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Impact of Renally Adjusted Methotrexate Dosing on Safety and Efficacy Outcomes in Allogeneic Hematopoietic Cell Transplant Patients

Year: 2024

Type: article

Abstract: Tacrolimus (TAC)/methotrexate (MTX) is an important regimen for graft versus host disease (GVHD) prophylaxis. Standard MTX dosing is 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6 and +11 (Ratanatharathorn 1998). Dose modifications or omissions may be warranted due to HCT- or MTX-related toxicities. Reducing or omitting MTX has shown to negatively impact GVHD incidence and no standard exists (Martinez-Cibrian 2021; Bensinger 2006). At Moffitt Cancer Center, standard dosing for TAC/MTX GVHD prophylaxis consists of full dose MTX (above). In renally impaired recipients, empiric dose adjustments are applied based on creatinine clearance (CrCL). We aimed to validate this renal protocol and its impact on GVHD development, relapse, or death from any cause post allogenic (allo) hematopoietic cell transplantation (HCT). We retrospectively analyzed 314 adult allo HCT recipients who received >/= 1 planned MTX dose for GVHD prophylaxis. Patients were categorized into 3 dose cohorts: standard (dose as above, N=206), renally adjusted (per Day+1 CrCL, N=71), and reduction/omission due to toxicity (N=37). The primary endpoint was the composite endpoint of GRFS (GVHD, Relapse Free Survival (RFS)) between the standard and renally adjusted cohorts (Holtan 2015). Multivariable analyses (MVA) were conducted for all outcomes to control for baseline characteristics. The dose reduction/omission cohort was included as a post hoc analysis. Patients included were primarily leukemia/myelodysplastic syndromes who received a matched donor, peripheral blood HCT using myeloablative conditioning (Table 1). Median follow-up was 37.3 months. Median GRFS was 6.8 months in the renally adjusted versus 8.1 months in the standard cohort (p=0.3, Figure 1C). On MVA, only KPS and rising bilirubin were associated with worsening GRFS. A similar incidence of grade II-IV acute GVHD (p=0.98), and moderate-severe chronic GVHD (p=0.86) was seen across all three cohorts (figure 1A-1B). A lower incidence of all grade (77% vs 92%, p=0.001) and grade III-IV (49% vs 61%, p=0.022) mucositis was found in the renally adjusted compared to standard cohort, respectively. RFS and OS were shorter in the renally adjusted cohort compared to standard dose (25.7 vs 52.5 months, p=0.047, and 52.7 months vs not reached, p=0.035, Figure 1D), respectively. Non-relapse mortality was found to be negatively impacted by serum creatinine elevations. In our evaluation, we did not see a significant impact on GRFS with renally adjusted MTX compared to standard dose. RFS and OS were shorter with the renally adjusted cohort, possibly related to differences in baseline characteristics. Renally adjusted MTX was associated with lower incidence and severity of mucositis. These results support the use of our renal protocol and should be validated prospectively in a homogenous population.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2023.12.363