Red Marrow Dosimetry and Stem Cell Reinfusion in High Dose ⁹⁰Y - Ibritumomab Tiuxetan.

BACKGROUND: Red marrow (RM) is the critical organ in Radioimmunotherapy (RIT) with ⁹⁰Y-ibritumomab tiuxetan, especially at myeloablative activities. Different methods for the evaluation of the adsorbed dose in RM have been investigated. The blood method relates the blood time-activity curve to RM by a factor that accounts for the activity concentration ratio between RM and blood. Alternative dosimetric approaches including image analysis and marrow aspirations (MA) were introduced for RM dose comparison in order to collect information about the dose delivered and to verify the correct time of Autologous Stem Cells Transplantation (ASCT).

PATIENTS AND METHODS: Twenty-six patients affected by resistant/refractory B-cell Non Hodgkin Lymphoma (NHL) were enrolled in a phase I/II study to determine the feasibility and safety of High Activity (HA) of ⁹⁰Y-ibritumomab tiuxetan followed by ASC support. Three ⁹⁰Y-ibritumomab tiuxetan activity levels were planned: 30 MBq/kg (4 patients), 45 MBq/kg (4 patients), 56 MBq/kg (18 patients). One week before treatment all patients underwent dosimetry with ¹¹¹Inibritumomab tiuxetan. The activity concentration was measured in 9 serial blood samples up to 7 days post injection (pi) and planar images in all patients, in MA in 8 out of 18 patients planned at 56 MBq/kg (4 patients at 160 h pi; 4 patients on day planned for ASCT, i.e. day 0). ASC were reinfused 13 days after ⁹⁰Y-ibritumomab tiuxetan. ASCT was considered at low risk when the adsorbed dose to reinfused stem cells (rSC) (i.e. dose to RM at time of ASCT) was < 50 mGy. Engraftment was considered delayed if on day 28 from reinfusion ANC did not reach 1.0x10⁹/L or PLT were not ≥ 20.0x10⁹/L.

RESULTS: A median of 4,25x10⁶/kg (1,45–20x10⁶/kg) CD34+ cells were reinfused for each patient. A delay of engraftment occurred in only 1 patient who received 56 MBq/kg with a baseline ANC count of 0.20x10⁹/L. Bone marrow biopsies were negative for disease localization in all patients at baseline, but 10 out of 26 had shown prior lymphoma infiltration. Considering the blood method the adsorbed dose to rSC resulted < 50 mGy in all patients with a median adsorbed dose of 11 mGy (4 – 28 mGy). ASC would be reinfused earlier in all patients except one. In particular, the 1st day with a dose to rSC < 50 mGy ranged from day -9 to day -5 at 30 MBq/kg; from day -8 to day -4 at 45 MBq/kg; from day -9 to day 0 at 56 MBq/kg, with a median value on day -3. We observed a possible correlation between total activity administered, dose delivered to RM and dose detectable on day of reinfusion, with higher doses to RM and rSC for those patients planned to received the highest activity. We also evaluated the dose to rSC if reinfusion would be performed 7 days after RIT: only 6 out of 26 patients showed a dose to SC < 50 mGy (2 at the 1^st activity level, 3 at the 2^nd and 1 at the 3^rd activity level). Considering the MA method, the median adsorbed dose to the rSC resulted 25 mGy (9 - 69 mGy): in 2 out of 8 patients evaluated the adsorbed dose to the rSC was > 50 mGy on day 0 (69 and 51 mGy respectively). Even if ASC would be reinfused earlier in 5 out of 8 patients, the first day with a dose to rSC < 50 mGy ranged from day -3 to day +1. Despite bone marrow biopsy being negative in all patients at baseline, scintigraphic images (L2–L4 uptake) showed spine marrow uptake in almost all patients.

CONCLUSIONS: Although alternative methods investigated - MA and imaging - are affected by uncertain factors (blood contamination of MA, difficult L2-L4 uptake image quantification), both indicate comparable results, about 2.5-folds higher, suggesting that the blood method provides an underestimate of RM dose. ASCT performed 13 days after HA ⁹⁰Y-ibritumomab tiuxetan is generally safe. We suggest caution in anticipating the timing of ASCT with respect to ⁹⁰Y-ibritumomab tiuxetan in those patients planned to receive an activity > 45 MBq/kg: alternative dosimetric approaches including image analysis and MA should be considered.