Highlights
– In the randomized phase III REACH2 final analysis (24 months), ruxolitinib improved failure‑free survival compared with best available therapy (BAT) in steroid‑refractory acute graft‑versus‑host disease (SR‑aGVHD): median 4.86 versus 1.02 months (P < .001).
– Median overall survival (OS) and event‑free survival (EFS) favored ruxolitinib (OS 10.7 v 5.8 months; EFS 8.3 v 4.2 months).
– Duration of response was longer with ruxolitinib (median 167 days) than BAT (median 106 days); nonrelapse mortality and malignancy relapse/progression events were similar between arms.
Background: disease burden and unmet need
Acute graft‑versus‑host disease (aGVHD) remains one of the principal complications after allogeneic hematopoietic cell transplantation (Allo‑HCT), affecting approximately 30%–50% of recipients and accounting for substantial morbidity, nonrelapse mortality (NRM), and impaired quality of life. First‑line therapy is high‑dose systemic corticosteroids, but up to half of patients have steroid‑refractory (SR) disease and require second‑line therapy. Options for SR‑aGVHD historically have been heterogeneous and largely unsatisfactory, with modest durable response rates and poor long‑term survival. The JAK1/2 inhibitor ruxolitinib has immunomodulatory activity that targets cytokine signaling relevant to GVHD pathogenesis, and randomized data from REACH2 have helped define its role as a salvage option for SR‑aGVHD. The final 24‑month analysis reported by Mohty et al. (J Clin Oncol, 2025) provides longer‑term efficacy and safety outcomes versus BAT and informs clinical decision‑making for this high‑risk population.
Study design
REACH2 was a randomized, open‑label, phase III trial comparing ruxolitinib with investigator‑chosen best available therapy (BAT) in patients aged ≥12 years with steroid‑refractory aGVHD after Allo‑HCT. The BAT arm reflected contemporary clinical practice and therefore included a variety of agents considered appropriate by treating physicians. The primary analysis previously demonstrated superiority of ruxolitinib for key response endpoints; the report summarized here presents the final efficacy and safety outcomes after up to 24 months of follow‑up.
Key findings — efficacy
The final REACH2 analysis continued to favor ruxolitinib across several clinically meaningful outcomes.
Failure‑free survival (primary long‑term comparative finding)
Failure‑free survival (FFS), an endpoint incorporating death, relapse/progression of underlying malignancy, or addition of new systemic therapy for aGVHD, was significantly longer with ruxolitinib than with BAT. Median FFS was 4.86 months with ruxolitinib versus 1.02 months with BAT (P < .001). This statistically robust and clinically relevant separation indicates that ruxolitinib delayed treatment failure events and prolonged the interval without need for additional systemic interventions.
Overall survival and event‑free survival
Median overall survival favored ruxolitinib: 10.7 months (ruxolitinib) versus 5.8 months (BAT). Event‑free survival (EFS), which reflects time to treatment failure and includes components of progression and death, was also longer with ruxolitinib (median EFS 8.3 months) compared with BAT (4.2 months). These differences in survival endpoints suggest that the clinical benefit observed with ruxolitinib extends beyond initial response and translates into improved medium‑term outcomes.
Duration of response
Among responders, the cumulative median duration of response was longer with ruxolitinib: 167 days (range 22–677) versus 106 days (range 10–526) with BAT. This longer durability supports the idea that responses to ruxolitinib are not only more frequent (as shown in earlier analyses) but also more sustained.
Nonrelapse mortality and malignancy relapse/progression
Notably, the number of nonrelapse mortality events was similar across arms (72 events with ruxolitinib vs 71 with BAT), and malignancy relapse or progression events remained low and comparable between groups. These observations are important because targeted immunomodulation raises theoretical concerns about impairing graft‑versus‑tumor effects; in REACH2 final analysis there was no evidence of excess relapse with ruxolitinib.
Chronic GVHD incidence
Chronic GVHD rates were numerically higher with ruxolitinib than with BAT from 12 months onward; however, the reported 95% confidence intervals overlapped, limiting definitive interpretation. The trend warrants attention in follow‑up studies, given chronic GVHD’s significant impact on long‑term morbidity and the need to understand if prolonged JAK inhibition modifies chronic GVHD biology.
Safety findings
The safety profile reported in the final analysis was consistent with the primary analysis and the known safety spectrum of ruxolitinib. The study summary indicates no new safety signals emerged during extended follow‑up. Specific adverse events were not described in detail in the summary data provided here, but clinicians should remain vigilant for known toxicities of JAK inhibition, including cytopenias and infectious complications, and manage these through dose adjustments, monitoring, and supportive care as recommended.
Expert commentary and interpretation
The REACH2 final analysis strengthens the evidence that ruxolitinib is an effective salvage therapy for SR‑aGVHD, delivering both earlier and more durable disease control and translating into improved survival metrics compared with heterogeneous BAT. The observed improvement in FFS is particularly meaningful in this setting because it reflects postponement of clinically significant failure events and the need for additional immunosuppression, which themselves carry toxicity and infection risk.
Mechanistically, JAK1/2 inhibition addresses proinflammatory cytokine signaling central to aGVHD pathogenesis (for example, IL‑6, IFN‑γ, and other STAT‑driven pathways). By modulating T‑cell activation and cytokine release, ruxolitinib potentially decreases target‑organ inflammation while preserving graft‑versus‑tumor activity — a balance suggested by the comparable relapse rates between arms in REACH2.
That said, several limitations and caveats merit emphasis. First, the BAT comparator reflected multiple different agents and strategies, mirroring real‑world practice but reducing the ability to compare ruxolitinib head‑to‑head against any single established second‑line option. Second, although median OS and EFS were improved, absolute survival remained limited in both arms, underscoring the aggressive nature of SR‑aGVHD and the need for prevention and earlier effective strategies. Third, the numeric increase in chronic GVHD rates with ruxolitinib observed after 12 months merits close postmarketing surveillance and mechanistic investigation to understand whether JAK inhibition alters chronic GVHD risk or merely unmasks differences because patients survive longer.
From a clinical perspective, REACH2 results support use of ruxolitinib as a preferred second‑line therapy for SR‑aGVHD in patients who are eligible for JAK inhibition, with appropriate monitoring. Treatment decisions should still be individualized based on infection risk, cytopenias, comorbidities, and prior therapies. The data also highlight the importance of careful tapering strategies and longitudinal follow‑up for chronic GVHD and infectious complications.
Implications for practice and future research
Clinicians managing SR‑aGVHD can view ruxolitinib as a therapy that meaningfully prolongs FFS and improves survival metrics over heterogeneous BAT. Implementation requires established protocols for dose modification in cytopenias, infection surveillance (including viral reactivation), and coordination with infectious disease and transplant teams.
Future research priorities include: (1) identifying biomarkers that predict response and toxicity to JAK inhibition in GVHD; (2) defining optimal duration of therapy and tapering strategies to minimize chronic GVHD risk; (3) testing ruxolitinib earlier in the course of aGVHD or in combination approaches; and (4) direct comparative studies versus commonly used individual agents (for example, extracorporeal photopheresis or specific biologics) to delineate relative benefits and harms.
Conclusion
The 24‑month final analysis of REACH2 demonstrates that ruxolitinib provides clinically meaningful benefits over best available therapy in patients with steroid‑refractory acute GVHD, including longer failure‑free survival, improved median overall and event‑free survival, and a longer duration of response, without an increase in malignancy relapse and with a similar number of nonrelapse mortality events. These findings reinforce ruxolitinib’s role as a key therapeutic option for SR‑aGVHD, while highlighting areas for continued vigilance (infectious risk, cytopenias) and further study (impact on chronic GVHD and biomarker‑directed use).
Funding and clinicaltrials.gov
Funding and trial registration details are reported in the original publication: Mohty M et al., J Clin Oncol. 2025;43(34):3639‑3645.
References
Mohty M, Socié G, Szer J, Niederwieser D, Butler J, Wagner‑Drouet E, Or R, Rovenvald‑Zuckerman T, Bozdag SC, Forcade E, Grillo G, Kröger N, Stölzel F, Russo D, Sanz J, Sarkar R, Stefanelli T, Wilke C, Zeiser R, von Bubnoff N. Ruxolitinib Versus Best Available Therapy in Patients With Steroid‑Refractory Acute Graft‑Versus‑Host Disease: Final Analysis From the Randomized Phase III REACH2 Trial. J Clin Oncol. 2025 Dec;43(34):3639‑3645. doi: 10.1200/JCO‑25‑00809. Epub 2025 Oct 15. PMID: 41092247 IF: 41.9 Q1 ; PMCID: PMC12634147 IF: 41.9 Q1 .
