Low-Dose Methotrexate as Salvage Therapy for Refractory Graft-Versus-Host Disease (GVHD) after Reduced-Intensity Conditioning (RIC) for Allogeneic Stem Cell Transplantation (allo-SCT).

Background. RIC regimens are increasingly used for allo-SCT. Although such regimens are associated with a relatively low early transplant-related mortality (TRM) in comparison to standard myeloablative allo-SCT, GVHD remains a matter of concern. Of note, corticosteroid-resistant GVHD is associated with high morbidity and mortality, and therapeutic options are limited for those patients. Furthermore, patients undergoing RIC allo-SCT are older than patients undergoing myeloablative allo-SCT, and are thus more exposed to the side effects and complications of long term corticosteroids (CS) administration. Low dose methotrexate (MTX) therapy is a well established modality for prophylaxis of GVHD after standard myeloablative allo-SCT. However, little is known about the role of this drug in the treatment of CS-resistant GVHD.

Patients and Methods. The aim of this pilot single center study was to investigate the role and benefit of MTX in a curative setting after failure of CS treatment in 20 consecutive patients undergoing RIC allo-SCT. 20 patients experiencing severe GVHD received IV infusions of low dose MTX (5 mg/m²/infusion) at weekly intervals, for at least four weeks. Reasons for MTX administration were: refractory acute GVHD (after at least one week of 2 mg/Kg CS administration), CS-refractory chronic GVHD, chronic GVHD exacerbation after CS taper, or CS side effects and complications (CS-induced diabetes requiring insulin therapy, severe metabolic or psychiatric disorders). Responses to low dose MTX infusions were assessed one month after the last infusion in each involved organ.

Results. 12 patients were treated for severe acute GVHD, while 8 patients received MTX for extensive chronic GVHD. Median age of patients was 51 (range, 22–60). Median time of administration of MTX was day +89 (range, 32–300) after allo-SCT. Of note, none of the patients received any other concomitant therapy for refractory GVHD. 13 patients responded to MTX administration (65 %) with 5 complete responses (25%). Among the 12 patients treated for acute GVHD, 7 responded (58%) of whom 5 CRs (42%). 3 patients did not respond and died from resistant GVHD. Interestingly, 5 patients from the group of grade 3–4 acute GVHD responded. Among the 8 patients treated for chronic GVHD, 6 were responders (75%). In addition, MTX allowed a significant reduction of CS daily dosage ranging from 25% to 80%, as assessed one month after the last administration of MTX. With a median follow-up of 287 days, no increase of CS therapy was necessary among these 6 MTX-responding patients. In the whole study population, toxicity of low dose MTX administration was low (transient and mild reversible cytopenia in 3 cases, 15%). Among the 20 patients, 14 are still alive (70%) with a median follow-up of 293 (range, 65–513) days. Overall, 2 patients died of progressive disease, while 4 patients died from refractory GVHD.

Conclusions. In this study, the global response rate of severe GVHD to low dose MTX was impressively high (65%) if considered in terms of salvage therapy in this relatively elderly and high risk population. Low dose MTX appears to be a well-tolerated, inexpensive and likely steroid-sparing agent that is worthy of further investigation in prospective trials for treatment of refractory GVHD, but also as frontline therapy in combination with CS.