Steroid-resistant (SR) acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic stem cell transplantation. Vedolizumab is a monoclonal antibody that impairs homing of ...T cells to the gastrointestinal (GI) endothelium by blocking the α4β7 integrin. We retrospectively analyzed outcomes following vedolizumab administration for treatment of SR GI GvHD. Overall, 29 patients from three transplantation centers were included. Histopathology was available in 24 (83%) patients. The overall response rate (ORR) was 23/29 (79%); 8 (28%) patients had a complete response and 15 (52%) a partial response. Vedolizumab was administered as a 2nd-line or ≥3rd-line treatment in 13 (45%) and 16 (55%) patients, respectively. ORR in the former groups was 13/13 (100%) versus 10/16 (63%) in the latter (p = 0.012); corresponding CR rates were 7/13 (54%) versus 1/16 (6%) (p = 0.005). Early administration of vedolizumab was also associated with a greater likelihood of patients being off immunosuppression ((9/13 (69%) versus 3/16 (19%), p = 0.007) and free from fatal infectious complications (5/13 versus 14/16, p = 0.006). Overall, our data suggest that vedolizumab, especially if administered early in the disease course, may ameliorate severe SR GI aGvHD. The timing, role, and safety of vedolizumab should be further explored in prospective clinical trials.
The age of tissues and cells can be accurately estimated by DNA methylation analysis. The multitissue DNA methylation (DNAm) age predictor combines the DNAm levels of 353 CpG dinucleotides to arrive ...at an age estimate referred to as DNAm age. Recent studies based on short‐term observations showed that the DNAm age of reconstituted blood following allogeneic hematopoietic stem cell transplantation (HSCT) reflects the age of the donor. However, it is not known whether the DNAm age of donor blood remains independent of the recipient's age over the long term. Importantly, long‐term studies including child recipients have the potential to clearly reveal whether DNAm age is cell‐intrinsic or whether it is modulated by extracellular cues in vivo. Here, we address this question by analyzing blood methylation data from HSCT donor and recipient pairs who greatly differed in chronological age (age differences between 1 and 49 years). We found that the DNAm age of the reconstituted blood was not influenced by the recipient's age, even 17 years after HSCT, in individuals without relapse of their hematologic disorder. However, the DNAm age of recipients with relapse of leukemia was unstable. These data are consistent with our previous findings concerning the abnormal DNAm age of cancer cells, and it can potentially be exploited to monitor the health of HSCT recipients. Our data demonstrate that transplanted human hematopoietic stem cells have an intrinsic DNAm age that is unaffected by the environment in a recipient of a different age.
Introduction
For the majority of patients with acute myeloid leukemia (AML) an allogeneic stem cell transplant (SCT) in first complete remission (CR) is preferred. However, whether the number of ...courses required to achieve CR has a prognostic impact is unclear. It is unknown which factors remain important in patients requiring more than one course of induction to attain remission.
Methods
This Acute Leukaemia Working Party study from the European Society for Blood and Marrow Transplantation identified adults who received an allograft in first CR from either a fully matched sibling or 10/10 or 9/10 human leucocyte antigen (HLA)‐matched unrelated donor (HLA‐A, HLA‐B, HLA‐C, HLA‐DR, or HLA‐DQ). Univariate and multivariate analyses were undertaken to identify the prognostic impact of one or two courses of induction to attain CR.
Results
A total of 4995 patients were included with 3839 (77%) patients attaining a CR following one course of induction chemotherapy (IND1), and 1116 patients requiring two courses (IND2) to attain CR. IND2 as compared to IND1 was a poor prognostic factor in a univariate analysis and remained so in a multivariate Cox model, resulting in an increased hazard ratio of relapse (1.38; 95% confidence interval CI, 1.16–1.64; p = .0003) and of death (1.27; 95% CI, 1.09–1.47; p = .002). Adverse prognostic factors in a multivariate analysis of the outcomes of patients requiring IND2 included age, FLT3‐ITD, adverse cytogenetics, and performance status. Pretransplant measurable residual disease retained a prognostic impact regardless of IND1 or IND2.
Conclusion
Initial response to chemotherapy as determined by number of courses to attain CR, retained prognostic relevance even following SCT in CR.
Patients requiring two courses of induction to attain complete remission (CR) have a higher incidence of relapse and inferior survival as compared to those who require one course. Pretransplant measurable residual disease remains important in predicting outcomes following an allogeneic stem cell transplant in those requiring two courses of induction to achieve CR.
Background
Allogeneic hematopoietic cell transplantation (allo‐HCT) is the only cure for acute myeloid leukemia (AML) in second complete remission (CR2). Patients lacking a matched sibling donor ...(MSD) receive transplants from matched unrelated donors (MUDs), mismatched unrelated donors (MMUDs), haploidentical (haplo) donors, or cord blood.
Methods
This is a retrospective, registry‐based European Society for Blood and Marrow Transplantation study that investigates changes in patient‐ and transplant‐related characteristics and posttransplant outcomes over time.
Results
We identified 3955 adult patients (46.7% female; median age, 52 years range, 18–78 years) with AML in CR2 first transplanted between 2005 and 2019 from a MUD 10/10 (61.4%), MMUD 9/10 (21.9%), or haplo donor (16.7%) and followed for 3.7 years. A total of 725 patients were transplanted between 2005 and 2009, 1600 between 2010 and 2014, and 1630 between 2015 and 2019. Over the three time periods, there was a significant increase in patient age (from 48.7 to 53.5 years; p < .001), use of a haplo donor (from 4.6% to 26.4%; p < .001), and use of posttransplant cyclophosphamide (from 0.4% to 29%; p < .001). There was a significant decrease in total body irradiation and in vivo T‐cell depletion. In multivariate analysis, transplants performed more recently had better outcomes. Leukemia‐free survival (hazard ratio HR, 0.79; p = .002) and overall survival (HR, 0.73; p < .001) increased over time. Similarly, nonrelapse mortality (HR, 0.64; p < .001) decreased over time. We also observed better graft‐vs‐host disease (GVHD) rates (acute GVHD II–IV: HR, 0.78; p = .03; GVHD‐free, relapse‐free survival: HR, 0.69; p < .001).
Conclusions
Even in the absence of an MSD, outcomes of allo‐HCT in CR2 for AML have significantly improved over time, with most favorable outcomes achieved with a MUD.
Allogeneic transplantation remains the only curative option for patients with acute myeloid leukemia in second complete remission, with significant changes in patient and transplant characteristics and posttransplant outcomes over time. Even in the absence of matched sibling donors, outcomes have improved over time, with the best outcomes achieved with matched unrelated donors.
In the 2022 European LeukemiaNet classification, patients with nucleophosmin 1 (NPM1)‐mutated acute myeloid leukemia (AML) were classified in the adverse‐risk category in the presence of high‐risk ...cytogenetics (CG). Nonetheless, the impact of various CG aberrations on posttransplant outcomes remains to be unraveled. This registry study analyzed adult patients with NPM1‐mutated de novo AML who underwent their first allogeneic hematopoietic cell transplantation in the first complete remission from 2005 to 2021. A total of 3275 patients were identified, 2782 had normal karyotype, 493 had chromosomal aberrations including 160 with adverse‐risk CG, 72 patients had complex karyotype (CK), and 66 monosomal karyotype (MK). Overall, 2377 (73%) patients had FLT3‐ITD. On univariate analysis, only FLT3‐ITD, minimal/measurable residual disease (MRD) positivity and CK, but not abnormal CG, affected posttransplant outcomes. On multivariable analysis, CK was associated with lower overall survival (OS) (hazard ratio HR 1.72, p = .009). In the subgroup of 493 patients with aberrant CG, the 2‐year leukemia‐free survival (LFS) and OS were around 61% and 68%, respectively. On multivariable analysis for this subgroup, CK and MRD positivity were associated with increased risk of relapse (HR 1.7, p = .025; and 1.99, p = .003 respectively) and worse LFS (HR 1.62, p = .018; and 1.64, p = .011 respectively) while FLT3‐ITD, MK, or other CG abnormalities had no significant effect. Importantly, CK negatively affected OS (HR 1.91, p = .002). In the first complete remission transplant setting, CK was found as the only cytogenetic risk factor for worse outcomes in NPM1‐mutated AML. Nevertheless, even for this subgroup, a significant proportion of patients can achieve long‐term posttransplant survival.
Background
Mixed results surround the accuracy of commonly used prognostic risk scores to predict overall survival (OS) and non‐relapse mortality (NRM) in allogeneic hematopoietic stem cell ...transplant (allo‐HCT) recipients. We hypothesize that a simple prognostic score performs better than conventional scoring systems.
Patients and Methods
OS risk factors, HCT‐CI, age‐HCT‐CI, and augmented‐HCT‐CI were studied in 299 patients who underwent allo‐HCT for myeloid and lymphoid malignancies. A scoring system was developed based on results and validated in a different cohort of 455 patients.
Results
Two‐year OS was 51% (95% confidence interval (CI) 0.45–0.56); 2‐year NRM was 34% (95% CI 0.29–0.39). HCT‐CI and associated scores were grouped into 0–2 and ≥3. Age and HLA mismatch status were the only risk factors to affect OS in multivariate analysis (p = 0.02 and 0.05, respectively). HCT‐CI and associated scores were not informative for OS prediction. The weighted scoring system assigned 0 to 2 points for age < 50, 50–64, or ≥65, respectively, and 0–1 points for no HLA mismatch versus any mismatch (except HLA‐DQ). Distinct 2‐year OS (62%, 53%, and 38% p = <0.001) and NRM (24%, 34%, and 43% p = 0.02) groups were characterized. The scoring system was validated in a second independent cohort with similar results on OS and NRM (p < 0.001).
Conclusions
A simple scoring system based on recipient's age and mismatch status accurately predict OS and NRM in two distinct cohorts of allo‐HCT patients. Its simplicity makes it a helpful tool to aid clinicians and patients in clinical decision‐making.
Allogeneic hematopoietic cell transplantation (allo‐HCT) is recommended for core‐binding factor mutated (CBF) AML patients achieving second complete remission (CR2). However, approximately 20% of ...patients may relapse after transplant and donor preference remains unclear. We compared in this EBMT global multicenter registry‐based analysis the allo‐HCT outcomes using either haploidentical (Haplo), matched siblings donors (MSD), or 10/10 matched unrelated donors (MUD). Data from 865 de novo adult CBF AML patients in CR2 receiving allo‐HCT in 227 EBMT centers from 2010 to 2022 were analyzed, in which 329 MSD, 374 MUD, and 162 Haplo‐HCTs were included. For the entire cohort, 503 (58%) patients were inv(16)/CBFB‐MYH11 and 362 patients (42%) were t(8;21)/RUNX1‐RUNX1T1 AML. On multivariate analysis, Haplo‐HCT was associated with a lower Relapse Incidence (RI) compared to either MSD (hazard ratio HR = 0.56, 95% CI 0.32–0.97; p < .05) or MUD (HR = 0.57, 95% CI: 0.33–0.99, p < .05). No significant difference was observed among the 3 types of donors on LFS, OS and GRFS. CBF‐AML with t(8;21) was associated with both higher RI (HR = 1.79, 95% CI 1.3–2.47; p < .01) and higher NRM (HR = 1.58, 95% CI 1.1–2.27; p < .01) than CBF‐AML with inv(16), which led to worse LFS, OS and GRFS. To conclude, for CBF‐AML patients in CR2, Haplo‐HCTs were associated with a lower RI compared to MSD and MUD allo‐HCTs. There was no difference on LFS, OS or GRFS. CBF AML patients with inv(16) had a better progonosis than those with t(8;21) after allo‐HCT in CR2.
Allogenic hematopoietic stem cell transplantation is a therapeutic procedure performed over a wide range of donor and recipient age combinations, representing natural experiments of how the age of ...the recipient affects aging in transplanted donor cells in vivo. We measured DNA methylation and epigenetic aging in donors and recipients and found that biological epigenetic clocks are accelerated in cells transplanted into an older body and decelerated in a younger body. This is the first evidence that the age of the circulating environment influences human epigenetic aging in vivo.
Epigenetic aging is accellerated in cells living in an older body compared to cells living in a younger body.
FMS‐like tyrosine kinase 3 internal tandem duplication (FLT3‐ITD) mutational status is a pivotal prognosticator in acute myeloid leukemia (AML) patients and significantly increases the risk of ...disease relapse. However, it remains unclear whether in FLT3‐ITD patients referred for allogeneic stem cell transplantation (allo‐SCT), baseline cytogenetics significantly impacts clinical outcome. Using the European Society of Blood and Marrow Transplantation registry, we performed a retrospective analysis of 1631 FLT3‐ITD AML patients who underwent allo‐SCT with the aim of determining the influence of cytogenetic risk category on patient outcomes. Median patient age was 49 years and median follow‐up duration was 36 months. Two‐year leukemia‐free survival (LFS) and incidence of relapse were 54% and 31.6%, respectively. Non‐relapse mortality was experienced by 14.4% with a 2‐year overall survival (OS) of 60.1%. On multivariate analysis, LFS was significantly lower in patients with intermediate and adverse risk cytogenetics compared with those with favorable risk cytogenetics, (hazard ratio HR = 1.48, 95% confidence interval CI, 1.06–2.06; p = .02), and (HR = 01.65, 95% CI, 1.13–2.40; p = .009), respectively. OS was significantly lower in patients with adverse risk cytogenetics compared with patients with favorable risk cytogenetics (HR = 1.74, 95% CI, 1.16–2.61; p = .008) with a trend toward lower OS in patients with intermediate risk cytogenetics compared to those with favorable risk cytogenetics (HR = 1.43, 95% CI, 1.00–2.05; p = .052). In addition, adverse risk patients and intermediate risk patients experienced higher relapse rates compared with favorable risk patients (HR = 1.83, 95% CI, 1.13–2.94; p = .013 and HR = 1.82, 95% CI, 1.19–2.77; p = .005). Overall, cytogenetic studies aid in refinement of risk stratification in transplanted FLT3‐ITD AML patients.
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