Methotrexate for the Treatment of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Table 1

Studies included in the pooled analysis.

Study	Patients	Methotrexate	GVHD prophylaxis/treatment	Response	Survival	Toxicity	Reference
Giaccone; et al.	Steroid refractory cGVHD = 14; Progressive cGVHD = 8; Unimproved cGVHD = 5; Previously untreated; progressive cGVHD = 1	Dose = 10 (7.5–15) mg/m^2/w; Median number of doses = 25 (3–50) doses; PO = 12; IV = 2	N/A	OR: 10/14 (71%); Reduced previous; IS: = 4; Continued the same; IS: = 5; Increased previous; IS: = 4; Decided to discontinue IS: = 1	Median observation 25 w; OS: 13/14; Cause of death: relapsing leukemia = 1	Limited to grades; I-II; (i) Hematologic toxicity; (ii) Hepatic; (iii) GIT; (iv) Neurological	[35]
de Lavallade; et al.	= 20; (i) Steroid refractory aGVHD; = 12; (ii) Steroid refractory cGVHD; = 8	Dose = 5 mg/m^2/w; IV; Median number of doses = 4 doses	Prophylaxis: (i) CSA/MMF = 11; (ii) CSA = 9; Treatment: Methyl prednisolone; = 12; CSA = 8	OR: aGVHD 7/12; (5 CR and 2 PR); cGVHD 6/8; No loss of response to MTX; = 12	Median observation; 272 (22–558) days; Early death from aGVHD = 5; Disease progression; = 10	Grade ≥2 cytopenia = 14	[37]
Vettenranta; et al.	= 5; aGVHD of skin stages I-II	Dose = 7–15 mg/m^2/w; Number of doses = 2 doses	CSA/MTX	OR: 5/5	Mean observation; 10 (7–17.5) months; No mortality	G II cytopenia = 1/5	[34]
Huang; et al.	= 38; (i) aGVHD = 15 grade II; (ii) cGVHD = 17; (skin = 13, liver = 14, and thrombocytopenia = 12); (i) acute/chronic GVHD = 4; (ii) post-DLI = 2	Dose = 5–10 mg/m^2/3-4 days till response, treatment failure, toxicity, or intolerance; Total dose of MTX: (i) aGVHD 25 mg (5–60); (ii) cGVHD 40 mg; (15–70); (iii) a/c GVHD 55 mg (45–65)	CSA/MMF/MTX; = 36; CSA/methyl prednisolone = 2	Acute and acute/chronic GVHD OR: 18/19 (94.7%); Chronic and acute/chronic GVHD OR: 16/21 (76.2%); Limited cGVHD; OR: 5/9 (55.6%); Extensive cGVHD; OR: 11/12 (91.7%); Quiescent onset cGVHD; OR: 10/11 (90.9%); De novo presentation cGVHD OR: 6/10 (60%); Post-DLI cGVHD; OR: 2/2 (100%); Response by organ: (i) Skin OR 100%; (ii) Gut 75%; (iii) Mouth 75%; (iv) Eye 100%; (v) Liver 55.6%	Median follow-up; 24 (8–38) months; OS: 35/38; Causes of death: multiple organ failure, pneumonia, and relapse	Hematologic toxicity > grade II; (i) aGVHD group = 3/19 (15.8%); (ii) cGVHD group = 3/21 (14.3%)	[36]
Inagaki; et al.	= 27; (i) Steroid refractory/dependent aGVHD = 10; (ii) Steroid refractory/dependent   cGVHD = 17	Dose = 3–10 mg/m^2/w; (i) Median number of doses for aGVHD = 5 (1–7) doses; (ii) Median duration for; cGVHD = 18 months (1–68)	FK506/MTX = 17; CSA/MTX = 3; CSA = 7	OR: aGVHD 7/10; cGVHD 10/17; (CR = 4, PR = 6); Response by organ: (i) Skin OR 7/8 (88%); (ii) Gut 3/6 (50%); (iii) Liver 1/4 (25%); (iv) Eye 100%; (v) cGVHD oral mucosa 8/14 (57%); (vi) cGVHD of liver 6/11 (55%); (vii) cGVHD of skin 5/12 (42%)	Median observation; 18 (0–68) months	Grades III and IV hematologic or hepatic toxicity = 6/27	[38]
Wang; et al. 1	= 86; (i) Limited cGVHD; = 38; (ii) Extensive cGVHD = 48	Dose = 15 mg PO or; 10 mg IV Q 3-4 days; for 2 doses then Q weekly till response, treatment failure, toxicity, or intolerance; Minimum of 3 doses were given to all patients	CSA = 38; CSA/prednisone; = 25; Prednisone = 2; CSA/prednisone/MMF = 5; None = 6	OR: 71/86 (83%); CR: 53/86 (62%); Flare-up after initial response 25/71 (35%); Response to retreatment with MTX 17/25		(i) Cytopenia = grade II = 5; (ii) Oral mucosal toxicity = 7/86; (iii) No grade IV toxicity	[39]
Wang; et al. 2	= 32; First line therapy of aGVHD	Dose = 15 mg PO or; 10 mg IV Q 3-4 days; for 2 doses then Q weekly till response, treatment failure, toxicity, or intolerance	Methyl prednisone 0.5 mg/kg/day	OR: 26/32 (81%); aGVHD of skin 23/26 (88%); aGVHD of the liver 3/4 (75%); aGVHD of the gut 9/11 (81%)		Cytopenia; grade III = 3	[40]
Inagaki; et al. 2	= 35; Steroid refractory; aGVHD	10 mg/m^2 IV Q weekly; Median number of doses = 5 (1–48) doses	CSA/MTX = 4; FK506/MTX = 31	OR: = 16/35; CR: = 13/35; PR: = 3/35; aGVHD of skin = 16/23; aGVHD of liver; = 3/4; aGVHD of GIT; = 11/23	Median follow-up: 60 (7–124) months; OS: 22/35; OS at 6 months: 82.9%; OS at 12 months: 65%	Cytopenia > grade II; = 26/35; Transaminases > grade II; = 2/35; Infectious complications; = 17/35	[41]

aGVHD: acute graft-versus-host disease; cGVHD: chronic graft-versus-host disease; MTX: methotrexate; N/A: not assessable; CSA: cyclosporin A; MMF: mycophenolate mofetil; OR: overall response; CR: complete response; PR: partial response; NR: no response; IS: immune suppression; OS: overall survival.