Folinic acid administration after MTX GVHD prophylaxis in pediatric allo-SCT

Abstract

Cyclosporine (CsA) and MTX are commonly used for GVHD prophylaxis in pediatric allo-SCT. Mucositis and hepatic toxicity frequently restrict the delivery of the fourth dose of MTX. Folinic acid (FA) may ameliorate MTX toxicity. We conducted a retrospective chart review of all pediatric patients who received CsA and MTX for GVHD prophylaxis from January 2000 to July 2010. Patients treated before July 2007 (N ¼ 29) did not receive FA and those treated from July 2007 onward did receive FA (N ¼ 18). Patients who received FA were significantly more likely to receive day þ11 MTX (odds ratio (OR) 10.42, 95% confidence interval (CI): 1.21-262.27) but there was no significant difference in Grade III-IV GVHD between the two groups (OR 1.15, 95% CI: 0.08-18.14). FA did not impact relapse-free survival (RFS) (P ¼ 0.82). Increased likelihood of receiving day þ11 MTX suggests that FA ameliorates MTX toxicity, such as severe mucositis. FA administration for MTX GVHD prophylaxis should be studied in a prospective, randomized fashion. Keywords: MTX; folinic acid; GVHD INTRODUCTIONAs the annual number of transplants continues to increase worldwide, GVHD remains a leading cause of non-relapse mortality after allo-SCT. 1 Earliest efforts at utilizing immunosuppressive agents to reduce GVHD used single-agent therapy, with no notable decreases in acute GVHD when Cyclosporine (CsA) was compared with MTX. 2-4 After the successful combination of CsA and MTX in canine BM transplantation models, seminal trials in humans demonstrated the superiority of the combined regimen over CsA alone in reducing acute GVHD. [5][6][7][8] From this first report, however, it was noted that there was a significantly increased incidence of severe oral mucositis and hyperbilirubinemia in patients receiving CsA and MTX. In addition, only 58% (25/43) of the patients received full-dose MTX due to renal impairment. 7 Administration of folinic acid (FA) after MTX decreased toxicity without increasing GVHD in canine transplantation models, and later the administration of FA with MTX appeared to reduce toxicities compared with CsA alone in humans as well. 8,9 Consequently, several adult BMT studies have supported the reduction of regimen-related toxicity by the administration of FA rescue with CsA and MTX combination therapy. 10,11 Despite this, FA administration after MTX has not been widely adopted in practice. An European Group for Blood and Marrow Transplantation (EBMT) survey regarding GVHD prophylaxis and treatment in 1995 revealed that 46% (37/81) gave FA after MTX. There was considerable variation, however, in the administration schedule. 12 Similarly, a survey of allo-SCT centers in Australia and New Zealand reported that 44% (8/18) of responding centers routinely administered FA after MTX. 13 Although there are no published studies examining the effects of FA rescue with CsA and MTX combination therapy in pediatric patients, the EBMT

The effect of bone marrow graft composition on pediatric bone marrow transplantation outcomes

“…Methotrexate dosing was based on the type of donor. Patients with matched family donors received methotrexate at 5 mg/m 2 on days +1, +3, and +6 while all others received 15 mg/m 2 on days +1 followed by 10 mg/m 2 on days +3, +6, and +11 with folinic acid rescue as previously described . Patients did not receive granulocyte colony‐stimulating factor.…”

Hematopoietic stem cell transplantation for patients with acute lymphoblastic leukemia and Down syndrome

“…Due to the high TRM rate, it is not acceptable to consider HSCT as the standard treatment option for patients with DS‐ALL. Discovering appropriate GVHD prophylaxis is one of the solutions to improve survival, such as the use of folinic acid after administering the MTX dose which might allow the use of standard doses of MTX . Reducing the intensity of the conditioning regimens is another conceivable option, although it might be associated with an increased risk of ALL relapse.…”