Treatments for Steroid-Refractory cGVHD
Therapies for steroid-refractory chronic graft-vs-host disease, ibrutinib, ruxolitinib, and belumosudil, are explored in a comprehensive analysis.
Robert Zeiser, MD: Ibrutinib is a selective and irreversible inhibitor of Bruton tyrosine kinase, BTK, which is a nonreceptor tyrosine kinase which belongs to the TEC family of kinases. It is mainly expressed in B-cells and not that much in other cells in particular; not in T-cells or in K-cells. It inhibits signaling downstream of the B-cell receptor and therefore blocks B-cell activation. Ibrutinib also blocks I2 [interleukin-2] inducible kinase, ITK, and ITK controls proximal TCR [T-cell receptor] signaling and thereby also ibrutinib is not inhibiting B-cells alone but also interferes with NF kappa B [nuclear factor kappa B] and MOB [Mps 1 binder co-activator proteins] kinase signaling T-cells. This drug, ibrutinib, was tested in adult patients with chronic graft-vs-host-disease [cGVHD] that had failed first line systemic therapy, and this was a phase 1/2 open label multicenter trial. Here in this trial, the primary efficacy end point was best cGVHD overall response rate [ORR]. Of note inflammatory skin or mouth involvement was a requirement to be enrolled, and in this trial 42 patients with cGVHD were enrolled. The ORR was 67 %with a complete response [CR] rate of 21 and a partial response [PR] rate of 45%. Based on these promising results, ibrutinib was approved by the US FDA in August 2017 after failure of 1 or more lines of systemic therapy for GVHD.
Ruxolitinib is a TKI that targets the JAK1/JAK2. JAK1/2 mediate downstream effects of multiple cytokines including the IL-2 [Interleukin 2 protein] receptors, the IL-6 receptor, interferon gamma, IL-7 or IL-15 receptor as well as other common gamma chain cytokine receptors.
To test ruxolitinib for cGVHD at randomized open label multicenter clinical trials, ruxolitinib compared with best available therapy [BAT] was performed and this trial included patients with corticosteroid refractory or dependent cGVHD. The trial was called the REACH3 trial [NCT03112603]. This randomized trial involved 329 patients that were randomly assigned 1:1 to receive either ruxolitinib 10 mg twice daily or 1 of 10 possible investigator selected BATs. ORR was higher in the ruxolitinib group compared with the BAT group at week 24. The median failure-free survival was longer in the ruxolitinib group compared with the control group with more than 18.6 months vs 5.6 months and a higher symptom response was observed according to the modified symptom scale in the ruxolitinib arm compared with the BAT arm with 24% vs 11%. Based on these results in September 2021, the FDA approved ruxolitinib 10 mg twice daily for cGVHD disease after failure of 1 or 2 lines of systemic therapy for cGVHD in adult patients and pediatric patients aged 12 years or older.
Belumosudil is a first-in-class selective inhibitor of Rho-associated coiled-coil containing protein kinase 2, ROCK2 [Rho kinase 2] and this kinase ROCK2 is activated downstream of cytokines and growth factor receptors as well as … and it inhibits the production of pro-inflammatory cytokines in particular IL-21 and IL-17. To test the efficacy of this ROCK inhibitor, belumosudil, patients were included into phase 1/tw2o trial. This was an open label dose finding study of belumosudil and it enrolled 54 patients with chronic GVHD that had to receive 1 to 3 prior lines of therapy. Here, the investigators measured the best overall response of belumosudil, l and they observed that giving belumosudil at a dosage of 200 mg daily led to a response of 74%, [and] 200 mg twice daily had a response of 77%. Thus, based on these results, belumosudil 200 mg daily was approved by the FDA in July 2021 for adults and pediatric patients aged 12 years or older with cGVHD after failure of at least 2 prior systemic therapy lines.
Transcript edited for clarity.
