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Can ruxolitinib be safely combined with regulatory T cells to enhance efficacy in treating cGVHD?

Aug 11, 2020

Although previous experience with ruxolitinib has shown high overall response rates in chronic graft-versus-host disease (cGvHD), complete response rates remain low. Regulatory T cells (Tregs) are known to control innate adaptive immune response with immunomodulatory properties. The use of JAK 1/2 inhibitors has been shown to decrease the proliferation and activation of effector T cells, however, their effect on Tregs remains to be explored. Virginia Escamilla Gómez and colleagues conducted a study to investigate whether adding Tregs to ruxolitinib can improve response, and presented the results during the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress.1

Study design and methodology1

This study comprised three different levels of investigation:

  • In vitro studies
    • Isolated human lymphocytes were activated with anti-CD3 and -CD28 antibodies, treated with increasing doses of ruxolitinib (0 μM, 0.1 μM, 0.3 μM and 1 μM), and analyzed on Days 2, 5, and 8
  • Mouse model
    • Donor mice with cGvHD were randomized to receive either (i) ruxolitinib, 30 mg/kg per day; (ii) 3 × 105 donor Tregs in a single infusion; (iii) both 3 × 105 Tregs and ruxolitinib 30 mg/kg per day; (iv) the vehicle of both treatments
  • Phase I clinical trial
    • To investigate the additional benefit of a single-donor Treg infusion in patients with steroid-refractory cGVHD who had a partial response after ≥ 4 weeks of ruxolitinib treatment, patients were included in a prospective clinical trial within the TREGeneration consortium (H2020). Patients were divided into three cohorts to receive increasing amounts of donor Tregs: Level A, 0.5 × 106 Treg/kg; Level B, 1 × 106 Treg/kg; Level C, 2 × 106 Treg/kg. Laboratory and clinical assessments were conducted at Weeks 1, 2, 4, 6, 8, 12, 24, and 36 following Treg infusion

Patient characteristics1

A total of 12 patients with a median age of 53 years (40-68) were included in the study; half of the patients had severe GvHD prior to Treg infusion. The numbers of patients transplanted with stem cells from a related or unrelated donor were 7 and 5, respectively. The diagnosis varied among patients; acute myeloblastic leukemia (n = 3), acute lymphoblastic leukemia  (n = 1), myelodysplastic syndromes (n = 3), non-Hodgkin lymphoma (n = 2), other (n = 3). The median number of prior therapy lines was 3.5 (range, 2–7).

Key findings1

In vitro study and mouse model

The analysis from the in vitro study showed that ruxolitinib significantly increased Treg levels over 8 days of culture and did not impair suppressive capacity of Tregs. In contrast, Treg levels decreased over time in cultures not treated with ruxolitinib.

In the cGvHD mouse model, survival was significantly longer (p = 0.0102), clinical GvHD scores were improved, and weight loss was decreased in mice treated with the combination of ruxolitinib and Treg infusion. Infused Tregs could be detected in the bone marrow of mice for up to 34 weeks.

Phase I trial

Eleven patients received Treg infusion and were included in the analysis.

Eight patients experienced Grade ≤ 2 adverse events only (most of these were respiratory infections, gastrointestinal events including diarrhea and vomiting, fever, and musculoskeletal events including cramps), and none of these were considered to be related to Treg infusion. Grade ≥ 3 adverse events were seen in three patients: avascular necrosis (n = 1), septic shock and death (n = 1), and pneumonia (n = 1).

Preliminary clinical efficacy analysis showed that

  • An improvement in the National Institute of Health clinical GvHD score was seen in eight patients, while seven patients reported improved joint symptoms in the JOINT/Patient-Reported Outcome Measures score
  • Ten patients were able to reduce their immunosuppressive treatments. Reduction of corticosteroids, as well as other immunosuppressive agents, was possible


Preliminary analysis show that the combination of Treg infusion and ruxolitinib can be safely applied in patients with cGvHD, inducing clinical improvement and decreasing the need for immunosuppressive treatment. Further data will be needed to interpret the risks and benefits of such combined treatment modality.

  1. Escamilla Gómez V, Rodríguez Gil A, García-Guerrero E, et al. Combined treatment of chronic graft versus host disease using regulatory T cells and ruxolitinib. Oral abstract #S253. 25th European Hematology Association Annual Congress; June 12, 2020; Virtual.

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