Abstract
Background: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Despite its efficacy in combination with calcineurin inhibitors, methotrexate (MTX) may increase the risk of complications such as mucositis and delayed hematopoiesis and can contribute to hepatic and renal toxicities. As a result, doses are often omitted in the setting of treatment-related toxicities. Herein we report outcomes in the setting of omitting doses of mini-MTX (5 mg/m2 IV days 1, 3, 6, and 11) and describe management when these doses are omitted.
Methods: This retrospective study identified patients aged 18 years or older who underwent HCT between 1/2008 and 12/2015 with planned GVHD prophylaxis of mini-MTX for four doses with a calcineurin inhibitor (cyclosporine or tacrolimus). Outcomes were compared between patients who had 1-3 doses omitted (group 1) and those who received all four planned doses of mini-MTX (group 2). Differences in baseline characteristics were determined using Chi-square, Fisher's exact, or Wilcoxon Rank-Sum tests as appropriate. Overall and relapse free survival (OS, RFS, respectively) were estimated using the Kaplan-Meier method with differences assessed with a log-rank test. The cumulative incidence method for competing risks was used in estimating non-relapse mortality (NRM), GVHD, as well as GVHD-related mortality, with differences assessed with Gray's test. Relapse was considered a competing risk for NRM while relapse or death were considered competing risks for GVHD. Non-GVHD related death was considered a competing risk for GVHD related mortality. For all analyses related to the number of MTX doses received, a landmark analysis was conducted at day 11 (scheduled date of 4th dose).
Results: Of the 188 consecutive patients that were identified, 29 had 1-3 doses of MTX omitted. Baseline characteristics are summarized in Table 1. Notably, no patient in group 1 had ATG (0% vs 10.7%, p = 0.079). Omission of MTX was most commonly due to mucositis (14/29 patients), followed by hyperbilirubinemia, pleural effusions, acute kidney injury, and anasarca/ascites. When any mini-MTX was omitted, the most common strategies were to initiate mycophenolate mofetil (MMF) at 1g IV Q8H (17/29 patients) or corticosteroids (8/29 patients; both MMF and steroids were used in 4 patients). Overall, there was a non-significant increase in the incidence of acute grade 2-4 GVHD when comparing groups 1 and 2 (100-day incidence: 60.7% vs 50.9% respectively, p = 0.501) as well as more severe, grade 3-4 acute GVHD (100-day incidence 28.6% vs. 17%, p = 0.163). Similarly, there was an absolute, non-significant increase in the cumulative incidence of GVHD-related mortality (Table 2). Overall survival and NRM were negatively impacted when MTX was omitted (OS at 12 months: 55.2% vs 73%, respectively, p = 0.015; NRM at 12 months 32.1% vs. 10.1%, respectively, p = 0.003). The most common cause of NRM in both groups was GVHD (group 1: 6/11 patients vs. group 2: 20/29 patients), but organ toxicity was the second leading cause in group 1 (3/11 patients) compared to zero patients in group 2. Other results are summarized in Table 2.
Conclusion: While limited by a small number of patients in group 1, it appears our management strategy of introducing an alternative agent (e.g. MMF ± corticosteroids) may ameliorate some of the increased risk of acute GVHD. The patients in group 1 did have worse OS and NRM compared to group 2. The presence of toxicities that caused the omission of MTX may have contributed to these findings. These results appear consistent with recent reports on outcomes, when the planned course of full-dose MTX as GVHD prophylaxis was not administered (Hamilton BK et al., Blood Cancer J 2015). The impact of omitting MTX doses on chronic GVHD incidence in this population will be reported in the future.
No relevant conflicts of interest to declare.
