Phase I/II trial of GN-BVC, a gemcitabine and vinorelbine-containing conditioning regimen for autologous hematopoietic cell transplantation in recurrent and refractory hodgkin lymphoma

Abstract

Autologous hematopoietic cell transplantation with augmented BCNU regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL); however, BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m(2), and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had 1 or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pretransplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9%-24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n = 24), 1 (n = 37), 2 (n = 23), or 3 (n = 8) risk factors, respectively. Regression analysis identified PET status pretransplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.

Figure 1

Overall survival, event-free survival, freedom from progression for the entire group of 92 patients. Overall survival (OS): at 2 years 83% (CI 75% to 91%). Event-free survival (EFS) at 2 years was 67% (CI 57% to 77%), and freedom from progression (FFP) at 2 years was 71% (CI 61% to 81%).

Figure 2a

FFP in 92 patients according to number of risk factors. 0 (n=24), 1 (n=37), 2 (n=23), 3 (n=8).

Figure 2b

FFP according to induction failure (IF) vs induction response (non-IF). Induction failure (n=36), induction response (n=56).

Figure 2c

FFP according to presence of B symptoms at relapse (n=39) vs absence of B symptoms at relapse (n=53).

Figure 3a

FFP in 77 patients according to pretransplant PET status. PET negative (n=48), PET positive (n=29).

Figure 3b

FFP in patients who are PET positive, symptomatic (n=15), PET positive, asymptomatic (n=14), PET negative, symptomatic (n=19) and PET negative, asymptomatic (n=29). 3 degrees of freedom log rank test for equality over 4 groups, p <0.0001. Pairwise significant differences: between PET+Bsx+ and PET+Bsx-, p =0.004; between PET+Bsx+ and PET-Bsx+, p <0.0001; between PET+Bsx+ and PET-Bsx-, p <0.0001.