Phase II study of low-dose methotrexate to reduce the incidence of human anti-mouse antibodies in patients receiving I-131 tositumomab as first-line treatment for follicular lymphoma.

Abstract

e19519 Background: I-131 tositumomab is a radiolabeled murine anti-CD20 antibody. In a frontline phase II follicular lymphoma (FL) trial, treatment with I-131 tositumomab produced a 95% ORR with 75% CR (NEJM 352:441, 2005). Median PFS was 6.1 yrs. However, 30% of patients (pts) developed high levels of human anti-mouse antibodies (HAMA) and a serum sickness syndrome within 7 weeks of treatment (early onset HAMA). The 5-yr PFS for this group was 35% compared to 70% for the others (p = 0.003). Low-dose oral methotrexate (mtx) reduces the incidence of human anti-chimeric antibody (HACA) formation in rheumatoid arthritis pts receiving infliximab. We hypothesized that low-dose mtx would likewise reduce the incidence of early onset HAMA when given in combination with I-131 tositumomab. Methods: This is a single arm, phase II study in pts with FL, grade 1-2, stage III or IV disease without limits on marrow involvement, and ≥ 1 of the GELF criteria. Prior therapy, other than focal radiotherapy, is not allowed. Pts must have adequate hematologic, hepatic and renal function, and serum HAMA levels ≤ ULN. I-131 tositumomab is given as a dosimetric dose followed within 1-2 weeks by a therapeutic dose of 75cGy of total body radiation. Pts take mtx 7.5 mg orally once weekly for 3 weeks prior to their dosimetric dose, followed by 7 additional weekly doses. The primary endpoint is the rate of HAMA formation within 7 wks of I-131 tositumomab treatment. Secondary endpoints are overall HAMA incidence, ORR, CR, PFS OS, and safety. Results: Between 8/2011 and 10/2012, 15 pts were enrolled. Median age was 56 (39-83); 11 were male. Three pts had serum HAMA levels >ULN at baseline. One pt had a spontaneous remission prior to starting treatment, leaving 11 evaluable pts. One pt developed early onset HAMA (9%). ORR = 82%, CR = 64%. Two pts progressed with DLBCL. Grade 3 or 4 toxicities included thrombocytopenia n = 3, neutropenia n = 2 and pain n = 3. Conclusions: These preliminary results show that concurrent low-dose oral mtx appears to reduce the incidence of early onset HAMA in FL patients receiving first- line I-131 tositumomab (9% vs. 30% in historical controls) while preserving efficacy. Clinical trial information: NCT01389076.