3.1、Study selection
The detail flowchart of the search and selection results is presented in Figure 1.The search strategy identified 296 articles that were screened for inclusion.82 articles were excluded because of duplication. After the screening of titles and abstracts,174 articles were excluded according to the inclusion criteria.Of the remaining 40 articles, 18 were excluded because they were conference abstract(n=18),duplicate publications(n=3),unpublished registered clinical trials (n=7)、Preconditioning before transplantation(n=1)、letter(n=1)、non-English report(n=1) and Phase 1 clinical trial (n=1),Finally, 7 articles were included for further meta-analysis.
3.2、Study Characteristics and quality assessment
There were 7 studies(4 phase 2 clinical trails;2 retrospective cohort studies,1 real-world multicenter study) including 1082 patients of whom 259 patients were newly-diagnosed,723 patients were relapsed or refractory. Among them, 340 patients were in the chidamide alone therapy group and 573 patients in the group chidamide+chemotherapy.
Quality assessments for individual studies using a modified Downs and Black checklist are provided in the Table 2.
Table 1:Characteristics of included studies
Study
|
Course of disease
|
Type of Study
|
Treatment regimen
|
Number
|
Male(%)
|
median age
(range)
|
published magazines
|
Chai Y,2022[6]
|
Newly-diagnosed
|
Phase 2
NCT04511351
|
GDP+ chidamide
GDP+ placebo
|
37
37
|
26 (70.3)
29 (78.4)
|
46 (19-67)
50 (24-69)
|
International Journal of Radiation Oncology Biology Physics
|
Shi Y,2015[7]
|
Relapsed or refractory
|
Phase 2
ChiCTR-TNC-10000811
|
chidamide
|
79
|
53(67%)
|
53(20-77)
|
Annals of Oncology
|
Liu W;2021[1]
|
Relapsed or refractory
|
Real-world multicenter study
|
Chidamide :
Chidamide+ChT:
|
261
287
|
341(62.2%)
|
57(18-89)
|
Frontiers in Oncology
|
Wang J;2021[8]
|
Relapsed or refractory
|
Retrospective study
|
ChT
Chidamide+ChT
chidamide± targeted agents
|
42
37
17
|
28(66.7%)
22(59.5%)
17(70.6%)
|
55(30-90)
56(29-76)
66.5(25-90)
|
Leukemia Research
|
Wang J,2022[9]
|
Newly-diagnosed
|
Retrospective study;
|
ChT :
ChT+chidamide :
|
73
31
|
24(32.9%)
13(41.9%)
|
59(24-87)
60(27-84)
|
Frontiers in Immunology
|
Wang Y,2022[10]
|
Newly-diagnosed
|
Phase 2
NCT03273452
|
chidamide +prednisone,+etoposide+thalidomide
|
68
|
49(72%)
|
63(25-83)
|
American Journal of Hematology
|
Zhang W,2021[11]
|
Newly-diagnosed
|
Phase 1/2
NCT02987244
|
CHOEP+chidamide
|
113
|
72 (63.7%)
|
54(20-70)
|
Cancer Biology and Medicine
|
GDP=gemcitabine+cisplatin+dexamethasone
ChT=chemotherapy
CHOEP=cyclophosphamide+doxorubicin,+vincristine+prednisone
Table 2:Modified Downs and Black checklist
Study (year of publication)
|
Reporting (items 1-10; max. 11 points)
|
External validity
(items 11-13; max. 3 points)
|
Internal validity;
bias (items 14-20;
max. 7 points)
|
Internal validity; confounding (items 21-26; max. 6 points)
|
Power (item 27; max. 1 point)
|
Total
|
Shi Y,2015
|
6
|
3
|
6
|
3
|
0
|
18
|
Liu W,2021
|
10
|
2
|
4
|
2
|
0
|
18
|
Wang J,2021
|
6
|
2
|
3
|
2
|
0
|
13
|
Zhang W,2021
|
9
|
2
|
5
|
4
|
0
|
20
|
Wang J,2022
|
8
|
2
|
5
|
2
|
0
|
17
|
Wang Y,2022
|
10
|
2
|
4
|
1
|
0
|
17
|
3.3、Efficacy
Both CR and ORR rate were analyzed in this meta-analysis. Heterogeneity of studies was determined using Cochran Q and I2 indices and significant heterogeneity (I2 > 75%) was further explored with sensitivity analyses.Subgroup analyses were planned for newly-diagnosed or relapsed or refractory . All analyses were performed with Comprehensive Meta-Analysis (CMA version 3.7, Biostat).
7 studies were analyzed by random-effects model and the results showed pooled overall CR rate and ORR rate after treatment with containing Chidamide regimen was 35.2%(95% CI, 24.2-48%, Figure 2)and 65.8%(95% CI, 54.4-75.6%, Figure 2), respectively;the CR rates and ORR rate of 7 trials were highly heterogeneous (Q=74.026, I2 = 90.544%,, P=0.000, Figure 2A&Q=65.065, I2 = 89.242%,, P=0.000, Figure 2B).
Subgroup analysis
To explore the heterogeneity of the included studies, subgroup analysis according to different treatment protocols was constructed. The results showed that CR rate of Chi+ChT(Chidamide combination with chemotherapy ) was 43.2% (95% CI: 28.6–59.0%; Figure 3A) and that of Chidamide monotherapy was 19.7%(95% CI: 15.7–24.3%; Figure 3B), which suggested that Chidamide combination with chemotherapy had higher effects in peripheral T-cell lymphoma patients.There were also highly heterogeneous in group of Chi+ChT,(Q=49.490, I2 = 89%,, P=0.000). subgroup analysis according to different disease course was further constructed.Use of chidamide-based therapy showed pooled overall CR rate was 55.1%(95% CI, 37.6-71.3%, I2 = 83%, Figure 3D) in newly-diagnosed patients,the overall CR rate was 22.2%(95% CI, 19.2-25.6%, I2 = 41%, Figure 3D) for Relapsed or refractory patients.
3.4、Sensitivity analysis
Sensitivity analysis was performed by removing individual studies in turn and observing changes in the pooled rate, which showed that the pooled rates were all within the CI of the overall pooled rate, suggesting that the results were stable.Sensitivity analysis results calculated for 7 studies were stable.
3.4、Adverse evnets
Toxicities associated with Chidamide-based treatment protocol were mentioned in 7 articles,Mainly hematological toxicities,Common adverse effects (AEs) were hematological toxicities,thrombocytopenia, anemia, and neutropenia were the most common grade 3 and 4 adverse events (AEs),6 studies including 7 groups mentioned the pooled rate of neutropenia was 25%(95% CI, 12.4-44.3%, I2 = 49%, Figure 3(A)). The pooled rate of grade 3–4 anemia was 13.9%(95% CI, 13.9-24.9%, I2 =89%, Figure 3(B)).The pooled rate of grade 3–4 thrombocytopenia was 18%(95% CI, 11.1-27.9%, I2 = 87%, Figure 3(C)).