T-cell receptor (TCR) γδ cells are perceived as innate-like effector cells with the possibility of mediating graft-vs. -tumor (GVT) without causing graft-vs.-host disease (GVHD) in the setting of ...hematopoietic allogeneic stem cell transplantation (HSCT). We conducted a prospective study to assess the clinical impact of TCR γδ cell immune reconstitution on overall survival, relapse-free-survival, relapse and GVHD. The impact of CD3, CD4, and CD8 T cells together with NK cells including subtypes were analyzed in parallel. A total of 108 patients with hematological malignancies transplanted with HLA-matched, T cell replete stem cell grafts were included for analyses of absolute concentrations of CD3, CD4, and CD8 positive T cells and NK cells together with a multi-color flow cytometry panel with staining for TCRαβ, TCRγδ, Vδ1, Vδ2, CD3, CD4, CD8, HLA-DR, CD196, CD45RO, CD45RA, CD16, CD56, CD337, and CD314 at 28, 56, 91, 180, and 365 days after transplantation. Immune reconstitution data including subsets and differentiation markers of T and NK cells during the first year after transplantation was provided. Patients with TCR γδ cell concentrations above the median value of 21 (0-416) × 10
cells/L 56 days after transplantation had significantly improved overall survival (
= 0.001) and relapse-free survival (
= 0.007) compared to patients with concentrations below this value. When day 56 cell subset concentrations were included as continuous variables, TCR γδ cells were the only T cell subsets with a significant impact on OS and RFS; the impact of TCR γδ cells remained statistically significant in multivariate analyses adjusted for pre-transplant risk factors. The risk of death from relapse was significantly decreased in patients with high concentrations of TCR γδ cells 56 days after transplantation (
= 0.003). Also, the risk of acute GVHD was significantly lower in patients with day 28 TCR γδ cell concentrations above the median of 18 × 10
cells/L compared to patients with low concentrations (
= 0.01). These results suggest a protective role of TCR γδ cells in relapse and GVHD and encourage further research in developing adaptive TCR γδ cell therapy for improving outcomes after HSCT.
Mature immunocompetent cells from the stem cell graft as well as early robust immune reconstitution are essential for the graft-vs. -tumor (GVT) effect to eliminate residual malignant cells after ...allogeneic hematopoietic stem cell transplantation (HSCT). In this prospective study we characterized graft composition of T- and NK cell subsets in 88 recipients of peripheral blood stem cell grafts with multicolor flowcytometry. Our primary aim was to analyze the impact of graft composition on immune reconstitution and clinical outcomes after transplantation. Patients transplanted with graft NK cell doses above the median value of 27 × 10
/kg had significantly increased relapse-free-survival compared to patients transplanted with lower doses, HR 2.12 (95% CI 1.01-4.45,
= 0.04) Peripheral blood concentrations of NK cells obtained from donors before G-CSF mobilization were significantly correlated to graft NK cell doses (Spearman's ρ 0.53,
= 0.03). The dose of transplanted NK cells/kg correlated significantly with NK cell concentrations in patients early after transplantation (Spearman's ρ 0.26,
= 0.02, and ρ = 0.35,
= 0.001 for days 28 and 56, respectively). Early immune reconstitution above median values of NK cells was significantly associated with improved relapse-free survival (HR 2.84 95% CI 1.29-6.28,
= 0.01, and HR 4.19 95% CI 1.68-10.4,
= 0.002, for day 28 and 56, respectively). Early concentrations above the median value of the mature effector CD56dim NK cell subset were significantly associated with decreased relapse incidences at 1 year, 7% (95% CI 1.8-17) vs. 28% (95% CI 15-42),
= 0.04, and 7% (95% CI 1.8-18) vs. 26% (95% CI 14-40) %,
= 0.03, for days 28 and 56, respectively. The results suggest a protective effect of high doses of NK cells in grafts and during early immune reconstitution and support the perception of NK cells as innate effector cells with anti-tumor effects in the setting of allogeneic stem cell transplantation.
Therapeutic management of patients with primary or secondary myelofibrosis (MF) who experience relapse or graft failure following allogeneic haematopoietic cell transplantation (allo-HCT) remains ...heterogeneous. We retrospectively analyzed 216 patients undergoing a second allo-HCT for either relapse (56%) or graft failure (31%) between 2010 and 2017. Median age was 57.3 years (range 51-63). The same donor as for the first allo-HCT was chosen in 66 patients (31%) of whom 19 received an HLA-identical sibling donor, whereas a different donor was chosen for 116 patients (54%). Median follow-up was 40 months. Three-year overall survival (OS) and relapse-free survival (RFS) were 42% and 39%, respectively. Three-year non-relapse mortality (NRM) and relapse rates were 36% and 25%, respectively. Grade II-IV and III-IV acute GVHD occurred in 25% and 11% of patients, respectively, and the 3-year incidence of chronic GVHD was 33% including 14% for extensive grade. Graft-failure incidence at 1 year was 14%. In conclusion, our data suggest that a second allo-HCT is a potential option for patients failing first allo-HCT for MF albeit careful patient assessment is fundamental to identify individual patients who could benefit from this approach.
Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid ...organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 51% SOT and 192 49% HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8-48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry.
Mucormycosis is a life threatening infection in patients with haematological disease. We introduced a Mucorales-PCR and an aggressive, multidisciplinary management approach for mucormycosis during ...2016-2017 and evaluated patient outcomes in 13 patients diagnosed and treated in 2012-2019. Management principle: repeated surgical debridement until biopsies from the resection margins were clean as defined by negative Blankophor microscopy, Mucorales-PCR (both reported within 24 h), and cultures. Cultured isolates underwent EUCAST E.Def 9.3.1 susceptibility testing. Antifungal therapy (AFT) (mono/combination) combined with topical AFT (when possible) was given according to the minimal inhibitory concentration (MIC), severity of the infection, and for azoles, specifically, it was guided by therapeutic drug monitoring. The outcome was evaluated by case record review. All patients underwent surgery guided by diagnostic biopsies from tissue and resection margins (195 samples in total). Comparing 2012-2015 and 2016-2019, the median number of patients of surgical debridements was 3 and 2.5 and of diagnostic samples: microscopy/culture/PCR was 3/3/6 and 10.5/10/10.5, respectively. The sensitivity of microscopy (76%) and Mucorales-PCR (70%) were similar and microscopy was superior to that of culture (53%;
= 0.039). Initial systemic AFT was liposomal amphotericin B (
= 12) or posaconazole (
= 1) given as monotherapy (
= 4) or in combination with isavuconazole/posaconazole (
= 3/6) and terbinafine (
= 3). Nine patients received topical amphotericin B. All received isavuconazole or posaconazole consolidation therapy (
= 13). Mucormycosis related six month mortality was 3/5 in 2012-2015 and 0/7 patients in 2016-2019 (one patient was lost for follow-up). Implementation of combination therapy (systemic+topical AFT/combination systemic AFT) and aggressive surgical debridement guided by optimised diagnostic tests may improve the outcome of mucormycosis in haematologic patients.
We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at ...reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.
•In the whole cohort, no evidence of disease was 69% two years post-AHSCT.•Data suggests that CY is as effective as BEAM with less adverse events.•We had no treatment related mortality and only few ...severe adverse events.•AHSCT of patients with aggressive RRMS was an effective and safe treatment in Denmark.
Autologous hematopoietic stem cell treatment (AHSCT) is considered an effective treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). Still there are few randomized and controlled studies of AHSCT to shed light on the safety and efficacy of the treatment, and therefore experiences from single centers are important.
To describe the Danish experience with AHSCT regarding patient characteristics, safety, and efficacy.
Nationwide retrospective single center study of patients with multiple sclerosis (MS) treated with AHSCT.
A total of 32 patients were treated with AHSCT from May 2011 to May 2021. Seven were treated with carmustine, etoposide, cytarabine arabinoside, and melphalan (BEAM) as well as antithymocyte globulin (ATG). Twenty-five patients were treated with cyclophosphamide (CY) and ATG. In the whole cohort, relapse-free survival (RFS) was 77% (95% CI: 64–94%), worsening-free survival (WFS) was 79% (95% CI: 66–96%), MRI event-free survival (MFS) was 93% (95% CI: 85–100%), and no evidence of disease (NEDA-3) was 69% (95% CI: 54–89%) at the end of year two post-AHSCT. We had no treatment related mortality and only few severe adverse events (AEs).
AHSCT of patients with aggressive RRMS was an effective and relatively safe treatment with few serious AEs and no mortality in Danish patients.
Malignant hematologic diseases resistant to chemotherapy can be cured by immune cellular therapy. Bone marrow transplantation (BMT) elicits a "pan-immunologic" attack, whereas therapy with chimeric ...antigen receptor (CAR)-T is a targeted attack. The immunologic activity after BMT can be adjusted by selection of donor cells before transplantation, or with post-BMT sequential chemotherapy. Many haematologic diseases are clonal, and the development of CAR-T cellular therapy directed against a variety of epitopes is under development as summarised in this review.
Low pre-transplantation plasma vitamin E levels have been associated with increased risk of acute graft-versus-host disease (GvHD) after myeloablative allogeneic hematopoietic cell transplantation ...(allo-HCT). We aimed to investigate the association between pre-transplantation plasma vitamin E levels and acute GvHD in patients undergoing allo-HCT with non-myeloablative conditioning.
In a cohort of 194 adults who underwent non-myeloablative allo-HCT at Rigshospitalet between July 2015 and December 2019, we measured pre-transplantation plasma vitamin E levels by high-performance liquid chromatography in stored plasma samples. Univariable ordinary least squares linear models were used to investigate associations between vitamin E levels and patient characteristics. A multivariable logistic regression model was used to estimate the association between vitamin E levels and grade II–IV acute GvHD, adjusted for recipient age, donor age, female-male donor-recipient pairing, and donor type.
The median (Q1, Q3) pre-transplantation plasma vitamin E level was 32.3 (26.4, 40.4) μmol/L. No patients had a vitamin E level below the normal reference range. Vitamin E levels were higher in females (mean difference: 8.0 μmol/L, 95% confidence interval CI: 4.9, 11.1 μmol/L) and in patients transplanted for acute leukemia (mean difference: 6.2 μmol/L, CI: 3.0, 9.4 μmol/L). Grade II–IV acute GvHD developed in 33 (17%) patients. Patients who developed acute GvHD had similar pre-transplantation vitamin E levels compared with patients who did not develop grade II–IV acute GvHD (mean difference: 0.7 μmol/L, bootstrap CI: −3.3, 4.7 μmol/L). In the adjusted logistic regression model, an increase in the pre-transplantation vitamin E level from 26.4 (Q1) to 40.4 (Q3) μmol/L was associated with an odds ratio of grade II–IV acute GvHD of 1.17 (CI: 0.64, 2.12).
Contrary to the previously reported association between pre-transplantation vitamin E levels and acute GvHD after myeloablative allo-HCT, we did not find support for an association in patients who received non-myeloablative conditioning. The potential protective effects of vitamin E may not be efficacious in the reduced inflammatory response following non-myeloablative conditioning.
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