Chronic graft-versus-host disease and the risk of primary disease relapse: A meta-analysis
2019; Elsevier BV; Volume: 74; Linguagem: Inglês
10.1016/j.exphem.2019.04.004
ISSN1873-2399
AutoresKittika Poonsombudlert, Jakarin Kewcharoen, Chanavuth Kanitsoraphan, Chattip Prueksapraopong, Nath Limpruttidham,
Tópico(s)Acute Myeloid Leukemia Research
Resumo•Both PDR and cGVHD have long been the dreaded outcomes for patients with hematologic malignancies.•We conducted a random effect meta-analysis of 11 studies involving 64,239 participants and found a significant decreased risk of developing PDR in patients with cGVHD, with a pooled risk ratio of 0.49 (95% CI: 0.40–0.61, I2 = 69.3%).•We concluded that patients with cGVHD have a significantly lower risk of developing PDR compared with patients without cGVHD.•According to regression meta-analysis, use of ATG and HLA mismatch grafts had a potential modifying effect on the association between cGVHD and PDR. Both primary disease relapse (PDR) and chronic graft-versus-host disease (cGVHD) have long been the dreaded outcomes for patients with hematologic malignancies. Previous theories have speculated an inverse relationship between the two; therefore, we attempted to verify the described association. We searched for titles of articles in MEDLINE (PubMed), Cochrane library, and EMBASE database that evaluated the association between PDR and cGVHD and conducted a random effect meta-analysis of 11 studies involving a total of 64,239 participants. We found a significantly decreased risk of developing PDR in patients with cGVHD, with a pooled risk ratio of 0.49 (95% confidence interval: 0.40–0.61, I2 = 69.3%). We concluded that patients with cGVHD have a significantly lower risk of developing PDR compared with patients without cGVHD. Both primary disease relapse (PDR) and chronic graft-versus-host disease (cGVHD) have long been the dreaded outcomes for patients with hematologic malignancies. Previous theories have speculated an inverse relationship between the two; therefore, we attempted to verify the described association. We searched for titles of articles in MEDLINE (PubMed), Cochrane library, and EMBASE database that evaluated the association between PDR and cGVHD and conducted a random effect meta-analysis of 11 studies involving a total of 64,239 participants. We found a significantly decreased risk of developing PDR in patients with cGVHD, with a pooled risk ratio of 0.49 (95% confidence interval: 0.40–0.61, I2 = 69.3%). We concluded that patients with cGVHD have a significantly lower risk of developing PDR compared with patients without cGVHD. Primary disease relapse (PDR) and graft-versus-host disease (GVHD) have long been dreaded consequences of many malignant hematologic conditions. Active research is ongoing to further characterize and find effective methods to circumvent these complications.GVHD is commonly divided into acute GVHD (aGVHD) and chronic GVHD (cGVHD), with a cutoff of 100 days per National Institutes of Health (NIH) consensus criteria [1Jagasia MH Greinix HT Arora M et al.National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report.Biol Blood Marrow Transplant. 2015; 21: 389-401.e381Abstract Full Text Full Text PDF PubMed Scopus (1295) Google Scholar]. On further exploration into its pathogenesis, cGVHD has been hypothesized to occur via complicated pathways involving host antigen presenting cells (APCs) and effector and regulatory T cells, as well as pro-inflammatory cytokines and co-stimulatory mediators [2Cooke KR Luznik L Sarantopoulos S et al.The biology of chronic graft-versus-host disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease.Biol Blood Marrow Transplant. 2017; 23: 211-234Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 3Zhang L Chu J Yu J Wei W Cellular and molecular mechanisms in graft-versus-host disease.J Leukoc Biol. 2016; 99: 279-287Crossref PubMed Scopus (44) Google Scholar] causing a constellation of clinical findings in various organs, most commonly involving the skin, alimentary tract, liver, and lungs [1Jagasia MH Greinix HT Arora M et al.National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report.Biol Blood Marrow Transplant. 2015; 21: 389-401.e381Abstract Full Text Full Text PDF PubMed Scopus (1295) Google Scholar, 4Margaix-Munoz M Bagan JV Jimenez Y Sarrion MG Poveda-Roda R Graft-versus-host disease affecting oral cavity: A review.J Clin Exp Dent. 2015; 7: e138-e145Crossref PubMed Scopus (24) Google Scholar]. As cGVHD is one of the most debilitating long-term consequences in the transplant era [5Socie G Stone JV Wingard JR et al.Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry.N Engl J Med. 1999; 341: 14-21Crossref PubMed Scopus (587) Google Scholar, 6Wingard JR Majhail NS Brazauskas R et al.Long-term survival and late deaths after allogeneic hematopoietic cell transplantation.J Clin Oncol. 2011; 29: 2230-2239Crossref PubMed Scopus (427) Google Scholar], circumventing this devastating side effect would prove to be a tremendous stride in the advancement of transplant medicine.There are theories that try to explain the relationship between PDR and cGVHD. Falkenburg et al. [7Falkenburg JHF Jedema I Graft versus tumor effects and why people relapse.Hematolog. 2017; 2017: 693-698Crossref Scopus (20) Google Scholar] speculated that the graft-versus-tumor (GVT) effect is the primary mechanism underlying the prevention of PDR because of the strong alloreactivity from the T cells in the setting of allogenic stem cell transplant.As human stem cell transplantation (HSCT) is being performed more frequently, the rate of cGVHD, as well as that of PDR, has increased because of both better detection technique and more widespread understanding of cGVHD and its manifestations. Therefore, we attempted to evaluate the association between cGVHD and PDR in the context of HSCT for malignant hematologic conditions.MethodsWe searched for titles of articles in MEDLINE (PubMed), the EMBASE database, and the Cochrane library. We performed a search in January 2019 and did not restrict publication dates. The main search terms used were hematopoietic stem cell transplant, hematologic malignancy, chronic graft-versus-host disease, and relapse. The full search strategy is detailed in Figure 1.All published non-randomized trials that evaluated the outcome of cGVHD and PDR were included. Observational studies—prospective cohort, retrospective cohort, and cross-sectional studies—were included. Review articles, case reports, letters, commentaries, abstracts, unpublished studies, and studies in languages other than English were excluded.Patient age, data sources, GVHD prophylaxis regimen, degree of HLA matching, and study location were not restricted. We included patients with all disease statuses as well as all conditioning regimens. Because of the various criteria for diagnosis of cGVHD and relapse, these data were not restricted. Studies done in vitro or on animal models were excluded. We included only studies specific to hematologic malignancy patients who have undergone transplantation.Our primary outcome was the relative incidences of cGVHD and PDR.Data extraction and quality assessmentTwo investigators independently extracted the following data: authors, publication year, country of origin, study design, baseline patient's characteristics, interventions, and outcomes. Any conflicting opinions on data extraction were resolved by consensus of the investigators.The Newcastle−Ottawa Quality Assessment Scale (NOS) was used to assess the quality of the nonrandomized studies based on selection of the study groups, comparability of the study groups, and ascertainment of exposure/outcome. Studies with total scores >6 and <4 were considered to be of high and low quality, respectively. We excluded any studies indicated as poor quality by the meta-analysis. The studies were randomized according to each study's criteria but there were no blinded control trials.Statistical methodsThe primary outcome is the relative incidences of cGVHD and PDR. We used a random-effects model for our included studies, which were all retrospective observational studies. We conducted sensitivity analysis and subgroup analysis to explore the heterogeneity of the included studies [8Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560Crossref PubMed Scopus (38377) Google Scholar]. We also used the funnel plot (Figure 2) and Egger's test to assess for publication bias. All analyses were performed using Stata 13 software at the 0.05 level of significance.Figure 2Funnel plot for risk of relapse with 95% confidence limits.View Large Image Figure ViewerDownload Hi-res image Download (PPT)ResultsDescription of included studiesThe initial search yielded 2,764 articles; 2,727 were excluded from the title and abstract review as they did not pertain to our study, had been conducted in animal or in vitro models, or were published in languages other than English (Table 1). A total of 37 articles underwent full-length review; 26 of them were excluded because they did not have an eligible study population, had no proper control group, or did not directly measure the association between cGVHD and PDR. Finally, we included 11 studies, which were all retrospective observational studies, comprising a total of 64,239 participants. The median age range was 9–51 years, and the median follow-up duration ranged from 24 to 96 months.Table 1Study characteristicsTrial nameCountryPublication yearStudy designPopulationMedian age% MaleConditioning regimen (%)Transplant indicationGraft sourceGVHD diagnosisGVHD ppx (%)ATG (%)Alem (%)HLA matching (%)Average follow up time (mo)NOS scoreBoyiadzis et al. 9Boyiadzis M Arora M Klein JP et al.Impact of chronic graft-versus-host disease on late relapse and survival on 7,489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia.Clin Cancer Res. 2015; 21: 2020-2028Crossref PubMed Scopus (75) Google ScholarCIBMTR registry2015ROS7,4893657MAC 100AML, ALL, CML, MDSBM 72%PB 28%CIBMTR criteriaCsA 77 CNI 13 Other 1014N/AMRD 52MUD 19PMUD 18MMUD 11939Cho et al. 17Cho BS Lee SE Song HH et al.Graft-versus-tumor effect according to type of graft-versus-host disease defined by National Institutes of Health consensus criteria and associated outcomes.Biol Blood Marrow Transplant. 2012; 18: 1136-1143Abstract Full Text Full Text PDF PubMed Scopus (20) Google ScholarKorea2012ROS7753655MAC 70RIC 30AML, CML, MDS, ALL, PCDBM 62% PB 38%NIH criteria 2005CNI 100N/AN/AMRD 63MUD 20PMUD 13MMUD 4419Craddock et al. 10Craddock C Versluis J Labopin M et al.Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.J Intern Med. 2018; 283: 371-379Crossref PubMed Scopus (14) Google ScholarEBMT2018ROS20285151MAC 51 RIC 49AML in CR1BM21%PB79%N/AN/A937MRD 44MUD 56367Gustafsson Jernberg et al. 11Gustafsson Jernberg A Remberger M Ringden O Winiarski J Graft-versus-leukaemia effect in children: Chronic GVHD has a significant impact on relapse and survival.Bone Marrow Transplant. 2003; 31: 175-181Crossref PubMed Scopus (59) Google ScholarSweden2003ROS169963MAC 100ALL, AMLBM 92PB 8%N/ACsA 73 Other 2729N/AMRD 63MUD 19MMRD 9MMUD 9848Kanda et al. 18Kanda J Morishima Y Terakura S et al.Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation.Leukemia. 2017; 31: 663-668Crossref PubMed Scopus (41) Google ScholarJapan2017ROS25585056MAC 65RIC 35AL, MDSUC 100%NIH criteria 2005CsA/CNI based 100N/AN/AMUD 6PMUD 94359Kanda et al. 15Kanda Y Izutsu K Hirai H et al.Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate.Leukemia. 2004; 18: 1013-1019Crossref PubMed Scopus (41) Google ScholarJapan2004ROS15143561MAC 100AML, ALL CML, MDSBM 100%Seattle criteriaCsA/MTX 100%N/AN/AMRD 100N/A9Mo et al. 12Mo XD Zhang XH Xu LP et al.Salvage chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation: Prognostic factors and clinical outcomes.Eur J Haematol. 2016; 96: 297-308Crossref PubMed Scopus (32) Google ScholarChina2015ROS1012655MAC 100AL, MDSBM + PB 100%NIH criteria 2005CsA 80 MTX 2143N/AMRD 43PMRD 57249Signori et al. 13Signori A Crocchiolo R Oneto R et al.Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors.Bone Marrow Transplant. 2012; 47: 1474-1478Crossref PubMed Scopus (27) Google ScholarItaly2012ROS8024156MAC 67RIC 33AML, ALL, CML, CLL, PCD, HL, NHLBM 57%PB 43%Seattle criteriaCsA/MTX 10068N/AMUD 100259Socié et al. 14Socie G Schmoor C Bethge WA et al.Chronic graft-versus-host disease: Long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.Blood. 2011; 117: 6375-6382Crossref PubMed Scopus (234) Google ScholarGermany2011ROS2014053MAC 100AML, CML, ALL, MDS, OMFBM18% PB 82%Seattle criteriaCsA/MTX 10051N/AMUD 17MMUD 83368Stern et al. 16Stern M de Wreede LC Brand R et al.Sensitivity of hematological malignancies to graft-versus-host effects: An EBMT megafile analysis.Leukemia. 2014; 28: 2235-2240Crossref PubMed Scopus (72) Google ScholarEBMT2014ROS48,1114458MAC 60 RIC 33%AML, ALL, CML, CLL, PCD, HL, NHLBM27PB71%, UC 2%Seattle criteriaN/AN/AN/AMRD 58MUD 30MMUD 12N/A9Van Rhee et al. 19van Rhee F Szydlo RM Hermans J et al.Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: A report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.Bone Marrow Transplant. 1997; 20: 553-560Crossref PubMed Scopus (135) Google ScholarEBMT1997ROS3733156MAC 100%CMLBM 100%Seattle criteriaCsA based 100N/AN/AMRD 100969Zikos et al. 20Zikos P Van Lint MT Lamparelli T et al.Allogeneic hemopoietic stem cell transplantation for patients with high risk acute lymphoblastic leukemia: Favorable impact of chronic graft-versus-host disease on survival and relapse.Haematologica. 1998; 83: 896-903PubMed Google ScholarItaly1998ROS1182263MAC 100%ALLBM83% PB 17%Seattle criteriaCsA/MTX 80MTX 7N/A13MRD 87MMRD 11MUD 2729CIBMTR registry=Center for International Blood and Marrow Transplant Research; EBMT=European Group for Blood and Marrow Transplantation; ROS=retrospective observational study; MAC=myeloablative; RIC=reduced intensity conditioning; AML=acute myeloid leukemia; CML=chronic myeloid leukemia; ALL=acute lymphoid leukemia; CLL=chronic lymphoid leukemia; MDS=myelodysplastic syndrome; PCD=plasma cell disorder; HL=Hodgkin's lymphoma; NHL=non-Hodgkin's lymphoma; OMF=osteomyelofibrosis; BM=bone marrow stem cell; PB=peripheral blood stem cell; UC=umbilical cord blood stem cell; CsA=cyclosporine; CNI=calcinurin inhibitor; MTX=methotrexate; ATG=anti-thymocyte immunoglobulin; Alem=alemtuzumab; MRD=match-related donor; MUD=match unrelated donor; PMUD=partially match-unrelated donor; MMRD=mismatch-related donor; MMUD=mismatch-unrelated donor; MD=match donor; PMD=partially match donor; NOS=Newcastle-Ottawa Quality Assessment Scale. Open table in a new tab Meta-analysis resultsEleven studies were included in this meta-analysis. Using a random-effects model, we found a significant decrease in the risk of PDR in the cGVHD group, compared with the control group (no-cGVHD group), with the pooled risk ratio being 0.49 (95% confidence interval [CI]: 0.40–0.61, I2 = 69.3%) (Figure 3). There were no significant changes in pooled risk ratios after we conducted sensitivity analysis by removing each study from the pooled cohorts.Figure 3Main meta-analysis result.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The funnel plot revealed publication bias, which was not statistically significant according to Egger's test (p = 0.066). This was likely due to the lower likelihood of negative studies being selected for publication.Subgroup analysisWe conducted a subgroup analysis to assess the effect of ATG use and degree of HLA mismatch on the primary outcome.First, for the use of ATG, we categorized the studies into one group in which ATG was part of the in vivo T-cell depletion process [9Boyiadzis M Arora M Klein JP et al.Impact of chronic graft-versus-host disease on late relapse and survival on 7,489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia.Clin Cancer Res. 2015; 21: 2020-2028Crossref PubMed Scopus (75) Google Scholar, 10Craddock C Versluis J Labopin M et al.Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.J Intern Med. 2018; 283: 371-379Crossref PubMed Scopus (14) Google Scholar, 11Gustafsson Jernberg A Remberger M Ringden O Winiarski J Graft-versus-leukaemia effect in children: Chronic GVHD has a significant impact on relapse and survival.Bone Marrow Transplant. 2003; 31: 175-181Crossref PubMed Scopus (59) Google Scholar, 12Mo XD Zhang XH Xu LP et al.Salvage chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation: Prognostic factors and clinical outcomes.Eur J Haematol. 2016; 96: 297-308Crossref PubMed Scopus (32) Google Scholar, 13Signori A Crocchiolo R Oneto R et al.Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors.Bone Marrow Transplant. 2012; 47: 1474-1478Crossref PubMed Scopus (27) Google Scholar, 14Socie G Schmoor C Bethge WA et al.Chronic graft-versus-host disease: Long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.Blood. 2011; 117: 6375-6382Crossref PubMed Scopus (234) Google Scholar] and another group in which ATG was not used [15Kanda Y Izutsu K Hirai H et al.Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate.Leukemia. 2004; 18: 1013-1019Crossref PubMed Scopus (41) Google Scholar, 16Stern M de Wreede LC Brand R et al.Sensitivity of hematological malignancies to graft-versus-host effects: An EBMT megafile analysis.Leukemia. 2014; 28: 2235-2240Crossref PubMed Scopus (72) Google Scholar, 17Cho BS Lee SE Song HH et al.Graft-versus-tumor effect according to type of graft-versus-host disease defined by National Institutes of Health consensus criteria and associated outcomes.Biol Blood Marrow Transplant. 2012; 18: 1136-1143Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 18Kanda J Morishima Y Terakura S et al.Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation.Leukemia. 2017; 31: 663-668Crossref PubMed Scopus (41) Google Scholar, 19van Rhee F Szydlo RM Hermans J et al.Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: A report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.Bone Marrow Transplant. 1997; 20: 553-560Crossref PubMed Scopus (135) Google Scholar, 20Zikos P Van Lint MT Lamparelli T et al.Allogeneic hemopoietic stem cell transplantation for patients with high risk acute lymphoblastic leukemia: Favorable impact of chronic graft-versus-host disease on survival and relapse.Haematologica. 1998; 83: 896-903PubMed Google Scholar]. The pooled risk ratio for the ATG group was 0.45 (95% CI: 0.35–0.59, I2 = 46.2%), and the pooled risk ratio for the group that did not use ATG was 0.53 (95% CI: 0.39–0.72, I2 = 75.3%) (Figure 4).Figure 4Main meta-analysis result: 11 studies included in this meta-analysis. Using a random-effects model; we found a significant decrease in the risk of PDR in the cGVHD group, compared to the control group with the pooled risk ratios of 0.49, 95% CI 0.40-0.61, I2=69.3%.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Second, when we categorized the studies based on the HLA matching process, the first group used only stem cells with well matched or partially matched HLA [10Craddock C Versluis J Labopin M et al.Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.J Intern Med. 2018; 283: 371-379Crossref PubMed Scopus (14) Google Scholar, 11Gustafsson Jernberg A Remberger M Ringden O Winiarski J Graft-versus-leukaemia effect in children: Chronic GVHD has a significant impact on relapse and survival.Bone Marrow Transplant. 2003; 31: 175-181Crossref PubMed Scopus (59) Google Scholar, 12Mo XD Zhang XH Xu LP et al.Salvage chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation: Prognostic factors and clinical outcomes.Eur J Haematol. 2016; 96: 297-308Crossref PubMed Scopus (32) Google Scholar, 13Signori A Crocchiolo R Oneto R et al.Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors.Bone Marrow Transplant. 2012; 47: 1474-1478Crossref PubMed Scopus (27) Google Scholar, 15Kanda Y Izutsu K Hirai H et al.Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate.Leukemia. 2004; 18: 1013-1019Crossref PubMed Scopus (41) Google Scholar, 18Kanda J Morishima Y Terakura S et al.Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation.Leukemia. 2017; 31: 663-668Crossref PubMed Scopus (41) Google Scholar, 19van Rhee F Szydlo RM Hermans J et al.Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: A report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.Bone Marrow Transplant. 1997; 20: 553-560Crossref PubMed Scopus (135) Google Scholar]. The other group included HLA-mismatched grafts [9Boyiadzis M Arora M Klein JP et al.Impact of chronic graft-versus-host disease on late relapse and survival on 7,489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia.Clin Cancer Res. 2015; 21: 2020-2028Crossref PubMed Scopus (75) Google Scholar, 14Socie G Schmoor C Bethge WA et al.Chronic graft-versus-host disease: Long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.Blood. 2011; 117: 6375-6382Crossref PubMed Scopus (234) Google Scholar, 16Stern M de Wreede LC Brand R et al.Sensitivity of hematological malignancies to graft-versus-host effects: An EBMT megafile analysis.Leukemia. 2014; 28: 2235-2240Crossref PubMed Scopus (72) Google Scholar, 17Cho BS Lee SE Song HH et al.Graft-versus-tumor effect according to type of graft-versus-host disease defined by National Institutes of Health consensus criteria and associated outcomes.Biol Blood Marrow Transplant. 2012; 18: 1136-1143Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 20Zikos P Van Lint MT Lamparelli T et al.Allogeneic hemopoietic stem cell transplantation for patients with high risk acute lymphoblastic leukemia: Favorable impact of chronic graft-versus-host disease on survival and relapse.Haematologica. 1998; 83: 896-903PubMed Google Scholar]. We found that the group that utilized mismatched stem grafts had a pooled risk ratio of 0.44 (95% CI: 0.37–0.52, I2 = 0%), and the group that did not use HLA-mismatched grafts had a pooled risk ratio of 0.53 (95% CI: 0.39–0.71, I2 = 73%) (Figure 5).Figure 5Subgroup analysis based on ATG use: Studies that used ATG had pooled risk ratio of 0.45, 95% CI 0.35-0.59, I2=46.2% and the group that did not use ATG had pooled risk ratio of 0.53, 95% CI 0.39-0.72, I2=75.3%.View Large Image Figure ViewerDownload Hi-res image Download (PPT)For graft source, we divided the graft sources into peripheral blood (PB), bone marrow (BM), and umbilical cord (UC). We found that the study that used both PB and BM [10Craddock C Versluis J Labopin M et al.Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.J Intern Med. 2018; 283: 371-379Crossref PubMed Scopus (14) Google Scholar, 11Gustafsson Jernberg A Remberger M Ringden O Winiarski J Graft-versus-leukaemia effect in children: Chronic GVHD has a significant impact on relapse and survival.Bone Marrow Transplant. 2003; 31: 175-181Crossref PubMed Scopus (59) Google Scholar, 12Mo XD Zhang XH Xu LP et al.Salvage chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation: Prognostic factors and clinical outcomes.Eur J Haematol. 2016; 96: 297-308Crossref PubMed Scopus (32) Google Scholar, 13Signori A Crocchiolo R Oneto R et al.Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors.Bone Marrow Transplant. 2012; 47: 1474-1478Crossref PubMed Scopus (27) Google Scholar, 14Socie G Schmoor C Bethge WA et al.Chronic graft-versus-host disease: Long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.Blood. 2011; 117: 6375-6382Crossref PubMed Scopus (234) Google Scholar, 17Cho BS Lee SE Song HH et al.Graft-versus-tumor effect according to type of graft-versus-host disease defined by National Institutes of Health consensus criteria and associated outcomes.Biol Blood Marrow Transplant. 2012; 18: 1136-1143Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 20Zikos P Van Lint MT Lamparelli T et al.Allogeneic hemopoietic stem cell transplantation for patients with high risk acute lymphoblastic leukemia: Favorable impact of chronic graft-versus-host disease on survival and relapse.Haematologica. 1998; 83: 896-903PubMed Google Scholar] had a risk ratio (RR) of 0.46 (95% CI: 0.38–0.56, I2 = 25.1%). For the group that used only BM [15Kanda Y Izutsu K Hirai H et al.Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate.Leukemia. 2004; 18: 1013-1019Crossref PubMed Scopus (41) Google Scholar, 19van Rhee F Szydlo RM Hermans J et al.Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: A report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.Bone Marrow Transplant. 1997; 20: 553-560Crossref PubMed Scopus (135) Google Scholar], the RR was 0.54 (95% CI: 0.26–1.11, I2 = 66%), and for the group that included UC [16Stern M de Wreede LC Brand R et al.Sensitivity of hematological malignancies to graft-versus-host effects: An EBMT megafile analysis.Leukemia. 2014; 28: 2235-2240Crossref PubMed Scopus (72) Google Scholar, 18Kanda J Morishima Y Terakura S et al.Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation.Leukemia. 2017; 31: 663-668Crossref PubMed Scopus (41) Google Scholar], the RR was 0.55 (95% CI: 0.26–1.15, I2 = 93.1%) (Figure 6).Figure 6Subgroup analysis based on HLA matching Studies that only include well matched graft had pooled risk ratio of 0.53, 95% CI 0.39-0.71, I2=73% while the studies that include mismatch graft had pooled risk ratio of 0.44, 95% CI 0.37-0.52, I2=0%.View Large Image Figure ViewerDownload Hi-res image Download (PPT)And lastly, for the GVHD prophylaxis regimen, we divided the regimen into cyclosporine A-based (CsA), calcineurin inhibitor-based (CNI), methotrexate-based (MTX), and other regimens. We found that the group that used CsA-based regimens [9Boyiadzis M Arora M Klein JP et al.Impact of chronic graft-versus-host disease on late relapse and survival on 7,489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia.Clin Cancer Res. 2015; 21: 2020-2028Crossref PubMed Scopus (75) Google Scholar, 11Gustafsson Jernberg A Remberger M Ringden O Winiarski J Graft-versus-leukaemia effect in children: Chronic GVHD has a significant impact on relapse
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