Dose-escalated radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced-intensity conditioning regimen for allogeneic haematopoietic cell transplantation in patients with advanced aggressive non-Hodgkin's lymphoma

Allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) regimens offers a potential curative therapy to patients with advanced aggressive NHL. RIC HCT induces potent graft-versus-lymphoma effects with best results in patients with low tumor burden at time of HCT. Combined use of radioimmunotherapy (RIT) with RIC may increase anti-lymphoma activity of RIC. In addition to the graft versus lymphoma effect, HCT provides rescue from hematologic toxicity of RIT which may allow dose escalation of RIT. 20 patients have been enrolled in a multicenter phase I/II dose escalation study of RIT using yttrium-90-ibritumomab tiuxetan (Y90-CD20, Zevalin) at two dose levels (0,6 (22 MBq) and 0,8 (30 MBq) mCi/kg) in 10 patients each, combined with RIC for treatment of patients with aggressive NHL. Patients received dosimetry with In111-CD20 on day -21 and RIT with an escalated dose of Y90CD20 (0,6-0,8 mCi (22-30 MBq)/kg) on day -14 followed by RIC using fludarabine (30 mg/[m.sup.2] day -8 to -4), melphalan (140 mg/ [m.sup.2] day -3) and alemtuzumab (20-30 mg day -3 to -2). For postgrafting immunosuppression cyclosporine was administered. Diagnoses were diffuse large B-cell lymphoma (n=13), transformed chronic lymphocytic leukaemia (n=4), blastoid mantle cell lymphoma (n=2) and follicular lymphoma grade 3 (n=1). Median age was 51 (range, 30-69) years. PBSC grafts were either from matched related (n=5) or matched unrelated donors (n=15). All patients were high risk with refractory disease or relapse after preceding autologous HCT. Disease status at time of HCT was CR=4, PR=15 and SD=1. No additional toxicity due to RIT was observed in comparison to our previous experience with the same RIC alone. Engraftment was rapid and sustained with no graft rejections. Median time to >500 granulocytes/ µL was 15 (range, 9-32) days and to >20000 platelets/µL 11 (range, 9-56) days. TRM at day +100 was 0% and overall 20%. Incidence of grade II-IV GVHD was 50% (II=8, III=1, IV=1). To date, chronic extensive GVHD occurred in 6 patients. Causes of death were relapse=6, suspected suicide=1, infection=3 and GVHD=1. 9/20 patients (45%) are alive with a median follow-up of 258 (range, 81-497) days. Disease status of patients alive is CR=7, PR=2 and Relapse=1. In conclusion, dose escalation of RIT and combined use with RIC is feasible with no additional toxicity due to RIT and with stable engraftment in all patients. Long-term disease-free survival remains to b