Video consultation and treatment in the community smoking cessation therapy success rates in patients with mental illness: a randomized controlled trial.

PURPOSE: Smoking is the single factor with the highest impact on reducing life expectancy of patients with mental illness. Patients experience difficulty in participating in smoking cessation programs but are concerned about the impact of tobacco on their health and finances. Smoking cessation advice via videoconferencing might be an alternative to an ordinary in-person consultation. MATERIAL AND METHOD: Randomized controlled trial with follow-up at 6 months. We included patients with diagnoses of schizophrenia and affective disorder from psychiatric outpatient clinics. Intervention 1 involved daily video consultations; intervention 2 was treatment as usual. RESULTS: Seventy patients were included. For both/all groups/interventions, rates of smoking cessation were 45% and predictors for a 50% reduction in smoking were antipsychotic medication load [odds ratio (OR) 0.54; p = 0.045] and number of nicotine patches (OR 1.02; p = 0.06). Predictors for a reduction in the number of cigarettes to < 10 were antipsychotic medication load (OR 0.52; p = 0.04), number of nicotine patches (OR 1.01; p = 0.02) and number of cigarettes at baseline [OR 0.95 (p = 0.09); adjusted OR 0.94 (p = 0.02)]. Patients prevented weight gain during the cessation period. CONCLUSION: The smoking cessation rate was high. One of the reasons for the high cessation rate was that the intervention was carried out by highly experienced and professionally qualified staff. In addition, we used free nicotine patches to increase the patients' motivation to quit smoking. It is very important that we introduce these results into our clinical work with the patients.

Patient-Specific Measurable Residual Disease Markers Predict Outcome in Patients With Myelodysplastic Syndrome and Related Diseases After Hematopoietic Stem-Cell Transplantation.

PURPOSE: Clinical relapse is the major threat for patients with myelodysplastic syndrome (MDS) undergoing hematopoietic stem-cell transplantation (HSCT). Early detection of measurable residual disease (MRD) would enable preemptive treatment and potentially reduced relapse risk. METHODS: Patients with MDS planned for HSCT were enrolled in a prospective, observational study evaluating the association between MRD and clinical outcome. We collected bone marrow (BM) and peripheral blood samples until relapse, death, or end of study 24 months after HSCT. Patient-specific mutations were identified with targeted next-generation sequencing (NGS) panel and traced using droplet digital polymerase chain reaction (ddPCR). RESULTS: Of 266 included patients, estimated relapse-free survival (RFS) and overall survival (OS) rates 3 years after HSCT were 59% and 64%, respectively. MRD results were available for 221 patients. Relapse was preceded by positive BM MRD in 42/44 relapses with complete MRD data, by a median of 71 (23-283) days. Of 137 patients in continuous complete remission, 93 were consistently MRD-negative, 39 reverted from MRD+ to MRD-, and five were MRD+ at last sampling. Estimated 1 year-RFS after first positive MRD was 49%, 39%, and 30%, using cutoff levels of 0.1%, 0.3%, and 0.5%, respectively. In a multivariate Cox model, MRD (hazard ratio [HR], 7.99), WHO subgroup AML (HR, 4.87), TP53 multi-hit (HR, 2.38), NRAS (HR, 3.55), and acute GVHD grade III-IV (HR, 4.13) were associated with shorter RFS. MRD+ was also independently associated with shorter OS (HR, 2.65). In a subgroup analysis of 100 MRD+ patients, presence of chronic GVHD was associated with longer RFS (HR, 0.32). CONCLUSION: Assessment of individualized MRD using NGS + ddPCR is feasible and can be used for early detection of relapse. Positive MRD is associated with shorter RFS and OS (ClinicalTrials.gov identifier: NCT02872662).

Donor Lymphocyte Infusion Is a Feasible Way to Improve Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Who Relapse after Allogeneic Stem Cell Transplantation.

INTRODUCTION: Donor lymphocyte infusion (DLI) is used to induce remission in patients who relapse after allogeneic stem cell transplantation (allo-HSCT). During the last decade, the hypomethylating agent Azacitidine has been used together with DLI for a synergistic graft-versus-leukemia (GVL) effect. Here we report results of DLI/Azacitidine treatment from a retrospective single-center study. METHODS: 50 AML/MDS patients treated for relapse after allo-HSCT between 2001 and 2020 with DLI at the Department of Hematology, at Rigshospitalet, Copenhagen University Hospital were included for analyses. A subgroup of patients who obtained complete remission (CR) after reinduction chemotherapy, received DLI in combination with low-dose (32 mg/m2) Azacitidine. RESULTS: Overall survival in all patients after DLI treatment was 59% at 2 years and 20% at 5 years. Relapse-free survival in patients in CR prior to DLI was 32% after 2 years and 7% after 5 years. In the DLI+low-dose-Azacitidine group, 5-years relapse-free survival was 40%. CONCLUSION: DLI remains an effective treatment in post-transplant relapse leaving one fifth of patients long-term survivors. Our results support the concomitant use of low-dose Azacitidine in the future use of DLI in order to enhance the GVL effect of donor lymphocytes.

Triple-Drug Graft-versus-Host Disease Prophylaxis after HLA-Matched Unrelated Donor Nonmyeloablative Allogenic Hematopoietic Stem Cell Transplantation.

Adding sirolimus to graft-versus-host disease (GVHD) prophylaxis with cyclosporin and mycophenolate mofetil (MMF) reduced the risk of grade II-IV acute GVHD after nonmyeloablative (NMA) allogenic hematopoietic stem cell transplantation (HSCT) with an HLA-matched unrelated donor in a randomized clinical trial. We analyzed real-life data to investigate the impact of implementing the triple-drug regimen with cyclosporin, MMF and sirolimus as standard GVHD prophylaxis after NMA HSCT with an HLA-matched unrelated donor at our institution. We studied all adult patients (age ≥18 years) who underwent NMA HSCT with an HLA-matched unrelated donor at Rigshospitalet, Copenhagen University Hospital, Denmark between 2018 and 2021 and received GVHD prophylaxis with cyclosporin, MMF and sirolimus (triple-drug group [TDG]). Comparisons were made with a historical cohort who received tacrolimus and MMF as GVHD prophylaxis after HLA-matched unrelated donor NMA HSCT between 2014 and 2017 (control group [CG]). Outcomes were grade II-IV and grade III-IV acute GVHD, chronic GVHD, relapse, nonrelapse mortality (NRM) and overall survival (OS). A total of 264 patients were included (TDG, n = 137; CG, n = 127). Median age was 66 years (interquartile range [IQR], 58 to 69 years) in the TDG and 63 years (IQR, 57 to 68 years) in the CG. Acute myeloid leukemia and myelodysplastic syndrome were the most frequent indications for HSCT in both groups (TDG, 33% and 23%, respectively; CG, 36% and 22%, respectively). The cumulative incidence at day +110 of grade II-IV GVHD was 17% (95% confidence interval [CI] 11% to 23%) in the TDG versus 29% (95% CI, 21% to 37%) in the CG (P = .02, Gray's test) and that of grade III-IV acute GVHD was 3% (95% CI, 0 to 6%) versus 5% (95% CI, 1% to 8%), respectively (P = .4, Gray's test). In a Cox regression model adjusted for age, donor age and female donor to male recipient the risk of grade II-IV acute GVHD was lower in the TDG compared to the CG (hazard ratio [HR], .51; 95% CI .30 to .86; P = .01). The 2-year OS was 77% (95% CI, 70% to 84%) in the TDG and 69% (95% CI, 61% to 77%) in the CG (P = .04), and this difference remained significant after adjustment for age and Karnofsky Performance Status (HR, .65; 95% CI, .42 to .99; P = .04). The 2-year cumulative incidences of chronic GVHD, relapse and NRM were 60% (95% CI, 51% to 69%), 21% (95% CI, 13% to 28%), and 12% (95% CI, 6% to 17%), respectively, in the TDG and 62% (95% CI, 54% to 71%), 27% (95% CI, 19% to 35%) and 14% (95% CI, 8% to 20%), respectively, in the CG. Multivariable analyses revealed no difference in the risk of chronic GVHD (HR, .91; 95% CI, .65 to 1.26; P = .56), relapse (HR, .70; 95% CI, .42 to 1.15; P = .16) or NRM (HR, .56; 95% CI, .31 to 1.05; P = .07). After changing the standard GVHD prophylaxis in patients undergoing NMA HSCT with an HLA-matched unrelated donor from tacrolimus and MMF to cyclosporin, MMF and sirolimus, we observed a reduction in the incidence of grade II-IV acute GVHD and improved 2-year OS.

Pretransplantation Plasma ST2 Level as a Prognostic Biomarker of 1-Year Nonrelapse Mortality in Allogeneic Hematopoietic Cell Transplantation.

Soluble ST2 is established as a prognostic biomarker of nonrelapse mortality (NRM) when measured early after allogeneic hematopoietic cell transplantation (HCT). However, less is known about the prognostic value of ST2 measured before transplantation. We hypothesized that pretransplantation plasma ST2 level was associated with 1-year NRM and could add to our current prognostic assessment. Moreover, we aimed to investigate the associations between pretransplantation plasma ST2 levels and patient characteristics and other plasma biomarkers and to reproduce previous associations between post-transplantation plasma ST2 levels and outcomes of HCT. We conducted this cohort study of 374 adults who underwent allogeneic HCT at our center between July 2015 and December 2019 (median age, 59 years; 55% with a nonmyeloablative conditioning regimen). ST2 levels were measured by enzyme-linked immunosorbent assay in stored plasma samples obtained at a median of 23 days before HCT and also in samples obtained on days +7 and +14 post-HCT. A logistic regression model of 1-year NRM was fitted using an a priori defined set of covariates consisting of age, Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI), and conditioning intensity (myeloablative versus nonmyeloablative), to which the pretransplantation ST2 level was added as a variable to assess its incremental prognostic value. Models also were fitted of 1-year all-cause mortality, relapse, and grade II-IV acute graft-versus-host disease (GVHD) for pretransplantation and post-transplantation ST2 levels. The median pretransplantation plasma ST2 level was 20.4 ng/mL (interquartile range, 15.2 to 27.2 ng/mL). Pretransplantation ST2 levels were higher in males compared with females (median, 22.2 ng/mL versus 18.1 ng/mL; P < .001) and were correlated with HCT-CI (Spearman ρ = .18; P < .001), body mass index (ρ = .10; P = .05), and plasma levels of C-reactive protein (ρ = .34; P < .001), creatinine (ρ = .17; P = .001), and albumin (ρ = -.17; P < .001). Pretransplantation ST2 levels added prognostic information about 1-year NRM to age, HCT-CI, and conditioning intensity (adjusted odds ratio [OR] of 1-year NRM per 10 ng/mL increase in ST2, 1.32; 95% confidence interval [CI], 1.05 to 1.65; P = .02). Although adding pretransplantation ST2 levels did not notably improve model discrimination (.674 to .675, ΔAUC = .001), it increased the diversity of the predicted risks (P = .02, likelihood ratio test). Pretransplantation ST2 levels also were prognostic of 1-year all-cause mortality (adjusted OR per 10-ng/mL increase, 1.23; 95% CI, 1.02 to 1.48; P = .03), but not of relapse (P = .47) or acute GvHD (P = .81). Plasma ST2 levels at day +7 were prognostic of 1-year NRM, all-cause mortality, relapse, and acute GVHD, whereas levels at day +14 were prognostic of 1-year NRM and all-cause mortality. Our results show that pretransplantation plasma ST2 levels added prognostic information about 1-year NRM to age, HCT-CI, and conditioning intensity, and suggest that ST2 has potential as a biomarker of pretransplantation vulnerability and should be considered in future developments of prediction models of NRM after allogeneic HCT.

Pulmonary function is a strong predictor of 2-year overall survival and non-relapse mortality after allogenic hematopoietic cell transplantation.

OBJECTIVES: The purpose of the study was to assess the validity of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and of pulmonary comorbidity prior to HCT in terms of predicting non-relapse mortality (NRM) and overall survival (OS). METHODS: In this retrospective single-center study of 663 consecutive adult recipients of HCT, we stratified patients into groups by pulmonary comorbidity: low-risk, intermediate-risk, and high-risk. The predictive value of this pulmonary comorbidity score (PCS) was compared to HCT-CI. RESULTS: In univariate analysis, the HCT-CI and the PCS were associated with OS after transplantation when comparing patients in high-risk groups with patients in low-risk groups. Using the PCS, the hazard ratios (HRs) of the 2-year OS in the entire population and in the myeloablative conditioning (MAC) group were 1.98 (p < .001) and 3.27 (p < .001), respectively, whereas the HRs using the HCT-CI were 1.83 (p < .001) and 2.57 (p = .002). The 2-year NRM incidence in the three risk-groups in the entire population was significant using both indexes. In the MAC group, the 2-year NRM was significant using the PCS (p = .003), but not using the HCT-CI (p = .23). CONCLUSIONS: Our study suggest that pulmonary function alone is a strong predictor of 2-year OS and NRM after HCT.

Pre-transplantation vitamin E levels and acute graft-versus-host disease after non-myeloablative allogeneic hematopoietic cell transplantation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Improved survival after allogeneic transplantation for acute lymphoblastic leukemia in adults: a Danish population-based study.

We investigated trends of survival in a population-based cohort study of all 181 adults who received HCT for ALL in Denmark between 2000-2019. Patients had a median (min-max) age of 36 (18-74) years at HCT and were followed for a median of eight years. Overall survival (OS) improved over time with an estimated 2-year OS of 49% (CI 27-66%) in year 2000 versus 77% (CI 59-88%) in year 2019. More patients achieved cure over time (OR for cure per year 1.07, CI 1.00-1.15), while the rate of death in non-cured patients remained stable (HR of excess mortality per year 0.99, CI 0.93-1.06). Relapse decreased over time (HR 0.92 per year, CI 0.87-0.98), whereas non-relapse mortality did not change notably (HR 0.98 per year, CI 0.93-1.04). In conclusion, survival after HCT in adults with ALL has improved over the past two decades, primarily due to more patients achieving cure.

Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelomonocytic Leukemia: Clinical and Molecular Genetic Prognostic Factors in a Nordic Population.

Chronic myelomonocytic leukemia (CMML) is an aggressive disease in which survival after allogeneic hematopoietic stem cell transplantation (HCT) remains relatively poor. An assessment of prognostic factors is an important part of treatment decision making and has the potential to be greatly improved by the inclusion of molecular genetics. However, there is a significant knowledge gap in the interpretation of mutational patterns. This study aimed to describe outcomes of allogeneic HCT in patients with CMML in relation to clinical and molecular genetic risk factors. This retrospective study included 64 patients with CMML who underwent allogeneic HCT between 2008 and 2018, with a median follow-up of 5.4 years. Next-generation sequencing using targeted myeloid panels was carried out on saved material from 51 patients from the time of transplantation. Kaplan-Meier and Cox regression were used for analysis of overall survival (OS), and cumulative incidence with competing risks and Fine and Gray models were used for analysis of relapse and nonrelapse mortality (NRM). Mutations were detected in 48 patients (94%), indicating high levels of minimal residual disease (MRD) positivity at transplantation, even among those in complete remission (CR) (n = 14), 86% of whom had detectable mutations. The most frequently mutated genes were ASXL1 (37%), TET2 (37%), RUNX1 (33%), SRSF2 (26%), and NRAS (20%). Risk stratification using the CMML-specific Prognostic Scoring System molecular score (CPSS-Mol) resulted in 45% of patients moving to a higher risk-group compared with risk stratification using the CPSS. High leucocyte count (≥13 × 109/L), transfusion requirement, and previous intensive chemotherapy were associated with higher incidence of relapse. Being in CR was not linked to better outcomes. Neither ASXL1 nor RUNX1 mutation was associated with a difference in OS, relapse, or NRM, despite being high risk in the nontransplantation setting. TET2 mutations were associated with a significantly higher 3-year OS (73% versus 40%; P = .039). Achieving MRD-negative CR was rare in this CMML cohort, which may explain why we did not observe better outcomes for those in CR. This merits further investigation. Our analyses suggest that the negative impact of ASXL1 and RUNX1 mutations can be overcome by allogeneic HCT; however, risk stratification is complex in CMML and requires larger cohorts and multivariate models, presenting an ongoing challenge in this rare disease.

Pre-transplantation plasma vitamin D levels and acute graft-versus-host disease after myeloablative hematopoietic cell transplantation in adults.

BACKGROUND: The association between vitamin D and acute graft-versus-host disease (GvHD) remains controversial, especially for patients receiving myeloablative conditioning. METHODS: We measured pre-transplantation plasma vitamin D (25-hydroxyvitamin D3 + D2) levels by competitive electrochemiluminescence in plasma samples from 116 adult patients who underwent a myeloablative allogeneic transplantation at Rigshospitalet, Copenhagen between July 2015 and August 2018. RESULTS: The median (Q1, Q3) pre-transplantation plasma vitamin D level was 64 (47, 85) nmol/L (normal range: 50-160 nmol/L). Vitamin D insufficiency (<50 nmol/L) and moderate deficiency (<25 nmol/L) were observed in 29% and 8% of patients, respectively. No patients had a severe deficiency (<12 nmol/L). Pre-transplantation vitamin D levels were slightly higher in patients who later developed grade II-IV acute GvHD (mean difference: 8.1 nmol/L), but the 95% confidence interval [CI] encompassed clinically insignificant differences (CI: -2.2, 19.2 nmol/L). From multivariable logistic regression, we found that a patient with a pre-transplantation vitamin D level of 85 nmol/L (Q3) had 1.5 times higher odds of grade II-IV acute GvHD than a patient with a level of 47 nmol/L (Q1; CI of odds ratio: 0.84, 2.7; adjusted for patient age, donor type, use of anti-thymocyte globulin, and use of 12 Gy total-body irradiation). Patients with pre-transplantation vitamin D insufficiency (N = 34) had a cumulative incidence of grade II-IV acute GvHD similar to that of patients with vitamin D sufficiency (26% [CI: 11%, 42%] versus 35% [CI: 25%, 46%], respectively). CONCLUSIONS: Our data did not support an association between pre-transplantation vitamin D levels or vitamin D insufficiency and acute GvHD in adult patients receiving myeloablative conditioning.

Functional immune reconstitution early after allogeneic haematopoietic cell transplantation: A comparison of pre- and post-transplantation cytokine responses in stimulated whole blood.

We aimed to use a novel standardized whole-blood stimulation system to evaluate differences in the functional immune reconstitution in patients early after allogeneic haematopoietic cell transplantation (HCT). Between April and September 2018, 30 patients undergoing HCT had whole blood samples collected around day -21 (day 0 being the day of haematopoietic cell infusion) and day +28. Whole blood was transferred to TruCulture assays comprising prefilled incubation tubes with cell culture medium and a standardized stimulus. We used a panel of four stimuli (lipopolysaccharide, resiquimod, heat-killed Candida albicans and polyinosinic:polycytidylic acid) and a blank, designed to evaluate the function of critical extra- and intracellular immunological signalling pathways. For each stimulus, the cytokine response was assessed by the concentration of interferon-γ, interleukin (IL)-12p40, IL-10, IL-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-17A and tumour necrosis factor-α using a multiplex Luminex assay. Pre-HCT cytokine responses were globally decreased across several different stimuli. Despite patients receiving immunosuppressive prophylaxis at the time, post-HCT cytokine responses were higher and less intercorrelated than pre-HCT responses, also after adjusting for differences in the leukocyte differential counts. For the resiquimod and heat-killed Candida albicans stimuli, we identified a cluster of patients in whom post-HCT responses were lower than average across several cytokines, indicating a possible functional immune deficiency. Our findings suggest that the standardized whole blood stimulation system can be used to reveal heterogeneity in the in vitro cytokine responses to various stimuli after HCT. Larger studies are needed to address if the functional immune reconstitution after HCT can predict the risk of infections.

Vitamin E and acute graft-versus-host disease after myeloablative allogeneic hematopoietic cell transplantation.

OBJECTIVES: Vitamin E has antioxidant and immunomodulatory effects that might influence the development of acute graft-versus-host disease (GvHD). We investigated the association between plasma vitamin E levels and acute GvHD. METHODS: We studied 115 adults who underwent myeloablative allogeneic hematopoietic cell transplantation between July 2015 and August 2018. Vitamin E was measured by high-performance liquid chromatography in stored plasma samples obtained pre-transplantation at day -23 (±15 days) and post-transplantation at day +28 (±3 days). RESULTS: Pre-transplantation vitamin E levels were inversely associated with grade II-IV acute GvHD (hazard ratio 0.68 per 10 µmol/L increase, 95% confidence interval [CI]: 0.47-0.98). The association remained after adjustment for known prognostic factors for acute GvHD. Patients with levels below the median had a cumulative incidence of grade II-IV acute GvHD of 46% (CI: 33-59%) versus 21% (CI: 10-32%) in patients with levels above the median. No clear association with non-relapse mortality, relapse, or chronic GvHD was found. Post-transplantation vitamin E levels (measured in 72 [63%] patients) were correlated with pre-transplantation levels (ρ = .31) but were not associated with subsequent grade II-IV acute GvHD. CONCLUSIONS: High pre-transplantation vitamin E levels were associated with less acute GvHD.

Improved Relapse-Free Survival in Patients With High Natural Killer Cell Doses in Grafts and During Early Immune Reconstitution After Allogeneic Stem Cell Transplantation.

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 × 106/kg had significantly increased relapse-free-survival compared to patients transplanted with lower doses, HR 2.12 (95% CI 1.01-4.45, p = 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, p = 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, p = 0.02, and ρ = 0.35, p = 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], p = 0.01, and HR 4.19 [95% CI 1.68-10.4], p = 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), p = 0.04, and 7% (95% CI 1.8-18) vs. 26% (95% CI 14-40) %, p = 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.

Improved Outcomes after Allogenic Hematopoietic Stem Cell Transplantation with Fludarabine/Treosulfan for Patients with Myelodysplastic Syndromes.

While allogeneic hematopoietic stem cell transplantation (allo-HCT) currently offers the only curative option for patients with myelodysplastic syndrome (MDS), there is still a high risk of relapse or transplant-related complications. We collected data on all patients who had undergone allo-HCT at our center (Copenhagen University Hospital) between 2000 and 2018. In total, 215 patients with MDS (n = 196) or chronic myelomonocytic leukemia (n = 19) were included. Estimated 1-year overall survival (OS) was 70.3% (95% confidence interval [CI], 64.2% to 77.0%), and the median survival was 7.7 years (95% CI, 4.7 to indeterminable). There was a significant improvement in OS over time (P = .011, comparing 2000 to 2010, 2010 to 2014, and 2014 to 2018). Treatment was standardized throughout the study period, allowing comparison between patients receiving nonmyeloablative (NMA, n = 124), standard myeloablative (SMA, n = 36), and fludarabine and treosulfan (FluTreo, n = 55) conditioning. FluTreo has myeloablative properties but lower toxicity and replaced standard myeloablative conditioning at our center in 2014. The FluTreo group was significantly older and had more comorbidities than the SMA group but similar disease severity. One-year OS was 84.0% (95% CI, 74.3% to 94.9%), 58.3% (95% CI, 44.3% to 76.9%), and 68.3% (95% CI, 60.2% to 77.5%) for FluTreo, SMA, and NMA, respectively (P = .04). In univariate analysis, Revised International Scoring System (IPSS-R) (high versus low), donor sex mismatch, and cytomegalovirus status mismatch were significant factors for OS. In multivariate analysis of OS including age, IPSS-R, and HCT specific comorbidity index, NMA was borderline inferior to FluTreo (P = .073) while SMA was significantly inferior to FluTreo with a hazard ratio of 6.89 (95% CI, 2.53 to 18.77, P < .001). The introduction of FluTreo allowed us to administer a myeloablative regimen to a broader patient group and shows promising results.

Role of Age and Hematopoietic Cell Transplantation-Specific Comorbidity Index in Myelodysplastic Patients Undergoing an Allotransplant: A Retrospective Study from the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative option for myelodysplastic syndromes (MDSs) but is severely limited by nonrelapse mortality (NRM), especially in this mostly older population. Comorbidity assessment is crucial to predict NRM and often assessed with the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). Moreover, the impact of age on NRM still remains a matter of debate. In recent years, the age at which transplants are made has been progressively increasing, and patients with comorbidities have become more common. Extricating the respective roles of age and comorbidities in toxic mortality is all the more important. This study by the European Group for Blood and Marrow Transplantation registry included 1245 adult patients who underwent a first allogeneic stem cell transplantation for MDSs between 2003 and 2014. Overall, 4-year NRM and overall survival were 32% and 47%, respectively. When considered as continuous predictors, HCT-CI score and age were associated with an increased hazard ratio (HR) for NRM. In multivariate analysis, age band (HR, 1.13; 95% CI, 1.02 to 1.25; P= .016), HCT-CI ≥3 (HR, 1.34; 95% CI, 1.04 to 1.73; P = .022), and Karnofsky Performance Status ≤80 (HR, 2.03; 95% CI, 1.52 to 2.73; P< .0001) were significantly predictive of a worse NRM. In our large cohort, both comorbidities, evaluated by the original HCT-CI score, and chronological age significantly affected NRM. Thus, age should be part of the transplant decision-making process and should be integrated in future scoring systems predicting outcomes of HSCT in MDSs.

Rehabilitation during intensive treatment of acute leukaemia including allogenic stem cell transplantation: a qualitative study of patient experiences.

OBJECTIVES: The diagnosis and treatment of acute leukaemia (AL) affect physical, psychosocial and existential functioning. Long-lasting treatment periods with impaired immune system, hygienic and social restrictions challenge patient well-being and rehabilitation as compared with other individuals with cancer. This study elucidates how AL patients, treated with curative intent in an outpatient setting, assess their physical, psychosocial and existential capability during and following treatment, and furthermore reports on the health initiatives offered to support their rehabilitation. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: We conducted qualitative, semi-structured individual interviews with 16 AL patients, 6 months after end of treatment in the patients' homes. This was the final interview, in a line of three, carried out as part of a larger qualitative study. RESULTS: The data were analysed thematically through an inductive ongoing process consisting of four steps. The final step, selective coding, resulted in the three categories: physical activity, mental well-being and social activity. None of the patients were satisfied with their physical capability at the time of interview and experienced substantial impairment of functional capabilities. All patients struggled with anxiety and expressed a need for continuous progress in treatment and well-being to feel safe. It took an unexpected large effort to regain a meaningful social life, and patients still had to prioritise activities. CONCLUSIONS: AL patients suffered physically, psychologically and existentially throughout their illness trajectory. Rehabilitation initiatives deriving from the healthcare system and municipalities held room for improvement. Future programmes should pay attention to the contextual changes of treatment of this patient group and individuals' changing needs and motivation of physical exercise.

Improved Overall Survival, Relapse-Free-Survival, and Less Graft-vs.-Host-Disease in Patients With High Immune Reconstitution of TCR Gamma Delta Cells 2 Months After Allogeneic Stem Cell Transplantation.

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 TCRαß, 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) × 106 cells/L 56 days after transplantation had significantly improved overall survival (p = 0.001) and relapse-free survival (p = 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 (p = 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 × 106 cells/L compared to patients with low concentrations (p = 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.