Multipotent stem cells in the bone marrow: © Juan Gärtner – stock.adobe.com
New long-term data from the phase 3 REACH3 study (NCT03112603) demonstrate that ruxolitinib (Jakafi) provides sustained efficacy and a manageable safety profile over 3 years in patients with steroid-refractory/dependent chronic graft-vs-host-disease (SR/D-cGVHD). The findings underscore ruxolitinib’s role as an effective treatment option for this challenging patient population, confirming and extending the positive results of the primary 24-week analysis.
The study, which randomized 329 patients (165 to ruxolitinib, 164 to best available therapy [BAT]), showed a significantly longer median failure-free survival (FFS) with ruxolitinib at 38.4 months compared with 5.7 months for BAT (HR 0.36; 95% CI, 0.27-0.49).This sustained benefit was evident at 36 months, with a 56.5% probability of FFS for patients treated with ruxolitinib vs 18.2% for those on BAT. Similarly, the median duration of response (DOR) was not reached for ruxolitinib in contrast to 6.4 months for BAT, indicating a more durable response with the JAK inhibitor.At 36 months, 59.6% of ruxolitinib-treated patients maintained a response, compared with 26.7% in the BAT arm.
Further, study authors noted that, “…ruxolitinib provided clinical benefits whether given as a second- or third-line option, which is consistent with an analysis showing that response was not influenced by the timing of ruxolitinib initiation. However, ruxolitinib is recommended for second-line use for cGVHD.”
cGVHD is a severe complication of allogeneic hematopoietic stem cell transplantation, with corticosteroids serving as the cornerstone of first-line treatment. However, a significant proportion of patients develop steroid refractoriness or dependence, necessitating alternative therapeutic strategies.Ruxolitinib, a potent and selective inhibitor of JAK1 and JAK2, has emerged as a crucial second-line agent for cGVHD, gaining approval based on the initial positive outcomes of the REACH3 trial and subsequently being recommended in clinical guidelines.
3D render of white blood cells with nucleus and granule: © stockdevil – stock.adobe.com
The long-term follow-up of REACH3 aimed to evaluate the extended efficacy and safety of ruxolitinib and assess responses in patients who crossed over from BAT to ruxolitinib. The open-label, multicenter study allowed patients initially randomly assigned to BAT to cross over to ruxolitinib after week 24 if their condition warranted.
Overall survival (OS) was not reached in either arm, with no significant difference in the risk of death between the groups (HR, 0.85; 95% CI, 0.54-1.33). The study also reported low rates of nonrelapse mortality (NRM) and malignancy relapse/recurrence, with overlapping incidence curves between the 2 arms. Notably, corticosteroid doses declined over the study period in both groups, with 55.3% of the ruxolitinib arm and 36.4% of the BAT arm achieving complete taper-off of corticosteroids. The probability of maintaining a long-term response with ruxolitinib was observed irrespective of baseline organ involvement, including difficult-to-treat organs like the lung and liver.
An important aspect of the study was the crossover analysis, which included 70 patients who switched from BAT to ruxolitinib. In this cohort, the overall response rate (ORR) at week 24 of the crossover period was 50.0%, and the best overall response (BOR) was 81.4%. These response rates were consistent with those observed in the primary analysis of patients initially randomized to ruxolitinib, suggesting that ruxolitinib provides clinical benefits even when initiated as a later-line option. Furthermore, nearly three-quarters of these crossover patients maintained their response for more than 2 years.
Regarding safety, the long-term profile of ruxolitinib remained consistent with previous reports, with no new safety signals identified.The median duration of exposure was significantly longer for ruxolitinib (52.9 weeks) compared with BAT (24.1 weeks). After adjusting for exposure duration, the incidence rates of grade ≥3 adverse events (AEs) and serious AEs were lower in the ruxolitinib arm. Anemia was the most common AE and grade ≥3 AE associated with ruxolitinib, while pneumonia was the most frequent AE leading to discontinuation.
Infections were the most common AEs of special interest, though most were grade 2. The incidence of cytomegalovirus infection was similar across both arms. On-treatment deaths were primarily attributed to cGVHD in both groups. The AE profile in the crossover population mirrored that of the randomized ruxolitinib arm, further supporting its consistent and long-term safety.