Optimizing dose for Lu-177 DOTA-rituximab lymphoma therapy
Radioimmunotherapy with Lu-177 DOTA-rituximab represents a novel and well-matched treatment for B-cell Lymphoma, but no consensus on standardized dosimetry was available, until now, according to research published in the July issue of Journal of Nuclear Medicine.
Flavio Forrer, MD, from the Institute of Nuclear Medicine at University Hospital Basel in Basel, Switzerland, and colleagues evaluated the maximum tolerated dose of chimeric anti-CD20 antibody rituximab conjugated with luteum-177 treating patients with recurrent or refractory CD20-positive mantle cell, follicular or marginal zone and other indolent lymphomas in this prospective, single-center and open-label phase I/II dose escalation study.
Rituximab is thought to be an important component of treatment for patients with CD20-positive B-cell neoplasms and works by way of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Lu-177 DOTA-rituximab differs from other approved radioimmunotherapies such as Zevalin (Y-90 ibritumomab) and Bexxar (I-131 tositumomab) due to the energy of Lu-177, which has the potential to be better tailored to these lymphomas.
“Lu-177 is a low-energy b-emitter (maximum energy, 0.497 MeV) with a relatively short tissue penetration range (maximum, 1.6 mm),” wrote Forrer et al. “Because malignant lymphoma cells often infiltrate normal tissues in a diffuse manner, we decided to use the lower b-energy and shorter tissue penetration of Lu-177 as these may result in a more favorable tumor-to-nontumor ratio. In addition, Lu-177 emits g-radiation (113 keV, 7 percent; 208 keV, 11 percent) that can be used for scintigraphic imaging, allowing immediate control of distribution and dosimetry in treated patients. The fraction and energy of its g-emissions are lower than those of I-131 (362 keV), whose physical characteristics necessitate a prolonged hospital stay for treated patients in many countries.”
Dose was adjusted to subjects’ body surface area and final maximum tolerated dose after escalated treatment using Lu-177 DOTA-rituximab was determined to be 1,665 MBq/m2 of body surface area. Dose-limiting toxicities were few and identified as leukopenia and thrombocytopenia. Nonhematologic toxicity was insignificant and anemia only became an issue once the dose was raised to 1,850 MBq/m2 of body surface area. The median recovery time to a decreased step of toxicity was seven days.
A total of 31 patients were included in the study. Of these subjects, 29 out of 31 responded to therapy and dosimetry was completed successfully for 20 patients. Dosing began at 740 MBq per square meter of body surface area and was escalated to 250 MBq per square meter of body surface area on days 1 and 8. On the eighth day patients were administered the radiopharmaceutical after an infusion of a second dose of antibody. Thereafter dose was escalated to 185 MBq per square meter of body surface area. The maximum tolerated dose was defined as the dose at which at least one patient had exhibited more than one nonhematologic grade-two toxicity and more than one hematologic grade-four toxicity. Patients had blood tests weekly up to week 10 or until recovery from nadir and whole-body contrast-enhanced CT and F-18 FDG PET or F-18 FDG PET/CT was performed at baseline and 8–12 weeks following treatment.
“We observed clinical responses at all dose levels and for all lymphoma entities,” the authors wrote. “Some of the responses were durable; the longest follow-up is currently over 8 years. At present, 11 patients are alive and 8 patients are disease-free.”