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Positive results from the phase III REACH3 trial of ruxolitinib for patients with SR cGvHD

Jan 4, 2021
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Systemic steroids are a standard first-line therapy for chronic graft-versus-host disease (cGvHD), however, up to 50% of patients will eventually become steroid refractory (SR) or steroid dependent. Currently there is no standard second-line treatment for these patients.

Ruxolitinib—a first-in-class oral inhibitor of the tyrosine kinases JAK1 and JAK2—is approved for the treatment of polycythemia vera and myelofibrosis in adults and acute GvHD in both adults and pediatric patients ≥ 12 years of age.1 The REACH3 trial investigated ruxolitinib against the best available therapies (BAT) for patients with SR cGvHD and was reported on by Robert Zeiser at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.2 This article will provide a summary of the data presented.

Trial design

The REACH3 trial (NCT03112603) is a phase III, randomized trial of 329 patients with SR cGvHD.

Patients were randomized to receive either ruxolitinib or their physician’s choice of BAT, as shown in Figure 1.

Physician’s choice of BAT could include extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, or ibrutinib.

Eligibility criteria for inclusion in the trial:

  • Age ≥ 12 years
  • Received allogeneic hematopoietic cell transplant
  • Moderate or severe SR/steroid-dependent cGvHD, defined as:
    • Lack of response or disease progression after prednisone ≥ 1 mg/kg/day for ≥ 1 week, or
    • Disease persistence without improvement with prednisone > 0.5 mg/kg/day or 1 mg/kg/every other day for ≥ 4 weeks or
    • Increase in prednisone dose to > 0.25 mg/kg/day after two unsuccessful attempts to taper the dose2
  • Myeloid and platelet engraftment

Figure 1. REACH3 trial design2

BAT, best available therapy; BID, twice daily; C1D1, Cycle 1 Day 1; C7D1; Cycle 7 Day 1; CNI, calcineurin inhibitor; EOT, end of trial; Rux, ruxolitinib. 

The primary endpoint was overall response rate (ORR) at Week 24.

Secondary endpoints included:

  • Failure free survival (FFS)
  • Modified Lee Symptom Scale (mLSS) at Week 24
  • Best overall response
  • Duration of response

The baseline patient characteristics were well balanced between arms (Table 1). The median time from onset of cGVHD to randomization was 24.9 weeks (range, 1.0–288.1) in the ruxolitinib arm and 21.4 weeks (range, 1.4–278.1) in the BAT arm.  The two treatment arms were well balanced, and the majority of patients were between 18 and 65 years old and with severe cGvHD.

Table 1. Baseline patient characteristics2

BAT, best available therapy; cGvHD, chronic graft-versus-host disease; CMV, cytomegalovirus; mLSS, modified Lee Symptom Score.

*Protocol deviation as the inclusion criterium was for moderate to severe GvHD.
n = 149.
n = 141.
§ Some patients > 1 transplant.
|Data not available.

Characteristic

Ruxolitinib (n = 165)

BAT (n = 164)

Median age, years (range)

49.0 (13.0−73.0)

50.0 (12.0–76.0)

12 to < 18 years, %

2.4

4.9

18 to 65 years, %

86.7

81.7

> 65 years, %

10.9

13.4

cGvHD severity, %

 

 

Mild*

0

0.6

Moderate

41.2

44.5

Severe

58.8

54.9

Total mLSS score, median (range)

18.67 (0–79.6)

18.54 (0.7–54.4)

Median time from cGvHD onset to randomization, weeks (range)

24.9 (1.0–288.1)

21.4 (1.4–278.1)

Stem cell source, %

 

 

Peripheral blood

85.5

79.9

Bone marrow

13.3

18.9

Single cord blood

1.2

1.2

Donor type, %§

 

 

Related

54.5

52.1

Unrelated

45.5

47.9

Donor/recipient CMV status, %

 

 

–/–

30.9

27.4

–/+

18.2

17.1

+/–

9.7

10.4

+/+

40.6

44.5

Unknown|

0.6

0.6

Patient disposition

Treatment was discontinued in 49.7% of patients treated with ruxolitinib and 74.4% of patients treated with BAT.

Main reasons for discontinuation were lack of efficacy (ruxolitinib, 14.5% compared with BAT, 42.7%) and adverse events (ruxolitinib, 17% compared with BAT, 4.9%). In total, 37.2% of patients on BAT crossed over to the ruxolitinib treatment arm.

Key findings

  • ORR (complete response [CR] and partial response [PR]) at 24 weeks: 49.7% with ruxolitinib compared with 25.6% for BAT (odds ratio, 2.99; 95% CI, 1.86−4.80; p < 0.0001)
    • Ruxolitinib: CR, 6.7% and PR, 43.0%
    • BAT: CR, 3.0% and PR, 22.6%
  • FFS was not reached for ruxolitinib vs 5.7 months for BAT (hazard ratio, 0.370; 95% CI 0.268−0.510; p < 0.0001)
  • mLSS at 24 weeks: 24.2% in the ruxolitinib group compared with 11.0% for BAT (odds ratio, 2.62; 95% CI, 1.42−4.82; p = 0.0011)
  • Best overall response (patients achieving CR or PR at any time up to Week 24): ruxolitinib group achieved 76.4% compared with 60.4% in the BAT group
    • Ruxolitinib: CR, 12.1% and PR, 64.2%
    • BAT: CR, 6.7% and PR, 53.7%
  • Median duration of response was not reached in the ruxolitinib arm and 6.24 months in the BAT arm

The safety profile for the two groups is shown in Figure 2. Median duration of exposure was 41.3 weeks (range, 0.7–127.3) in the ruxolitinib group and 24.1 weeks (range, 0.6–108.4) for BAT. The number of deaths between the two treatment arms was not significantly different (ruxolitinib, 31 vs BAT 27; the most common causes of death were cGvHD and infections).

Figure 2. Safety profile of the two treatment arms up to 24 weeks

AEs, adverse events; BAT, best available therapy; Rux, ruxolitinib. 

The safety profile of ruxolitinib was consistent with previous reports, with anemia and thrombocytopenia being the most frequent adverse events (AEs). While the majority of AEs were similar in incidence between the two treatment arms, anemia and thrombocytopenia were more common in the ruxolitinib group (Table 2).

Table 2. Adverse events (≥ 10%) up to Week 24 in the two treatment arms2

ALT, alanine aminotransferase; BAT, best available therapy; Rux, ruxolitinib.

Event, %

Rux (n = 165)

BAT (n = 158)

 

Any grade

Grade ≥ 3

Any grade

Grade ≥ 3

Hematologic

 

 

 

 

Anemia

29.1

12.7

12.7

7.6

Thrombocytopenia

21.2

15.2

14.6

10.1

Neutropenia

10.9

8.5

5.1

3.8

Gastrointestinal

 

 

 

 

Diarrhea

10.3

0.6

13.3

1.3

Nausea

9.1

0

10.1

1.3

Infections

 

 

 

 

Pneumonia

10.9

8.5

12.7

9.5

Lab abnormalities

 

 

 

 

ALT increased

15.2

4.2

4.4

0

Creatinine increased

13.9

0

4.4

0.6

Hypokalemia

7.9

1.8

10.1

4.4

Other

 

 

 

 

Hypertension

15.8

4.8

12.7

7.0

Pyrexia

15.8

1.8

9.5

1.3

Cough

10.3

0

7.0

0

Fatigue

10.3

0.6

7.6

1.9

In terms of infections, there was no significant difference between the treatment arms in the number of viral or bacterial infections observed (ruxolitinib: viral 33.9%, bacterial 27.9%; BAT: viral 29.1%, bacterial 25.9%). A higher percentage of patients in the ruxolitinib group experienced fungal infections (11.5%) compared with the BAT group (5.7%). Cytomegalovirus infection/reactivation occurred in 5.5% of patients in the ruxolitinib arm and 8.2% in the BAT arm.

Conclusion

This is the first successful randomized, phase III study in adolescents and adults with SR cGvHD in which ruxolitinib demonstrated greater efficacy compared with the BAT. The trial met its primary endpoint, with a significantly higher ORR observed with ruxolitinib compared with BAT. Treatment with ruxolitinib (compared with BAT) was also associated with a significant improvement in patient-reported symptoms, FFS, and a higher rate of best overall response. The safety profile of ruxolitinib was deemed acceptable and consistent with the known safety profile. These trial results will form the basis of a submission to the U.S. Food and Drug Administration (FDA) for the approval of ruxolitinib in patients with steroid-refractory or steroid-dependent cGvHD.

Expert Opinion

  1. Jakafi prescribing information. https://www.jakafi.com/pdf/prescribing-information.pdf. Published Jan 1, 2020. Accessed Jan 4, 2020.
  2. Zeiser, R. Ruxolitinib (RUX) vs best available therapy (BAT) in patients with steroid-refractory/steroid-dependent chronic graft-vs-host disease (cGVHD): Primary findings from the phase 3, randomized REACH3 study. Oral abstract #77. 62nd ASH Annual Meeting and Exposition; Dec 6, 2020; Virtual.

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