Association of cytotoxic T-lymphocyte antigen-4 (CTLA-4) single nucleotide polymorphism in donors with clinical outcome after allogeneic hematopoietic stem cell transplantation: a meta-analysis

Figures & data

Figure 1. Flow diagram for study selection according to PRISMA.

Table 1. Characteristics of studies included in the meta-analysis.

Study	Country	Patients’ Age (y)	No of patients(n)	Patients’ sex (n)	Donor type	Underlying diseases	Conditioning intensity	GVHD prophylaxis	Genotype method	HWE	NOS score
Perez-Garcia,2007[15]	Spanish	34(0-59)	536	311 M 255 F	MSD	AML (163); ALL (124); CML (158); MDS (34); NHL (35); others (22)	Cy + TBI (206); Bu + Cy (308); others (20)	CsA + MTX (485); CsA (29); CsA + MTX + corticosteroids (2); CsA + corticosteroids (20)	PCR-RFLP	Y	8
Azarian,2007[16]	French	23(1-56)	225	82 M 143 F	MSD	AML (54); ALL (60); CML (45); MDS (21); AA (24); NHL (8); others (13)	Myeloablative	CsA + MTX	PCR-RFLP	N/A	6
Vannucchi,2007[17]	Italian	N/A	147	N/A	MUD	N/A	Myeloablative	CsA + MTX + ATG	PCR-RFLP	N/A	6
Piccioli,2010[18]	Italian	40(17-65)	133	87 M 46 F	MSD	AML (39); ALL (17); MDS (11); CML (44); others (22)	Myeloablative with TBI (81); Myeloablative without TBI (45); RIC (7)	CsA + MTX	T-ARMS-PCR	Y	8
Sellami,2011[19]	Tunisian	21.85(4-49)	112	63 M 49 F	MSD	AML (37); ALL (23); CML (9); AA (18); others (25)	Bu + Cy (48); TBI + Cy (14); TBI+ vp-16 (13); Bu + Cy + ATG (8); Flu + Cy (6); others (23)	CsA +/- MTX (88); CsA (24)	SSP-PCR	Y	7
Bosch-Vizcaya,2012[20]	Spanish	40(17-59)	136	75 M 61 F	MSD	Acute leukemia/MDS (87); others (48)	TBI (90); others (46)	CSA (80); CsA + MTX (17); CSA + corticosteroids (30); others (9)	PCR-RFLP	Y	8
Harkensee,2012[21]	Japanese	4–40	460	269 M 191 F	MUD/MMUD	ALL (266); others (200)	Cy + TBI (334); Bu/Cy (53); TBI based (73)	CsA based (279); tacrolimus based (177); others (4)	Taqman	N/A	7
Orru,2012[22]	Italian	12.9(5-20)	72	41 M 31 F	MUD	thalassemia	Bu + thiotepa + Flu (43); Bu + thiotepa + Cy (29)	CsA + MTX	Sequence	Y	8
Xiao,2012[23]	Chinese	27(10-52)	138	68 M 70 F	UD	AML (54); ALL (44); CML (35); MDS (3); others (2)	Myeloablative (120); Reduced intensity (18)	CsA + MTX + MMF	Taqman	Y	7
Mossallam,2013[24]	Egyptian	34(2-54)	94	55 M 39 F	MRD	AML (59); MDS (15); CML (20)	Bu/Cy (4); Bu/Flu (72); Flu/Melphalan (18)	Cy/MTX (76); Cy/MMF (18)	PCR-RFLP	Y	7
Karabon,2015[25]	Poland	33(18-57)	302	166 M 146 F	Mixed	AML (148); ALL (66); MDS (19); CML (18); AA (17); others (44)	Myeloablative (190) Reduced toxicity myeloablative (86); RIC (29); ATG + Cy (7)	N/A	Taqman	Y	7
Qin,2016[26]	Chinese	23(2-55)	152	85 M 67 F	MMRD	AML (69); ALL (83)	Myeloablative	CsA + MTX + MM	Taqman	Y	7
Cunha,2017[27]	Mixed	16(0.3-69)	696	389 M 307 F	CBT	AML (220), ALL (274), MDS (72); CML (34); CLL (5); lymphoma (55); others (36)	Myeloablative (556); Nonmyeloablative (130)	CsA +/- others (596); MTX +/- others (30); thoers (13)	Taqman	Y	8
Hammrich,2019[28]	German	11(0.7-23)	88	51 M 37 F	Mixed	AML (30), ALL(58)	TBI 45; Bu 38; Treosulfan 5	CsA only 18; CsA + MTX 65; others 5	Taqman	Y	6
Romaniuk,2019[29]	Russian	32(19-60)	33	9 M 24 F	MUD	AML (20), ALL(13)	RIC 20, MAC (13)	ATG + CsA + MMF + MTX	Sequencing	Y	7

F: female, M: male, PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism, SSP-PCR: sequence-specific primers polymerase chain reaction, T-ARMS-PCR: tetra-primer amplification refractory mutation system polymerase chain reaction, MSD: HLA-matched sibling donor, MUD: HLA matched unrelated donor, MRD: HLA matched related donor, MMUD: HLA mismatched unrelated donor, CBT: unrelated cord blood transplantation, N/A: not recorded or available, AML: acute myeloid leukemia, ALL: acute lymphoid leukemia, CML: chronic myeloid leukemia, NHL: non-Hodgkin’s lymphoma, CLL: chronic lymphoid leukemia, MDS: myelodysplastic syndrome, AA: aplastic anemia, RIC: reduced intensity conditioning, MAC: myeloablative conditioning, CsA: cyclosporine, Bu: busulfan, Flu: fludarabine, MTX: methotrexate, MMF: mycophenolate mofetil, Cy: cyclophosphamide, ATG: Anti-Thymocyte Globulin, TBI: total body irradiation, HWE: Hardy-Weinberg equilibrium (‘Y’ means conformity with HWE, P > 0.05).

Figure 2. Forest plots of CTLA-4 + 49A/G polymorphism with cGVHD risk in recessive model(GG vs GA + AA).

Table 2. Meta-analyses results of the association between CTLA-4 polymorphisms and transplant outcome.

Genotype	Comparison	No. of studies	Outcome	Association OR (95%CI)				Heterogeneity		Publication bias
				HR/OR	95%CI	P value	Model	I^2(%)	P value	P value Begg	P value Egger
+49A/G	GG + GA vs AA	6	OS	0.829	0.617-1.113	0.211	F	0	0.572	0.707	0.442
		3	aGVHD	1.147	0.757-1.738	0.519	F	0	0.995	0.296	0.431
		4	cGVHD	1.279	0.702-2.329	0.421	F	26.5	0.253	0.308	0.359
		3	Relapse	0.425	0.109-1.654	0.217	R	83.1	0.003	1.000	0.183
		2	DFS	1.523	0.603-3.846	0.373	F	41.1	0.193	NA	NA
+49A/G	GG vs GA + AA	3	OS	1.753	0.907-3.388	0.095	R	64.4	0.060	0.296	0.318
		2	aGVHD	1.362	0.673-2.755	0.390	R	70.5	0.066	NA	NA
		2	II-IV aGVHD	1.802	0.578-5.617	0.310	F	34.7	0.216	NA	NA
		4	cGVHD	1.701	1.124-2.573	0.012	F	34.7	0.204	0.734	0.743
		3	DFS	0.869	0.458-1.646	0.666	F	0	0.945	1.000	0.437
CT60	GG + GA vs AA	3	OS	1.440	1.045-1.984	0.026	F	0	0.621	1.000	0.088
		4	II-IV aGVHD	0.787	0.570-1.085	0.143	F	0	0.449	0.308	0.135
		3	III-IV aGVHD	0.619	0.426-0.899	0.012	F	0	0.415	1.000	0.979
		3	cGVHD	0.919	0.384-2.203	0.850	R	56.1	0.102	0.396	0.227
		3	Relapse	0.583	0.166-2.052	0.401	R	88.7	0.000	1.000	0.214
		3	DFS	0.611	0.345-1.082	0.091	R	69.5	0.038	1.000	0.932
CT60	GG vs GA + AA	3	OS	1.422	1.080-1.872	0.012	F	0	0.474	0.296	0.708
		2	cGVHD	0.592	0.194-1.809	0.358	R	56.7	0.129	NA	NA
		2	Relapse	1.188	0.961-1.468	0.111	F	0	0.950	NA	NA
		3	DFS	0.841	0.461-1.534	0.572	R	84.8	0.001	1.000	0.371

F: Fixed Effects Model; R: Random Effects Model. No of studies: numbers of studies used in each analysis.

Figure 3. (a) Forest plots of CTLA-4 CT60 polymorphism and overall survival in dominant model(GG + GA vs AA). (b) Forest plots of CTLA-4 CT60 polymorphism and the occurrence of III-IV aGVHD in dominant model (GG + GA vs AA). (c) Forest plots of CTLA-4 CT60 polymorphism and overall survival in recessive model (GG vs GA + AA).

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