Observational studies have suggested that physical activity may be associated with improved survival after cancer treatment. However, data from controlled clinical trials are required. We analyzed ...survival data of 103 patients from a previously published randomized controlled trial in allogeneic stem cell transplant patients who were randomized to either an exercise intervention (EX) or to a social contact control group. EX patients trained prior to hospital admission, during inpatient treatment, and for 6–8 weeks after discharge. Survival analyses were used to compare both total mortality (TM) and non‐relapse mortality (NRM) after discharge and transplantation during an observation period of 2 years after transplantation. Analyses were corroborated with Cox and Fine & Gray regression models adjusting for potential confounders. After discharge, EX patients had a significantly lower TM rate than controls (12.0 vs. 28.3%, p = 0.030) and a numerically lower NRM rate (4.0 vs. 13.5%, p = 0.086). When the inpatient period was included, absolute risk reductions were similar but not significantly different (TM: 34.0 vs. 50.9%, p = 0.112; NRM: 26.0 vs. 36.5%, p = 0.293). The number needed to treat (NNT) to prevent one death with EX was about 6. Furthermore, regression analyses revealed that baseline fitness was protective against mortality. The data suggest that exercise might improve survival in patients undergoing allo‐HCT. However, the results should be interpreted with caution as the study was not designed to detect differences in survival rates, and as no stratification on relevant prognostic factors was carried out.
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Exercise can benefit cancer patients by improving quality of life, but it may also prolong survival after cancer treatment, according to observational data. The present study lends clinical evidence to that idea, using a randomized controlled trial to investigate outcomes among exercising patients undergoing allogeneic stem cell transplantation. Exercising patients showed reductions in total mortality and non‐relapse mortality rates over a two‐year observation period following transplantation. Baseline physical fitness offered significant protection against mortality. The results are of major clinical relevance and should encourage oncologists and hematologists to promote exercise in this patient group.
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.
To validate current donor selection strategies based on previous international studies, we retrospectively analyzed 2646 transplantations performed for hematologic malignancies in 28 German ...transplant centers. Donors and recipients were high resolution typed for HLA-A, -B, -C, -DRB1, and -DQB1. The highest mortality in overall survival analysis was seen for HLA-A, -B, and DRB1 mismatches. HLA-DQB1 mismatched cases showed a trend toward higher mortality, mostly due to HLA-DQB1 antigen disparities. HLA incompatibilities at >1 locus showed additive detrimental effects. HLA mismatching had no significant effect on relapse incidence and primary graft failure. Graft source had no impact on survival end points, neither in univariate nor in multivariate analysis. Higher patient age, advanced disease, transplantations before 2004, patient C2C2 killer cell immunoglobulin-like receptor (KIR)-ligand phenotype, and unavailability of a national donor adversely influenced outcomes in multivariate analysis. Our study confirms the association of HLA-A, -B, -C, and -DRB1 incompatibilities with adverse outcome in hematopoietic stem cell transplantation (HSCT). The relevance of HLA-DQB1 disparities in single mismatched transplantations remains unclear. Similar hazard ratios for allele and antigen mismatches (possibly with an exception for HLA-DQB1) highlight the importance of allele level typing and matching in HSCT. The number of incompatibilities and their type significantly impact survival.
•HLA mismatches at the allele and antigen level (possibly with the exception of HLA-DQB1) should be treated equally in donor selection.•HLA mismatches at >1 locus (including HLA-DQB1) have additive detrimental effects.
We analyzed the prognostic impact of donor and recipient cytomegalovirus (CMV) serostatus in 16 628 de novo acute leukemia patients after allogeneic stem cell transplantation (allo-SCT). Compared ...with CMV-seronegative recipients who underwent allograft from a CMV-seronegative donor, cases of CMV seropositivity of the donor and/or the recipient showed a significantly decreased 2-year leukemia-free survival (44% vs 49%, P < .001) and overall survival (50% vs 56%, P < .001), and increased nonrelapse mortality (23% vs 20%, P < .001). Both groups showed a comparable relapse incidence and 2-year probability of graft-versus-host disease. The negative prognostic effects of CMV seropositivity of the donor and/or the recipient (vs CMV seronegativity of both) were significantly stronger for acute lymphoblastic leukemia (ALL) than for acute myeloid leukemia (AML), resulting in a markedly reduced 2-year overall survival (46% vs 55% for ALL compared with 52% vs 56% for AML). The important prognostic impact of donor/recipient CMV serostatus remained in a multivariate Cox regression analysis including the other prognostic variables. We conclude that donor and/or recipient CMV seropositivity is still associated with an adverse prognosis in de novo acute leukemia patients after allo-SCT despite the implementation of sophisticated strategies for prophylaxis, monitoring, and (preemptive) treatment of CMV.
•Donor and/or recipient CMV seropositivity is still associated with an adverse prognosis in de novo acute leukemia patients after allo-SCT.
Summary Background Routine prophylactic platelet transfusion is the standard of care for patients with severe thrombocytopenia. We assessed the effect of a new strategy of therapeutic platelet ...transfusion on the number of transfusions and safety in patients with hypoproliferative thrombocytopenia. Methods We did a multicentre, open-label, randomised parallel-group trial at eight haematology centres in Germany. Patients aged 16–80 years, who were undergoing intensive chemotherapy for acute myeloid leukaemia or autologous haemopoietic stem-cell transplantation for haematological cancers, were randomly assigned via a computer-generated randomisation sequence to receive either platelet transfusion when bleeding occurred (therapeutic strategy) or when morning platelet counts were 10×109 per L or lower (prophylactic strategy). Investigators undertaking interventions were not masked to group assignment. The primary endpoint was the number of platelet transfusions. Analysis was by intention to treat. This trial is registered, NCT00521664. Findings 197 patients were assigned the prophylactic strategy and 199 the therapeutic strategy. Of 391 patients analysed, the therapeutic strategy reduced the mean number of platelet transfusions by 33·5% (95% CI 22·2–43·1; p<0·0001) in all patients (2·44 2·22–2·67 in prophylactic group vs 1·63 1·42–1·83 in therapeutic group), 31·6% (18·6–42·6; p<0·0001) in those with acute myeloid leukaemia (2·68 2·35–3·01 vs 1·83 1·58–2·10), and 34·2% (6·6–53·7; p=0·0193) in those who had had autologous transplantation (1·80 1·45–2·15 vs 1·18 0·82–1·55. We noted no increased risk of major haemorrhage in patients who had undergone autologous transplantation. In those with acute myeloid leukaemia, risk of non-fatal grade 4 (mostly CNS) bleeding was increased. We recorded 15 cases of non-fatal haemorrhage: four retinal in each transfusion group, and one vaginal and six cerebral in the therapeutic group. 12 patients died in the study: two from fatal cerebral haemorrhages in the therapeutic group, and ten (five in each treatment group) unrelated to major bleeding. Interpretation The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia. The new strategy should be used by some haematology centres only if the staff are well educated and experienced in the new approach and can react in a timely way to first signs of CNS bleeding. Funding Deutsche Krebshilfe eV (German Cancer Aid).
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.
To evaluate the role of a second allogeneic hematopoietic stem-cell transplantation (HSCT2) given for relapsed acute leukemia (AL) after related or unrelated first hematopoietic stem-cell ...transplantation (HSCT1) and to analyze the role of donor change for HSCT2 in both settings.
We performed a retrospective registry study on 179 HSCT2s given for relapse after HSCT1 from matched related donors (n = 75) or unrelated donors (n = 104), using identical or alternative donors for HSCT2. Separate analyses were performed according to donor at HSCT1.
Independent of donor, 74% of patients achieved complete remission after HSCT2, and half of these patients experienced relapse again. Overall survival (OS) at 2 years was 25% ± 4% (39% ± 7% after related HSCT2; 19% ± 4% after unrelated HSCT2). Long-term survivors were observed even after two unrelated HSCT2s. Multivariate analysis for OS from HSCT2 confirmed established risk factors (remission duration after HSCT1: hazard ratio HR, 2.37; 95% CI, 1.61 to 3.46; P < .001; stage at HSCT2: HR, 0.53; 95% CI, 0.34 to 0.83; P = .006). Outcome of HSCT2 was better after related HSCT1 than after unrelated HSCT1 (2-year OS: 37% ± 6% v 16% ± 4%, respectively; HR, 0.68; 95% CI, 0.47 to 0.98; P = .042, multivariate Cox regression). After both related and unrelated HSCT1, selecting a new donor for HSCT2 did not result in a relevant improvement in OS compared with HSCT2 from the original donor; however, donor change was not detrimental either.
After relapse from allogeneic HSCT1, HSCT2 can induce 2-year OS in approximately 25% of patients. Unrelated HSCT2 is feasible after related and unrelated HSCT1. Donor change for HSCT2 is a valid option. However, a clear advantage in terms of OS could not be demonstrated.
Reduced intensity conditioning regimen (RIC) is increasingly used in hematopoietic stem cell transplantation (HSCT). Unrelated donor (UD) transplants have more complications. We wanted to examine if ...RIC is a valid treatment option using UD in acute myeloblastic leukemia (AML).
Between 1999 and 2005, 401 patients with AML were treated with RIC and 1,154 received myeloablative conditioning (MAC), using UD and reported to the European Group for Blood and Marrow Transplantation Registry. Patients < and > or = 50 years of age were analyzed separately.
Patients receiving RIC were older, received transplants more recently, received peripheral blood stem cells more frequently, and were treated with total-body irradiation less often. In multivariable analysis, in patients younger than 50 years of age, nonrelapse mortality (NRM) was similar using RIC (hazard ratio HR, 0.85; P = .41), relapse was increased (HR, 1.46; P = .02) and leukemia-free survival (LFS) was the same (HR, 0.88; P = .28), as compared with MAC. In patients > or = 50 years of age, NRM was decreased in the RIC group (HR, 0.64; P = .04), relapse probability was not significantly different (HR, 1.34; P = .16) and LFS was similar (HR, 1.04; P = .79) compared with MAC. CONCLUSION RIC-UD transplants are associated with higher relapse in AML patients younger than 50 years of age and decreased NRM in those > or = 50 years compared with MAC-UD. LFS was similar after both conditioning regimens, regardless of age. Therefore, RIC-UD extend the use of allotransplants for elderly patients and strategies that decrease relapse should be considered mainly in younger patients with AML.
Summary Background Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins ...(ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F). Methods Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III–IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343. Findings The number of patients in the ATG-F group who had severe aGVHD grade III–IV or who died within 100 days of transplantation was 12 and 10 (21·4%, 95% CI 13·4–29·3), respectively, compared with 24 and nine (33·7%, 24·3–43·0) patients, respectively, in the control group (adjusted odds ratio 0·59, 95% CI 0·30–1·17; p=0·13). The cumulative incidence of aGVHD grade III–IV was 11·7% (95% CI 6·8–19·8) in the ATG-F group versus 24·5% (17·3–34·7) in the control group (adjusted hazard ratio HR 0·50, 95% CI 0·25–1·01; p=0·054), and cumulative incidence of aGVHD grade II–IV was 33·0% (n=34; 95% CI 25·1–43·5) in the ATG-F group versus 51·0% (n=50; 95% CI 42·0–61·9) in the control group (adjusted HR 0·56, 0·36–0·87; p=0·011). The 2-year cumulative incidence of extensive chronic GVHD was 12·2% (n=11; 95% CI 7·0–21·3) versus 42·6% (n=34; 95% CI 33·0–55·0; adjusted HR 0·22, 0·11–0·43; p<0·0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes. Interpretation The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors. Funding Fresenius Biotech GmbH.
Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with ...t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio HR = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.
