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Salvage chemotherapy followed by high dose chemotherapy with autologous stem cell transplant (ASCT) is the standard of care for refractory/relapsed Hodgkin’s lymphoma (HL r/r), leading to durable responses in approximately 50% of relapsed patients. The pre-transplantation achievement of CR is the strongest prognostic factor in this setting. The combination of gemcitabine and vinorelbine and ifosfamide (IGEV) demonstrated to be an highly active salvage regimen, with a high CR rate (48%) and low toxic profile. Bendamustine, as single agent, has been reported to induce objective responses in an high percentage of pts with HL recurring after autologous stem cell transplant (ASCT).

This study has been conducted with the aim of improving the CR rate of induction salvage chemotherapy in comparison to historical IGEV data by combining Bendamustine  with Gemcitabine and Vinorelbine (BeGEV).

This was a Fleming’s single-stage phase II multi-centric trial in HL r/r patients before ASCT. Aim of the study was to assess the activity of BeGEV in term of CR rate. Assuming an improvement of 15% (50 to 65%), with a 10% rejection error and a power of 85%, at least 35 CR out of 59 patients had to be observed. Secondary end points were overall response, cell mobilization, toxicity, progression free survival (PFS) and overall survival (OS). Patients were eligible if they had relapsed or refractory classic HL after first line chemotherapy. The treatment schedule was: Bendamustine (90 mg/sqm, days 2-3), Gemcitabine (800 mg/sqm, day 1 and 4) and Vinorelbine (25 mg/sqm, day) every 3 weeks for a total of 4 courses.

Between August 2011 and March 2014, 59 consecutive patients with relapsed (45.8%) or refractory (54.2%) HL were enrolled. The median age was 33 years (range 18-68).

Out of 59 enrolled patients, 43 (72.9%) achieved a CR, 6 (10.2%) a partial response (PR) for an overall response rate of 83.1%. The remaining 10/59 patients (16.9 %) were evaluated as non responders for: 1 (1.7%) stable disease, 8 (13.6 %), PD, 1 (1.7 %) toxicity. Adequate CD34+ cell collection was achieved in 55 out of 57 (96.5%) mobilized patients.

Considering the 49 responsive patients, 42 proceeded to ASCT (37/43 in CR, 5/6 in PR). The remaining 7 patients did not proceed to ASCT due failed mobilization (2 cases), allogenic transplant (1 case), physician’s decision (2 cases), early relapse (1 case), and patient refusal (1 case).

With a median follow up of 16 months, the PFS and OS at 2 years were respectively 50.9% and 68.8% for all series, without significant difference among relapsed and refractory patients. The 2-year PFS for the 49 responsive pts was 61% for CR and 63% for CR+PR, respectively. The 2-year OS reached 85.5% for CR+PR vs 14.3% induction failures (p value < 0.001). Hematological and non-hematological side effects were acceptable. Out of 204 evaluated cycles, 23 (11%) had to be delayed and 4 (2%) reduced, respectively; only 1 patient stopped therapy for toxicity. Three non-hematologic G4 toxicity (2 infection and 1 hepatic failure unlikely related to treatment), were observed. No toxic death occurred.

The BeGEV regiment achieved a CR (72.9%) and overall response rate (83.1 %) overcoming the expected results. The study highlights the activity of this combination as well as the good toxicity profile and the high mobilizing potential. These data provide strong support for further development of  BeGEV.