A phase I dose-finding trial of recombinant interleukin-21 and rituximab in relapsed and refractory low grade B-cell lymphoproliferative disorders

Abstract

Purpose: We conducted a phase I study to determine the safety, maximum-tolerated dose (MTD), and efficacy of weekly bolus recombinant human interleukin-21 (rIL-21) plus rituximab in patients with indolent B-cell malignancies.

Experimental design: One week after a lead-in rituximab dose, cohorts of three patients were treated with 30, 100, or 150 μg/kg rIL-21 weekly for four weeks, concurrent with four weekly doses of rituximab. Patients with stable disease or better were eligible for a second course of therapy.

Results: Twenty-one patients with relapsed small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL, n = 11), follicular lymphoma (n = 9), or marginal zone lymphoma (n = 1) were enrolled, with 19 completing at least one course of therapy. The MTD for rIL-21 was 100 μg/kg, based on observed toxicities including nausea, vomiting, diarrhea, hypotension, edema, and hypophosphatemia. Clinical responses were seen in 8 of 19 evaluable patients (42%; 3 CR/CRu, 5 PR), with 4 of longer duration than the patient's previous response to rituximab-based treatment (median 9 months vs. 3 months).

Conclusions: Outpatient therapy of indolent B-cell malignancies with rituximab and weekly rIL-21 was well tolerated and clinically active, with durable complete remissions in a small subset of patients. Additional studies of rIL-21 and anti-CD20 antibodies in lymphoma and SLL/CLL are warranted.

Figure 1. Trial design and clinical response results for rIL-21 plus rituximab

(A) Schema for combination immunotherapy with rIL-21 plus rituximab. The week 0 dose of rituximab alone was given to separate any first-dose rituximab infusion reactions from those associated with IL-21 administration. (B) Maximum percent change in SPD for target lesions after treatment among patients evaluable for response (N=19). SPD = sum of the products of diameters for the 6 largest measurable index lesions.

Figure 1. Trial design and clinical response results for rIL-21 plus rituximab

(A) Schema for combination immunotherapy with rIL-21 plus rituximab. The week 0 dose of rituximab alone was given to separate any first-dose rituximab infusion reactions from those associated with IL-21 administration. (B) Maximum percent change in SPD for target lesions after treatment among patients evaluable for response (N=19). SPD = sum of the products of diameters for the 6 largest measurable index lesions.