Y-90-Ibritumomab Tiuxetan, Fluadarabine and TBI Based Non-Myeloablative Allogeneic Transplant Conditioning for High-Risk B-Cell Lymphoma

Non-myeloablative allogeneic transplantation (NMAT) can provide prolonged remissions in patients with advanced B-cell lymphoma (B-NHL) via the graft versus lymphoma (GVL) effect, though inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy (RIT) can safely induce responses in B-NHL with little non-hematologic toxicity. We hypothesized that ⁹⁰Y-ibritumomab tiuxetan-based NMAT would safely facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft which would also abrogate the hematologic toxicity of the RIT.

Forty patients with relapsed, high-risk B-NHL and persistent disease who were not deemed appropriate for standard NMAT due to disease factors and not considered appropriate for myeloablative transplant due to age, pretreatment, or co-morbidities were enrolled in this phase II trial. Conditioning included 0.4 mCi/kg (max 32mCi) ⁹⁰Y-ibritumomab tiuxetan (day-14), fludarabine (days -7 to -5) and 2 Gy total body irradiation (day 0) followed by transplantation from matched related (n=15) or unrelated (n=25) donors along with post-grafting immunosuppression with cyclosporine and mycophenolate mofetil. Baseline features included: median age = 58 years (range 29–69 years), median prior regimens = 6 (range 3 to 12), chemosensitive disease = 6 (15%), CR pretransplant = 0 (0%), bulk >5 cm = 17 (range 5.2–18.6cm, 43%), >25% bone marrow involvement with B-NHL = 10 (25%, range of marrow involvement 40–95%), comorbidity score ≥1 = 35 (85%), median comorbiditiy score 3 (range 0–10), pretransplant IPI ≥3=21 (53%). Histologies included: DLBCL (14, including 6 that had transformed from indolent disease), CLL/SLL (10), mantle cell lymphoma (8), FL (6), hairy cell leukemia (1), and marginal zone lymphoma (1).

Early objective responses attributable to the conditioning regimen at 1 and 3 months were observed in 19 (48%, 3 CR/CRU, 16 PR) and 24 (60%, 13 CR/CRU, 11 PR) patients, respectively, including 17 (59%) objective responses in the 29 patients with known chemoresistant disease and 10 (59%) of 17 with bulk > 5cm. In total, 33 (83%) patients experienced reduction in the measurable disease burden by day 84. The estimated OS and PFS at 30 months were 54.1%, and 31.1%, respectively. The regimen was well tolerated and all patients experienced sustained engraftment with no graft rejection. The neutrophil and platelet nadirs were 50/μ L and 12,000/μ L and occurred a median of 12 and 8 days after transplant, respectively. The median duration of neutropenia <500/μ L was 11 days and thrombocytopenia < 50,000/μ L was 8 days. Grade III acute GVHD occurred in 4 patients (10%) but none had grade IV. Chronic extensive GVHD occurred in 8 patients (20%). Non-relapse mortality at 100 days and 30 months were 2.5% and 15.9%, respectively. Multivariable analysis identified early response (p<0.001), baseline platelet counts >25,000/μ L (p=0.002), indolent histology (p<0.001), and related donors (p=0.04) as associated with improved survival.

The addition of ⁹⁰Y-ibritumomab tiuxetan to NMAT is safe, feasible, and can be readily employed yielding early responses and prolonged disease control in a subset of the highest risk B-NHL patients.

Gopal:Biogen-Idec: Research Funding. Off Label Use: Zevalin for transplant conditioning. Maloney:Spectrum: Consultancy, Honoraria; Genetech: Consultancy, Honoraria.