High-Dose Myeloablative Zevalin Radioimmunotherapy with Tandem Stem-Cell Autografting Has Minimal Toxicity and Full Feasibility in an Outpatient Setting.

Abstract

Background : High dose chemotherapy has an established, albeit limited role, in the management of non-Hodgkin lymphoma (NHL). In fact, because of its toxicity, in particular mucositis, neutropenia and thrombocytopenia, myeloablative regimens with autologous stem cell support can be safely delivered only to clinically fit and younger pts, require prolonged hospitalization, and have a restricted impact in the therapy of NHL. With the primary aim of widening the applicability of myeloablative regimens, we designed a pilot study using high-dose Zevalin with tandem stem-cell support in a prospective cohort of 13 refractory or relapsed NHL patients, unable to safely undergo a BEAM chemotherapy course. Methods : Prior to Zevalin, all pts received one cycle of high-dose cyclophosphamide plus rituximab, and one cycle of high-dose cytarabine and rituximab, at patient-adapted doses. Hematopoietic stem cells were harvested from the peripheral blood during the post-cyclophosphamide and/or the post-cytarabine recovery phase, and tested for MRD. Zevalin was administered at twice the MTD (0.8 mCi/kg), and followed by tandem autografting of a small amount of CD34+ (0.8–2 x 106/kg) on day +7, and an optimal amount (>=5 x 106 CD34+ cells/kg) on day +14, respectively. The former reinfusion (supportive autografting) was done still in the presence of potentially myelotoxic doses of circulating radioactivity, and its aim was solely to achieve an immediate albeit transient hematopoietic recovery. At the time of the second reinfusion (reconstituting autografting) the calculated radiation dose to the reinfused stem cells was less than 5 cGy, in order to ensure a complete and long lasting hematopoietic reconstitution. Results: From July 2004 through March 2005, 13 overall NHL patients entered into the study (DLBCL 5, follicular 3, mantle cell 2, marginal zone nodal 1, small lymphocytic 1, lymphoplasmacytoid 1). Median age was 60 yrs (29–69). The number of prior chemotherapy regimes was 1 (4 pts), 2 (5 pts), 3 (3 pts) and 4 (1 pt), respectively. Neutropenia grade 1 or higher was documented in all but 1 patient, and lasted a median of 7 days (1–15), while grade 4 neutropenia was observed in 8 pts, in which lasted a median of 3.5 days only (1–10). Grade >=1 thrombocytopenia was observed in all patients (median 16 days, range 7–30), while grade 4 thrombocytopenia occurred in 10 pts for a median duration (in the thrombocytopenic pts) of 6 days (1–13). Eight patients required platelet transfusions (median 2, range 1–6), and 9 pts received 1 RBC transfusion each. No extra-hematologic toxicity was observed, and all but 4 patients were cared for as outpatients. The 4 hospital admissions lasted 2 (2 pts) and 4 days (2 pts) respectively, and were required for FUO that rapidly resolved upon antibiotic administration. After a median follow-up of 6 months (1–11), 11 pts are alive, of which 10 in continuous CR. Conclusions : High-dose Zevalin with tandem stem-cell transplantation was minimally toxic in this heavily pretreated patient population, and fully applicable in an outpatient setting. Its administration at 0.8 mCi/kg (and possibly up to 1.2 mCi/kg) as a final consolidation step, warrants prospective comparison with conventional-dose regimens in a minimally selected NHL patient population.

High activity 90Y‐ibritumomab tiuxetan (Zevalin®) with peripheral blood progenitor cells support in patients with refractory/resistant B‐cell non‐Hodgkin lymphomas

“…Three escalating 90 Y‐ibritumomab‐tiuxetan activity levels were chosen based on previously reported data using standard‐activity treatment (14·8 MBq/kg) (Wiseman et al , 2003) and RIT/CT combination approaches (Winter et al , 2001, 2004; Devizzi et al , 2005; Krishnan et al , 2005; Nademanee et al , 2005; Shimoni et al , 2005). Our experience in treating solid tumours with Yttrium‐based regimens was also taken into consideration (Paganelli et al , 2006).…”

“…High acitivity (HA) 90 Y‐ibritumomab tiuxetan has been delivered only in combination with HD‐CT, demonstrating that it can be administered safely, with no significant increase in transplant‐related toxicities when rescued by ASCT (Press et al , 1993; Juweid et al , 2000; Gopal et al , 2001, 2005; Winter et al , 2001, 2004; Devizzi et al , 2005; Krishnan et al , 2005; Nademanee et al , 2005; Shimoni et al , 2005).…”

Dosimetric Considerations in Radioimmunotherapy and Systemic Radionuclide Therapies: A Review

“…High-dose and escalated-dose 90 Y-ibritumomab tiuxetan as monotherapy in conditioning regimen with tandem SCT was investigated by Devizzi et al [41] Zevalin was administered at doses of 0.8 or 1.2 mCi/kg. Toxicity was as expected, but absence was noted of the frequent severe complications seen with conventional highdose chemotherapy.…”