Role of folinic acid in methotrexate-based prophylaxis of graft-versus-host disease following hematopoietic stem cell transplantation

Figures & data

Table 1. FA in MTX-based GvHD Prophylaxes for Adult Patients

Reference	Type of BMT	Conditioning intensity	Patient group	FA regimen	GvHD prophylaxis	Outcomes
						Mucositis	GvHD	Survival	Graft rejection
[10]	Full HLA MRD	MAC/RIC	140 adult patients	10 mg/m^2 IV q.6 h  × 4 doses in total, commencing 24 h post-MTX	Standard MTX 33% vs. 39% prophylactic corticosteroids	No significant association between FA and mucositis grade or duration of high-grade mucositis FA → longer total duration of mucositis, especially with 677CT transplant	No FA → earlier + more severe GvHD in patients who received a 677CC transplant	FA → decreased survival and EFS in patients administered a 1298AC transplant FA → decreased survival in patients administered a 677CT transplant FA → increased survival in patients receiving 677CC transplant	NR
[11]	MRD-BM/PB or MUD-BM/PB	MAC/RIC	118 adult patients	FA administered 12, 18, and 24 h after MTX on D1 and D3; 24, 30, and 36 h after MTX on D6 (29 patients) FA mouthwash (13%) 4× daily D1-D7	MTX + CsA (44) MTX + FK (74) MTX on D1 (15 mg TID); MTX on D3, D6 (15 mg QID): 15-10-10 mg/m^2 10-10-10 mg/m^2 10-7-7- mg/m^2	Oral mucositis incidence significantly reduced (IV FA) Tendency to reduce oral mucositis with FA mouthwash	No change in acute GvHD incidence on D100	No significant difference in non-relapse mortality	NR
[12] (Abstract)	60% MUD	MAC	65 adult patients	FA (15 mg) administered PO q.6 h × 4 doses, 12 h post-MTX on D3, D6, and D11	MTX + FA	Shorter duration	Unchanged	NR	Shorter time to neutrophil engraftment
[13] (Abstract)	68% MUD in FA group 62% MUD in control	MAC	51 adult patients	15 mg PO q.6 h × 4 doses 12 h post-MTX on D3, D6, and D11	MTX + FA	Shorter duration Suggested lower incidence	Unchanged	NR	Unchanged
[14]	Related	NR in abstract	32 adult patients	NR in abstract	MTX + CsA Broad-spectrum antibiotics	Lower incidence of regimen-related toxicity (somatic/hepatic)	No difference in Grade II-IV GvHD incidence No difference in chronic GvHD	EFS unchanged	Shorter time to engraftment
[15]	19% MMD and/or UD	NR in abstract	69 adult patients	5 mg q.6 h, starting 24 h post-MTX and continuing until 6 h before the next MTX dose	Standard MTX + CsA	Improved tolerance to MTX, all doses given	No effect on GvHD prevention by MTX	NR	NR
[16]	MSD	MAC	57 adult patients	1:1 with MTX, 24 h post-MTX	26 CsA 31 MTX + FA Standard MTX	NR	No increase in GvHD with MTX + FA compared to CsA Reduced renal/hepatic toxicity with MTX + FA.	NR	NR
[16]	29% MSD in FA group 37% MSD in control group Remaining % MUD	MAC	52 adult patients	15 mg t.i.d., started 24 h post-MTX 15 mg q.i.d. on D3, D6	Standard MTX + CsA + ATG for MUDs	No significant difference in rate, duration, or severity with FA compared to placebo	No significant difference in rate of acute or chronic GvHD	No significant difference in OS at 9 months FU	NR
[17]	NA	NA	Pediatric and adult centers	NA	NA	Examination of the use of FA in 18 transplantation centers in Australia and New Zealand in 2004-2005. 66% used FA routinely
[18]	NA	NA	Pediatric and adult centers	NA	NA	Survey of GvHD prophylaxis use in EBMT centers in 1994-1995. 93% of centers used MTX + CsA 42% of centers administered FA after MTX

Abbreviations:

• Standard MTX = 15 mg/m² on D1 and 10 mg/m² on D3, D6, and D11

• Type of BMT: MSD (matched sibling donor), MRD (matched related donor), MUD (matched unrelated donor), and MMU (mismatched unrelated)

• Conditioning intensity: MAC (myeloablative conditioning) vs. RIC (reduced intensity conditioning)

NR = not reported, NA = not applicable, D = day, LD = low dose, HD = high dose, FA = folinic acid, MTX = methotrexate, EFS = event-free survival, RFS = relapse-free survival, CsA = cyclosporine A, VP = etoposide, FK = tacrolimus, TBI = total body irradiation, CY = cytarabine

Selection Criteria: Journal articles and conference abstracts detailing human studies of MTX in combination with FA published before March 2020 were included. Individual characteristics such as conditioning, type of BMT, MTX and FA dose, and study outcomes did not affect inclusion/exclusion.

Table 2. FA in MTX-based GvHD Prophylaxes for Pediatric Patients

Reference	Type of BMT	Conditioning Intensity	Patient group	FA dose	GvHD prophylaxis	Outcomes
						Mucositis	GVHD	Survival	Graft rejection
[23]	23 MRD 88 MUD	MAC	111 pediatric patients	LD-FA: 4 × 15 mg/m^2 IV, 24 h post-MTX HD-FA: MTX1: 3 × 15 mg/m^2 IV starting 12 h post-MTX MTX2: 6 × 10 mg/m^2 IV starting 12 h post-MTX MTX 3 + 4: 8 × 10 mg/m^2 IV starting 24 h post-MTX	Standard MTX + FK Standard MTX + CsA	No difference in stomatitis severity	Peak ALT lower with HD-FA	No difference in 3-year survival	Shorter time to neutrophil engraftment with HD-FA compared to LD-FA No association with graft rejection
[24]	MUD/MRD/MMU	MAC	47 pediatric patients	15 mg/m^2 IV 12 h post-MTX	Standard MTX + CsA	Increased likelihood of receiving day +11 MTX (94% vs 48%)	No effect on Grade III-IV GvHD risk All MMU-BM patients received FA (suggesting that FA eliminated GvHD risk in these patients)	No effect on RFS	NR
[25]	27 HLA-MRD, 41 MUD, 19 MM	MAC (sub-study of RIC)	87 pediatric patients	10 mg/m^2 1: Daily from D −1 2: D −1, +2, +4, +7, +8, +9, +12, and then daily 3: Late – starting D +15	MTX + CsA (53%), Also, CsA + prednisolone, FK + sirolimus, and other combinations	NR	No correlation between FA administration and GvHD ≥ Grade II Late administration of FA had no impact on GvHD	No association between FA and relapse	Higher FA dose until D +21 → graft rejection RIC patients: higher FA dose → graft rejection Late administration of FA had no impact on rejection
[22]	NA	NA	Pediatric centers	NA	NA	Report on GvHD prophylaxis strategies Most use MTX + CsA FA is used to avoid MTX side effects Agreed dose of 15 mg/m^2 daily, starting 24 h post-MTX

Abbreviations:

• Standard MTX = 15 mg/m² on D1 and 10 mg/m² on D3, D6, and D11

• Type of BMT: MSD (matched sibling donor), MRD (matched related donor), MUD (matched unrelated donor), and MMU (mismatched unrelated)

• Conditioning intensity: MAC (myeloablative conditioning) vs. RIC (reduced intensity conditioning)

NR = not reported, NA = not applicable, D = day, LD = low dose, HD = high dose, FA = folinic acid, MTX = methotrexate, EFS = event-free survival, RFS = relapse-free survival, CsA = cyclosporine A, VP = etoposide, FK = tacrolimus, TBI = total body irradiation, CY = cytarabine

Selection Criteria: Journal articles and conference abstracts detailing human studies of MTX in combination with FA published before March 2020 were included. Individual characteristics such as conditioning, type of BMT, MTX and FA dose, and study outcomes did not affect inclusion/exclusion.

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