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Frontline ruxolitinib plus methylprednisolone for acute GvHD treatment following haplo-SCT

Oct 24, 2020

Besides disease relapse, graft-versus-host disease (GvHD) is one of the main causes of death following stem cell transplantation (SCT). Single-agent frontline corticosteroid therapy is the recommended first-line treatment of GvHD. Nevertheless, only about half of the patients respond, and a significant subset develops glucocorticoid-refractory GvHD. Furthermore, extended corticosteroid therapy comes with considerable side effects, which makes new effective and more tolerable GvHD treatments crucial.1

Therefore, Cheng Hou et al.1 investigated in a phase I/II trial (NCT04397367) the safety and efficacy of ruxolitinib in combination with low-dose methylprednisolone as first-line treatment for acute GvHD (aGvHD) following haplo-SCT. The results of this study were recently published in Biology of Blood and Marrow Transplantation and are summarized below.


Study design

  • Prospective study in patients who received peripheral blood haplo-SCT between January and December 2019 and required treatment for newly diagnosed high- or intermediate-risk aGvHD (based on the Minnesota aGvHD score and MAGIC biomarker)
  • Patients received 1 mg/kg methylprednisolone together with ruxolitinib at a median initial dose of 5 mg daily. In patients who achieved a complete response (CR), early tapering to limit the cumulative dose was allowed first for methylprednisolone, then cyclosporin A (CsA), and then ruxolitinib
  • Patients with chronic GvHD (cGvHD), late aGvHD after donor lymphocyte infusion (DLI) or who had received previous therapy for aGvHD were excluded from the trial
  • Primary endpoint was the complete remission rate of aGvHD at Day 28 after inclusion. Secondary endpoints were the recurrence rate of aGvHD, response duration time, and non-relapse mortality (NRM)
  • The definition for failure-free survival (FFS) was survival with no evidence of non-relapse-related death, relapse or progression of hematologic disease, or addition of new systemic therapy for aGvHD
  • A historical group of patients with aGvHD who received 2mg/kg methylprednisolone daily from January to December 2018 was used as control
  • The following GvHD prophylaxis was used:
    • Anti-thymocyte globulin (ATG): from Day −5 to −2 at a total dose of 10 mg/kg
    • CsA: from Day −10 at a dose of 2 mg/kg (first month target concentration: 150–250 ng/ml
    • Standard mycophenolate mofetil and methotrexate dosing
  • All patients received anti-viral prophylaxis with ganciclovir




From the 100 patients who underwent haplo-SCT between January–December 2019, 62 developed Grade 1–4 aGvHD. Of those, 32 had Grade 2–3 aGvHD and an intermediate- or high-risk MAGIC biomarker score and received frontline methylprednisolone in combination with ruxolitinib. These 32 patients had a median age of 35.7 years (range, 14.0–63.0) and a diagnosis of aGvHD at a median of 23.0 days after haplo-SCT. Organ involvement included the gastrointestinal tract (GIT; n = 13), skin (n = 9), liver (n = 1), skin and GIT (n = 8) or skin, GIT and liver (n = 1).


The efficacy outcomes of frontline methylprednisolone and ruxolitinib for the treatment of 2–3 aGvHD are shown below in Table 1. In brief, the overall response rate (ORR) was 96.8% at Day 56 of treatment, with one patient dying before response assessment due to disease relapse. GvHD recurrence occurred in 31.2% of patients who achieved a CR or partial response (PR) with the main reasons being:

  • Therapeutic DLI (n = 1)
  • Reduction of CsA and ruxolitinib (n = 8)


Table 1. Outcomes following frontline methylprednisolone plus rituximab1

aGvHD, acute graft-versus-host disease; cGvHD, chronic GvHD; CI, confidence interval; CR, complete response; DFS, disease-free survival; FFS, failure-free survival; GRFS, GvHD-free, relapse-free survival; NRM, non-relapse mortality; ORR, overall response rate; OS, overall survival


Methylprednisolone + ruxolitinib (n = 32)

Historical control group (n = 31)

p value

ORR (at Day 56), %



CR rate at Day 28, %



< 0.001

Median time to CR, days (range)

7.9 (1–56)

aGvHD recurrence after prior response, %




< 0.001

2-year cumulative cGvHD incidence rate, %



1-year NRM, %






1-year OS, %






1-year GRFS, % (95% CI)






1-year FFS, % (95% CI)





< 0.001


No deaths due to NRM were observed in patients with late aGvHD. Additional secondary systemic immunosuppression was needed in five patients either due to recurrent aGvHD (n = 2) or due to mild cGvHD (n = 3). Leukemia-free survival was achieved by 26 patients with 10 of them having discontinued all immunosuppressive GvHD prophylactic treatment within a year after haplo-SCT. Twelve patients were maintained on ruxolitinib for a median of 176 days (range, 43–383) and six died within 1 year.


Ruxolitinib treatment (median initial dose of 5 mg) was continued for a median of 123 days (range, 6–422). The main reasons for ruxolitinib discontinuation were:

  • Thrombocytopenia (n = 6)
  • Relapse of malignancies (n = 4)
  • Pneumonia (n = 2)
  • Recurrence of aGvHD (n = 1)
  • Posttransplant lymphoproliferative disease (n = 1)
  • Cytomegalovirus encephalitis (n = 1)


No hepatotoxicity, neutropenia or life-threatening hemorrhages were observed but cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation occurred in 78.1% and 87.5% of cases, respectively, without EBV associated mortality.


As far as methylprednisolone was concerned, the mean dose was 17.6 ± 8.2 mg/kg with a mean time to discontinuation of 42.6 ± 16.8 days. Methylprednisolone was stopped within 1 year following haplo-SCT in all patients.


With regards to relapse and survival outcomes, these are shown in Table 1. Briefly, 15.6% of patients relapsed following haplo-SCT at a median on 139 days (range, 31–307). Two patients died due to CMV encephalitis or viral infection.


When assessing the outcomes (Table 1), GvHD recurrence was significantly higher in the historical control group than in the methylprednisolone + ruxolitinib group, while the CR/PR rate at Day 28 was significantly lower. Moreover, the 1-year FFS was significantly lower in the control group compared with the methylprednisolone + ruxolitinib group.




The preliminary results from this prospective trial indicate that frontline therapy with methylprednisolone plus rituximab might be beneficial for patients with intermediate- or high-risk Grade 2–3 aGvHD. The observed ORR was 96.8% with patients achieving CR irrespective of aGvHD severity or organ involvement. Limitations of this trial include its small sample size, non-prospective control group comparisons, and the low mean age of the enrolled patients that could explain the high efficacy outcomes. Thus, further large-scale, prospective clinical trials are needed to validate the efficacy and safety of daily frontline methylprednisolone (1 mg/kg) plus rituximab (5 mg) in this patient subset.


  1. Hou C, Dou L, Jia M, et al. Ruxolitinib combined with corticosteroids as first-line therapy for acute graft-versus-host disease in haploidentical peripheral blood stem cell transplant patients. Biol Blood Marrow Transplant. 2020; S1083-8791. DOI: 10.1016/j.bbmt.2020.09.015