety. Septic shock after PEG preparation is an extremely rare complication. Herein, we describe a case of septic shock that occurred immediately after colonoscopy preparation with PEG. CASE PRESENTATION: A 75-year-old Japanese male who had previously developed diabetes after total pancreatectomy received PEG in preparation for colonoscopy. He had been admitted to the emergency intensive care unit 4 days earlier due to hematochezia presenting with shock. He ingested PEG to prepare for a colonoscopy examination, which was performed to identify the source of his bleeding over a 5-h period, but suddenly exhibited septic shock and markedly elevated procalcitonin levels. A blood culture subsequently revealed Citrobacter braakii. Immediate resuscitation and intensive care with appropriate antibiotics improved his condition. CONCLUSIONS: Clinicians should be aware of the possibility of deteriorating conditions after bowel preparation with PEG among severely ill patients with recent episodes of hemorrhagic shock.