Abstract

Interleukin-21 (IL-21) is a member of the common gamma chain cytokine family, which includes IL-2, IL-7 and IL-15, and serves to activate NK cells and CD8+ T cells, as well as modulate B cell functions. Like IL-2, IL-21 can enhance antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, unlike IL-2, IL-21 can render effector T cells resistant to suppression by T reg cells, and can have direct anti-tumor effects against malignant B cells. IL-21 has been shown to promote apoptosis in follicular lymphoma cells, and to induce granzyme B expression in chronic lymphocytic leukemia cells and sensitize them to apoptosis. In a human lymphoma xenograft model, combination treatment with rituximab plus recombinant IL-21 (rIL-21) led to increased survival compared to either agent alone. To further evaluate the potential safety, pharmacokinetics, and anti-tumor effects of combining rIL-21 with rituximab, a phase 1, two-part dose-escalation study was initiated in patients with relapsed CD20+ B cell lymphomas. For dose escalation, cohorts of 3 patients each received weekly rituximab (375 mg/m2) on days -7, 0, 7, 14, and 21, and rIL-21 at 1 of 3 dose levels (30, 100, or 150 g/kg) on days 0, 7, 14, and 21. Patients without disease progression at day 36 were eligible to receive a second cycle beginning 2 weeks later, and CT scan assessments were repeated at day 50 of cycle 2. Enrollment to an expansion cohort of up to 12 additional patients for treatment at the maximum tolerated dose was initiated. A total of 15 patients have been enrolled to date, including 9 dose-escalation patients, all of whom are evaluable for clinical response. The latter include 4 with follicular lymphoma, 4 with small lymphocytic leukemia (SLL), and 1 with marginal zone lymphoma. The median number of prior regimens was 3 (range 1–8), with 8/9 patients having had prior rituximab (1–3 cycles). No patient receiving 100 g/kg or higher of rIL-21 had disease progression, and 7 of 9 patients completed 2 treatment cycles. Overall best responses included 2 CR, 3 PR (including 2 patients whose last response to rituximab lasted < 6 months), and 3 SD by Cheson criteria, for an overall response rate of 56%. No dose limiting toxicities occurred in the first cycle at any dose. Most adverse events were grade 1–2 and included flu-like symptoms, fatigue, pruritus, insomnia, and diarrhea. Laboratory abnormalities were generally mild to moderate and included lymphopenia, transaminase elevations, thrombocytopenia in one patient and hypophosphatemia. Retreatment at 150 g/kg was associated with transient grade 3 nausea, vomiting, and diarrhea in one patient, while a second patient had grade 2 lower extremity edema. Thus, the 100 g/kg dose was chosen for cohort expansion. Combination treatment with interleukin-21 plus rituximab for up to two 4-week cycles is generally well-tolerated and associated with clinical responses, even in subjects heavily pre-treated with rituximab. Enrollment in the 100 g/kg expansion cohort is ongoing. These encouraging results support further evaluation of this combination in phase 2 trials.

Author notes

Disclosure:Employment: Diana Hausman, Todd DeVries and Muriel Siadak are employees of ZymoGenetics, Inc.