Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma. Combined results of two prospective phase II trials from the French GOELAMS group

Abstract

Background There is currently no international consensus for first-line treatment (prior to autologous stem cell transplantation) in mantle cell lymphoma patients. Here, we investigated the efficacy and tolerance of VAD associated with chlorambucil (VAD+C) and rituximab or not before autologous stem cell transplantation.

Design and methods: Between 1996 and 2005, 113 previously untreated mantle cell lymphoma patients were enrolled in two consecutive prospective phase II studies. Responses and response factors to the (R)VAD+C regimen were evaluated. The survival prognostic value of the MIPI score and Ki67 were also analyzed.

Results: The induction phase of 4 courses of (R)VAD+C showed very low hematologic and extra-hematologic toxicity (grade 3-4 thrombopenia and neutropenia, 9% and 2.7%, respectively and grade 3-4 extra-hematologic toxicities, 1.6%). Overall and complete response rates were 73% and 46%, respectively, and rose to 83% and 51% for the 70% of patients with less than two independent response factors (LDH, B symptoms and lymphocytosis). At the end of treatment, 65% of patients were in complete remission. Progression free and overall survival were significantly better in the transplanted population. The MIPI score was confirmed as a predictor of survival. Ki67, serum LDH, Performance Status (PS) and B symptoms were identified as independent prognostic factors of survival. A prognostic scoring system could stratify patients into three risk groups with markedly different median overall survival of 112, 44 and 11 months, respectively. Conclusions The (R)VAD+C is an effective regimen with very low toxicity. In addition to the MIPI score, Ki67 expression provides additional independent prognostic information for the prediction of overall survival (ClinicalTrials.gov Identifier: NCT00285389).

Figure 1.

Study design of the LM 1996 and LM 2001 trials and number of responders at the intermediate and final step of evaluation. N= number of patients recruited in each arm. VAD+C: vincristine 0.4 mg/D, D1 to D4; doxorubicin 9 mg/m²/D, D1 to D4; dexamethasone 40 mg/D, D1 to D4; chlorambucil 12 mg/D, D20 to D29 ; 2 cycle delay 35 days. RVAD+C: rituximab 375 mg/m², D1 of each VAD cycle. H1 and H2: stem cell harvest; H1, steady state manner; H2, cyclophosphamide mobilization 4 g/m² and in vitro purge with rituximab 375 mg/m². 2(R)VAD+C*, one RVAD+C followed by one VAD+C. ^§Melphalan 140 mg/m² and TBI 8 gy/4 fractions.

Figure 2.

(A) Overall Survival (OS) as intent to treat of 78 young and 35 elderly patients receiving first-line (R)VAD+C regimen followed or not by auto-SCT. (B) Overall survival. (C) Progression free survival, of the 49 transplanted patients (Tr) versus 64 non-transplanted patients (no Tr).

Figure 3.

(A) Progression free survival and (B) overall survival, of the transplanted patients after RVAD+C or VAD+C regimen.

Figure 4.

(A) Overall survival according to the GOELAMS index related to the number of criteria observed at diagnosis among 4 pejorative prognostic factors (PF): Ki67>26%, ECOG>1, B symptoms and LDH>N. g1 = group with 3 or 4 PF, g2 = group with 1 or 2 PF and g3 = group without PF. (B) Overall survival according to the MIPI, Low=low-risk, Int = intermediate-risk and High = high-risk.