Phase 1/2 study of fractionated 131I-rituximab in low-grade B-cell lymphoma: the effect of prior rituximab dosing and tumor burden on subsequent radioimmunotherapy

Abstract

The effect of induction therapy with multiple doses of rituximab on the subsequent efficacy and toxicity of anti-CD20 radioimmunotherapy is unknown. We evaluated a novel protocol using 4 weekly infusions of 375 mg/m 2 rituximab followed by 2 fractions of 131 I-rituximab, preceded by a 100-mg/m 2 predose of rituximab, in relapsed indolent B-cell lymphoma. Induction therapy with rituximab significantly increased the effective half-life of 131 I-rituximab (P ‫؍‬ .003) and high serum levels of rituximab after induction therapy correlated with increased effective half-life of the radioimmunoconjugate (P ‫؍‬ .009). Patients with large tumor burdens experienced significant increases in the effective half-life of 131 I-rituximab between delivery of the first and second fractions (P ‫؍‬ .007). Induction therapy with multiple doses of rituximab did not appear to compromise the clinical efficacy or increase toxicity of subsequent 131 I-rituximab radioimmunotherapy. The overall response rate was 94%, with complete response rate 50%.The median time to progression was 20 months, significantly longer than for the last qualifying chemotherapy (P ‫؍‬ .001). Fractionation of 131 I-rituximab allowed cumulative whole-body doses of more than 120 cGy, approximately 60% greater than those previously achieved with a single administration of a murine radioimmunconjugate, to be delivered without significant hematologic toxicity.

Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients

“…31 After infusion of 375 mg/m 2 rituximab, a more favorable biodistribution with selective tumor targeting of 131 I-rituximab at sites of nodal disease was seen. 31 In vitro studies imply that the sequential use of anti-CD20 mAb may result in the inhibition of binding of the second anti-CD20 mAb, 32 but prior rituximab did not adversely affect the response to 131 I-rituximab in a phase 2 clinical study, 7 compared with rituximabnaïve patients. Whether the pre-RIT rituximab dose affects the response to RIT in vivo has not been conclusively demonstrated, but recent studies suggest an enhanced efficacy.…”

“…Whether the pre-RIT rituximab dose affects the response to RIT in vivo has not been conclusively demonstrated, but recent studies suggest an enhanced efficacy. 31 Induction therapy with high-dose rituximab administered before 131 I-rituximab RIT increased the effective circulating half-life from 45 to more than 90 hours. 31 Induction therapy did not appear to compromise the clinical effects of RIT with 131 I-rituximab or increase myelotoxicity.…”

When is a predose a dose too much?

“…We found that induction therapy with rituximab significantly increases the effective half-life of subsequent 131 I-rituximab and correlated with increased effective half-life of the 131 I-rituximab. 7 Importantly, we demonstrated that multiple doses of rituximab did not appear to compromise the clinical efficacy or increase the myelotoxicity of subsequent anti-CD20 targeted RIT.…”

“…However decreased targeting leading to decreased efficacy of RIT has not thus far been observed in the clinic and if there is a deleterious effect with large amounts of mAb predosing, this does not appear to substantially affect the clinical efficacy. 7 Perhaps of greater concern in improving outcomes for patients with follicular lymphoma is the gross under usage of RIT. In an era where immunochemotherapy has substantially improved outcome, it is perhaps easier to become complacent that using such an effective treatment is not required in the treatment algorithm of follicular lymphoma.…”

Update on the rational use of (90)Y-ibritumomab tiuxetan in the treatment of follicular lymphoma

“…Also, neither clinical efficacy of RIT did appear to be compromised, nor toxicity increased. 20 Similarly, in 2 trials using rituximab + chemotherapy combination therapy before 90 Y-IT application, 28,29 a significant rate of conversion from partial response (PR) to complete response (CR) was observed, again indicating that prior rituximab therapy does not hamper RIT. Since 2002, 90 Y-IT is approved in the United States (US) for patients with CD20+FL or transformed B-cell NHL, refractory to or relapsed after rituximab.…”