Trial Information

Efficacy of 6x R-CHOP Followed by Myeloablative Radiochemotherapy and Autologous Stem Cell Transplantation vs. 3 x (R-CHOP/R-DHAP) Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation

Recently, a prospective randomized intergroup trial of the European MCL Network has shown
that a myeloablative radio-chemotherapy followed by autologous stem cell transplantation
(PBSCT) improves event-free survival (EFS) when compared to a interferon alpha maintenance
therapy after a CHOP-like induction. However, the CR rate after the CHOP induction was still
low (<20%). Thus, several studies have been conducted to increase the CR rate of induction
therapy to further improve event-free and overall survival. Two recent phase II trials
suggest that induction regimens containing high dose Ara-C may significantly improve the CR
rate up to 80%. In addition, a number of studies provide evidence that the humanized
anti-CD20 antibody Rituximab may induce significant responses in relapsed MCL. A prospective
randomized study of the GLSG demonstrated that a combined immuno-chemotherapy (CHOP plus
Rituximab) induces a significantly higher response rate than CHOP alone.

The aim of this study is the comparison of the current standard (R-CHOP followed by
myeloablative radio-chemotherapy and subsequent blood stem cell transplantation) to a new
alternating induction regimen containing high dose Ara-C (R-CHOP/DHAP) followed by a high
dose ARA-C containing myeloablative radio-chemotherapy and PBSCT.

This study will be performed as a prospective, randomized, open-label multicenter phase III
trial. All patients will be initial randomized for standard treatment versus experimental
treatment.

REFERENCE ARM:

The induction therapy consists of 6 cycles of a CHOP chemotherapy in combination with
Rituximab. If the mantle cell lymphoma is progressive after 4 cycles of chemotherapy,
patients will be taken off study. Patients achieving at least a partial remission after 6
cycles R-CHOP will proceed to intensified consolidation (Dexa-BEAM) with stem cell
collection and subsequent myelo-ablative radio-chemotherapy (TBI/High Dose Cyclophosphamide)
with autologous stem cells transplantation

EXPERIMENTAL ARM:

Initial cytoreductive chemotherapy comprises of alternating cycles of 3xCHOP and 3x DHAP
plus Rituximab. Patients with progressive disease after 2 treatment cycles R-CHOP and 2x
R-DHAP will be off study. Patients achieving at least a partial remission after 3x CHOP and
3x DHAP plus Rituximab will proceed to with stem cell collection. The subsequent
myeloablative radio-chemotherapy with stem cell transplantation consists of a radiotherapy
(TBI), high dose Ara-C and Melphalan.

The primary end point in this study is the time to treatment failure. The time to treatment
failure will be defined as time from start of initial therapy until first failure. A failure
will be defined as failure of initial therapy or progression of the lymphoma or death of the
patient.

Using the data of the PBSCT group in the former European mantle cell study as baseline in a
proportional hazard model, the improvement for the time to treatment failure expected by the
new strategy can be expressed by reduction of relative risk (rr). A risk reduction to 52%
which would correspond to a improvement of 20% in failure free survival after 3 years seems
to be a clinical relevant improvement. For a working significance level alpha=0.05 and a
power of 95% the number of events necessary for a one sided fixed sample trial is about 105.
During this study the time to treatment failure will be monitored using an equivalent
one-sided triangular sequential test.

In order to evaluate the impact of therapy on overall survival in this patients, a total
follow up of about 12 years for this study is expected.