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[Effects of chemotherapy combined with donor lymphocyte infusion on chronic graft-versus-host disease and prognosis in minimal residual disease positive patients after allogeneic hematopoietic stem cell transplantation]
Shi, Y. X., Zhang, X. H., Xu, L. P., Wang, Y., Yan, C. H., Chen, H., Chen, Y. Y., Liu, K. Y., Huang, X. J., Mo, X. D.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2019;40(9):713-719
Abstract
Objective: To explore clinical features and severity of chronic graft- versus- host disease (cGVHD) after chemotherapy plus donor lymphocyte infusion (Chemo-DLI) in a consecutive cohort of acute leukemia patients who were minimal residual disease (MRD) positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: The global scoring system proposed by National Institutes of Health (NIH) Consensus Conference was used to identify the characteristics and severity of cGVHD in patients who MRD positive after Chemo-DLI. Results: 54 (59.3%) patients were diagnosed with cGVHD after Chemo-DLI, with the median time of onset of 70 (13-504) days. There were 6 cases (6.6%) of mild cGVHD, 21 cases (23.1%) of moderate cGVHD and 27 cases (29.7%) of severe cGVHD.The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9% (95%CI 45.3%-78.5%) , 15.1% (95%CI 1.1%-29.1%) , and 26.6% (95%CI 9.2%-44.0%) (chi(2)=18.901, P<0.001) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9% (95%CI 45.3%-78.5%) , 19.9% (95%CI 8.1%-31.7%) , and 28.6% (95%CI 0.0%-65.0%) (chi(2)=18.307, P<0.001) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. cGVHD was not associated with non-relapse morality after Chemo-DLI. Probabilities of 5-year leukemia-free survival (LFS) after Chemo-DLI were 24.0% (95%CI 9.1%-38.9%) , 77.2% (95%CI 60.8%-93.6%) , and 64.9% (95%CI 45.7%-84.1%) (chi(2)=24.447, P<0.001) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. Probabilities of 5-year LFS after Chemo-DLI were 24.0% (95%CI 9.1%-38.9%) , 75.5% (95%CI 62.7%-88.3%) , and 42.9% (95%CI 1.8%-84.0%) (chi(2)=25.665, P<0.001) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. Probabilities of 5-year overall survival (OS) after Chemo-DLI were 50.0% (95%CI 31.1%-68.9%) , 87.9% (95%CI 74.7%-100.0%) , and 71.0% (95%CI 52.0%-90.0%) (chi(2)=9.517, P=0.009) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. Probabilities of 5-year OS after Chemo-DLI were 50.0% (95%CI 31.1%-68.9%) , 83.9% (95%CI 72.8%-95.0%) , and 51.4% (95%CI 6.2%-96.6%) (chi(2)=10.673, P=0.005) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. In multivariate analysis, patients receiving allo-HSCT in first complete remission stage and classical cGVHD after Chemo-DLI were associated with lower relapse risk and better survival. Conclusions: These findings highlight the close relation between cGVHD and the graft-versus-leukemia effect in patients who were MRD positive and received Chemo-DLI after allo-HSCT. However, overlap syndrome could not improve the clinical outcomes of these patients.
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Impact of alemtuzumab pharmacokinetics on T-cell dynamics, graft-versus-host disease and viral reactivation in patients receiving allogeneic stem cell transplantation with an alemtuzumab-based T-cell-depleted graft
Loeff, F. C., van Egmond, E. H. M., Moes, Djar, Wijnands, C., Von Dem Borne, P. A., Veelken, H., Falkenburg, J. H. F., Jedema, I., Halkes, C. J. M.
Transplant immunology. 2019
Abstract
Administration of alemtuzumab (targeting the CD52 antigen) to the patient (in-vivo) or to the graft (in-vitro) before allogeneic stem cell transplantation (alloSCT) decreases the incidence of graft-versus-host disease (GvHD). Effectiveness of this treatment relies on depletion of donor T cells. Currently, no data are available on alemtuzumab pharmacokinetics and pharmacodynamics in patients who received combined in-vivo and in-vitro alemtuzumab-based T-cell depletion. In this prospective study, we analyzed alemtuzumab pharmacokinetics and its effect on the circulating T cells in 36 patients who received an allogeneic T-cell-depleted graft by addition of 20mg alemtuzumab "to the bag" with or without prior alemtuzumab (30mg cumulative dose intravenously) as part of the conditioning regimen. Effective T-cell depletion was shown for all patients, even though alemtuzumab plasma levels varied considerably. Peak alemtuzumab levels were observed directly after graft infusion and were not associated with the number of circulating T cells pre-infusion, but with plasma volumes of the patients. All patients engrafted, confirming feasibility of this transplantation protocol. Only three patients with low alemtuzumab levels developed acute GvHD (grade II in 2 patients and grade III in 1 patient). Persistence of circulating alemtuzumab at 3weeks after transplantation had prevented reconstitution of CD52-positive T cells when alemtuzumab plasma levels were above 0.7mug/mL. However, overall T-cell reconstitution did not correlate with the levels of alemtuzumab exposure, due to early reconstitution of CD52-negative alemtuzumab-resistant T cells. The protective effect of these cells likely explains the low incidence of Epstein-Barr-virus- and cytomegalovirus-related disease despite circulating alemtuzumab.
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Occurrence and Severity of DLI associated Chronic GVHD Influence the Clinical Outcomes in Relapsed Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation
Yu, W. J., Mo, X. D., Zhang, X. H., Xu, L. P., Wang, Y., Yan, C. H., Chen, H., Chen, Y. H., Han, W., Wang, F. R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
The aim of this study was to investigate the occurrence and severity of chemotherapy plus donor lymphocyte infusion (Chemo-DLI) associated chronic graft-versus-host disease (cGVHD) in a consecutive cohort of patients with acute leukemia who experienced relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT; n=104). The 5-year cumulative incidence of complete remission (CR) after Chemo-DLI was 81.0% (95% CI, 73.3-88.7%) and 84.6% (95% CI, 74.5-94.7%) in the moderate and severe cGVHD groups, respectively, which was significantly higher than that of the mild cGVHD 40.9% (95% CI, 29.3-52.5%) and non-cGVHD groups 29.2% (95% CI 23.1-35.3%). The cumulative incidence of non-relapse mortality was comparable between patients with and without cGVHD. The 5-year probabilities of progression-free survival after Chemo-DLI were 42.9% (95% CI, 26.2-70.2%) and 34.6% (95% CI, 15.3-78.2%) in moderate and severe cGVHD groups, respectively, which were both significantly higher than those of mild cGVHD 9.1% (95% CI, 2.4-34.1%) and non-cGVHD groups 8.3% (95% CI 3.3-21.3%). The 5-year probabilities of overall survival after Chemo-DLI were 56.7% (95% CI, 38.9-82.7%) and 43.1% (95% CI, 22.1-84.0%), in moderate and severe cGVHD groups, respectively, which were both significantly higher than those of the mild cGVHD 9.1% (95% CI 1.8-47.1%) and non-cGVHD groups 14.9% (95% CI, 7.3-30.2%). Our observations highlight the close relation between cGVHD and immune-mediated graft-versus-leukemia (GVL) effect in patients with relapse receiving Chemo-DLI; however, mild cGVHD may not be associated with a sufficiently strong GVL effect to induce remission and improve survival.
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Low-dose alemtuzumab for GvHD prevention followed by prophylactic donor lymphocyte infusions in high-risk leukemia
Tsirigotis, P., Liga, M., Gkirkas, K., Stamouli, M., Triantafyllou, E., Marangos, M., Pessach, I., Sarantopoulos, A., Spyridis, N., Spyridonidis, A.
Bone Marrow Transplantation. 2017;52(3):445-451
Abstract
We analyzed the use of low-dose alemtuzumab in a cohort of 158 consecutive patients who underwent allogeneic PBSC transplantation. Patients with high-risk acute leukemia were prospectively screened for prophylactic donor lymphocyte infusion (pDLI). Lymphocytes were administered repeatedly at low and non-escalating doses (0.5-1 x 106/kg). Low-dose alemtuzumab was effective in prevention of acute GvHD after sibling or well-matched unrelated transplantation, whereas a more intensified approach was needed after mismatched transplantation. The cumulative incidence of chronic moderate/severe chronic-GvHD (cGvHD) was 15.6%. In total, 63 high-risk leukemia patients were eligible for pDLI. Only 1 out of the 39 pDLI recipients relapsed as compared with 7 out of the 24 recipients, who did not receive pDLI due to logistical hurdles. In multivariate analysis, the use of adjuvant lymphocyte therapy was significantly associated with reduced incidence of relapse and improved disease-free survival. In summary, low-dose alemtuzumab confers to a low cGvHD incidence and the administration of pDLIs in this context is very likely to reduce relapse risk in high risk leukemia patients. This is translated in an estimated 5-year probability of GvHD-free and relapse-free survival of 43.3% for the 136 leukemia patients.
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[Sclerodermatous chronic graft-versus-host disease after hematopoietic stem cell transplantation: incidence, clinical characteristics and risk factors]. [Chinese]
Yang, H., Li, Z. T., Lin, R., Fan, Z. P., Huang, F., Jiang, Q. L., Zhou, H. S., Liu, Q. F., Sun, J.
Nan Fang Yi Ke Da Xue Xue Bao = Journal of Southern Medical University. 2016;36(6):807-13
Abstract
OBJECTIVE To investigate the incidence and risk factors of sclerodermatous chronic graft-versus-host disease (ScGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS The clinical data of 259 patients undergoing allo-HSCT in Nanfang Hospital between January, 2012 and December, 2014 were analyzed. RESULTS Chronic GVHD following allo-HSCT occurred in 134 (51.7%) cases, among whom 22 patients showed sclerodermatous features at a median of 12.5 months (range 4-28 months) after the transplantation. The overall incidence of ScGVHD was 8.49% (22/259) in the recipients and 16.4% (22/134) in those with cGVHD. Univariate analysis showed that the conditioning regimen with total body irradiation (P=0.031), GVHD prophylaxis with MMF (P=0.046), presence of chronic GVHD (P=0.008), and donor lymphocyte infusion (P=0.001) were all closely associated with the occurrence of ScGVHD. Multivariate analysis identified chronic GVHD (RR=3.512, 95%CI: 1.235-9.987, P=0.018) and donor lymphocyte infusion (RR=5.217, 95%CI: 1.698-16.029, P=0.004) as the independent risk factors of ScGVHD. CONCLUSION ScGVHD following allo-HSCT is not a common complication, and cGVHD and donor lymphocyte infusion are the independent risk factors for ScGVHD.