Y-90 Ibritumomab Tiuxetan as Consolidation Following Three Cycles of Fludarabine-Cyclophosphamide-Rituximab Chemoimmunotherapy in Patients with Relapsed Follicular, Indolent or Mantle-Cell Lymphoma: A Prospective “Dose”-Finding Study.

BACKGROUND: Tumed sequential treatment with fludarabine/cyclophosphamide/rituximab (FC-R) followed by Y-90 ibritumomab tiuxetan (IT) radioimmunotherapy may improve progression-free survival in patients (pts) with CD20+ NHL. However, even unpretreated pts submitted to four to six cycles of a fludarabine-containing combination and then IT at an Y-90 activity of 15 MBq/kg will experience severe prolonged, transfusion-dependent and only partially reversible pancytopenia, thus limiting its use in a non-curative setting (Jurczak et al., ASH 2005).

AIM: We report on a trial including anthracycline-pretreated pts with relapsing CD20+ lymphoma > age 50 and unsuitable for myeloablative treatment. These received 3 cycles of FC-R. If at least stable disease was achieved and neutrophil as well as platelet counts had normalized (2.5 vz. 150/nl) within 8 weeks, this was immediately followed by IT at 11 or 15 MBq/kg Y-90 activity. Primary endpoint was the rate of dose-limiting toxic events (DLT) induced by consolidation IT as a function of Y activity employed. DLT was defined as NIH-CTC grade 4 neutropenia or thrombocytopenia for > 14 days or non-hematological toxicity of > grade 2 for > 7 days. Per level of activity, a maximum of 1 DLT episode occurring in two cohorts of 3 pts was considered acceptable.

RESULTS: We recruited 21 patients into the trial (10 follicular, 9 mantle cell, 2 other). Median age was 70 years, all were stage III/IV and median no. of pretreatments was 1 (range 1 to 3). 9 had marrow involvement (< 25%), and 7 elevated LDH. 8 pts went off treatment before IT, mostly because of persistent cytopenia or progression. 13 received IT. Pt characteristics in this subcohort were comparable to the baseline cohort. Hematologic nadirs occurred at median 6 weeks post-IT. Median ANC nadir was 0.45/nl, with 1 pt in the 11 MBq and 2 in the 15 MBq activity level sustaining grade 4 neutropenia of > 2 weeks duration. Median PLT nadir was 26/nl. Grade 4 thrombocytopenia was found in only 1 pt at the 15 MBq level (duration 10 days) who did not require transfusion. Median ANC and PLT counts normalized by week 12, one showing persistent otherwise unexplained thrombocytopenia. Non-hematological toxicitiy including fever or infections was rare and < grade 3. No correlation was found with extent/type of pretreatment, baseline cell counts or presence of marrow involvement. With median 8 months follow-up, 1 has so far improved remission status to CR, and 1 pt in stable disease and 1 in PR before IT have progressed.

CONCLUSIONS: In order to avoid neutropenia grade 4 of > 2 weeks duration, IT following 3 cycles of FC-R should be performed at an Y activity level of 11 MBq/kg. Nevertheless, the possibly higher incidence of prolonged severe neutropenia following IT at 15 MBq does not translate into a higher rate of infections or persistence of neutropenia and may therefore be regarded safe.