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

Characteristic	Ruxolitinib (n = 165)	BAT (n = 164)
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.
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

Event, %	Rux (n = 165)		BAT (n = 158)
ALT, alanine aminotransferase; BAT, best available therapy; Rux, ruxolitinib.
	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.

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Arnon NaglerSteering Committee Member

Arnon NaglerSteering Committee Member