High Dose Zevalin (90Yttrium Ibritumomab Tiuxetan) Treatment with PBSC Support in Refractory-Resistant NHL Patients: Preliminary Results of a Phase I/II Study.

Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT or for those pts relapsing after ABMT. Zevalin has been already demonstrated active in elderly pts with resistant-primary refractory DLBCL at dose of 0.4 mCi/kg, however duration of response is short. Increasing RIT dose intensity might improve efficacy. There are no data about the use of Zevalin at myeloablative dosage. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. Three Zevalin dose-levels were fixed: 0.8, 1.2, 1.5 mCi/kg; from April 2004 to July 2005 12pts were enrolled, 4pts at each dose level. Median age was 66,5 ys (28–73), 83% male. All pts had stage III/IV at diagnosis; 7DLBCL; 3MCL, 1FL, 1transformed MZL. 7pts had received more than 3 previous CT regimens. All pts had received prior rituximab, 3pts RT, 6pts HD-CT. BM was negative in all pts before RIT. 1Week prior to Zevalin all pts underwent dosimetry and if no abnormal uptake was observed they received the planned dose. On Day −7 and 0 imaging and therapeutic doses were preceded by rituximab 250mg/mq. On Day13 pts were reinfused with PBSC previously harvested. On Day28 from reinfusion engraftment was considered to be delayed if WBC/ANC were<1.0x10⁹/L or PLT<20x10⁹/L. All pts engrafted promptly after PBSCT with median time to WBC/ANC>1.0x10⁹/L and PLT>20x10⁹/L of 19 (range 0–23) and 12 days (0–22) from PBSCT. PLT and ANC count nadirs were observed at 21 (0–24) and 25 (0–31) days after Zevalin with median values of 11x10⁹/L(4–35) and 0.24x10⁹/L(0.01–1.09). Median time to recovery from nadir was 16,5 days (4–175) for PLT and 17days (7–175) for ANC. 8pts required PLT transfusions, 4pts RBC transfusions; median number of PLT transfusions:1(1–4). No G-CSF was administered. No significant differences in terms of haematologic toxicity were observed among the 3 levels. No pulmonary, renal or cardiac toxicity was observed. 11/12 pts are now evaluable for response: 5pts experienced a CR (2 at 0.8mCi/kg, 2 at 1.2mCi/kg, 1 at 1.5mCi/kg), 1 pt receiving 1.5 mCi/kg a PR (ORR 50%); to date 4 pts maintain CR at 12, 11, 9 and 8 months after treatment.

Conclusion: Zevalin at dosage higher than MTD is feasible with PBSC support. Even at dosage 4 times higher than standard, HD-Zevalin could be safely delivered in elderly and heavily pretreated pts, including those who previously received HD-CT. Clinical activity and mild treatment-related toxicities suggest that HD-Zevalin is an interesting modality treatment to be further investigated as an alternative therapeutic options for resistant-refractory NHL.