The Benda-EAM Conditioning Regimen Prior to ASCT – A Canadian Perspective by Dr. Mohamed Elemary

Despite the novel targeted agents that continue to enter the treatment armamentarium in lymphoma, autologous hematopoietic stem cell transplantation (ASCT) still plays a significant role in the management of both non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). For patients with HL treated at our centre (Saskatoon Cancer Center, Saskatchewan), high-dose chemotherapy followed by ASCT may be offered to patients with primary refractory disease or relapse after front-line therapy. Patients are treated with salvage chemotherapy to minimize the burden of disease prior to ASCT. For NHL, ASCT is indicated at our centre for patients with refractory or relapsed disease but patients must elicit chemosensitivity prior to ASCT. In addition to response assessment and indication, other factors such as organ function, comorbidity index, and patient preference must be considered before deciding to select ASCT as a treatment approach in patients with lymphoma.

The conditioning regimen prior to ASCT that was previously used at our centre was a combination of carmustine, etoposide, cytarabine, and melphalan (BEAM). However, due to the significant increases in cost of carmustine and associated toxicities (including interstitial pneumonitis), we began to search for alternatives to this agent. Many of the options we explored were too toxic and physicians were not comfortable using them in their patients (e.g., the combination of gemcitabine, busulfan, and melphalan). We are now using a combination of bendamustine, etoposide, cytarbine, and melphalan (Benda-EAM) for conditioning at our centre for patients with either HL or NHL. The Benda-EAM regimen has previously been studied in a phase I/II trial of heavily pretreated patients with lymphoma where it demonstrated good efficacy results and a manageable toxicity profile, suggesting it would be an acceptable alternative to carmustine-based regimens.1

At the American Society for Hematology (ASH) annual meeting this year, two Canadian retrospective studies were presented which evaluated the Benda-EAM conditioning regimen prior to ASCT in patients with lymphoma. One of these studies evaluated 146 consecutive patients with lymphoma treated at the Maisonneuve-Rosemont Hospital in Montreal, Quebec between January 2012 and September 2016.2 In this study, 96 patients who received carmustine-based conditioning regimens prior to ASCT were compared with 50 patients who received the Benda-EAM regimen. Patient age and gender were well matched between the two groups. The majority of patients in this study were diagnosed with NHL (75% and 86% in the carmustine and bendamustine groups, respectively). Interestingly, in this study 23% and 36% of the carmustine and bendamustine groups, respectively, received ASCT as consolidation modality following first-line treatment. This is not the standard approach used at our centre. The indication for consolidation therapy in these cases was not detailed in this poster.

Also notable was that more patients in the Benda-EAM group were in complete remission (76% vs. 49%) prior to ASCT, which, as the authors mention, may have contributed to the increased 2-year overall survival (OS) rate observed for patients receiving Benda-EAM as conditioning compared to carmustine-based regimens (95.7% vs. 81.3%, respectively).

This study reported an increased frequency of toxicities occurring in patients treated with Benda-EAM compared to carmustine-based regimens. Of interest was the almost 50% of patients in the Benda-EAM group who required parenteral nutrition (compared to 22% in the carmustine group), which consequently increased the rate of bacteremia in these patients (26% compared to 6.3% in the carmustine group). At our centre, the frequency of parenteral nutrition is much lower than what was reported in this study. Although we do see a slight increase in mucositis in patients receiving Benda-EAM, this does not reach the severity that would require such a high occurrence of parenteral nutrition. The discrepancy in the frequency of parenteral nutrition given may be partly explained by between-centre differences in indication for this supportive care. The poster also reported more intensive care unit (ICU) admission days for patients who received Benda-EAM compared to carmustine-based regimens. Fortunately, despite the increased toxicities noted with Benda-EAM, this did not impact total hospital stay times or transplant-related mortality (TRM).

This study also performed a pharmaco-economical assessment on these two conditioning regimens, which showed that although the Benda-EAM regimen itself costs less than carmustine-based regimens, other factors such as certain supportive care measures (anti-emetics, platelet transfusion) and hospital stay were associated with slightly elevated costs for Benda-EAM. The cumulative cost of Benda-EAM was less expensive than carmustine-based regimens ($104,750.05 vs. $109,946.00, respectively); however, the difference in cost was not as significant as expected. This may partly be due to an older pricing of carmustine being used in this analysis as the cost listed for carmustine-based regimens in the presented poster was $21,640.97, whereas the current cost for BEAM in Saskatchewan is approximately $33,381.00. Overall, I think that the results from this trial support the use of Benda-EAM as an effective and potentially less costly conditioning regimen for patients with lymphoma undergoing ASCT, albeit with slightly increased toxicity.

Another retrospective study presented at ASH 2017 compared the efficacy and toxicity results for patients with relapsed/refractory HL who received Benda-EAM or BEAM prior to ASCT.3 This multicentre cohort study matched patients who received the two different conditioning regimens at the Hematology and Stem Cell Transplant Centre (Azienda Ospedaliera Ospedali Riuniti Marche Nord) in Pesaro, Italy and at the British Columbia Cancer Agency in Vancouver, BC. Patients who received Benda-EAM (n = 26) and BEAM (n = 52) were matched at a ratio of 1:2 according to relapsed versus refractory disease and according to chemosensitivity prior to ASCT. The groups were adequately matched with respect to patient and disease characteristics. However, of note is that patients who received BEAM were less pretreated than those who received Benda-EAM with a median of 1 (range: 0–2) line of therapy in BEAM patients versus 2 (range: 1–5) for Benda-EAM patients.

This study reported more grade 4 mucositis in patients who received Benda-EAM versus BEAM, as well as increased grade 1–3 nausea and vomiting. Sixty-two percent of patients who received Benda-EAM experienced grade 1 vomiting (compared to 8% in the BEAM group), which is quite significant. Importantly, however, the increased toxicity once again did not impact TRM (0 patients in both groups). With respect to efficacy outcomes, the 2-year progression-free survival was not significantly different between the two treatment groups (63% for Benda-EAM vs. 56% for BEAM) and 2-year post-ASCT OS and 4-year OS since diagnosis were also comparable.

I think these two Canadian studies will encourage other centres to review their efficacy and safety outcomes for patients receiving these two conditioning regimens. It would be interesting to see whether some of the safety signals, such as nausea, vomiting, and grade 4 mucositis are also observed at other centres, as the incidences of these adverse events appear to be higher than I would expect based on my practice. Together, the results of these two retrospective studies support the use of Benda-EAM as an effective alternative to carmustine-based conditioning regimens for lymphoma patients undergoing ASCT; however, it is difficult to draw conclusions based on retrospective studies with small sample sizes. Ideally, future prospective randomized control trials would be beneficial to understand the outcomes associated with both conditioning regimens.

References 1. Visani G, Malerba L, Stefani PM, et al. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood 2011;118(12):3419–25. 2. Boisjoly J-A, Bouchard P, Cohen S, et al. Impact of carmustine (BCNU) substitution for bendamustine in the conditioning regimen prior to autologous hematopoietic stem cell transplantation for the treatment of lymphoma. ASH Annual Meeting Abstracts 2017:2022. 3. Tsang ES, Villa D, Loscocco F, et al. Comparative effectiveness of high-dose Be-EAM vs BEAM in patients with relapsed/refractory classical Hodgkin lymphoma undergoing autologous stem cell transplantation. ASH Annual Meeting Abstracts 2017:3291.