Methotrexate dose delivery is more important than ciclosporin level in graft-versus-host disease prophylaxis following T-replete reduced-intensity sibling allogeneic stem cell transplant

Abstract

We investigated the contributions of methotrexate (MTX) and ciclosporin (CsA) prophylaxis to acute/chronic graft-versus-host disease (a/cGvHD) prevention following reduced-intensity conditioned allogeneic haematopoietic stem cell transplant (HSCT). Ninety-two fludarabine-melphalan sibling allo-SCT received CsA. Nine, 30 and 47 patients received no MTX, 2-3 doses and 4 doses, respectively. Cumulative CsA blood level to day 21 (CsA(21)) was calculated. Grades II-IV aGvHD incidence was 37.2%. In multivariate analysis, MTX omission and increasing donor age significantly associated with aGvHD incidence whilst MTX reduction and CsA(21) did not. Median duration of first immunosuppressive therapy (IST) for aGvHD was 68 days; duration of first IST was significantly longer in older patients but was not associated with MTX or CsA(21). Extensive cGvHD incidence was 60.6% at 1 year. Reduction of MTX to 2-3 doses, but not MTX omission or CsA(21), was associated with greater incidence of cGvHD affecting ≥3 organs. Median IST duration was 22 months; neither MTX nor CsA(21) influenced this. IST duration was significantly greater in patients receiving a CD34 dose below median. Neither MTX nor CsA(21) altered survival or relapse outcomes. MTX influences GvHD following T-replete RIC sibling HSCT.

Predictors and outcomes of dose reduction of methotrexate and cyclosporin graft‐versus‐host disease prophylaxis following allogeneic haemopoietic cell transplantation

“…12 Medd et al found MTX dose omission, but not reduction, significantly increased incidence of grades 2-4 acute GVHD in reduced-intensity conditioned sibling allogeneic transplants. 29 Conversely, others have shown no difference in incidence of acute GVHD in any grade; however, used a lower dosing regimen and tacrolimus instead of CYA. 11 Our findings of poorer survival associated with MTX omission have been replicated more consistently in previous work.…”

Evaluation of risk for graft-versus-host disease in children who receive less than the full doses of mini-dose methotrexate for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplantation

“…The overall effect of these omissions on subsequent acute and chronic GVHD incidence remains unclear. An earlier study showed that omission of the final day 11 MTX did not adversely affect incidence of severe acute GVHD and chronic GVHD 8) , while 2 later reports showed a greater risk for GVHD in patients who were not given all planned doses of MTX 9 , 10) . The majority of the patients in these 3 reports were adult recipients of HSCT.…”