High Dose 90Yttrium Ibritumomab Tiuxetan with PBSC Support in Refractory-Resistant NHL Patients.

We present feasibility and toxicity results of a phase I/II study of High Dose (HD) 90Yttrium (90Y) Ibritumomab Tiuxetan with PBSC support in resistant-refractory NHL patients. From 04/04 to 08/07 25 patients were enrolled. Median age was 68ys (21–75). 21/25 patients had advanced stage disease (III/IV) at diagnosis. 14 patients had Diffuse Large B Cell Lymphoma (DLBCL), 7 Mantle Cell Lymphoma (MCL), 2 Follicular Lymphoma (FL) G3, 1 transformed FL, 1 transformed Marginal Zone Lymphoma (MZL). Median number of prior therapies was 3 (1–6), including Rituximab, RT and HD-CT. Three 90Y-Ibritumomab Tiuxetan activity levels were fixed: 30 MBq/kg, 45 MBq/kg and 56 MBq/kg; 4 patients at the 1st, 4 at the 2nd and 17 at the 3rd level. One week before treatment all patients underwent dosimetry with Indium-111 (111In) ibritumomab-tiuxetan in order to assess organ doses and plan the activity level. PBSC were reinfused 13 days after 90Y-Ibritumomab Tiuxetan. On day 28 from reinfusion engraftment was considered to be delayed if ANC<1.0×109/L or PLT<20.0×109/L.

RESULTS: Dosimetry showed acceptable radiation-absorbed doses to normal organs in all cases except one: 1 patient showed an abnormal liver uptake still increasing up to 7 days post injection. The estimated absorbed dose to the liver was 11.3 Gy/GBq, meaning 50 Gy if the prescribed activity of 56 MBq/kg would be administered. Therefore, the patient was excluded from the treatment. The median (24 pts) adsorbed doses for 90Y-Ibritumomab Tiuxetan resulted (mGy/MBq): 0.80 (0.40–1.0), red marrow; 2.1 (1.1–5.4), heart wall; 1.7 (0.3–3.5), lungs; 2.8 (1.8–10.6), liver; 1.9 (0.8–5.0), spleen; 1.7 (0.6–3.8), kidneys; 2.8 (1.3–4.7), testes; 0.5 (0.4–0.8), total-body. Median activity of 90Y-Ibritumomab Tiuxetan delivered: 3.7 GBq, range 2.1–5.55 GBq. All patients engrafted promptly after PBSC transplantation. PLT and ANC-count nadirs were reached 8 and 4 days after transplantation, with median values of 11×109/L PLT (4–35) and 0.01×109/L ANC (0.01–1.09). The time of nadir did not change as a function of 90Y-ibritumomab tiuxetan dose. Median time to engraftment was 12 (0–22) and 20 (1–48) for PLT and ANC respectively. When data were analyzed per dose-level, no statistically significant differences in terms of hematological toxicity were observed. A drop in PLT-counts often occurs after engraftment as a sign of possible late toxicity, particularly in those patients who received more than 3 previous CT regimens. One transient acute G3 liver toxicity was observed at the 3rd level; 1pt died 4 months after treatment due to HCV reactivation; another pt died 2 months after 90Y-Ibritumomab Tiuxetan because of cerebral ischemia; finally we observed a myelodysplastic syndrome in 1pt who had received 45 MBq/kg 2 years after treatment. 22/24 patients are now evaluable for response: 9 CR, 4 PR, 1 SD, 8 PD.

CONCLUSION: 90Y-Ibritumomab Tiuxetan at myeloablative activity is feasible with PBSC support and it could be safely delivered also in elderly pts. We suggest dosimetry in order to avoid unpredictable toxicity and an activity of 45 MBq/kg in heavily pretreated patients. Clinical efficacy and mild treatment-related toxicities suggest HD-90Y-Ibritumomab Tiuxetan is an interesting modality treatment to be further investigated as an alternative therapeutic option in ABMT setting.