Abstract
LR131 is a novel radioconjugate consisting of B Lymphocyte Stimulator (BLyS) protein, a B cell maturation factor of the TNF family that binds selectively to immunoglobulin-positive B cells, labeled with Iodine I 131. BLyS receptors are present on normal B cells and B cell malignancies. Ten subjects with relapsed, refractory follicular non-Hodgkin’s lymphoma (8M/2F, age 33–61) have been entered on study at the Cross Cancer Institute as part of a multicenter phase 1 dose escalation trial. FDG-PET and CT imaging were performed prior to and following LR131 therapy to evaluate tumor response and recurrence. Previous therapies for these patients included single and multiagent chemotherapy, limited field external beam radiation therapy and Rituximab with/without concomitant chemotherapy. Patients had an average of 2.6 previous therapies (range 1–4). Patients received an imaging/dosimetry dose of 5–7 mCi of LR131 followed 1–2 weeks later by the therapeutic dose. CT and PET confirmed specific tumor localization in all patients. Ten of ten patients targeted sites of disease seen on CT and PET with LR131 although one patient with rapidly progressing end stage disease did not uniformly target a very large tumor mass in the abdomen/pelvis. Administered activities for therapy were 0.35 mCi/kg (10 m g/kg BLyS), 0.70 mCi/kg (30 m g/kg BLyS), 1.35 mCi/kg (75 m g/kg BLyS) and 1.70 mCi/kg (75 m g/kg BLyS) for the first four cohorts, respectively. Of 8 evaluable patients through at least 12 weeks of follow-up there were 2 CRu, 2 PR and 1 SD. In the two patients with CRu, follow-up PET scanning was negative for FDG accumulation in all areas of previous activity. One patient had significantly decreased activity on PET (4 weeks) later confirmed as PR by CT. Two patients have been retreated including one CRu (1 year) who showed renewed positive activity on PET imaging (negative CT) which returned to negative following retreatment and 1 PR. There have been no dose limiting toxicities seen to date on initial or retreatment. Time activity curves were generated after drawing ROIs and analyzed with SAAM II. Doses were calculated using MIRDOSE 3.1 (Stabin 1996). Deposited doses to critical organs were 0.48, 0.55, 2.13, 0.49, 0.37 cGy/mCi to the liver, lung, kidney, marrow and total body, respectively, and were significantly lower than those seen with the approved iodine labeled anti-CD20 monoclonal antibody (3.03, 2.92, 7.25, 2.41, 0.89 cGy/mCi for the same organs). LR131 demonstrated rapid clearance from blood and normal organs with retained activity in sites of tumor. Tumor deposited doses ranged from 45 cGy in the patient that did not target to 3600 cGy.
CONCLUSION: LR131, at the administered doses studied to date, has been well tolerated with only mild to moderate reversible toxicity. LR131 has demonstrated targeting and clinical efficacy that has correlated with CT and PET imaging
B lymphocyte stimulator: a new target for treating B cell malignancies