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

Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT. Zevalin has been demonstrated active in elderly pts with resistant-primary refractory DLBCL at injected activity of 0.4 mCi/kg, however response is usually of short duration. Increasing RIT dose-intensity could improve and prolong efficacy. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. From 04/04 to 05/06, 18 pts were enrolled. Median age was 66.5ys (21–75). 17/18 pts had advanced stage disease (III/IV) at diagnosis. 11 had DLBCL, 4 MCL, 2 FL, 1 transformed MZL. Median number of prior therapies was 3 (1–6), including Rituximab, RT and HD-CT. Three activity-levels were fixed: 0.8, 1.2, 1.5 mCi/kg. 4pts received 0.8, 5pts 1.2 and 9pts 1.5 mCi/kg. One week prior to Zevalin all pts underwent dosimetry: if no abnormal uptake was observed they received the planned dose. On d13 pts were reinfused with PBSC previously harvested. On d28 from reinfusion engraftment was considered to be delayed if ANC<1.0x10⁹/L or PLT<20.0x10⁹/L. Dosimetry showed acceptable radiation-absorbed doses to normal organs in all cases. Median adsorbed doses (mGy/MBq): 0.8±0.2 (RM), 3.0±1.7 (heart wall), 1.7±0.8 (lungs), 3.9±2.3 (liver), 2.5±1.6 (spleen), 2.2±1.1 (kidneys), 3.0±1.0 (testes), 0.6±0.1 (total-body). Only 1 pt received 30Gy to the liver, without developing toxicity. Median activity of ⁹⁰Y-Zevalin delivered: 95 mCi (3,5 GBq), range 57–150 mCi (2,1 – 5, 55 GBq); 9pts received more than 100 mCi (3,7 GBq). All pts but 1 engrafted promptly. PLT and ANC nadirs were observed 21 and 17 days after Zevalin (median values: 11x10⁹/L and 0.01x10⁹/L). The time of nadir did not change as a function of ⁹⁰Y-ibritumomab tiuxetan dose. For all activity levels, the median time for PLTs to reach >20x10⁹/L was + 25 days (0–35) and the median time for ANC>1.0x10⁹/L was + 33 days (14–61). A non statistically significant difference in terms of hematologic toxicity exists in PLT recovering for pts receiving 1.5 mCi/kg, in respect to other levels, but this phenomenon is probably influenced by PLT count at baseline. A drop in PLT count occurs after engraftment in those pts who had received treatment with a PLT count <100x10⁹/L, as a sign of late toxicity. Non-haematologic toxicity: 1febrile neutropenia, 1HZV-infection at 2^nd level; 2febrile neutropenia, 1 G3 liver toxicity (quickly recovered), 1bacterial pneumonia, 1HZV-infection, 1HCV reactivation (pt died 4 months after treatment) at the 3^rd level. No pulmonary, renal or cardiac toxicity was observed. All pts are evaluable for response: 7CR, 4PR, 1SD, 6PD.

Conclusions: Zevalin at myeloablative activity is feasible with PBSC support and it could be safely delivered in elderly and heavily pretreated pts, including those who previously received HDCT. MTD could be defined according to dosimetry and clinical evaluation. We suggest an activity of 1.5 mCi/kg for those pts with normal PLT count, while 1.2 mCi/kg could be considered for pts with a PLT count <150x10⁹. It is not advisable, in our opinion, to administer elevated Zevalin activity to pts having PLT counts <100x10⁹/L and/or affected by chronic diseases of the liver. Clinical efficacy and mild treatment-related toxicities suggest further investigation.