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First-line escalated BEACOPP does not hinder stem cell collection and transplantation strategy in patients with relapsed/refractory Hodgkin’s lymphoma

Several trials have demonstrated the superiority of escalated BEACOPP over ABVD or other regimens in advanced stage Hodgkin’s lymphoma (HL) in terms of disease control and relapse rate.1, 2, 3, 4, 5, 6 This efficacy comes, however, at the price of increased chemotherapy-related early and late toxicities,7, 8, 9 raising concerns about its long-term benefits. Whether first-line escalated BEACOPP is associated with better long-term overall survival remains a conflicting issue.10, 11 In relapsed/refractory patients, second-line treatment strategy usually relies on high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). Compared with standard dose BEACOPP or ABVD, escalated BEACOPP is an intensive regimen with higher drug dosage (in particular a 100% increase of etoposide) that displays significant bone marrow toxicity and may have deleterious effects on stem cells. The impact BEACOPP may have on stem cell collection and hence on the therapeutic strategy in relapsing patients has not been evaluated.

To answer this question, we conducted a study on patients enrolled in the 20012 Intergroup Randomized Phase III Trial, which compared treatment with four cycles of escalated BEACOPP, followed by four cycles of BEACOPP at the baseline dose with eight cycles of the standard ABVD regimen in patients with high-risk stage III–IV Hodgkin's disease.9 Among the 549 patients enrolled in the trial, we identified, at the time of analysis in 2012, 91 patients (67 in the ABVD arm and 24 in the BEACOPP arm) with a relapsed/refractory HL who had been considered for ASCT. Additional data on stem cell collection, transplantation and engraftment outcome were requested for 75 patients (Belgium, Egypt, France, Hungary, Sweden and The Netherlands). A total of 64 forms were completed and returned.

The primary objective was to study the rate of stem cell collection success (defined by more than 2 × 106 CD34+ cells/kg) or failure in patients who were considered for salvage ASCT. The secondary objectives were (i) to determine the total number of mobilization attempts and days of cytaphereses required to obtain a sufficient graft and (ii) to analyze the hematopoietic reconstitution in patients who could proceed to ASCT.

The characteristics of 64 patients (46 in the ABVD arm and 18 in the BEACOPP arm) at baseline, that is, prior to randomization are displayed in Table 1. The number and regimen used in the 64 relapsed/refractory HL are shown in Table 1. The vast majority of patients (91% in the ABVD and 89% in the BEACOPP arm) received one or two lines of salvage chemotherapy.

Table 1 Baseline characteristics of the patients prior to randomization and type of salvage treatments used at relapse/progression

A flow chart on the mobilization, cytapheresis and transplantation procedures is shown in Figure 1. At least one mobilization was attempted out in 48 patients, 35 in the ABVD arm and 13 in the BEACOPP arm. Data were incomplete in two patients, one in each arm, who were excluded from further analysis. Fourteen patients were not mobilized because of death, refractory disease or ineligibility for high-dose chemotherapy. A single mobilization procedure was sufficient for stem cell collection in 91% of patients in the ABVD arm. This number dropped to 69% in BEACOPP patients. Three (9%) ABVD patients required a second mobilization, whereas four (31%) of BEACOPP patients needed two mobilizations or more (range 2–5).

Figure 1
figure1

Flow of study participants. PD, progressive disease.

Among patients who underwent mobilization, about half of ABVD and 31% (95% confidence interval: 9–61%) of BEACOPP patients needed a single cytapheresis session. Thirty-two percent of ABVD and 23% of BEACOPP patients required two sessions. By contrast, only 14% of ABVD patients needed more than two sessions, whereas it was the case in nearly half (46%) the patients in the BEACOPP arm (range 3–5). No patient in either arm received plerixafor, which was not widely available at the time of the study.

A stem cell number >2 × 106 cells/kg was obtained in all 48 patients (range 2.45–34 × 106 CD34+ cells/kg). ASCT using BEAM conditioning regimen could be performed in 41/48 patients, 10 in the BEACOPP arm and 31 in the ABVD arm. It was canceled in six patients because of death or progressive disease and in one per physician’s decision though he had a 2.77 × 106 CD34+ cells/kg graft. Tandem autologous transplantation using BEAM conditioning followed 45–90 days later by TAM6 is not a standard procedure but has been advocated by some groups, especially in France, in very-high-risk disease.12 Tandem ASCT could be carried out in nearly all (13/14) patients in whom it had been planned except one (BEACOPP arm) because of an insufficient stem cell yield (2.55 × 106 CD34+ cells/kg). Thirty-nine of the 41 patients who proceeded to ASCT had a successful engraftment and hematopoietic recovery. Two patients both in the ABVD arm had engraftment failure.

The results of the Phase III EORTC 20012 Intergroup Trial have been published elsewhere.9 At the time of analysis, median overall survival in the patients of our study, counted from the date of randomization, was 5.8 years in the ABVD arm and 4.3 years in the BEACOPP arm.

Our study is limited by the small number of patients, especially in the BEACOPP arm, which reflects the considerable improvement in the treatment of HL and the superiority of BEACOPP in terms of disease control. Second, as data were not available for all the relapsing/refractory patients of the trial, we missed six patients in the BEACOPP arm, which may introduce a bias. Despite these limitations, we believe our findings provide evidence that although first-line BEACOPP is associated with a greater difficulty to harvest stem cells, it does not seem have an influence on the salvage therapeutic strategy as we did not observe any stem cell collection failures in either arm and all patients could proceed to at least a single ASCT.

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Acknowledgements

We are indebted to Drs Lugtenburg (EORTC), Jaubert (LYSA), Blanc (LYSA), Pignon (LYSA), Eisenmann (LYSA), Gonzales (LYSA), Kernels (LYSA), Devidas (LYSA), Helias (LYSA), Thyss (LYSA), Christian (LYSA), Coiffier (LYSA), Bron (EORTC), Castaigne (LYSA), Eghbali (LYSA), Baars (EORTC), Fitoussi (LYSA), Raemaekers (EORTC) and Van Imhoff (EORTC), who contributed to this research. We also thank the EORTC Headquarters team, in particular, Bart Meulemans and Alice Preumont. This publication was supported by Fonds Cancer (FOCA) from Belgium.

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Ghez, D., Fortpied, C., Mounier, N. et al. First-line escalated BEACOPP does not hinder stem cell collection and transplantation strategy in patients with relapsed/refractory Hodgkin’s lymphoma. Bone Marrow Transplant 52, 310–312 (2017). https://doi.org/10.1038/bmt.2016.271

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