PS1243 JAK‐INHIBITION WITH RUXOLITINIB IN PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA: A PHASE II, OPEN LABEL, MULTICENTER CLINICAL TRIAL (JERICHO)
Authors: Gillessen S. , Pluetschow A. , Vucinic V. , Ostermann H. , Kobe C. , Broeckelmann P.J. , Fuchs M. , Momotow J. , Borchmann P. , Engert A. , von Tresckow B. 
Published: June 2019

Background:About 15 % of classical Hodgkin Lymphoma (cHL) patients relapse after 1st‐line therapy of which only half, if transplant‐eligible, can be cured with high dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Patients relapsing after HDCT and ASCT have a dismal prognosis and eventually progress also after subsequent administration of brentuximab vedotin (BV) or anti‐PD1‐antibodies. New therapeutic approaches exploiting specific cHL pathways in thereby avoiding side effects known from conventional therapies are hence warranted in relapsed or refractory (r/r) cHL.Aims:In cHL 9p24.1 amplification is a disease‐specific structural alteration that induces Janus kinase 2 (JAK2) signaling and increases PD‐1 ligand expression. As the JAK/STAT pathway is involved in PD‐L1 upregulation, which is a hallmark of cHL, it is a highly attractive clinical target. Ruxolitinib is an oral potent selective inhibitor of JAK1 and JAK2 kinases. Potentially leveraging this promising data, the phase II JeRICHO trial evaluated treatment with ruxolitinib in patients with r/r cHL.Methods:JeRICHO (NCT02164500) adopted a two‐stage phase II design (Simon 1989). If ≥1 overall response (OR) was observed among the 12 evaluable patients enrolled into the first stage, 25 additional patients would be recruited for the second stage. Patients aged 18–99 years with histologically confirmed r/r cHL requiring treatment after at least one appropriate therapy regimen, including HDCT + ASCT if transplant eligible, were included. 25 mg ruxolitinib were administered orally twice daily in continuous 28‐day cycles until progression or unacceptable toxicity. The primary endpoint was the PET/CT‐based OR‐rate (ORR, complete response (CR) or partial response (PR)) after two cycles. Secondary endpoints included progression free survival (PFS) and overall survival (OS) as well as treatment feasibility (dose reductions, treatment duration and adverse events).Results:From 10/2015 to 05/2017 14 patients were enrolled, 2 were excluded afterwards due to disconfirmed cHL diagnosis. At the time of recruitment patients were between 18 and 76 years old (median = 55.5 years) and had received up to 11 (median = 4) previous HL‐therapies (7/12 HDCT + ASCT, 2/12 allogeneic SCT, 12/12 BV). For qualified patients, median treatment duration was 10 weeks (range: 7–38) and the median number of ruxolitinib cycles received was 3 (range: 2–13). Response evaluation was performed at least once for 11 of 12 qualified patients. After 2 cycles, PR was observed in 2, stable disease (SD) in 3 and progressive disease (PD) in 6 patients (ORR: 2/11 evaluable patients, 18%). Best response to treatment was PR, SD or PD for 3, 2, and 6 patients, respectively. Median PFS was 3.6 months and the 1‐year PFS estimate was 8.3 %. The 1‐year OS estimate was 50.6% (median not reached). The toxicity profile was favorable with no grade 4 or 5 toxicities observed. Hematological toxicity was low with no grade 3/4 toxicity except for one case of grade 3 leukocytopenia. Two observed deaths were considered Hodgkin lymphoma related. Detailed data on efficacy, toxicity and treatment administration will be presented.Summary/Conclusion:Ruxolitinib showed modest activity and a favorable side effect profile in r/r cHL. However, the median PFS was only 3.6 months, and no CR was achieved. Even though the formal stopping criterion after stage I was not met, it was decided, that the trial would not continue to stage II due to the low response rate observed.