A Novel High Dose Chemotherapy Strategy with Bendamustine In Adjunct to Etoposide, Cytarabine and Melphalan (BeEAM) Followed by Autologous Stem Cell Rescue Is Safe and Highly Effective for the Treatment of Resistant/Relapsed Lymphoma Patients: a Phase I-II Study on 44 Patients
Authors: Visani Giuseppe , Malerba Lara , Stefani Pietro Maria , Capria Saveria , Galieni Piero , Gaudio Francesco , Specchia Giorgina , Meloni Giovanna , Gherlinzoni Filippo , Giardini Claudio , Falcioni Sadia , Loscocco Federica , Cuberli Francesca , Gobbi Marco , Santoro Armando , Sarina Barbara , Rocchi Marco , Isidori Alessandro 
Published: October 2019

Abstract
Abstract 31

Background:
BEAM (Carmustine, etoposide, cytarabine, and melphalan) regimen is the most used conditioning regimen before autologous stem cell transplant (ASCT) in lymphoma patients. However, patients receiving BEAM show a significant number of side effects, and relapse rate after transplant is still a matter of concern. Therefore, new regimens with a higher efficacy and a better toxicity profile in comparison to BEAM are highly needed.

Aims:
We designed a phase I-II study to evaluate the safety and the efficacy of increasing doses of Bendamustine for the conditioning regimen to ASCT for resistant/relapsed lymphoma patients.

Methods:
Forty-four patients (median age 47 years, range 18–70) with resistant/relapsed non-Hodgkin (29) or Hodgkin (15) lymphoma were consecutively enrolled in the study. The new conditioning regimen consisted of increasing doses of Bendamustine coupled with fixed doses of Etoposide (200mg/m2/day on days -5 to -2), Cytarabine (400mg/m2 on days -5 to -2) and Melphalan (140 mg/m2 on day -1) (BeEAM regimen). Three cohorts of 3 patients each were treated starting with Bendamustine 160 mg/m2/daily given on days -7 and -6. The dose of Bendamustine was then escalated according to the Fibonacci's increment rule until the onset of severe adverse events and/or the attainment of the expected MTD, but not higher than 200 mg/m2. Patients were carefully monitored for adverse events. The study was registered at EMEA with the EUDRACT no 2008–002736-15.

Results:
The administration of Bendamustine was safe in all the 3 cohorts of patients. The major side effect was a grade III-IV oral mucositis developed by 9 patients during neutropenia. We then fixed the dose of Bendamustine 200 mg/m2 as safe and effective for the Phase II study. A median number of 5.68×106CD34+/kg cells (range 2.4–15.5) collected from peripheral blood was reinfused to patients. All patients engrafted, with a median time to ANC>0.5×109/l of 10 days. Median times to achieve a platelet count >20×109/l and >50×109/l were 13 and 16 days respectively. Twenty-two out of 44 patients presented a fever of unknown origin (50%). The median number of days with fever was 2 (range: 0–7), with a median number of 9 days of intravenous antibiotics (range: 3–22). All patients received G-CSF after transplant for a median time of 9 days (range: 8–25). Two patients developed a viral infection (1 HSV-6, 1 CMV) early after transplant. Thirty-nine out of 44 patients are evaluable up to now for the response to treatment. All evaluable patients are alive. 32/39 are in complete remission whereas 4/39 are in partial response, after a median follow-up of 11 months from transplant. Three out of 39 patients relapsed after a median time of 3 months from transplant. It is of note that 4/39 patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell rescue.

Conclusions:
The new BeEAM regimen is safe and seems to have a high efficacy in heavily pretreated lymphoma patients. Basing on this experience, future studies incorporating Bendamustine in conditioning regimens pre-ASCT in lymphoma patients should use Bendamustine 200 mg/m2/day over 2 days.

Acknowledgments:
supported in part by AIL Pesaro Onlus.

Disclosures:
Malerba: celgene, Janssen-Cilag: Honoraria.