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Comparison of ruxolitinib with other therapies for steroid-refractory acute GvHD

May 25, 2020

Acute graft- versus-host disease (aGvHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a leading cause of early nonrelapse mortality. Despite prophylactic measures, approximately 50% of allo-HSCT recipients subsequently develop aGvHD. With the new treatment options, allowing more patients to undergo transplantation, the incidence of aGvHD is rising. However, a substantial proportion of patients do not respond to systemic, high-dose glucocorticoids, the standard first-line treatment option. Steroid-refractory aGvHD (SR-aGvHD) is associated with poor survival and lacks a standardized treatment approach, mainly due to a lack of data confirming the superiority of one therapy over the others.

In the phase II study REACH1, ruxolitinib, an oral inhibitor of the Janus kinases (JAK) 1 and 2, has shown to induce a response in 54.9% of the patients with Grade 2–4 SR-aGvHD. Based on those results, ruxolitinib was approved by the U.S. Food and Drug Administrationfor patients aged ≥ 12 years with SR-aGvHD. More recently, Robert Zeiserand colleagues 1conducted a phase III study REACH2 ( NCT02913261) comparing the efficacy and safety of ruxolitinib with nine commonly used therapies in patients with glucocorticoid-refractory aGvHD. The results have been published in the New England Journal of Medicine.

Study design

Recipients of allo-HSCT aged ≥ 12 years with Grade 2–4 SR-aGvHD after a failure of systemic immunosuppressive therapy were eligible for this multicenter, randomized, open-label, study. Exclusion criteria included tumor relapsed after allo-HSCT in the previous 6 months, a relapsed primary cancer after transplantation, ≥ 1 previous treatment for glucocorticoid-refractory aGvHD, or any JAK inhibitor therapy after the initiation of allo-HSCT conditioning.

Eligible patients were randomized 1:1 to up to 24 weeks, as follows:

  • Experimental arm
    • ruxolitinib 10 mg twice daily orally, tapered after Day 56 in responding patients
  • Control arm consisting of one of the following treatments
    • anti-thymocyte globulin
    • extracorporeal photopheresis
    • mesenchymal stromal cells
    • low-dose methotrexate
    • mycophenolate mofetil
    • everolimus
    • sirolimus
    • etanercept
    • infliximab

In addition, continued use of calcineurin inhibitors and glucocorticoids as well as standard supportive therapy was allowed in both treatment groups. However, simultaneous treatment with aspirin, nonsteroidal anti-inflammatory drugs, heparin, warfarin, or related medications was prohibited.

  • Primary endpoint: Overall response at Day 28
  • Secondary endpoints: Durable overall response at Day 56, duration of response, best overall response, failure-free survival, overall survival, cumulative glucocorticoid use until Day 56, nonrelapse-related death, relapse or progression of cancer, and safety

Results

The data cutoff date was July 25, 2019.

Patient characteristics

  • In total, between April 12, 2017, and May 30, 2019, 309 patients were randomized: 154 to the ruxolitinib and 155 to the control arm
    • Forty-nine patients crossed over from the control to ruxolitinib on or after Day 28
  • Baseline patient characteristics were generally similar between ruxolitinib and control groups, except for a higher proportion of white patients and a lower proportion of Asian patients in the ruxolitinib vscontrol (72% vs66% and 12% vs19%, respectively)
  • Median age was 54 (12–73) years
    • Overall, the majority of patients were aged 18–65 years, while 3% of patients were < 18 years and 15% were > 65 years
  • In both treatment groups, most of the patients were male (59%)
  • 34% of patients had Grade 2 aGvHD, 44% had Grade 3, and 20% had Grade 4
  • The median follow-up was 5.04 months (0.03–24.02) in the ruxolitinib group and 3.58 months (0.03–23.62) in the control group

Efficacy

  • Overall response and durable overall response at Day 28 were significantly greater in the ruxolitinib group than in the control group ( Table 1)
  • The estimated cumulative incidence of loss of response at 6 months was lower in the ruxolitinib group than in the control group (10% vs39%)
  • By Day 56, glucocorticoids could be discontinued more often in patients in the ruxolitinib group, than in the control group (21% vs14%)

Table 1. Efficacy at Day 58

 

Ruxolitinib

Control

p value

Overall response, %

Complete response

Partial response

62.3

34.4

27.9

39.4

19.4

20.0

< 0.001

Durable overall response

39.6

21.9

< 0.001

  • The median failure-free survival was significantly longer in patients treated with ruxolitinib than control therapy (5 vs1 month; HR, 0.46; 95% CI, 0.35–0.60)
  • Cumulative incidence of relapse or progression of hematologic disease, nonrelapse-related death, or addition of new systemic therapy for aGvHD at 1 month was lower in the ruxolitinib group than the control group (18% vs49%) and remained lower for up to 18 months (61% vs82%)
  • The cumulative incidence of nonrelapse-related death at 18 months was similar in both groups (49% with ruxolitinib and 51% with control therapy)
  • The median overall survival was 11.1 vs5 months in the ruxolitinib and the control group, respectively (HR, 0.83; 95% CI, 0.60–1.15)

Safety

  • 72% of patients discontinued ruxolitinib treatment and 85% of patients discontinued therapy in the control group
    • The most frequent reason for discontinuation was lack of efficacy (21% and 44%, respectively)
  • Median duration of therapy was 63 days in the ruxolitinib group and 29 days in the control group
  • The majority of patients in both treatment groups experienced adverse events (AEs)
    • Any grade: 95% of patients in the ruxolitinib and 93% in the control group, with thrombocytopenia, anemia, and cytomegalovirus infection as the most frequent AEs up to Day 28
    • Grade ≥ 3: 78% of patients in both groups ( Table 2), with thrombocytopenia, anemia, and infection as the most frequent
      • Rates of infections up to Day 28 were 22% with ruxolitinib and 19% with control therapy, and rose to 37% and 28% at the data cut-off
    • Frequency of serious AEs up to Day 28 was 38% in the ruxolitinib group and 34% in the control group
    • Up to Day 28, AEs caused more dose modifications and treatment discontinuation in patients who received ruxolitinib than those on control therapy (38% vs9% and 11% vs5%, respectively)
    • By the data cut-off date, deaths were recorded in 47% patients in the ruxolitinib and 51% of patients in the control group, with aGvHG attributing to 22% and 25% of deaths, respectively

Table 2.Most common Grade ≥ 3 adverse events occurring up to Day 28

Adverse event

Ruxolitinib group, %

 (n = 152)

Control group, %

 (n = 150)

Hematological

 

 

Thrombocytopenia

27

15

Anemia

22

19

Neutropenia

13

9

Non-hematological

Infection

22

19

Sepsis

7

3

Hypokalemia

6

6

Conclusion

The data from this study demonstrated a significant improvement in Day 28 response rates with ruxolitinib over other commonly used therapies for the treatment of patients with Grade 2–4 SR-aGvHD. Additionally, ruxolitinib therapy was associated with a higher durable overall response at Day 56, a longer duration of response, and a longer failure-free survival. With a data cutoff at Day 56, overall survival data are not mature to evaluate the impact on patients’ survival. The safety profile of ruxolitinib was consistent with previously reported results.  Patients receiving ruxolitinib showed an increased risk of thrombocytopenia, as well as a modestly higher incidence of anemia, and infections compared to patients receiving control therapy.

Expert Opinion

  1. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med.2020;382(19):1800-1810. DOI: 10.1056/NEJMoa1917635