Allogeneic hematopoietic stem cell transplantation (alloSCT) carries the promise of cure for many malignant and non-malignant diseases of the lympho-hematopoietic system. Although outcome has ...improved considerably since the pioneering Seattle achievements more than 5 decades ago, non-relapse mortality (NRM) remains a major burden of alloSCT. There is increasing evidence that endothelial dysfunction is involved in many of the life-threatening complications of alloSCT, such as sinusoidal obstruction syndrome/venoocclusive disease, transplant-associated thrombotic microangiopathy, and refractory acute graft-versus host disease. This review delineates the role of the endothelium in severe complications after alloSCT and describes the current status of search for biomarkers predicting endothelial complications, including markers of endothelial vulnerability and markers of endothelial injury. Finally, implications of our current understanding of transplant-associated endothelial pathology for prevention and management of complications after alloSCT are discussed.
Purpose To compare the outcome of patients with Hodgkin lymphoma who received post-transplantation cyclophosphamide-based haploidentical (HAPLO) allogeneic hematopoietic cell transplantation with the ...outcome of patients who received conventional HLA-matched sibling donor (SIB) and HLA-matched unrelated donor (MUD). Patients and Methods We retrospectively evaluated 709 adult patients with Hodgkin lymphoma who were registered in the European Society for Blood and Marrow Transplantation database who received HAPLO (n = 98), SIB (n = 338), or MUD (n = 273) transplantation. Results Median follow-up of survivors was 29 months. No differences were observed between groups in the incidence of acute graft-versus-host disease (GVHD). HAPLO was associated with a lower risk of chronic GVHD (26%) compared with MUD (41%; P = .04). Cumulative incidence of nonrelapse mortality at 1 year was 17%, 13%, and 21% in HAPLO, SIB, and MUD, respectively, and corresponding 2-year cumulative incidence of relapse or progression was 39%, 49%, and 32%, respectively. On multivariable analysis, relative to SIB, nonrelapse mortality was similar in HAPLO ( P = .26) and higher in MUD ( P = .003), and risk of relapse was lower in both HAPLO ( P = .047) and MUD ( P < .001). Two-year overall survival and progression-free survival were 67% and 43% for HAPLO, 71% and 38% for SIB, and 62% and 45% for MUD, respectively. There were no significant differences in overall survival or progression-free survival between HAPLO and SIB or MUD. The rate of the composite end point of extensive chronic GVHD and relapse-free survival was significantly better for HAPLO (40%) compared with SIB (28%; P = .049) and similar to MUD (38%; P = .59). Conclusion Post-transplantation cyclophosphamide-based HAPLO transplantation results in similar survival outcomes compared with SIB and MUD, which confirms its suitability when no conventional donor is available. Our results also suggest that HAPLO results in a lower risk of chronic GVHD than MUD transplantation.
Before, during, and after allogeneic hematopoietic stem cell transplantation (allo-HSCT), patients experience considerable physical and psychologic distress. Besides graft-versus-host disease and ...infections, reduced physical performance and high levels of fatigue affect patients' quality of life. This multicenter randomized controlled trial examined the effects of a partly self-administered exercise intervention before, during, and after allo-HSCT on these side effects. After randomization to an exercise and a social contact control group 105 patients trained in a home-based setting before hospital admission, during inpatient treatment and a 6- to 8-week period after discharge. Fatigue, physical performance, quality of life, and physical/psychologic distress were measured by standardized instruments at baseline, admission to, and discharge from hospital and 6 to 8 weeks after discharge. The exercise group showed significantly improvement in fatigue scores (up to 15% improvement in exercise group vs up to 28% deterioration in control; P < .01-.03), physical fitness/functioning (P = .02-.03) and global distress (P = .03). All effects were at least detectable at one assessment time point after hospitalization or repeatedly. Physical fitness correlated significantly with all reported symptoms/variables. In conclusion, this partly supervised exercise intervention is beneficial for patients undergoing allo-HSCT. Because of low personnel requirements, it might be valuable to integrate such a program into standard medical care.
No biomarker panel is established for prediction of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), a major complication of allogeneic stem cell transplantation (alloSCT). We ...compared the potential of the Endothelial Activation and Stress Index (EASIX), based on lactate dehydrogenase, creatinine, and thrombocytes, with that of the SOS/VOD CIBMTR clinical risk score to predict SOS/VOD in two independent cohorts. In a third cohort, we studied the impact of endothelium-active prophylaxis with pravastatin and ursodeoxycholic acid (UDA) on SOS/VOD risk. The cumulative incidence of SOS/VOD within 28 days after alloSCT in the training cohort (Berlin, 2013-2015, n=446) and in the validation cohort (Heidelberg, 2002-2009, n=380) was 9.6% and 8.4%, respectively. In both cohorts, EASIX assessed at the day of alloSCT (EASIX-d0) was significantly associated with SOS/VOD incidence (p<0.0001), overall survival (OS) and non-relapse mortality (NRM). In contrast, the CIBMTR score showed no statistically significant association with SOS/VOD incidence, and did not predict OS and NRM. In patients receiving pravastatin/UDA, the cumulative incidence of SOS/VOD was significantly lower at 1.7% (p<0.0001, Heidelberg, 2010-2015, n=359) than in the two cohorts not receiving pravastatin/UDA. The protective effect was most pronounced in patients with high EASIX-d0. The cumulative SOS/VOD incidence in the highest EASIX-d0 quartiles were 18.1% and 16.8% in both cohorts without endothelial prophylaxis as compared to 2.2% in patients with pravastatin/UDA prophylaxis (p<0.0001). EASIX-d0 is the first validated biomarker for defining a subpopulation of alloSCT recipients at high risk for SOS/VOD. Statin/UDA endothelial prophylaxis could constitute a prophylactic measure for patients at increased SOS/VOD risk.
Summary Background Reduced-intensity conditioning regimens have been developed to minimise early toxic effects and deaths after allogeneic haemopoietic cell transplantation. However, the efficacy of ...these regimens before this procedure has not been investigated in a randomised trial. In this prospective, open-label randomised phase 3 trial we compared a reduced-intensity fludarabine-based conditioning regimen with a standard regimen in patients with acute myeloid leukaemia in first complete remission. Methods Patients were aged 18–60 years and had intermediate-risk or high-risk acute myeloid leukaemia (defined by cytogenetics) in first complete remission; an available HLA-matched sibling donor or an unrelated donor with at least nine of ten HLA alleles; and adequate renal, cardiac, pulmonary, and neurological function. Between Nov 15, 2004, and Dec 31, 2009, patients were randomly assigned (1:1, by a computer-based minimisation procedure that balanced patients for age, cytogenetic risk, induction therapy, and donor type) to receive either reduced-intensity conditioning of four doses of 2 Gy of total-body irradiation and 150 mg/m2 fludarabine or standard conditioning of six doses of 2 Gy of total-body irradiation and 120 mg/kg cyclophosphamide. All patients were given ciclosporin and methotrexate as prophylaxis against graft-versus-host disease. Neither investigators nor patients were blinded to study treatment. Our primary endpoint was the incidence of non-relapse mortality, analysed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , number NCT00150878. Findings The trial was stopped early on Dec 31, 2009, because of slow accrual of patients. 99 patients were randomly assigned to receive reduced-intensity conditioning and 96 to receive standard conditioning. The incidence of non-relapse mortality did not differ between the reduced-intensity and standard conditioning groups (cumulative incidence at 3 years 13% 95% CI 6–21 vs 18% 10–26; HR 0·62 95% CI 0·30–1·31). Relapse incidence (cumulative incidence 3 years 28% 95% CI 19–38 vs 26% 17–36; HR 1·10 95% CI 0·63–1·90), disease-free survival (3 year disease-free survival 58% 95% CI 49–70 vs 56% 46–67; HR 0·85 95% CI 0·55–1·32), and overall survival (3 year overall survival 61% 95% CI 50–74 vs 58% 47–70; HR 0·77 95% CI 0·48–1·25) did not differ significantly between groups. Grade 3–4 of oral mucositis was less common in the reduced-intensity group than in the standard conditioning group (50 patients in the reduced-intensity conditioning group vs 73 patients in the standard conditioning group); the frequency of other side-effects such as graft-versus-host disease and increased concentrations of bilirubin and creatinine did not differ significantly between groups. Interpretation Reduced-intensity conditioning results in a similar incidence of non-relapse mortality and reduced toxic effects compared with standard conditioning without affecting survival outcomes, and thus could be preferentially used in patients younger than 60 years with acute myeloid leukaemia transplanted in first complete remission. Funding Medical Faculty of Dresden University.
Morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). We evaluated 80 seropositive patients ...transplanted consecutively between March 2018 and March 2019 who received letermovir (LET) prophylaxis from engraftment until day +100 and retrospectively compared them with 80 patients without LET allografted between January 2017 and March 2018. The primary endpoint of this study was the cumulative incidence (CI) of clinically significant CMV infection (CS-CMVi) defined as CMV reactivation demanding preemptive treatment or CMV disease. With 14% CI of CS-CMVi at day +100 (11 events) was significantly lower in the LET cohort when compared to the control group (33 events, 41%; HR 0.29;
p
< 0.001). Whereas therapy with foscarnet could be completely avoided in the LET group, 7 out of 80 patients in the control cohort received foscarnet, resulting in 151 extra in-patient days for foscarnet administration (
p
= 0.002). One-year overall survival was 72% in the control arm vs 84% in the LET arm (HR 0.75 95%CI 0.43–1.30;
p
< 0.306). This study confirms efficacy and safety of LET for prophylaxis of CS-CMVi after alloHCT in a real-world setting, resulting in a significant patient benefit by reducing hospitalization needs and exposure to potentially toxic antiviral drugs for treatment of CMV reactivation.
The aim of this project was to define indications for hematopoietic stem cell transplantation in follicular lymphoma in Europe. In the absence of evidence-based data, a RAND-modified Delphi procedure ...was used by an expert panel. After pre-defining statements, these were individually/anonymously scored by each participant using a 9-point scale. Consensus was reached that: 1) high-dose therapy with autologous stem cell rescue is not an appropriate option to consolidate first remission in patients responding to immuno-chemotherapy outside clinical trials; 2) in patients with first chemo-sensitive relapse, high-dose therapy with autologous stem cell rescue is an appropriate option to consolidate remission, especially in patients with a short response after immuno-chemotherapy or with high-risk FLIPI; 3) high-dose therapy with autologous stem cell rescue is also appropriate in second/subsequent chemo-sensitive relapses; 4) allotransplant (preferably a reduced intensity conditioning-allotransplant) should be considered at relapse after high-dose therapy with autologous stem cell rescue. No consensus was reached on the role of high-dose therapy with autologous stem cell rescue in low-risk first relapse, or on when an allotransplant should be preferred over high-dose therapy with autologous stem cell rescue. In the absence of evidence-based data, the consensus method used was a valuable tool to define indications for hematopoietic stem cell transplant in follicular lymphoma.
Physical capacity prior allogeneic stem cell transplantation (allo-HCT) has been shown as a relevant prognostic factor for survival after transplant. Therefore, we evaluated feasibility and ...preliminary efficacy of a high-intensity interval training (HIIT) and moderate to high-intensity resistance exercise (RE) to increase physical capacity in patient's prior allo-HCT. In this multicentre single arm pilot study, a supervised exercise program was performed twice weekly for 4-12 weeks prior allo-HCT, depending on the individual time remaining. Outcomes were feasibility (recruitment, adherence, safety), physical capacity (cardiorespiratory fitness VO2peak, muscle strength) and patient reported outcomes (physical functioning, fatigue). Thirty patients were intended, 16 could be included, and 14 completed post intervention assessment (75% male, 55 ± 11 years). The study was stopped early due to a low recruitment rate. Nine patients (64%) reached the initial minimum planned number of eight exercise sessions. Individual adherence was high with 92% for HIIT and 85% for RE. 87% of all performed exercise sessions were completed without complaints and VO2peak increased significantly from 20.4 to 23.4 ml/kg/min. The low recruitment rate suggests that initiation of the intervention concept immediately before allo-HCT is feasible only in a small number of patients. In particular, the timeframe directly prior allo-HCT seems too short for exercise interventions, although the exercise program was designed to improve outcomes in a very short time frame. HIIT and RE were feasible, effective and well accepted by the included patients.
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