Leucovorin Following Methotrexate Graft-Vs-Host Disease Prophylaxis in Myeloablative Allogeneic Hematopoietic Transplantation Shortens the Duration of Mucositis and Hospitalization
Authors: Freyer Craig W. , Ganetsky Alex , Timlin Colleen , Babushok Daria V. , Frey Noelle V. , Gill Saar I. , Hexner Elizabeth O. , Loren Alison W. , Mangan James K. , Martin Mary Ellen , McCurdy Shannon R. , Perl Alexander E. , Luger Selina , Smith Jacqueline , Stadtmauer Edward , Porter David L. 
Published: October 2019

Abstract
Introduction: Grade 2-4 mucositis is a major complication after myeloablative (MAC) allogeneic hematopoietic transplantation (HCT) in about 90% of patients. Graft-vs-host-disease (GVHD) prophylaxis with methotrexate (MTX) exacerbates mucositis and delays engraftment. Severe mucositis precludes administration of all 4 MTX doses which increases the risk of GVHD and can prolong hospitalization due to infection, pain control, and the use of total parenteral nutrition (TPN). Leucovorin (LCV) prophylaxis following MTX is advised by the EBMT-ELN adult working group, but not universally accepted given the absence of prospective trials. Our group implemented routine LCV prophylaxis following MAC alloHCT with MTX GVHD prophylaxis in 8/2017. We compared the outcomes of these patients with historical controls.
Methods: We treated 22 consecutive adults receiving MAC alloHCT with MTX GVHD prophylaxis with LCV 15 mg PO q6h x 4 doses, starting 12 h after the d +3, +6, and +11 MTX doses. Twenty-nine consecutive patients undergoing similar MAC conditioning and MTX GVHD prophylaxis were retrospectively identified as the control. Routine LCV was not given to control patients, but could have been added following d +6 or +11 MTX to limit toxicity at physician discretion. The primary endpoint was the incidence of grade 2-4 mucositis. Secondary endpoints included the duration of grade 2-4 mucositis, time to engraftment, incidence of neutropenic fever (NF) and bacteremia pre-engraftment, duration of antibacterials for NF, ability to receive all MTX doses, incidence and duration of TPN and patient-controlled analgesia (PCA) use, duration of hospitalization, incidence of acute and chronic GVHD, graft failure, and relapse.
Results: Baseline characteristics between the two groups were similar (table 1). All patients received tacrolimus and MTX GVHD prophylaxis with the majority receiving Cy/TBI conditioning. Approximately 30% of controls received ≥ 1 dose of LCV (most following d +11 MTX) to limit toxicity. Although the incidence of grade 2-4 mucositis was similar with between groups (82% vs 91%, p = 0.38), a lower incidence of grade 3-4 mucositis was observed with LCV, although this did not reach statistical significance (32% vs. 55%, p = 0.16). The LCV group had a significantly shorter duration of grade 2-4 mucositis (5.6 vs. 9.7 d, p = 0.01) and less frequent PCA use (32% vs. 62%, p = 0.048). The LCV group needed TPN less often (18% vs. 38%, p = 0.21) and when needed, had a shorter duration of TPN (10 vs. 21 d, p = 0.15), although these findings did not reach statistical significance. The LCV group had a significantly shorter duration of hospitalization (28 d vs. 33.7 d, p = 0.03). Platelet engraftment seemed to be more rapid (16.5 vs 22.2 d, p = 0.097) without reaching statistical significance. The addition of LCV did not appear to impact the incidence of acute GVHD (grade 2-4: 23% vs. 14%, p = 0.47; grade 3-4 14 % vs 3%, p = 0.3) by d +100 or chronic GVHD at 1 year (14% vs. 21%, p = 0.44). No differences were observed in the time to neutrophil engraftment, or in the incidence of nephrotoxicity, hepatotoxicity, graft failure, or relapse between the arms. No other obvious practice change was implemented during the study period that would have been anticipated to impact any of these endpoints.
Conclusions: The addition of LCV to MAC alloHCT with MTX GVHD prophylaxis resulted in significant reductions in the duration of grade 2-4 mucositis, frequency of PCA use, and duration of hospitalization compared to a similar historical control. We also observed less frequent grade 3-4 mucositis, more rapid platelet engraftment and less TPN use with LCV, but these findings did not reach statistical significance. Our sample size was small, which may have limited our power to detect small differences between the groups. In addition, about 30% of controls received at least 1 dose of LCV which could have biased our results toward the null. There was no increase in acute or chronic GVHD, graft failure, or relapse risk with the addition of LCV; however follow up remains relatively short. LCV prophylaxis following MTX GVHD prophylaxis warrants prospective evaluation to more definitely assess effects on mucositis, engraftment, GVHD and relapse, as well as to clearly determine the impact on resource utilization such as use of TPN, PCA, and length of hospitalization.

Disclosures
Frey: Novartis: Consultancy; Servier Consultancy: Consultancy. Gill:Extellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Equity Ownership; Novartis: Research Funding. Perl:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees. Stadtmauer:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Porter:Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board; Genentech: Other: Spouse employment.