Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic ...haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear.
To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1–3 plus mitoxantrone (10 mg/m2 intravenously) on days 3–5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537.
281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI –5·8 to 12·6) for the ITT population and 2·7% (–6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 21% of 140 patients vs 86 61% of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7–64) versus 42 days (27–121, U test p<0·0001), respectively.
Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia.
DKMS and the Gert and Susanna Mayer Stiftung Foundation.
The
loci are closely linked to the
gene. Mismatches in these loci occur with a frequency of about 8%-12% in otherwise 10/10 HLA-matched transplant pairs. There is preliminary evidence that these ...disparities may associate with increased acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large cohort of German patients and their donors for
compatibility and to correlate the
matching status with the outcome of unrelated hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their respective donors were
and
typed by amplicon-based next-generation sequencing (NGS). All patients included received their first allogeneic transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in the antigen recognition domain (ARD) of
genes were correlated with clinical outcome.
incompatibility was seen in 12.5% (n = 296) and 17.8% (n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively.
mismatches in the ARD associated with a worse overall survival (OS), as shown in univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses hazard ratio (HR) 1.25, 95% CI 1.02-1.54, p = 0.034 in the otherwise 10/10 HLA-matched subgroup. The worse outcome was mainly driven by a significantly higher non-relapse mortality (HR 1.35, 95% CI 1.05-1.73, p = 0.017). In the 9/10 HLA-matched cases, the effect was not statistically significant. Our study results suggest that mismatches within the ARD of
genes significantly impact the outcome of otherwise fully matched uHSCT and support their consideration upon donor selection in the future.
T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute ...GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided.
ObjectivePatients with severe refractory systemic lupus erythematosus (srSLE) exhibit failure to respond to treatments, progressive organ damage, and high mortality. Traditionally manufactured ...CD19-directed CAR T-cell therapies have potential to promote full clinical remission in srSLE. YTB323 (rapcabtagene autoleucel) is a novel, rapidly manufactured, autologous CD19-directed CAR T-cell therapy. The objective of this study is to determine the safety, efficacy and cellular kinetics of YTB323 in patients with srSLE.MethodsAn open-label, single-arm, multicentre phase 1/2 study (NCT05798117) to assess the safety, efficacy and cellular kinetics of YTB323 in patients with srSLE is currently ongoing. Safety data including adverse events (AEs), severe AEs, deaths, vital signs, electrocardiogram and laboratory assessments and preliminary efficacy data including SLE Disease Activity Index (SLEDAI) and Physician’s Global Assessment (PhGA) were collected. Pharmacokinetics (PK) data monitored by quantitative polymerase chain reaction and flow cytometry, and biomarker data including levels of B cells, T cells, immunoglobulin (Ig)G, IgA, IgM, complement C3 and C4 and anti-dsDNA were also collected.ResultsWe present safety, preliminary efficacy and biomarker data for six patients (data cutoff: December 2023), and available PK data for two patients who received YTB323 treatment (data cutoff: August 2023). Transient lymphodepletion-related cytopenia (grade 3 or 4) was observed in all six patients, as expected. Hypogammaglobulinaemia, which did not require intravenous immunoglobulin treatment, was a common AE. Cytokine release syndrome (grade 1 n=1 or 2 n=3) was observed in four of six patients, and all events resolved following treatment with tocilizumab. No events of immune cell-associated neurotoxicity syndrome were reported. Infectious complications included pneumonia in one patient (grade 2). Preliminary efficacy and biomarker data for six patients indicated considerable reductions in SLEDAI (figure 1a) and PhGA (figure 1b) accompanied by improvements in relevant disease biomarkers such as anti-dsDNA (figure 1c), complement levels (figure 2a-b), and proteinuria, as well as deep B-cell depletion with subsequent B-cell recovery. PK assessment confirmed CAR T-cell expansion for the two patients with evaluable PK data.Abstract LBP1 Figure 1Individual efficacy parameters over timeAbstract LBP1 Figure 2Complement levels over timeConclusionsInterim data from this clinical trial suggest favourable safety, CAR T-cell expansion, B-cell depletion and initial efficacy of YTB323 in srSLE, supporting its continued evaluation.
BackgroundBNT211 is a chimeric antigen receptor (CAR)-T cell product candidate that targets the tumor specific antigen Claudin-6 (CLDN6). Preclinical studies demonstrated that combining these ...engineered cells with a CAR-T cell Amplifying RNA Vaccine (CARVac) leads to in vivo expansion of adoptively transferred CAR-T cells, resulting in their improved persistence and functionality.MethodsThis first-in-human, open label, multi-center trial involves a bifurcated 3+3 design with separate CLDN6 CAR-T cell dose escalations (single flat-dose) for monotherapy (part 1) and the combination with CARVac (part 2) based on 3 dose levels (DL). In part 2, CARVac is applied every 3 weeks starting at day 4 post transplantation including a one-step intra-patient dose escalation. Patients with CLDN6-positive relapsed or refractory solid tumors without further standard treatment options and ECOG 0 or 1 are eligible for recruitment.ResultsAs of July 23rd 2021, 8 patients have been treated. DL1 of part 1 has been completed, while dosing of part 1 DL2 and part 2 DL1 is ongoing. One patient with cancer of unknown primary was treated with a dose below DL1 in combination with CARVac; the underlying diseases of the other 7 treated patients were testicular, ovarian and endometrial cancer as well as soft-tissue sarcoma. No acute or dose-limiting toxicities and no serious adverse events related to the drug product have been reported. Manageable cytokine release syndrome (CRS, grade 1-2, the latter managed with Tocilizumab) without any signs of neurotoxicity have been observed in both patients of part 1 DL2. Only transient and moderate elevations of IL-6 and CRP serum levels occurred in remaining patients. Notably, administration of CARVac resulted in transient flu-like symptoms resolving within 24h. Analysis of CAR-T cell frequency in peripheral blood revealed robust engraftment followed by decline after day 17. Further expansion was noted in two patients with liver metastases accompanied by elevated levels of ALT, AST and AP, while total bilirubin was not affected. First tumor assessment 6 weeks after transplantation available for 5/8 patients revealed 4 SD (3 transitioned into PD after an additional 6-18 weeks) and 1 PD. Strikingly, three patients showed initial tumor shrinkage according to RECIST1.1 (reduction of target sum: -18%, -21% and -27%).ConclusionsCLDN6 CAR-T cells +/- CARVac show a favorable safety profile at doses tested and encouraging signs of efficacy. Updated data from open cohorts and especially for combination with CARVac will be presented.AcknowledgementsBNT211-01 is funded by BioNTech Cell & Gene Therapies GmbH.Trial RegistrationClinicaltrialsgov: NCT04503278ReferencesN/A Ethics ApprovalEthics & Institutional Review Board approvals were obtained from the respective participating countries prior to initiation of the trial.ConsentN/A
Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Measuring CMV-specific cellular immunity may improve the risk ...stratification and management of patients. IFN-γ ELISpot assays, based on the stimulation of peripheral blood mononuclear cells with CMV pp65 and IE-1 proteins or peptides, have been validated in clinical settings. However, it remains unclear to which extend the T-cell response to synthetic peptides reflect that mediated by full-length proteins processed by antigen-presenting cells. We compared the stimulating ability of pp65 and IE-1 proteins and corresponding overlapping peptides in 16 HSCT recipients using a standardized IFN-γ ELISpot assay. Paired qualitative test results showed an overall 74.4% concordance. Discordant results were mainly due to low-response tests, with one exception. One patient with early CMV reactivation and graft-versus-host disease, sustained CMV DNAemia and high CD8
counts showed successive negative protein-based ELISpot results but a high and sustained response to IE-1 peptides. Our results suggest that the response to exogenous proteins, which involves their uptake and processing by antigen-presenting cells, more closely reflects the physiological response to CMV infection, while the response to exogenous peptides may lead to artificial in vitro T-cell responses, especially in strongly immunosuppressed patients.
Intestinal graft-versus-host disease (GvHD) is a potentially life-threatening condition after allogenic hematological stem cell transplantation (alloHSCT). Although efforts have been made to ...determine the best sites for endoscopic biopsies, an approach involving all accessible anatomical regions is lacking. We investigated 22 complete biopsy series, each comprising biopsies from 10 different sites of the upper and lower intestine from 21 patients. The majority of biopsies investigated revealed histological signs of acute GvHD. The highest incidence and most advanced grades of acute GvHD were found in the right colon and terminal ileum. We detected significant correlations between crypt or gland loss and histological grades of acute GvHD, and between the number of sites with crypt or gland loss and the time elapsed since alloHSCT. Our results indicate that the most informative biopsies for GvHD diagnosis were those from the right colon and terminal ileum, and from the duodenum for the upper intestine.
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