Methotrexate (MTX) has had a long history of use in graft versus host disease (GVHD) prevention in allogeneic hematopoietic cell transplantation (HCT) and is now most commonly used with a calcineurin inhibitor, such as cyclosporine (CSA) or tacrolimus (Tac). MTX, however, may contribute to severe mucositis and other organ toxicities, which in turn may result in the need to withhold MTX doses. It is not clear whether the omission of doses of MTX has a deleterious effect on relapse, GVHD, and survival. We therefore retrospectively reviewed the experience with MTX at our institution.
We identified 109 patients (pts) who underwent a myeloablative HCT with an HLA matched unrelated donor and received MTX in combination with Tac or CSA for GVHD prophylaxis from May 2003 until May 2011. Data was missing on 7 pts, and they were excluded. Of the remaining 102 pts, 70 received all 4 doses of MTX while 32 (31.4%) missed at least 1 dose of MTX. The dose of MTX used was 5mg/m2 on days 1, 3, 6, 11 from May 2003 until July 2009 and was then increased to 15mg/m2 day 1 followed by 10mg/m2 day 3, 6, 11 after July 2009. 80 pts received the lower dose of MTX, with 26 (32%) having missed a dose and 22 pts received the higher dose MTX after July 2009, with 6 (27%) having missed a dose. Severe mucositis or organ dysfunction were the primary reasons for dose omission in all pts and was based on physician discretion. Pts underwent HCT for acute myeloid leukemia (n=42), myelodysplastic syndrome (n=25), acute lymphoblastic leukemia (n=19), non Hodgkin lymphoma (n=6), chronic myeloid leukemia (n=6), myeloproliferative neoplasms (n=2), biphenotypic leukemia (n=1), and plasma cell leukemia (n=1). The two groups did not differ significantly in age, gender, disease, disease status, CMV status, or hematopoietic cell source, but did differ in the number of prior chemotherapy regimens to which the patient had been exposed. 43.8% of pts in the missed MTX group had received 3 or more prior chemotherapy regimens compared with 24.3% in the 4-dose group, (p=0.047). The conditioning regimen most commonly used was cyclophosphamide (Cy) with busulfan (Bu), n=56; but other preparative regimens included Bu/Cy and etoposide (VP-16), n=14; Cy in combination with total body irradiation (TBI), n=3; TBI/VP-16, n=20; and Cy/TBI in combination with ATG or ECP, n=9. There were no statistically significant differences in the preparative regimen or use of TBI between the two groups. Outcomes were compared between full and missed dose groups using the log-rank test or Pepe-Mori test.
With the omission of doses of MTX due to toxicities, there was no difference in time to hematopoietic recovery or length of hospital stay. Median time to neutrophil recovery for full dose MTX was 18 days, (range 9–75) compared to 16, (range 10–27) in the missed dose group, (p=0.55). Median time to platelet recovery was 25 days, range (13–51) for the 4 dose group compared to 21 (range 12–75, p=0.36). There was no significant difference in acute GVHD between full and missed dose groups (6 month incidence 38.6% versus 53.1% grade 2–4, p=0.35; 20.0% versus 9.4% grade 3–4, p=0.16). There was also no difference in chronic GVHD (2 year incidence 30.4% versus 41.8% any chronic, p=0.43; 20.0% versus 26.1% extensive chronic, p=0.74). Full dose and missed dose also did not differ with respect to relapse (5-year incidence 31.3% versus 37.7%, p=0.65), overall survival (OS) (5-year 41.3% versus 26.6%, p=0.14), or non-relapse mortality (NRM) (5-year incidence 32.6% versus 57.6%, p=0.13).
We have previously shown that severe mucositis is associated with inferior survival (Fanning et al, BJH 2006, 135:374). While the differences in GVHD, NRM and OS did not reach statistical significance, it did appear that those who missed a dose of MTX did worse than those who received all 4 doses; and one can speculate this may be related to the toxicity of severe mucositis. Even with the dose change in our cohort, there was interestingly no difference in the incidence of missed does between the groups assigned to receive low or standard dose MTX. This initial analysis provokes many additional questions, including whether a fourth dose of MTX is needed in all pts. Single nucleotide polymorphisms of the enzymes which MTX inhibits induce differential effects on MTX metabolism which may lead to increased toxicity and a potential protective effect for GVHD for a given dose. Further prospective study of dosing of MTX in GVHD prophylaxis is warranted.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.