A phase I-II study of rituximab, ifosfamide, mitoxantrone and etoposide (R-IME) for B cell non-Hodgkin's lymphoma prior to and after high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT).

This phase I-II study describes the safety of rituximab, ifosfamide, mitoxantrone and etoposide (R-IME) as an induction regimen prior to high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT), and rituximab given post-HDC-ASCT for B cell non-Hodgkins's lymphoma. This study also measured the effect on disease burden and stem cell contamination. Patients with relapsed, refractory or poor risk B cell lymphomas were eligible. Patients were treated with two cycles of R-IME; all non-progressing patients under-went a third cycle and peripheral blood stem cell (PBSC) collection. Patients underwent HDC-ASCT and those patients in remission after HDC-ASCT were treated with four additional doses of rituximab. Tumor cell contamination was measured at baseline and in the PBSC. Serial immunoglobulin levels were measured. Patients were followed for time to treatment failure (TTF) and overall survival (OS). Thirty-two patients were enrolled. Thirty patients had at least stable disease after two cycles of R-IME. Twenty-nine underwent stem cell collection. The response rate to R-IME induction was 77% (20/26) with 35% (9/26) complete response(CR). Stem cell mobilization was successful in 93% (27/29) of patients. The response rate to R-IME induction and HDC-ASCT was 95% with a confirmed CR of 68%. Median follow-up was 28 months; the median TTFand OS have not been reached. There was a significant decline in stem cell tumor cell contamination and a significant decline in IgG without an increase in infections. Forty-three per cent of patients had transient neutropenia after post-transplant rituximab. R-IME is an effective cytoreductive and mobilization regimen. There appears to be a reduction in the number of lymphoma cells in the stem cell product and the toxicity is manageable.

Rituximab and ifosfamide, mitoxantrone, etoposide (RIME) with Neupogen support for B-cell non-Hodgkin's lymphoma prior to high-dose chemotherapy with autologous haematopoietic transplant.

A phase I/II study was performed to analyse the ability of ifosfamide-based chemotherapy with rituximab to produce a turmour-free graft as well as the safety of retuximab prior to stem cell harvest and post high-dose chemotherapy. Twenty-two patients with B-cell non-Hodgkin's lymphoma were enrolled either having aggressive large-cell disease in relapse or at high/high-intermediate risk of relapse, or refractory lymphoma or mantle cell lymphoma, or indolent lymphoma. Chemotherapy consisted of ifosfamide 2 g/m2, days 1-3 with mesna, etoposide 100 mg/m2, days 1-3, and mitoxantrone 8 mg/m2 day 1, with figrastim. Rituximab was given at 375 mg/m2 for 4 doses. An encouraging overall response rate of 90%, including 11 CRs was achieved. CD34+ cells were successfully mobilized in 18 or 19 patients analysed so far with a median number of 3.4 x 10(6) cells/kg. The combination of ifosfamide-based chemotherapy with rituximab significantly reduced the number of contaminating B-cells in the stem cell product and so far there has only been a single relapse post high-dose chemotherapy with autologous haematopoietic transplant. The RIME regimen was generally well tolerated with minimal non-haematological toxicity and most of the treatment was done completely on an outpatient basis. Haematological toxicity was manageable with filgrastim, there were some infectious complications.

Immune reconstitution following high-dose chemotherapy with stem cell rescue in patients with advanced breast cancer.

The present study examines the nature of humoral and cellular immune reconstitution in 28 patients with advanced breast cancer following high-dose chemotherapy with stem cell rescue. Patients underwent testing of T, B, NK and dendritic cell function at serial time points until 1 year post transplant or until the time of disease progression. Abnormalities in T cell phenotype and function were observed following high-dose chemotherapy that persisted for at least 6-12 months. The vast majority of patients experienced an inversion of the CD4/CD8 ratio and demonstrated an anergic response to candida antigen. Mean T cell proliferation in response to PHA and to co-culture with allogeneic monocytes was significantly compromised. In contrast, mean IgG and IgA levels were normal 6 months post transplant and NK cell yields and function were transiently elevated following high-dose chemotherapy. Dendritic cells generated from peripheral blood progenitors displayed a characteristic phenotype and were potent inducers of allogeneic T cell proliferation in the post-transplant period. The study demonstrates that patients undergoing autologous transplantation for breast cancer experience a prolonged period of T cell dysfunction. In contrast, B, NK, and DC recover more rapidly. These findings carry significant implications for the design of post-transplant immunotherapy.