Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials

ObjectiveSteroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens.MethodsLiterature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method.ResultsEight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01–1.32, P = 0.04), especially in patients with severe (grade III–IV or grade C–D) aGVHD (RR = 1.26, 95% CI = 1.04–1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05–1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy.ConclusionsAdding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487

Forest plot for the association between CD11b expression level and disease-free survival (DFS) of AML patients.

<p>Forest plot for the association between CD11b expression level and disease-free survival (DFS) of AML patients.</p

Forest plot for the association between CD11b expression level and complete remission rate (CRR) of AML patients.

<p>Forest plot for the association between CD11b expression level and complete remission rate (CRR) of AML patients.</p

The funnel plots were largely symmetric suggesting there were no publication biases in the meta-analysis of CD11b expression level and prognosis of AML patients.

<p>The funnel plot from ten studies assessed the association between CD11b expression level and CRR of AML patients (a). The funnel plot from five studies assessed the association between CD11b expression level and OS of AML patients (b). The funnel plot from three studies assessing the association between CD11b expression level and DFS of AML patients (c).</p

Basic characteristics of includes studies.

<p>APAAP = alkaline phosphatase-anti-alkaline phosphatase complex method, HSCT = Hematopoietic stem cell transplantation, S.A = Saudi Arabia, CT = chemotherapy, NA = DATA not available, FHGC = ficoll-hypaque gradient centrifugation, BD = Becton Dickinson.</p><p>* means the equipment or antibody varied between different research centers in this study.</p><p>Basic characteristics of includes studies.</p

Forest plot for sensitivity analysis by only including high quality score studies for the association between CD11b expression level and CRR of AML patients (a) and for the association between CD11b expression level and OS of AML patients (b).

<p>Forest plot for sensitivity analysis by only including high quality score studies for the association between CD11b expression level and CRR of AML patients (a) and for the association between CD11b expression level and OS of AML patients (b).</p

Forest plot for the association between CD11b expression level and overall survival (OS) of AML patients.

<p>Forest plot for the association between CD11b expression level and overall survival (OS) of AML patients.</p

Flow chart of study selection and identification.

<p>Flow chart of study selection and identification.</p

High Doses of Daunorubicin during Induction Therapy of Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Prospective Clinical Trials

<div><p>The right dose of daunorubicin (DNR) for the treatment of newly diagnosed acute myeloid leukemia (AML) is uncertain. Previous trials have shown conflicting results concerning the efficacy of high or low doses of daunorubicin to induction chemotherapy for newly diagnosed AML. A systematic review and meta-analysis was conducted to resolve this controversial issue. We compared the efficacy and safety of high doses of daunorubicin (HD-DNR) and traditional low doses of daunorubicin (LD-DNR) or idarubicin (IDA) during induction therapy of newly diagnosed AML. Data of 3,824 patients from 1,796 articles in the literature were retrieved and six randomized controlled trials were analyzed. The primary outcomes were overall survival (OS), disease-free survival (DFS), and event-free survival (EFS). The secondary outcomes included complete remission (CR), relapse, and toxicity. The meta-analysis results suggest that comparing HD-DNR with LD-DNR, there were significant differences in CR (RR = 1.19, 95%CI[1.12,1.18], p<0.00001), OS(HR = 0.88, 95%CI[0.79,0.99], p = 0.002), and EFS (HR = 0.86, 95%CI [0.74, 1.00], p = 0.008), but not in DFS, relapse, and toxicity. There were no statistically significant differences in any other outcomes between HD-DNR and IDA. The analysis indicates that compared with LD-DNR, HD-DNR can significantly improve CR, OS and EFS but not DFS, and did not increase occurrence of relapse and toxicity.</p></div

Flow diagram depicting identification and retrieval of eligible studies for inclusion.

<p>Flow diagram depicting identification and retrieval of eligible studies for inclusion.</p