Phase I Study of Rituximab-Cyclophosphamide (R-CY) Stem Cell Mobilization and Rituximab-BEAM HDC with ASCT in Patients with Relapsed, Refractory or High Risk Intermediate Grade Non-Hodgkin’s Lymphoma.

The addition of rituximab to mobilization regimens does not adversely affect collection of adequate numbers of CD34+ PBSC and may decrease tumor cell contamination. Prior administration of rituximab may sensitize lymphoma cells to chemotherapy, but its use with high dose chemotherapy has not been studied. In this study, eligible patients had intermediate grade NHL either primary refractory, relapsed or in CR1 with a high or intermediate/high risk IPI score. Five patients with a median age of 38 years (28–53) have been treated. All patients had rituximab previously. At transplant, 4 patients had relapse, chemosensitive to salvage in 3 patients, and untested in 1 patient. One patient had primary refractory disease, chemosensitive to salvage. Stem cell mobilization was rituximab 375mg/M² followed by CY 2gm/M²/day for 2 doses and filgrastim 10ug/kg/d. Collection started when the CD34 count was ≥12/ul. High dose chemotherapy consisted of rituximab 375mg/M² on day −8, carmustine 300mg/M² on day −7, etoposide 200mg/M²/d on days −6 to −3, cytosine arabinoside 200mg/M² on days −6 to −3 (8 doses) and melphalan 140mg/M² on day −2. Patients received filgrastim post transplant and standard antibiotic prophylaxis. All patients are alive 11 to 306 days post transplant (median follow up 4.5 months). The median CD34+ cell dose collected was 8 x 10⁶/kg (1.1 to 17.6). One patient had an inadequate CD34+ cell dose and required bone marrow harvesting which yielded 0.72 x 10⁶/kg CD34+ cells. Engraftment of neutrophils and platelets occured at a median of 11 days post transplant. Infectious complications included febrile neutropenia in one patient following mobilization and in 4 patients following R-BEAM. Transient grade I–II (common toxicity criteria) hepatic enzyme elevation occurred in 2 patients following R-CY. Following R-BEAM, 3 patients developed grade II–IV LFT elevation without evidence of VOD, which resolved in two patients prior to discharge. The patient with grade IV hepatic toxicity had abnormal liver enzymes prior to study and known intrahepatic lymphoma. This patient continues to have grade III elevation of GGT 306 days post transplant with no evidence of infectious hepatitis or lymphoma (PET negative). One patient developed moderate hemorrhagic cystitis. One patient developed bilateral pulmonary infiltrates of unkown etiology (BAL negative for organisms) which resolved. R-CY was well tolerated as a mobilization regimen and led to adequate stem cell collection. R-BEAM HDC resulted in frequent elevations of LFTs. Further studies of rituximab with HDC warrant caution regarding hepatotoxicity.