The efficacy and adverse events of arsenic trioxide for the patients with myelodysplastic syndrome: a systematic review and component network meta-analysis

Figures & data

Figure 1. PRISMA flow diagram.

Table 1. Patient characteristics and trail quality assessment.

Trail	Treatment group		Control group		WHO Type(T/C)^a		Risk Category(T/C)^b		Risk of bias^c
	n1 (M/F)	Age 1	n2 (M/F)	Age 2	Not MDS-EB	MDS-EB	Lower Risk	Higher Risk	A	B	C	D	E	F
Bu [12]	51(31/20)	43.00	51(28/23)	45.00	–	–	51/51	0/0
Zeng [13]	20(14/6)	66.55	20(11/9)	–	–	–	20/20	0/0
Zeng [14]	43(26/17)	45.13	43(26/17)	44.98	35/34	8/9	–	–
Chen [15]	30(18/12)	–	29(17/12)	–	0/0	30/30	0/0	30/30
Dang [16]	38(19/19)	48.50	38(21/17)	45.50	23/26	15/12	–	–
Deng [17]	22(13/9)	54.40	23(13/10)	–	–	–	22/23	0/0
Guo [18]	20(11/9)	54.00	20(10/10)	56.00	0/0	20/20	–	–
Guo [19]	38(27/11)	51.00	38(25/13)	53.00	0/0	38/38	12/9	26/29
Huang [20]	30(18/12)	57.89	30(19/11)	56.43	20/21	10/9	–	–
Li [21]	27(14/13)	60.50	27(13/14)	58.40	0/0	27/27	–	–
Li [22]	34(26/8)	–	30(17/13)	–	8/8	27/22	–	–
Li [23]	51(28/23)	66.74	51(33/18)	66.74	0/0	51/51	0/0	51/51
Li [24]	25(16/9)	68.10	23(14/9)	70.30	12/16	13/7	13/11	12/12
Liang [25]	26(15/11)	62.30	26(16/10)	61.60	13/16	13/10	–	–
Liang [26]	26(15/11)	43.28	26(13/13)	48.36	20	32	26/26	0/0
Liu [27]	40(28/12)	53.50	42(29/13)	54.70	0/0	40/42	13/10	27/32
Liu [28]	26(17/9)	50.90	15(11/4)	51.00	–	–	–	–
Luo [29]	30(18/12)	42.79	30(16/14)	42.23	30/30	0/0	–	–
Su [30]	15(9/6)	53.00	14(8/6)	53.00	9/8	6/6	–	–
Sun [31]	30(18/12)	–	28(16/12)	–	0/0	30/28	–	–
Tian [32]	14(–/–)	–	13(–/–)	–	19	8	–	–
Wang [33]	22(14/8)	58.00	22(13/9)	61.00	10/12	12/10	–	–
Wang [34]	30(17/13)	47.98	30(16/14)	49.65	–	–	–	–
Wang [35]	42(23/19)	48.92	43(22/21)	50.25	–	–	–	–
Wang [36]	23(–/–)	–	23(–/–)	–	34	12	–	–
Wu [37]	12(7/5)	–	13(8/5)	–	0/0	12/13	0/0	12/13
Yang [38]	20(11/9)	–	34(20/14)	–	9/21	11/13	–	–
Yu [39]	5(2/3)	48.80	5(3/2)	49.90	–	–	–	–
Zhang [40]	20(11/9)	58.00	20(10/10)	61.00	0/0	20/20	–	–
Zhang [41]	17(–/–)	–	17(–/–)	–	–	–	0/0	17/17
Zhang [42]	21(14/7)	67.00	20(13/7)	65.00	0/0	21/20	0/0	21/20
Zhao [43]	30(18/12)	59.10	30(20/10)	60.50	13/15	17/15	–	–
Zhao [44]	40(27/13)	66.34	40(28/12)	66.14	–	–	24/25	16/15
Zhong [45]	34(18/16)	45.49	34(19/15)	44.26	21/21	13/13	–	–
Zhu [46]	35(20/15)	51.50	35(19/16)	51.30	–	–	–	–
Zuo [47]	20(11/9)	55.00	20(10/10)	53.00	0/0	20/20	0/0	20/20
Kropf [10]	23(–/–)	–	8(–/–)	–	–	–	23/8	0/0
Wei [11]	22(15/7)	57.09	22(10/12)	62.32	6/6	16/16	17/16	5/6
Zhang [48]	20(12/8)	59.47	20(13/7)	59.76	0/0	20/20	–	–

^a WHO Type: Based on the 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia, and MDS with excess blasts (MDS-EB) was defined as a subset with bone marrow excess blast over 5%.

^b Risk category: Lower risk included WPSS very low, low, intermediate, IPSS low or intermediate-1, IPSS-R very-low-, low-, intermediate-risk disease, while high risk included WPSS high, very high, IPSS intermediate-2, high, IPSS-R intermediate-, high-, very-high-risk disease [49].

^c Risk of bias: A: Randomization process, B: Deviations from intended interventions, C: Missing outcome data, D: Measurement of the outcome, E: Selection of the reported result, F: Overall. : Low risk, : Some concerns, : High risk. T/C: Treatment group/Control group. M/F: Male/Female.

Table 2. Treatment and efficacy.

Trail	ATO dosage^a		Treatment group regimen^b	Control group regimen^b	Efficacy criteria^c	Efficacy(T/C)^d
	mg/d	frequency				CR	PR	HI
Bu [12]	10	intermittent	ATO + T	T	②	0/0	0/0	32/26
Zeng [13]	10	intermittent	ATO + T + TCM	ATO + T	③	0/0	0/0	12/9
Zeng [14]	10	continuous	ATO + T	T	①	12/7	10/9	13/8
Chen [15]	10	intermittent	ATO + TCM	ATO	①	5/1	6/3	19/8
Dang [16]	10	continuous	ATO + T	ATO	③	5/2	8/3	16/10
Deng [17]	10	intermittent	ATO + T	ATO	③	5/2	1/2	7/8
Guo [18]	10	continuous	ATO	STonly	③	0/0	2/0	10/5
Guo [19]	10	continuous	ATO + Chem	Chem	①	17/14	10/8	7/5
Huang [20]	10	intermittent	ATO + T	T	③	9/13	14/15	NR
Li [21]	10	intermittent	ATO	Chem	③	9/8	7/9	4/5
Li [22]	7/m^2	intermittent	ATO + HMA	ATO	②	1/0	3/2	19/10
Li [23]	10	intermittent	ATO + Chem	Chem	①	24/18	16/13	NR
Li [24]	10	intermittent	ATO + Chem	Chem	①	2/1	9/6	8/5
Liang [25]	10	intermittent	ATO + T	STonly	③	10/7	5/2	4/3
Liang [26]	10	NR	ATO + T	T	①	10/4	8/7	5/8
Liu [27]	10	intermittent	ATO + Chem	Chem	①	18/15	11/9	7/6
Liu [28]	10	continuous	ATO + T	STonly	②	0/0	6/0	11/11
Luo [29]	10	NR	ATO + T	T	②	11/5	8/6	0/0
Su [30]	10	intermittent	ATO + T	ATO	③	2/0	4/1	8/7
Sun [31]	10	intermittent	ATO + TCM	ATO	③	2/1	6/5	11/4
Tian [32]	10	continuous	ATO + T	Chem	③	2/0	4/0	5/4
Wang [33]	10	continuous	ATO + T	Chem	③	5/0	6/2	8/7
Wang [34]	10	continuous	ATO + T	T	②	8/5	9/7	8/6
Wang [35]	10	continuous	ATO + T	T	③	12/7	13/9	0/0
Wang [36]	10	continuous	ATO + T	ATO	③	2/0	4/3	14/11
Wu [37]	10	continuous	ATO	Chem	③	7/3	3/4	9/6
Yang [38]	10	continuous	ATO	Chem	②	2/1	3/1	8/6
Yu [39]	10/m^2	continuous	ATO + T	T	③	1/1	2/1	2/1
Zhang [40]	10	intermittent	ATO	Chem	①	7/6	6/5	5/3
Zhang [41]	10	intermittent	ATO + T	Chem	③	2/0	4/2	5/4
Zhang [42]	10	intermittent	ATO + T	Chem + T	③	2/0	5/2	6/4
Zhao [43]	10	continuous	ATO + T	STonly	③	7/0	8/4	10/9
Zhao [44]	10	continuous	ATO + T	Chem	③	17/5	10/15	10/10
Zhong [45]	10	continuous	ATO + T	T	①	9/4	10/8	9/8
Zhu [46]	10	continuous	ATO + T	T	②	15/8	9/10	0/0
Zuo [47]	10	intermittent	ATO + Chem	Chem	③	9/6	5/4	3/3
Kropf [10]	0.15/kg	continuous	ATO + HMA	HMA	③	Total 12/3		NR
Wei [11]	10	intermittent	ATO + T	STonly	③	1/0	3/0	9/6
Zhang [48]	10	continuous	ATO + HMA	HMA	③	6/4	7/2	0/0

^a ATO intermittent administration means the drug would be injected for 2 weeks subsequently with 2 weeks for rest, while the continuous administration means continuous injection for 2–4 weeks.

^b ATO: arsenic trioxide, Chem: Chemotherapy, HMA: Hypomethylating agent, T: Thalidomide, TCM: Traditional Chinese Medicine, STonly: Supportive therapy only.

^c Efficacy criteria include ① Diagnosis and efficacy criteria of hematological disease (version 2) [50], ② International Working Group (IWG) 2001 response criteria [51], ③ International Working Group (IWG) 2006 response criteria [52].

^d T/C: Treatment group/Control group, CR: complete remission, PR: partial remission, HI: hematological improvement, AEs: adverse events, NR: Not recorded.

Figure 2. Network graph: ATO: Arsenic trioxide, Chem: Chemotherapy, HMA: Hypomethylating agent, T: Thalidomide, TCM: Traditional Chinese Medicine, STonly: Support therapy only. CR: complete remission, PR: partial remission, HI: hematological improvement, AEs: adverse events.

Figure 3. Forest plot of treatment efficacy: ATO: Arsenic trioxide, Chem: Chemotherapy, HMA: Hypomethylating agent, T: Thalidomide, TCM: Traditional Chinese Medicine, STonly: Support therapy only. CR: complete remission, PR: partial remission, HI: hematological improvement, AEs: adverse events. NMA: network meta-analysis, CNMA: component network meta-analysis.

Table 3. The relative rank of different treatment (SUCRA)

Intervention^a	CR^b	Intervention^a	ORR^b	Intervention^a	HI^b
ATO + T	0.79	ATO + T + TCM	0.88	ATO + TCM	0.92
ATO + TCM	0.73	ATO + HMA	0.86	ATO + HMA	0.81
ATO + HMA	0.65	ATO + TCM	0.82	ATO + T + TCM	0.69
ATO + T + TCM	0.65	ATO + T	0.75	HMA	0.62
T	0.56	HMA	0.47	ATO + T	0.48
HMA	0.51	T	0.47	ATO	0.47
STonly	0.50	ATO + Chem	0.45	ATO + Chem	0.42
ATO	0.35	ATO	0.33	STonly	0.35
ATO + Chem	0.31	Chem + T	0.22	Chem + T	0.26
Chem + T	0.31	Chem	0.14	T	0.26
Chem	0.16	STonly	0.10	Chem	0.21

^a ATO: Arsenic trioxide, Chem: Chemotherapy, HMA: Hypomethylating agent, T: Thalidomide, TCM: Traditional Chinese Medicine, STonly: Support therapy only.

^b CR: complete remission, PR: partial remission, HI: hematological improvement.

Table 4. The model characteristic of different endpoint and the effect of component

Outcome, model and component	OR(95%CI)	P
ORR (additive model vs standard model, Q = 2.79, df = 5, P = 0.733)
standard model (Q = 23.36, df = 29, P = 0.760)
additive model (Q = 26.14, df = 34, P = 0.830), $I^2=0\text{\%}$
ATO	2.09(1.61, 2.71)	<0.000
Chem	1.20(0.70, 2.06)	0.509
HMA	4.18(1.47, 11.89)	0.007
T	2.62(1.63, 4.23)	<0.000
TCM	3.08(1.60, 5.93)	0.001
CR (additive model vs standard model, Q = 3.19, df = 5, P = 0.671)
Standard model (Q = 13.53, df = 28, P = 0.990)
Additive model (Q = 16.72, df = 33, P = 0.991), $I^2=0\text{\%}$
ATO	1.66(1.25, 2.21)	0.001
Chem	0.81(0.42, 1.57)	0.534
HMA	2.73(0.11, 69.60)	0.543
T	2.32(1.23, 4.37)	0.009
TCM	2.89(0.63, 13.23)	0.171
HI (additive model vs standard model, Q = 1.19, df = 5, P = 0.946)
standard model(Q = 17.05, df = 26, P = 0.908)
additive model (Q = 18.24, df = 31, P = 0.967), $I^2=0\text{\%}$
ATO	1.33(0.96, 1.84)	0.089
Chem	0.89(0.50, 1.56)	0.678
HMA	2.53(0.92, 7.01)	0.073
T	0.98(0.64, 1.46)	0.887
TCM	3.17(1.58, 6.37)	0.001
AEs (additive model vs standard model, Q = 1.52, df = 3, P = 0.678)
Standard model (Q = 12.40, df = 17, P = 0.775)
Additive model (Q = 10.89, df = 14, P = 0.695), $I^2=0\text{\%}$
ATO	0.90(0.67,1.21)	0.485
Chem	3.11(0.97,9.98)	0.056
T	1.32(0.73,2.41)	0.356
TCM	0.34(0.15,0.76)	0.008

ATO: Arsenic trioxide, Chem: Chemotherapy, HMA: Hypomethylating agent, T: Thalidomide, TCM: Traditional Chinese Medicine, STonly: Support therapy only. CR: complete remission, PR: partial remission, HI: hematological improvement.

Figure 4. Forest plot for CNMA: Supportive therapy was treated as reference. ATO: Arsenic trioxide, Chem: Chemotherapy, HMA: Hypomethylating agent, T: Thalidomide, TCM: Traditional Chinese Medicine. CR: complete remission, PR: partial remission, HI: hematological improvement, AEs: adverse events.

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