Radioimmunotherapy-Augmented Nonmyeloablative Allogeneic Transplantation Improves Outcomes for Refractory Indolent B-Cell Non-Hodgkin Lymphoma: Results of an Adjusted Cohort Analysis

Background: Nonmyeloablative allogeneic hematopoietic cell transplantation (NMAT) can produce long-term remissions in patients (pts) with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL), yet relapse after NMAT is the major cause of failure. Radioimmunotherapy (RIT) is highly effective in relapsed B-NHL with rare non-hematologic toxicity, making it potentially useful in providing early post-NMAT disease control.  We thus performed a phase II study of ⁹⁰Y-ibritumomab tiuxetan prior to fludarabine/2 Gy total body irradiation (TBI)-based NMAT in pts with refractory B-NHL, which yielded the best outcomes in indolent B-NHL (iB-NHL) (Gopal, Blood, 2011). In order to estimate the potential benefit of RIT + NMAT in iB-NHL we compared outcomes of these patients with those treated without RIT prior to NMAT.

Methods: Comparison patients included consecutive individuals with iB-NHL who received NMAT from matched related or unrelated donors following fludarabine/2 Gy TBI and who met eligibility criteria for the phase II trial of RIT + NMAT but did not enroll. Frequencies of characteristics between groups were compared using a Fisher's exact test.  Kaplan-Meier (K-M) curves were used to estimate the probabilities of overall survival (OS) and progression-free survival (PFS).  To account for imbalanced covariates, adjusted estimates of survival were also generated (Storer, Lifetime Data Anal, 2008).

Results: The RIT + NMAT group included 18 pts with iB-NHL: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 10), follicular lymphoma (FL; 6), marginal zone lymphoma (MZL; 1), and hairy cell leukemia (HCL; 1).  Controls included 73 pts: CLL/SLL (53), FL (19), and MZL (1).  The RIT-treated pts had more bulky disease > 5 cm (61% vs 17%, p < 0.001), chemoresistant disease (72% vs 32%, p = 0.003), comorbidity index (HCT-CI) scores > 2 (72% vs 37%, p = 0.009), and pre-NMAT platelets < 25k/uL (33% vs 8%, p = 0.01).  In an unadjusted comparison, OS and PFS favored the RIT pts, but the differences were not statistically significant (hazard ratio [HR] for OS = 0.60, 95% confidence interval [CI]: 0.3-1.4, p = 0.24; HR for PFS = 0.75, 95% CI: 0.4-1.5, p = 0.41).  However, after adjusting for significant differences between these groups, outcomes for the RIT-treated group were significantly better (HR for OS = 0.30; 95% CI: 0.1-0.8, p = 0.007; HR for PFS = 0.42, 95% CI: 0.2-0.9, p = 0.02). With a median follow-up of 81 months in surviving patients, the 3-year adjusted estimates for the RIT and control groups were: OS 87% and 59%, PFS 71% and 44%, respectively (Figures 1 and 2).

Conclusions: These data suggest that the addition of ⁹⁰Y-ibritumomab tiuxetan prior to NMAT may result in improved OS and PFS for patients with persistent iB-NHL. These results set the stage for a prospective randomized comparison of these strategies in this setting.