A Trial Comparing the Two High-dose Chemotherapies BeEAM and BEAM Given Before Autologous Stem Cell Transplantation (ASCT) in Lymphoma Patients (BEB-trial)
Condition: Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell
MeSH terms: Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      In the treatment of patient with lymphoma the most common high-dose chemotherapy regimen used
      prior to autologous transplantation (ASCT) is the BEAM regimen. It consists of four
      chemotherapy drugs together (BCNU, etoposide, cyclophosphamide, melphalan), whose initial
      letters are grouped together for BEAM regimen. One of the most common organ damage this
      intensive treatment is caused by the drug BCNU; it involves a lung injury, which manifests
      itself in the months after ASCT with increasing shortness of breath and cough, and can result
      in pulmonary fibrosis. The drug bendamustine is used successfully in different lymphoma
      types, and its efficacy in lymphoma therapy is well documented. Moreover bendamustine doesn't
      cause lung injury. Initially experience with bendamustine instead of BCNU - in the so-called
      BeEAM scheme - shows that this scheme is quite effective and well tolerated, without lung
      injury. In BeEAM scheme therefore bendamustine replace the BCNU, while the other three drugs
      are administered in the same dosage and order. The aim of the present study conducted at four
      centers (Bern and Zurich in Switzerland, Vienna and Linz in Austria) is to compare these two
      high-dose chemotherapy schemas and to show that the BeEAM scheme causes significantly less
      lung injury than the BEAM regimen.
    

Detailed description: 
      Background

      High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is
      considered the treatment of choice for relapsed/refractory lymphomas. On the basis of the
      results of the PARMA study group trial, high-dose chemotherapy followed by ASCT has become
      the standard of care for patients with relapsed, chemo-sensitive aggressive lymphoma and it
      is the treatment of choice in patients relapsing with follicular lymphoma and Hodgkin's
      disease. The BEAM (BCNU, etoposide, cyclophosphamide, melphalan) chemotherapy regimen is the
      most frequently used conditioning regimen since more than thirty years. Toxic pneumonia with
      interstitial infiltration and impairment of the diffusion capacity of the lung is a
      recognized complication of HDCT regimens containing BCNU. Recently, it has been shown that
      the EAM regimen (thus omitting BCNU) is not sufficient to obtain equal response rates if
      compared with BEAM and poorer disease control resulted in impaired disease-free survival
      (DFS). Thus, it might be detrimental for patients just to eliminate BCNU without an
      appropriate substitution. Replacing BCNU by Bendamustine with its potential to eradicate
      residual or treatment-resistant lymphoma cells could be a promising clinical approach and
      should be investigated in a randomized phase II clinical trial comparing standard BEAM with
      BeEAM. Bendamustine combines the alkylating activity of the mustard group with the
      antimetabolite activity of the purine analogue and was studied in several entities of B-cell
      neoplasms and demonstrated significantly superior efficacy compared with standard therapies
      in the treatment of relapsed chronic lymphocytic leukemia (CLL) and indolent NHL and myeloma.
      The BRIGHT study confirmed the non-inferiority of a immunochemo-therapy with
      Rituximab-Bendamustine when compared with R-CHOP or Rituximab, Cyclophosphamide, Vincristine,
      Prednisone (R-CVP) in indolent lymphoma or mantle cell lymphoma. Recently, Visani et al have
      shown that Bendamustine, coupled with fixed doses of Etoposide, Cytarabine, and Melphalan
      (ie, BeEAM) in the conditioning regimen for ASCT for resistant/relapsed lymphoma (HD and NHL)
      patients is highly active and resulted in promising results concerning safety and efficacy.
      No treatment mortality was observed and no relevant pulmonary toxicity was seen.
      Non-hematological toxicity was moderate, and most prominent toxicities were gastroenteritis
      grade 3 to 4 in 34% and mucositis grade 3 to 4 in 35%, respectively. No grade 3 to 4 cardiac
      toxicity or toxic pneumonia was observed. Engraftment was rapid and trilinear, and stable
      hematopoiesis was observed. BeEAM was very effective, with 81% of patients in complete
      response after a median observation time of 18 months. A recent update of this study showed
      that at 41 months still 72% of the patients are still in complete remission and the 3-year
      performance status (PS) was 75%. Four patients showed a first remission ever with the
      Bendamustine containing regimen. In 35 patients treated at the Vienna centre according to the
      Visani BeEAM protocol, these encouraging data of Visani et al could be reproduced; similar
      toxicities and rapid and stable engraftment were observed. Finally, the combination of
      Bendamustine with sequential application of high-dose Cytarabine was reported to improve the
      response rates in relapsing lymphomas. In conclusion, it seems promising to integrate
      Bendamustine in myeloablative regimens in ASCT, but a randomized clinical trial is lacking so
      far.

      Objective

      Replacing the chemotherapeutic drug BCNU by Bendamustine within the four-drug chemotherapy
      regimen BEAM reduces the occurrence of early and late pulmonary toxicity in lymphoma patients
      undergoing high-dose chemotherapy with autologous stem cell transplantation. Primary
      Objective: To show a clinically meaningful reduction of lung toxicity - defined as a a
      decrease of the diffusion capacity of the lung for carbon monoxide (DLCO) by 20% or more from
      baseline before ASCT - from 25% of patients in the BEAM group to 4% of patients in the BeEAM
      group at 3 months after ASCT. Use Dinakara equation for adjusting DLCO for hemoglobin.
      Secondary Objectives: Acute and late toxicity/adverse events (CTCAE 4.0). Hematologic
      recovery and engraftment after 3 months. Early and late lung toxicity Cardiac assessment by
      ECHO/ECG and quality of life before,3 and 12 months after ASCT. Overall survival and
      progression free survival after 12 months and then yearly as routine follow-up assessments.

      Methods

      Two high-dose chemotherapy regimens (BeEAM versus BEAM) used for conditioning treatment
      before autologous stem cell transplantation will be compared in a 1:1 randomization. The
      experimental arm is the BeEAM regimen. The BEAM regimen is the control treatment. Lung
      toxicity will be assessed by spiroergometry at the 60% level of maximum exercise capacity, as
      well as by assessing the diffusion capacity of the lung for carbon monoxide (DLCO). This
      analysis will be performed before ASCT, as well as 3 months and 12 months after ASCT.
      Patients will be assessed for cardio-pulmonary toxicity before ASCT, as well as 3 and 12
      months after ASCT. Thereafter, patient follow-up will be performed clinically once per year.
    

Intervention name(s): BeEAM; BEAM
Intervention type(s): Drug; Drug
Intervention description(s): Chemotherapy regimen consisting of bendamustine intravenously on days -7 and -6 at 200 mg/m2; cytarabine, 400 mg/m2 intravenously daily from day -5 to day-2; etoposide, 200 mg/m2 intravenously daily from day -5 to day -2; and melphalan, 140 mg/m2 intravenously on day -1 before reinfusion of autologous stem cells; Chemotherapy regimen with carmustine (BCNU) 300 mg/m2 on day -6, cytarabine, 400 mg/m2 intravenously daily from day -5 to day-2; etoposide, 200 mg/m2 intravenously daily from day -5 to day -2; and melphalan, 140 mg/m2 intravenously on day -1 before reinfusion of autologous stem cells
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Diffuse large B-cell lymphomas (DLBC); Follicular lymphomas (FL); Mantle cell lymphomas (MCL)