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

Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1

Background: Niemann-Pick disease type C1 (NP-C1) is a rare, autosomal-recessive neurodegenerative disorder with no United States Food and Drug Administration (FDA)-approved drug. Lithium has been shown to have considerable neuroprotective effects for neurological disorders such as bipolar disorder, Alzheimer’s disease and stroke and has been tested in many clinical trials. However, the pharmacological effect of lithium on NP-C1 neurodegenerative processes has not been investigated. The aim of this study was to provide an initial evaluation of the safety and feasibility of lithium carbonate in patients with NP-C1.Methods: A total of 13 patients diagnosed with NP-C1 who met the inclusion criteria received lithium orally at doses of 300, 600, 900, or 1,200 mg daily. The dose was reduced based on tolerance or safety observations. Plasma 7-ketocholesterol (7-KC), an emerging biomarker of NP-C1, was the primary endpoint. Secondary endpoints included NPC Neurological Severity Scores (NNSS) and safety.Results: Of the 13 patients with NP-C1 (12–33 years) enrolled, three withdrew (discontinuation of follow-up outpatient visits). The last observed post-treatment values of 7-KC concentrations (128 ng/ml, SEM 20) were significantly lower than pretreatment baselines values (185 ng/ml, SEM 29; p = 0.001). The mean NNSS was improved after lithium treatment at 12 months (p = 0.005). Improvement in swallowing capacity was observed in treated patients (p = 0.014). No serious adverse events were recorded in the patients receiving lithium.Conclusion: Lithium is a potential therapeutic option for NP-C1 patients. Larger randomized and double-blind clinical trials are needed to further support this finding.Clinical Trial Registration:ClinicalTrials.gov, NCT03201627

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

Risk of bias.

<p>This figure was the summery for risk of bias within six studies. It was formed using Revman 5.2. The definition of sources of bias and methods of assessing risk of bias can be found in Cochrane Handbook for Systematic Reviews of Interventions.</p

Forest plots of the RR/HR for CR, OS, EFS, DFS in Group 1 and Group 2.

<p>SE, standard error;Fixed, fixed-effect model; CI, confidence interval. Pooled RRs and HRs were computed using fixed-effect models. The size of the squares reflects each study’s relative weight, andhorizontal lines through the squares represent 95% CIs. the diamond represents the aggregate RR/HR and 95%CIs. <b>A. CR in Group 1</b> Group 1, high doses of daunorubicin vs. low doses of daunorubicin; HD-DNR, high doses of daunorubicin; LD-DNR, low doses of daunorubicin; CR, complete remission. <b>B. CR in Group 2</b> Group 2, high doses of daunorubicin vs. idarubicin; HD-DNR, high doses of daunorubicin; IDA, idarubicin; CR, complete remission. There were two subgroups named 1_Pautas et al, 2010 and2_ Pautas et al, 2010 devided from the same literature. The first one corresponded to 80×3 mg/m² of daunorubicin vs. 12×3 mg/m² of idarubicin and the second one corresponded to 80×3 mg/m² of daunorubicin vs. 12×4 mg/m² of idarubicin. <b>C. OS in Group 1</b> Group 1, high doses of daunorubicin vs. low doses of daunorubicin; HD-DNR, high doses of daunorubicin; LD-DNR, low doses of daunorubicin; OS, overall survival. <b>D. OS in Group 2</b> Group 2, high doses of daunorubicin vs. idarubicin; HD-DNR, high doses of daunorubicin; IDA, idarubicin; OS, overall survival. There were two subgroups named 1_Pautas et al, 2010 and2_ Pautas et al, 2010 devided from the same literature. The first one corresponded to 80×3 mg/m² of daunorubicin vs. 12×3 mg/m² of idarubicin and the second one corresponded to 80×3 mg/m² of daunorubicin vs. 12×4 mg/m² of idarubicin. <b>E. EFS in Group 1</b> Group 1, high doses of daunorubicin vs. low doses of daunorubicin; HD-DNR, high doses of daunorubicin; LD-DNR, low doses of daunorubicin; EFS, event-free survival. <b>F. EFS in Group 2</b> Group 2, high doses of daunorubicin vs. idarubicin; HD-DNR, high doses of daunorubicin; IDA, idarubicin; EFS, event-free survival. There were two subgroups named 1_Pautas et al, 2010 and2_ Pautas et al, 2010 devided from the same literature. The first one corresponded to 80×3 mg/m² of daunorubicin vs. 12×3 mg/m² of idarubicin and the second one corresponded to 80×3 mg/m² of daunorubicin vs. 12×4 mg/m² of idarubicin. <b>G. DFS in Group 1</b> Group 1, high doses of daunorubicin vs. low doses of daunorubicin; HD-DNR, high doses of daunorubicin; LD-DNR, low doses of daunorubicin; DFS, disease-free survival.</p

Risk of bias within studies.

<p>This table was formed using Revman 5.2. The definition of sources of bias and methods of assessing risk of bias can be found in Cochrane Handbook for Systematic Reviews of Interventions.</p><p>Risk of bias within studies.</p