Manageable and Transient Hematologic Toxicity Associated with ⁹⁰Y-Ibritumomab Tiuxetan (⁹⁰Y-Zevalin) Consolidation of FCM Chemotherapy in Mantle Cell Lymphoma (MCL) Patients.

Background: We have shown that administration of ⁹⁰Y-Zevalin to consolidate the therapeutic effects of fludarabine, cyclophosphamide, and mitoxatrone (FCM) ± rituximab (R) in the FCM ± R à ⁹⁰Y-Zevalin MCL trial from the Polish Lymphoma Research Group (PLRG) Multicenter Study resulted in PRs with FCM ± R becoming CRs after ⁹⁰Y-Zevalin. This finding could potentially benefit many MCL patients whose disease prognosis is poor. Our initial findings indicate that hematologic toxicity, as measured by duration of PMNs < 1000/ml and PLTs < 50,000/ml, is manageable, with recovery complete within 7–13 wks after ⁹⁰Y-Zevalin. Other researchers have reported that low dose rate radiation therapy is known to cause prolonged marrow damage to progenitors and stromal cells and reduce stem cell yields. Therefore, we specifically studied the hematologic toxicity of this consolidation regimen with ⁹⁰Y-Zevalin and the radiosensitizing drug fludarabine.

Methods: We enrolled 10 histopathologically confirmed MCL patients (stage III-IV) who were ineligible for SCTs. Patients were treated with 3–6 cycles of FCM ± R. Patients were given 250 mg/m² of R followed 1 wk later with a second dose of R + ⁹⁰Y-Zevalin (11 or 15 MBq = 0.3 or 0.4 mCi/Kg based on PLT count; maximum dose = 32 mCi). Cytopenia was assessed with full blood counts every wk until recovery. Trephine biopsies were performed before ⁹⁰Y-Zevalin dosing and at 2 and 6 wks after ⁹⁰Y-Zevalin to assess marrow cellularity and stromal cells. At the same time points, mantle cell (CD19+CD20+CD5+CD23−) infiltration of bone marrow (BM) was assessed by flow cytometry; myeloid clonogenic capacity (CFU-GM, BFU-E, CFU-GEMM, CFU-Meg) was evaluated by cell culture; and BM stroma function was measured by assaying 5 cytokines: GM-CSF, EPO, TPO, IL-3, and SCF. Results were compared with 7 historical follicular lymphoma (FL) patients who received ⁹⁰Y-Zevalin without fludarabine following relapse after chemoimmunotherapy (R-CHOP).

Results: The level of neutro- and thrombocytopenia was greater in patients who received FCM ± R à ⁹⁰Y-Zevalin than in patients who received only ⁹⁰Y-Zevalin. A 2- to 4-fold greater degree of clonogenic capacity impairment was seen with FCM ± R ⁹⁰Y-Zevalin compared with only ⁹⁰Y-Zevalin, except for the CFU-Megs profiles, which were similar in both groups. A 7- to 10-fold ↓ in myeloid stem and progenitor cells in response to FCM + R à RIT was associated with a ↓ in PMNs and PLTs. However, hematopoietic recovery was not prolonged in the fludarabine-pretreated group and did not correlate with the duration of CFU-GM and CFU-GEMM suppression. Stromal cells experienced minimal, transitory (fully reversible by 2 wks) impairment, suggesting a negligible adverse effect of ⁹⁰Y-Zevalin on BM stroma. Compared with pre-⁹⁰Y-Zevalin values, GM-CSF levels ↓ 2-fold at wk 4, and TPO and IL-3 ↓ 30% and 3-fold, respectively, at wk 2. EPO levels ↓ 3-fold during the first 4 wks and paralleled decreases in BFU-Es.

Conclusions: The consolidation of FCM ± R with ⁹⁰Y-Zevalin in MCL patients is a promising therapeutic approach. The FCM + R ⁹⁰Y-Zevalin treatment resulted in significant damage to myeloid stem and progenitor cells and increased neutro- and thrombocytopenia compared with ⁹⁰Y-Zevalin alone, but cytopenias are still manageable and hematopoietic recovery occurs within 9–12 wks after ⁹⁰Y-Zevalin. Clinicians must monitor the amount of BM infiltration and the BM hypocellularity after FCM + R before administering ⁹⁰Y-Zevalin.