Pilot Study of Ruxolitinib in Relapsed or Refractory Hodgkin Lymphoma and Primary Mediastinal Large B-Cell Lymphoma

Background: Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL) are curable disorder by systemic chemotherapy. However, 10-20% of patients experience treatment failure, and the treatment outcome of relapsed or refractory HL and PMBCL is still poor. Thus, the treatment of patients with relapsed and refractory disease remains challenging, and novel treatment strategies are needed. The Janus kinase-Signal transducer and activator of transcription (JAK/STAT) pathway has been suggested as a novel therapeutic target of these diseases because the activation of JAK/STAT and the in vitro efficacy of JAK2 inhibitor in HL and PMBCL were reported in previous pre-clinical studies. Given the importance of JAK/STAT signaling as a survival pathway in tumor cells, the use of JAK inhibitor may be a possible treatment option for relapsed or refractory patients with HL and PMBCL. Therefore, we performed a pilot study with ruxolitinib, JAK1/Jak2 inhibitor for relapsed or refractory HL and PMBCL.

Methods: This study is a multi-center, single-agent, pilot study of ruxolitinib administered at a dose of 20 mg orally twice a day of a 28-day cycle. Patients with relapsed or refractory HL and PMBCL undergo treatment with ruxolitinib until disease progression or unacceptable toxicity are observed. Patients more than 18 years with measureable disease that was FDG-PET positive at baseline were eligible. Prior to the enrollment, patients should receive at least two types of previous treatment such as cytotoxic chemotherapy or autologous stem cell transplantation. Additional criteria included ECOG PS ≤2, adequate bone marrow, renal and hepatic function. The objectives of this study included characterization of anti-tumor activity and safety of ruxolitinib in relapsed or refractory HL and PMBCL patients. The response evaluation was performed according to Cheson criteria every two cycles, and the safety was assessed according to CTCAE v4. Details of the study are at ClinicalTrials.gov (NCT01965119).

Results: To date, 10 patients (median age, 47 [range 21 - 70]) including 7 HL and 3 PMBCL have been treated with ruxolitinib between November 2013 and May 2014. Median number of prior therapies was 4 (2 - 6) and five patients relapsed after autologous stem cell transplantation. Prior to ruxolitinib treatment, all patients failed to show objective response to salvage treatment including progressive disease (n=7) and stable disease (n=3). All patients had baseline lymphadenopathy, and seven patients had extranodal involvement. Antitumor activity was observed in 3 of 7 patients with HL including three partial responses at the end of 2^nd cycle scan. Among them, one patient exhibited progressive disease at the end of 4^th cycle. However, the other two patients who maintained their response are continuing treatment at the time of analysis. Thus, they finished their 5^th and 4^thcycle, respectively, and updated results will be presented. The toxicity profile was manageable without any grade 3 or 4 hematologic and non-hematologic toxicity. Grade 1 toxicity included AST/ALT elevation (n=1), abdominal pain (n=1), myalgia (n=1) and sore throat (n=1). Grade 2 toxicity included neutropenia (n=1) and thrombocytopenia (n=2). The FISH study with tumor tissue of patients who participated in the study showed the amplified signals representing JAK1/JAK2 amplification.

Conclusions: Ruxolitinib, a JAK1/JAK2 inhibitor, is well tolerated with an acceptable safety profile in patients with heavily treated HL and PMBCL, and shows significant single agent anti-tumor activity particularly for HL. Additional studies should be warranted to determine dosage and confirm efficacy of ruxolitinib in HL.