Summary
Allogeneic haematopoietic stem cell transplantation (HSCT) after a reduced‐intensity conditioning (RIC) regimen with fludarabine, melphalan and alemtuzmab is an effective therapy for ...haematological malignancies. Alemtuzumab, a monoclonal antibody against CD52, a glycosylphosphatidylinositol‐anchor‐bound surface protein on lymphocytes, depletes T cells to prevent graft‐versus‐host disease (GVHD). Despite this, acute and chronic GVHD (a/cGVHD) remain life‐threatening complications after HSCT. The aim of the present study was to identify parameters to predict GVHD. In 69 patients after HSCT, T‐cell subsets were functionally analysed. Reconstitution of CD52neg T cells and CD52neg regulatory T cells (Tregs) correlated with onset, severity and clinical course of aGVHD. Patients with aGVHD showed significantly lower levels of CD52pos T cells compared to patients with cGVHD or without GVHD (P < 0·001). Analysis of T‐cell reconstitution revealed a percentage of <40% of CD52posCD4pos T cells or CD52pos Tregs at day +50 as a risk factor for the development of aGVHD. In contrast, CD52neg Tregs showed significant decreased levels of glycoprotein A repetitions predominant (GARP; P < 0·001), glucocorticoid‐induced TNFR‐related protein (GITR; P < 0·001), chemokine receptor (CXCR3; P = 0·023), C‐C chemokine receptor type 5 (CCR5; P = 0·004), but increased levels of immunoglobulin‐like transcript 3 (ILT3; P = 0·001), as well as a reduced suppressive capacity. We conclude that reconstitution of CD52neg T cells and CD52neg Tregs is a risk factor for development of aGVHD.
The phase III study was designed to compare event‐free survival (EFS) after treosulfan‐based conditioning with a widely applied reduced‐intensity conditioning (RIC) busulfan regimen in older or ...comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre‐specified subgroup analyses of all 570 randomized patients with completed longer‐term follow‐up are presented. Patients presenting HCT‐specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m2 IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36‐months‐EFS rate 59.5% (95% CI, 52.2–66.1) vs. 49.7% (95% CI, 43.3–55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49–0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36‐month‐OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48–0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.
CD19-directed chimeric antigen receptor (CAR) T cells have evolved as new standard-of-care (SOC) treatment in patients with relapsed/refractory large B-cell lymphoma (LBCL). Here, we report the first ...German real-world data on SOC CAR-T cell therapies with the aim to explore risk factors associated with outcome.
Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. Main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS).
We report 356 patients who received axi-cel (n=173) or tisa-cel (n=183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, LDH, IPI, and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and need for bridging, respectively. With a median follow-up alive of 11 months, Kaplan-Meier estimates of OS, PFS, and non-relapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use.
In conclusion, this study suggests that important outcome determinants of CD19-directed CAR-T cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR-T cell therapy strategies.
BACKGROUND
The presence of TP53 mutations is associated with an unfavorable outcome in patients allografted for acute myeloid leukemia (AML), leading some to question the benefit of an allogeneic ...stem cell transplantation (allo‐SCT) for this patient group, although this has not been studied in a large cohort.
METHODS
A total of 780 patients with AML in first complete remission, with either intermediate‐ or adverse‐risk cytogenetics, whose TP53 mutation status was reported, were included in this study from the European Society for Blood and Marrow Transplantation.
RESULTS
Two‐year overall survival (OS) was impaired in patients (n = 179) with evidence of a TP53 mutation at diagnosis (35.1%; 95% confidence interval CI, 26.7–43.7) as compared to the cohort without (n = 601) (64%; 95% CI, 59.1–68.4; P = .001). In patients with mutant TP53 AML with no evidence of either chromosome 17p loss (17p–) and/or complex karyotype (CK) (n = 53, 29.6%), 2‐year OS was 65.2% (95% CI, 48.4–77.6). This was not significantly different to patients without TP53 mutations. In patients with mutant TP53 AML with either 17p– and/or CK (n = 126, 70.4%), the OS was lower (24.6%; 95% CI, 16.2–34; P = .001).
CONCLUSIONS
In summary, the adverse prognostic effect of TP53 mutations in AML following an allo‐SCT is not evident in patients with neither co‐occurring 17p– and/or CK, and these data inform decisions regarding allo‐SCT in patients with TP53 mutant AML.
Patients undergoing allogeneic hematopoietic stem cell transplantation have a high morbidity and mortality, especially after admission to intensive care unit (ICU) during peri-transplant period. The ...objective of this study was to identify new clinical and biological parameters and validate prognostic scores associated with ICU, short-and long-term survival. Significant differences between ICU survivors and ICU non-survivors for the clinical parameters invasive mechanical ventilation, urine output, heart rate, mean arterial pressure, and amount of vasopressors have been measured. Among prognostic scores (SOFA, SAPSII, PICAT, APACHE II, APACHE IV) assessing severity of disease and predicting outcome of critically ill patients on ICU, the APACHE II score has shown most significant difference (p = 0.002) and the highest discriminative power (area under the ROC curve (AUC) 0.74). An elevated level of lactate at day of admission was associated with poor survival on ICU and the most significant independent parameter (p < 0.001). In our cohort kidney damage with low urine output has a highly relevant impact on ICU, short- and long-term overall survival. The APACHE II score was superior predicting ICU mortality compared to all other tested prognostic scores for patients on ICU during peri-transplant period.
Acute graft versus host disease (aGvHD) is an important, life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). To investigate the value of multiple ...simultaneous colon biopsies in improving diagnostic accuracy in patients with aGvHD, we retrospectively analyzed 157 patients after alloHSCT. The biopsies were evaluated individually using three established histological grading systems (Lerner, Sale, and Melson). The maximum, minimum, median, and mean histological aGvHD grades were calculated for each patient, and the results were correlated with the Glucksberg grade of clinical manifestation of GvHD, steroid therapy status, and outcome. We found that multiple colon biopsies enhanced diagnostic sensitivity. Moreover, higher histological grades correlated with steroid therapy initiation and refractoriness; the latter particularly occurred when advanced damage was present in all samples and healthy colon mucosa was reduced or absent. On multivariate analysis, the minimal Lerner and Glucksberg grades for intestinal aGvHD were significantly associated with steroid treatment failure. Ninety-nine patients died. The median survival was 285 days after the biopsies were taken. Fifteen patients died from relapse of their underling disorder and 84 from other causes, mostly infection (53 patients) and GvHD (14 patients). Multivariate analysis revealed a significant association between none-relapse mortality and the mean Lerner grade, minimum Melson grade, Glucksberg organ stage, and platelet counts. Thus, we found the Lerner system to be superior to the other grading methods in most instances and histologic evaluation of multiple simultaneously obtained biopsies from the colon to result in a higher diagnostic yield, which helps plan systemic steroid treatment while predicting treatment response and outcome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although most patients with chronic graft-versus-host disease (cGVHD) show initial response to first-line therapy, long-term clinically meaningful success of first-line treatment remains rare. In a ...prospective multicentre phase II trial in 6 German centers, patients with newly diagnosed moderate or severe cGVHD received prednisone and everolimus for 12 months followed by a 1-year follow-up period. Primary endpoint was treatment success (TS) at 6 months defined as patient being alive, achieving PR or CR of cGVHD, having no relapse of underlying disease and requiring no secondary treatment for cGVHD. Of the 34 patients evaluable for efficacy, 19 (56%) had TS at 6 months with 22 and 52% of the patients in a CR and PR respectively. Overall 30 patients (88%) had a CR or PR as best response, nearly all responses (29/30) occurring within the first 6 weeks of treatment. The cumulative incidence of treatment failure at 1 year was 63%, corresponding to 37% TS. Predefined safety endpoint (thrombotic microangiopathy, pneumonitis, and avascular necrosis) were not observed in any patient. Addition of everolimus to prednisolone is well tolerated and may improve long-term treatment success. Larger studies are necessary to ascertain the possible role of everolimus in first-line treatment of cGVHD.
A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell ...transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.
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