Anti CD20 Radioimmunotherapy and mTOR Inhibition in Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas

A subset of patients with advanced or relapsed B-cell lymphomas can be cured with allogeneic hematopoietic cell transplantation (allo-HCT), but success is hampered by the risk of recurrence and GVHD. Here we report the results of a phase 2, single center trial combining anti-CD20 radioimmunotherapy (RIT) with I-131 tositumomab and mTOR inhibition with sirolimus for prevention of serious GVHD and reduction in risk of relapse. Subjects (n=10) received I-131tositumomab 75cGi therapeutic dose on day -12, fludarabine 25 mg/m2 IV on days -6 to -2 and melphalan 70 mg/m2 IV on days -3 and -2 followed by peripheral blood grafts from 7/8 or 8/8 HLA matched related or unrelated donors. GVHD prophylaxis consisted in sirolimus 12 mg PO loading dose on day -14 in order to overlap with the conditioning regimen, then 4 mg PO daily with target blood level of 3-12 ng/ml, and tacrolimus 0.02 mg/kg/day from day -3 for a target level of 5-10 ng/ml. In absence of significant GVHD, tacrolimus was tapered between days 60 and 100 and sirolimus between days 100 and 180. Characteristics of patients are displayed in Table 1. All patients reached engraftment after a median of 15 days (range 12-22) for neutrophis > 0.5×10⁹/L and 18 days (range 17-44) for platelets >20×10⁹/L. There were no deaths before day +100. 1 patient developed grade III aGVHD and 8 patients developed cGVHD. All patients had complete chimerism and were in complete remission at day +100 assessment. Median follow up is 18.4 months (8.9-63.6). There have been 5 relapses and 3 patients received donor lymphocyte infusion as part of the treatment strategy. 2 patients died from refractory disease, 1 patient died from pulmonary embolism, 2 patients are alive not in remission and 5 patients are alive with no evidence of disease. No patient has died of GVHD or infectious complications. Median progression free and overall survival are 10.2 (95% C.I. 4.5-63.6) and 18.4 (95% C.I. 8.9-63.6, Figure 1) months respectively.We conclude that a regimen with RIT and mTOR inhibition incorporated into allo-HCT could lead to adequate disease control with low risk of aGVHD. Strategies targeting host B-cells in combination with mTOR inhibitor should be explored further in the development of allo-HCT for treatment of advanced B-cell lymphomas.