17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Abstract

Background: Recent studies demonstrated that classical Hodgkin lymphoma (cHL) is characterized by chromosome 9p24.1 amplification with associated overexpression of PD-1 ligands and JAK2 tyrosine kinase activation. JAK2 signaling augments tumor cell proliferation. Given this biology, we tested the combined inhibition of PDL1 pathway and JAK2 signaling in cHL patients who had progressed after prior PD-1 blocking therapy. Methods: This is a Phase I/II multicenter, open-label, dose escalation/dose-expansion study to evaluate the safety and tolerability of JAK2 inhibitor ruxolitinib when combined with nivolumab in patients with R/R cHL (NCT03681561) who fail prior check-point inhibitor. Ruxolitinib was administered at 3 dose levels: 10, 15 or 20 mg orally twice a day continually with nivolumab at fixed dose 3 mg/kg IV every 2 weeks. Planned duration of therapy was 2 years. Results: We enrolled 21 patients with median age 41 years (range 22–76); 67% were males. Patients were 3.4 years from diagnosis (median; range 0.9–16.7 years), 81% had stage III-IV and 89% had prior stem cell transplant. All patients had experienced progressive disease following prior CPI; 78% were resistant to CPI. Ruxolitinib MTD of 20 mg BID was reached without DLTs. Median cycles administered was 9 (range 3–28). The combination was well tolerated; most AEs were grade 1 and 2. Three patients experienced immune mediated adverse events (LFT elevation: 3 Gr 1 and 1 Gr 2; 1 Gr 3 pneumonitis); all were reversible. Median follow-up was 20.7 months (range 3–52 months). In 19 patients evaluable for response (by LYRIC criteria), best disease control rate was 63% (12 of 19); including 5 complete response (26%), 3 partial response (16%) and 3 patients had stable disease (SD, 16%; with tumor bulk reduction ranging from 3 to 48%). One patient had indeterminate response (negative biopsy of new PET-avid site). Median duration of responses was 16.5 months (range 5.8 to 20.4 months). Two patients died, both with progressive disease and one from complications of subsequent experimental therapy. Progression-free survival at 2 years was 45% (95% CI: 22–66%). Correlative analysis demonstrated a ruxolitinib-driven modulation of classical monocytes and myeloid derived suppressor cells suggesting a synergistic antitumor effect with nivolumab. Correlative and in vitro data on mechanism of synergy will be presented. Conclusions: Therapy combining ruxolitinib with nivolumab is well tolerated and yield encouragingly high remission rates and durable responses in patients who failed previous CPI. Pharmacodynamic and correlative analyses suggest synergistic effect on adaptive and innate immune systems. The research was funded by: Incyte and BMS sponsored this trial as investigator initiated study Keywords: Hodgkin lymphoma, Immunotherapy Conflicts of interests pertinent to the abstract. V. Bachanova Research funding: Incyte and BMS supported this trial