Anti-CD19 chimeric antigen receptor T-cell therapy has less efficacy in Richter transformation than in de novo large B-cell lymphoma and transformed low-grade B-cell lymphoma.

The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL.

Fecal microbiota transplantation in capsules for the treatment of steroid refractory and steroid dependent acute graft vs. host disease: a pilot study.

Acute graft-versus-host disease (aGvHD) is a serious complication of allogeneic hematopoietic stem-cell transplantation with limited treatment options. The gut microbiome plays a critical role in aGvHD pathogenesis. Fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach to restore gut microbial diversity. In this prospective pilot study, 21 patients with steroid-resistant or steroid-dependent lower gastrointestinal aGvHD received FMT in capsule form. At 28 days after the first FMT, the overall response rate was 52.4%, with 23.8% complete and 28.6% partial responses. However, sustained responses were infrequent, with only one patient remaining aGvHD-free long-term. FMT was generally well-tolerated. Microbiome analysis revealed dysbiosis in pre-FMT patient stool samples, with distinct microbial characteristics compared to donors. Following FMT, there was an increase in beneficial Clostridiales and a decrease in pathogenic Enterobacteriales. These findings highlight the potential of FMT as a treatment option for steroid-resistant aGvHD. Trial registration number NCT #03214289.

[EXAMINING THE ASSOCIATION BETWEEN THE FETAL SUPRATENTORIAL BRAIN VOLUME AND THE SUBARACHNOID SPACE IN VARIOUS FETAL PATHOLOGIES USING MAGNETIC RESONANCE IMAGING].

INTRODUCTION: The subarachnoid space (SAS) is a potential space surrounding the brain where the cerebrospinal fluid (CSF) flows. Previous work demonstrated how the SAS width changes during pregnancy and measured the normal values per gestational week. OBJECTIVES: Studying the ratio between the fetal brain volume (STV) and the SAS width (SS ratio), as measured via fetal magnetic resonance imaging (MRI) in different fetal pathologies - macrocephaly and microcephaly, and studying the correlation between this ratio and the gestational week. METHODS: A retrospective study was conducted on 77 fetuses that underwent fetal MRI scans during gestational weeks 29-37, in three groups: 23 normocephaly, 27 macrocephaly, and 27 microcephaly. SAS width was measured in 10 points via fetal MRI scans, and a ratio was calculated between the width and STV. RESULTS: The SS ratio is largest in microcephaly group and smallest in normocephaly group, with the macrocephaly group between them. All comparisons were statistically significant except between the macrocephaly and normocephaly groups. There was a strong positive correlation between SS ratio and week of gestation. CONCLUSIONS: The SS ratio is statistically different between normocephalic fetuses and fetuses with macrocephaly or microcephaly. From week 29 this ratio enlarges with gestational age. DISCUSSION: The SAS affects the fetal head circumference, an important parameter of fetal growth, thus we decided to study the SS ratio in pathologies of the head circumference. Previous work demonstrated how the STV and the SAS width expand starting at a specific gestational age, thus the gestational week also affects the SS ratio. Summary: The SS ratio is affected by pathologies of the fetal head circumference and by gestational age.

Point-of-care anti-CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory follicular lymphoma.

Patients with relapsed/refractory follicular lymphoma (R/R-FL) often require multiple treatment lines. We performed a phase 1b/2 single-center clinical trial of autologous point-of-care anti-CD19 chimeric antigen receptor (CAR) T-cells in R/R-FL patients treated patients with ≥ 2 treatment lines. All 26 patients enrolled received CAR T-cell infusion at a median of 11 days after leukapheresis. Seventy-seven percent of patients had POD24. At enrollment, disease stage was III-IV in 85% of the patients, 77% had high-risk FLIPI score, and 77% had progressive disease. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 12% and 16% of the patients, respectively. Overall response rate at 1-month was 88%. The median follow-up was 15.4 months. One-year overall and progression-free survival were 100% and 63%, respectively. In conclusion, point-of-care CAR T-cell, manufactured within 11 days, induced a high response rate with an acceptable safety profile in patients with high-risk R/R-FL.

Anti-RBD IgG antibodies and neutralizing antibody levels after the second BNT162b2 dose in patients with plasma cell disorders.

Patients with plasma cell disorders (PCD) are at an increased risk for severe morbidity and mortality due to COVID-19. Recent data have suggested that patients with hematological malignancies, including those with PCD, have suboptimal antibody response to COVID-19 vaccination. We compared the antibody titers of 213 patients with PCD to those of 213 immunocompetent healthcare workers after the second vaccine dose of the BNT162b2 mRNA vaccine. Blood samples were taken 2-4 weeks after the second vaccination and analyzed for anti-receptor binding-domain immunoglobulin G (RBD-IgG) antibodies and neutralizing antibodies (NA). At a median of 20 days after the second vaccine dose, 172 patients (80.8%) developed anti-RBD-IgG antibodies with a geometric mean titer (GMT) of 2.7 (95% confidence interval [CI], 2.4-3.1). In the control group 210 (98.9%) developed anti-RBD-IgG antibodies after a median of 21 days, with a GMT of 5.17 (95%CI, 4.8-5.6), p<0.0001. NA were observed in 151 patients with MM (70.9%) and in 210 controls (98.9%). The GMT of NA in patients with MM and controls was 84.4 (95% CI, 59.0-120.6), and 420.2 (95% CI, 341.4-517.1), respectively (p<0.0001). Multivariable logistic regression revealed that the number of prior therapy lines and age were significant predictors of poor humoral response among patients with MM. Injection site reaction, headache and fatigue were the most common adverse events after vaccination. Adverse events were less common in patients with MM than in controls. In conclusion, a significant percentage of patients with MM developed protecting NA to the BNT162b2 mRNA vaccine, which appears to be safe in this patient population.

Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma.

Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57-69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6-11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10-4.72]), lack of response to CAR-T (2.33 [1.02-5.29]), age >65 years (HR 2.65 [1.49-4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61-5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.

Allogeneic Hematopoietic Cell Transplantation after Chimeric Antigen Receptor T Cell Therapy in Large B Cell Lymphoma.

Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy has transformed the care of patients with relapsed/refractory large B cell lymphoma (LBCL). However, approximately 60% of CAR-T recipients ultimately will experience disease recurrence or progression. Salvage therapies after CAR-T treatment failures are of limited efficacy and have a short duration of response. The objective of the present study was to evaluate the role of allogeneic hematopoietic cell transplantation (allo-HCT) after CAR-T therapy in LBCL patients. This was a multicenter observational study reporting the outcome of 39 adult LBCL patients who underwent allo-HCT following anti-CD19 CAR-T therapy. The median patient age was 47 years (range, 20 to 68 years). HLA-matched sibling, HLA-matched unrelated, and alternative donors were used in 36%, 36%, and 28% of transplantations, respectively. Conditioning regimens were primarily of low or intermediate intensity. Disease status at allo-HCT was complete response in 41%, partial response in 38%, and progressive disease in 21%. Allo-HCT was performed at a median of 127 days (range, 82 to 206 days) after CAR-T therapy. A high incidence of hepatic toxicity (28%), including sinusoidal obstruction syndrome (15.4%; 95% confidence interval; [CI], 6.2% to 28.5%), was observed. The 1-year cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) was 38.5% (95% CI, 23.2% to 53.6%) and 15.4% (95% CI, 6.1% to 28.5%), respectively. The 2-year cumulative incidence of moderate-severe chronic GVHD was 11.1% (95% CI, 3.3% to 24.3%). Overall, 2-year nonrelapse mortality and relapse/progression incidence were 26% (95% CI, 13% to 41%) and 43% (95% CI, 27% to 59%), respectively. With a median follow-up of 32 months, the 2-year overall survival (OS) and progression-free survival (PFS) were 45% (95% CI, 31% to 66%) and 31% (95% CI, 19% to 50%), respectively. In multivariable analyses, pre-HCT elevated lactate dehydrogenase level and transformed lymphoma were predictive of OS and PFS, respectively. Our data suggest that allo-HCT after anti-CD19 CAR-T treatment failure is feasible with a relatively promising efficacy but possibly high toxicity rate.

Point-of-care CAR T-cell therapy as salvage strategy for out-of-specification tisagenlecleucel.

Tisagenlecleucel (tisa-cel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed/refractory large B-cell lymphoma. Outcomes of patients with out-of-commercial specification (OOS) CAR T products are not well characterized. We therefore assessed 37 adult patients who underwent leukapheresis for tisa-cel therapy in a single center. In nine (24%) patients, manufactured tisa-cel was considered OOS. Three of them (33%) received tisa-cel after institutional review board approval; 2/9 (22%) did not receive tisa-cel due to disease progression; and 4/9 (44%) received academic point-of-care (POC) CAR T-cell as salvage therapy, at a median of 35 days following OOS notification. Three of those four patients achieved a complete response. In univariate analysis, risk factors for OOS were ≥ 4 prior therapies or previous bendamustine exposure. In conclusion, we report high OOS incidence of 24% in real-life setting. Forty-four percent of those patients received POC CAR T-cell as salvage therapy.

Point-of-care anti-CD19 CAR T-cells for treatment of relapsed and refractory aggressive B-cell lymphoma.

Anti CD19 chimeric antigen receptor (CAR) T-cell therapy has transformed the care of relapsed and refractory aggressive B-cell lymphoma. However, financial toxicity and manufacturing time represent barriers to its widespread implementation. Study applicability, toxicity, and efficacy of a locally produced autologous CD19-directed CAR T-cell product were studied. We performed a phase 1b/2 clinical trial with a point-of-care (POC) CAR T-cell product that contains a CD28 costimulatory domain. Adult patients with aggressive B-cell lymphoma or transformed low-grade lymphoma who received at least 2 prior regimens were eligible. A total of 73 patients, with a median age of 49 years, met inclusion criteria. CAR T-cell production time from apheresis was 10 days (interquartile range 10-11), negating the need for bridging chemotherapy. Overall and complete response rates were 62.5% and 37.5%. Median progression-free and overall survival were 3.7 and 12.1 months, respectively. Overall and progression-free survival at 12 months were 52.1% (confidence interval [CI]: 40.8%-66.5%) and 40% (CI: 30%-53.7%), respectively. Patients who achieved response had longer progression-free and overall survival. Grade 3-4 cytokine release syndrome was observed in 9.5% of the patients, and immune effector cell-associated neurotoxicity syndrome grade 3-4 in 21.9%. No deaths occurred due to CAR T-cell toxicity. Fifteen patients (20%) underwent allogeneic stem cell transplantation at a median time of 60 days after CAR T-cell therapy; 8 were alive at last follow-up. Of the 6 patients who underwent the transplantation in complete response 2 deceased because of toxicity. POC CAR T-cells are a feasible therapeutic option in aggressive B-cell lymphoma. They provide good efficacy while minimizing production time and the need for bridging therapy.

Fetal brain biometry in isolated mega cisterna magna: MRI and US study.

OBJECTIVE: To characterize the biometric parameters in ultrasound and brain MRI of fetuses with isolated mega cisterna magna (MCM). METHODS: Cross-sectional historical cohort study conducted at a single tertiary medical center between 2011 and 2018. All fetuses underwent US and brain MRI scans. Matching analysis was performed according to gender and gestational age. RESULTS: The study included a total of 103 fetuses; 44 fetuses with isolated MCM in the study group, and a control group of 59 fetuses with normal CNS. The study group had larger biparietal diameter (BPD) (86 vs. 79.8 mm, p = .001) and head circumference (HC) (318 vs. 292 mm, p < .001) on ultrasound. On MRI, study group had larger occipitofrontal diameter (OFD) (99 vs. 92 mm, p < .001) and BPD (77 vs. 72 mm, p < .001). Male fetuses' prevalence was higher in the study group (77.3% vs. 47.5%). After matching 20 fetuses from each group, the study group had larger HC (310.1 versus 300.7 mm, p = .029) and OFD (113.4 versus 108.3 mm, p = .009) on ultrasound, and larger OFD (97.4 versus 94.6, p = .013) on brain MRI. CONCLUSIONS: Isolated MCM may be related to other large fetal CNS biometric measurements in both ultrasound and MRI and might be influenced by fetal gender.

Immune imitation of tumor progression after anti-CD19 chimeric antigen receptor T cells treatment in aggressive B-cell lymphoma.

We present three patients with aggressive non-Hodgkin's B-cell lymphoma (NHL) who received anti-CD19 chimeric antigen receptor T (CAR T) cells therapy after failure of several lines of chemotherapy that developed pseudo-progression. One-week clinical and radiological findings were consistent with tumor progression. Positron emission tomography-computed tomography (PET-CT) at 1 month post CAR T cells administration was consistent with treatment response. The rapid tumor growth and subsequent resolution are suggestive of tumor pseudo-progression mediated secondary to infiltration and immune activation of CAR T cells. Overall, 56 adult patients with NHL were enrolled in a phase 1b/2 in house clinical study with CD19 CAR T cells. Out of them 22/56 patients progressed as per PET-CT the 1 month post CAR T cells. In 14 patients, signs of progression started 7-10 days after CAR T cells infusion. In 11/14 patients, it was true progression, while in 3 it was pseudo-progression. Additional studies are warranted to describe the extent of this phenomenon and evaluate correlation with the CAR T activity and long-term disease control.

Fetal Brain Biometry: Is there an Agreement among Ultrasound, MRI and the Measurements at Birth?

PURPOSE: Measurement of the fetal brain can be achieved by different modalities, we aimed to assess the agreement between these methods and the head circumference at birth. METHODS: A retrospective study conducted between 2011-2018 at a tertiary referral medical center. Sonographic head circumference (HC), 2D MRI bi-parietal diameter (BPD) and occipito-frontal diameter (OFD), 3D MRI supra-tentorial volume (STV), and head circumference (HC) at birth were measured and converted into centiles according to gestational age. Spearman's rank correlation coefficient was used to assess the correlation between the modalities. RESULTS: A total of 88 fetuses were included. Mean gestational age at the time of fetal US and brain MRI acquisition were 34.4 ±â€¯2.8 and 34.6 ±â€¯2.6 weeks, respectively. A correlation was found between prenatal sonographic HC and the 3D MRI STV centiles (Rs = 0.859, p < 0.001), the BPD in 2D MRI (Rs = 0.813, p < 0.001), and the OFD in 2D MRI (Rs = 0.840, p < 0.001). Sonographic HC, OFD on 2D MRI, and STV on 3D MRI were all found to be correlated with the HC at birth (Rs = 0.865, p < 0.001; Rs 0.816, p < 0.001; Rs = 0.825, p < 0.001, respectively). CONCLUSIONS: There is a statistically significant agreement among the different prenatal clinically used modalities for measuring fetal brain and the head circumference at birth, however, this correlation is not perfect. Further study is needed to investigate the long-term prognosis of these fetuses.

Patterns of salivary microbiota injury and oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation.

Oral mucositis (OM) is a common debilitating dose-limiting toxicity of cancer treatment, including hematopoietic stem cell transplantation (HSCT). We hypothesized that the oral microbiome is disturbed during allogeneic HSCT, partially accounting for the variability in OM severity. Using 16S ribosomal RNA gene sequence analysis, metabolomic profiling, and computational methods, we characterized the behavior of the salivary microbiome and metabolome of 184 patients pre- and post-HSCT. Transplantation was associated with a decrease in oral α diversity in all patients. In contrast to the gut microbiome, an association with overall survival was not detected. Among 135 patients given methotrexate for graft-versus-host disease prophylaxis pre-HSCT, Kingella and Atopobium abundance correlated with future development of severe OM. Posttransplant, Methylobacterium species were significantly enriched in patients with severe OM. Moreover, the oral microbiome and metabolome of severe OM patients underwent distinct changes post-HSCT, compared with patients with no or mild OM. Changes in specific metabolites were well explained by microbial composition, and the common metabolic pathway was the polyamines pathway, which is essential for epithelial homeostasis. Together, our findings suggest that salivary microbial composition and metabolites are associated with the development of OM, offering new insights on pathophysiology and potential avenues of intervention.

Early and late hematologic toxicity following CD19 CAR-T cells.

Autologous T cells transduced with CD19-directed chimeric antigen receptors have recently been approved by several regulatory agencies for the treatment of relapsed and refractory leukemia and lymphoma, after demonstrating remarkable remission rate in advanced patients. The most common adverse events reported are cytokine-release syndrome (CRS), neurotoxicity, and hematologic toxicity. Here, we focus on early and late cytopenia occurring after CD19 CAR-T cells in 38 patients treated with CD19 CAR-T cells. Neutropenia, thrombocytopenia, and anemia occur frequently (94, 80, and 51%, respectively) after CAR-T cell infusion, and are associated with a biphasic nature, as in 93% of patients hematologic toxicity occurs after 21 days from cell infusion. Late hematologic toxicity was more common in patients with high grade CRS and in patients treated after a recent stem cell transplantation. Interestingly, since these events occur late after the lymphodepleting chemotherapy and after resolution of CRS, we found perturbations in SDF-1 levels to correlate with events of late neutropenia, likely associated with B-cell recovery.