Safety and Clinical Activity of a Combination Therapy Comprising Two Antibody-Based Targeting Agents for the Treatment of Non-Hodgkin Lymphoma: Results of a Phase I/II Study Evaluating the Immunoconjugate Inotuzumab Ozogamicin With Rituximab

Abstract

A B S T R A C T PurposeInotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20 ϩ / CD22 ϩ B-cell non-Hodgkin lymphoma (NHL). Patients and MethodsA dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. ResultsIn all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m 2 ) was confirmed to be the same as that for single-agent INO (1.8 mg/m 2 ). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n ϭ 39), relapsed DLBCL (n ϭ 42), and refractory aggressive NHL (n ϭ 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL. ConclusionR-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20 ϩ / CD22 ϩ B-cell NHL.

Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial

“…The ORR in patients relapsing later than 6 months after previous therapy for DLBCL were as high as 72% and responses lasted for a median of 17 months. 22 According to our data the major target population for the R-GemOx regimen might be unfit and/or elderly patients, for whom no meaningful therapeutic options can be found. A phase II study to evaluate whether the addition of enzastaurin can enhance the efficacy of R-GemOx in patients with relapsed DLBCL or transformed indolent lymphoma has been conducted.…”

Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?

“…In some cases, dramatic responses have been observed; however, in general these agents have shown modest activity in relapsed and refractory DLBCL, with overall response rates ranging from 11 to 47%, CR rates from 1 to 16% and median durations of remission generally in the 2-6 months range (Table 1). [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] For many of these agents, studying specific subtypes of DLBCL (for example, the activated B cell subtype), or cases in which the target of the agent is known to be present, will likely prove to be more effective than simply enrolling all DLBCL cases. Therefore, some subtypes of DLBCL may ultimately prove to be amenable to maintenance therapy post transplant.…”

Prospects of targeted therapy of acute leukemias in children

“…Изначально IO был синтезирован для использования при лечении экспрессирующей CD22 неходжкинской лимфомы. На ранних фазах два исследования у 10 взрослых с рефрактерными НХЛ показали многообещающие клинические результаты при использовании его в ка-честве единственного препарата или в сочетании с ритуксимабом [55]. Клиническую активность IO про-демонстрировал в исследовании фазы II у взрослых и детей с рецидивирующим/рефрактерным CD22+ В-линейным ОЛЛ при дозировке 1,3-1,8 мг/м 2 каж-дые 3-4 недели.…”