Efficacy of Rituximab Combined in Salvage- and High Dose-Therapy (HDT) for Patients with Relapsed NHL; Interim Analysis of a Multicenter Phase II Study.

The introduction of Rituximab (R) in the treatment of B-NHL resulted in improvement in first line therapies for indolent (ind.) and aggressive (agg.) B-NHL. However, the value of R in intensive chemotherapy relapse strategies has not definitely been demonstrated. In a phase I/II clinical trial we have demonstrated safety of R as an in vivo purging agens in salvage and high dose therapy for relapsed/refractory B-NHL. This led, with promising response rates, to the initiation of a multicenter phase II trial to further prove therapeutic efficacy. Inclusion criteria were: Pt < 65 years, ECOG < 3, relapse or progression for patients with ind. NHL and induction failure or relapse for pts with agg. NHL. Salvage therapy consisted of 2 cycles of DexaBEAM in which R was included on day 1; stem cells were collected after cycle II. HDT, requiring at least stable disease to salvage therapy, consisted of BEAM (agg. NHL) or TBI/Cy (ind. NHL) with 2 additional doses of R. In 2000 the study was initiated at multiple centres and until now 77 patients have been enrolled. As of 06/04, data are available of 66 patients. Diagnosis in agg. entities include: Diffuse large cell lymphoma: 34pts; Follicle centre lymphoma (FCL) grade III: 3 patients or Mantle cell lymphoma: 5pts. Patients with ind. NHL had FCL grade I–II: 28pts or marginal zone lymphoma: 3pts. Median age was 53.5y (range 18–64y). For patients with agg. NHL (n=42) time from diagnosis to inclusion into the study was 1.3y, median number of pre-treatment was 1 and 18% of patients had received Rituximab in a prior treatment line, best response to last treatment was CR: 20, PR: 10 and inferior response in 7/37 pts. During salvage and mobilization therapy 13/39 (33%) patients were taken of study due to: progress: 8 pts., death not related to treatment: 1 and mobilization failure: 4 pts. Corresponding figures for ind. NHL were 2.5y from diagnosis to inclusion, median pre-treatment 1 with 20% pre-treatment with Rituximab. Reasons for inclusion were induction failure in 4, 1. rel. in 15 and >1. rel. in 3 pts. 4 pts did not complete treatment due to death (1 sepsis, 1 unrelated reason) or mobil. failure (2), respectively. HDT (n=18 agg. NHL, 19 ind. NHL) could be performed without uncommon toxicities, one septic death occurred. In the agg. NHL group response to treatment in evaluated patients was CR in 14/18, PR in 2 and PD in 2. Corresponding figures for ind. NHL are CR in 18/19 and PR in 1/19 pts. With a median follow up of 20 months for patients undergoing HDT PFS and OS rates are 63% and 79% for agg. NHL and 65% and 100% for ind. NHL, respectively.

In respect to historical data and in lack of randomized trials to test for the efficacy of R in HDT concepts, the result of this multicenter phase II study underlines the efficacy of this combined modality treatment approach in patients with chemosensitive disease. This seems to be favourable to prior experiences and probably reflects the benefit of the addition of R. However, as 1/4 of patients with agg. NHL still fail to respond to salvage therapy, the combination of R with intensive chemotherapy can not overcome chemoresistance in all patients, therefore defining a patient subgroup, for which more efficient strategies have to be developed.