Response to JAK 1/2 Inhibition in Patients with Corticosteroid-Refractory Acute Graft-Versus-Host Disease
Authors: Spoerl Silvia , Maas-Bauer Kristina , Verbeek Mareike , Apostolova Petya , Illert Anna Lena , Mathew Nimitha , Poeck Hendrik , Bertz Hartmut , Finke Jürgen , Peschel Christian , Duyster Justus , Zeiser Robert , von Bubnoff Nikolas 
Published: October 2019

Abstract
Acute corticosteroid-refractory graft-versus-host-disease (GvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reported mortality rates of 40-60%. Our previous study (Spoerl S et al. Blood 2014) had shown the induction of tolerogenic regulatory T cells after ruxolitinib treatment in the mouse and clinical responses in six patients with corticosteroid-refractory GvHD.
Here we report the outcome of 14 patients with GvHD refractory to steroids and at least two other lines of treatment who received ruxolitinib as a salvage treatment.
Ten patients were classified as acute and four as chronic GvHD involving the skin, intestinal tract and liver as detailed in Table 1. Patients were treated with ruxolitinib at a starting dose of 5 mg orally twice daily with a dose increase to 10 mg orally twice daily. Clinical and histopathological grading of skin, intestinal and liver GvHD was performed according to established criteria.
Of 14 patients, 13 responded with respect to clinical GvHD symptoms and serum levels of pro-inflammatory cytokines. Three patients with histologically proven acute skin or intestinal GvHD grade I, achieved a complete response. One non-responder discontinued ruxolitinib after one week because of lack of efficacy. In all other patients corticosteroids could be reduced after a median treatment of 1.5 weeks. Serum levels of IL-6 and soluble IL-2R were measured prior and after the start of ruxolitinib and declined in the majority of the analyzed patients (n=11). CMV reactivation was observed in four out of 14 patients and responded well to antiviral therapy. Two out of 14 patients developed cytopenia during ruxolitinib treatment that was mild and did not require dose reduction or transfusion.
Our results indicate that treatment of corticosteroid-refractory GvHD with ruxolitinib is safe and well tolerated. Despite the low number of patients treated so far, our results demonstrate that ruxolitinib reduces the severity of corticosteroid-refractory GvHD and support further development of therapeutic JAK1/2 inhibition as a salvage treatment in GvHD.
Table 1: GvHD and response to ruxolitinib Pt. no. 1 GvHD: organ/grade 2 Reduction of cortico-steroids after ruxolitinib Clinical response (PR / CR) 3 Time to response (weeks) Duration of response 4 / Current follow up (weeks) 5 01 Intestines / IV (acute) Yes CR 1 42 / 43 02 Skin / III (acute) Yes PR 1.5 46.5 / 48 03 Skin / IV liver / III (acute) Yes CR 1 57 / 58 04 Skin / III intestines / IV (acute) Yes PR 1.5 24.5 / 26 05 Skin / III (chronic) Yes PR 1 64 / 65 06 intestine/III-IV (acute) Yes PR 1 15 / 16 07 Skin/ III (chronic) Yes Response 1 46 / 47 08 Skin/ III (acute) Yes Response 1 2 / 3 09 Skin/ II intestine/II (chronic) Yes No response stopped after 1 week N/A N/A 10 Skin/ III liver/III (acute) Yes PR 1 1 / 2 11 intestines IV (acute) Yes PR 2 6 / 8 12 Skin/III (chronic) Yes Response 1 8 / 9 13 intestines/IV Skin/ II (late onset acute) Yes CR 1 17 / 18 14 intestines/IV Skin/ II (acute) Yes PR 1,5 3 / 4
1Pt.: patient, no: individual patient number, 2Acute and chronic GvHD were defined according to NIH criteria, 3PR: partial response, CR: complete response; 4Until last follow up, none of the patients experienced a relapse of GvHD. 5Follow up was calculated from the time of initiation of ruxolitinib treatment.
In patient 01, ruxolitinib was discontinued at week 16 because of complete resolution of all GvHD signs. The patient did not develop any signs of GvHD after discontinuation of ruxolitinib until last follow up.

Disclosures
Off Label Use: Ruxolitinib in GvHD.