Bendamustine-based salvage regimen induces responses in relapsed, refractory Hodgkin lymphoma

Salvage therapy with bendamustine, gemcitabine and vinorelbine induced complete response prior to autologous hematopoietic stem cell transplantation in a large proportion of patients with relapsed or refractory Hodgkin lymphoma, according to multicenter, open-label phase 2 study results.

“First-line chemoradiotherapy yields cure rates approaching 80% in patients with advanced-stage Hodgkin lymphoma,” Armando Santoro, MD, clinical research director, cancer center director and head of the medical oncology and hematology unit at Humanitas Clinical and Research Center in Milan, and colleagues wrote. “Patients who are refractory to or relapse after initial therapy usually have a worse prognosis, and second-line salvage treatment programs are required as early as possible to reduce the risk [for] treatment failure, avoid unnecessary toxicity and prolong survival.”

Santoro and colleagues developed the ifosfamide, gemcitabine and vinorelbine pretransplantation salvage regimen, which induced an 81% overall response rate and 54% complete response rate in a study of 91 patients.

Because bendamustine has shown promising activity in patients with relapsed Hodgkin lymphoma and has been proposed to improve the complete response rate as second-line treatment, Santoro and colleagues replaced ifosfamide with bendamustine as induction therapy prior to autologous HSCT in 59 patients (median age, 33 years; range, 18-68; 53% men) with relapsed or refractory Hodgkin lymphoma.

Fifty-four percent (n = 32) of patients had relapsed disease and 46% (n = 27) had primary refractory disease. The majority of relapsed patients (n = 22; 37%) experienced relapse within 12 months of initial treatment.

Patients received 800 mg/m² gemcitabine on days 1 and 4, 20 mg/m² of vinorelbine on day 1, and 90 mg/m² of bendamustine on days 2 and 3 for four 21-day cycles. They received 100 mg prednisolone each day.

Complete response after four cycles served as the study’s primary endpoint. Secondary outcome measures included ORR, stem cell mobilization activity and toxicity.

Median follow-up was 29.1 months (range, 3.4-49.1).

After four cycles, 43 patients (73%) achieved a complete response and six patients (10%) achieved a partial response, equating to an ORR of 83%.

Of the remaining patients, one (2%) had stable disease, eight (14%) experienced disease progression and one (2%) discontinued prematurely.

A univariate analysis showed that disease status at study entry contributed to the likelihood of achieving a complete response. A significantly higher proportion of patients with relapsed disease achieved complete response (84% vs. 59%; P = .031).

Forty-three responding patients (complete response, n = 38; partial response, n = 5) proceeded to HSCT; the remaining six responders did not proceed to HSCT due to mobilization failure (n = 2), physician choice (n = 2), patient refusal (n = 1) and early relapse (n = 1).

The cohort had a 2-year PFS rate of 62.2% and 2-year OS rate of 77.6%. Among patients who underwent autograft, the 2-year PFS rate was 80.8% and 2-year OS rate was 89.3%.

The researchers had access to cellular mobilization data from 57 patients, all but two of whom had successfully harvested CD34–positive cells. The median peak value of CD34–positive cells was recorded on day 12 after treatment (89 cells/L; range, 1-763).

Eight patients experienced grade 3 or grade 4 thrombocytopenia and neutropenia. Serious nonhematologic adverse events included febrile neutropenia (n = 7) and infection (n = 4).

Grade 1 or grade 2 adverse events included nausea (n = 10), fatigue (n = 5) and skin rash (n = 6).

“These findings provide a strong rationale for further development of the [bendamustine, gemcitabine and vinorelbine] regimen,” Santoro and colleagues wrote. “Because the number of novel agents that may be added in the pretransplantation therapy setting is growing, direct comparisons of combinations incorporating novel agents with [bendamustine, gemcitabine and vinorelbine] and other regimens will be necessary to identify the best salvage strategy for relapsed and refractory Hodgkin lymphoma.” – by Cameron Kelsall

Disclosure: Santoro reports consultant roles with Amgen, ArQule, Bayer HealthCare Pharmaceuticals, Eli Lilly and Takeda. Please see the full study for a list of all other researchers’ relevant financial disclosures.