Rituximab Plus Gemcitabine, Ifosfamide, Oxaliplatin (R-GIFOX), a New Effective Cytoreductive/Mobilizing Salvage Regimen for Relapsed and Refractory Hodgkin Lymphoma

Background: We evaluated the clinical activity, toxicity, and stem cells mobilizing capacity of a short-course (bi-weekly), dose intensive, salvage regimen (R-GIFOX) in patients with relapsed and refractory Hodgkin Lymphoma. The agents Gemcitabine, Ifosfamide, Oxaliplatin and Rituximab employed in this combination have been all accounted of cross-synergistic activity in both preclinical and early clinical studies in Hodgkin lymphoma.

Patients and methods: Patients were scheduled to receive three courses of therapy followed by mobilization and ASCT or three more courses if ineligible for ASCT. R-GIFOX consisted of Rituximab (375 mg/m2 on day 1), Gemcitabine (1000 mg/m2 on day 2), Oxaliplatin (130 mg/m2 on day 3) and Ifosfamide (5 g/m2 on day 3), as a 24-hour single infusion. Treatment was given every two weeks with G-CSF support (5 mcg/kg/day or 10 mcg/kg/day at the end of the third course for stem cells mobilization). Responses were evaluated by the integrated FDG-PET/IWC criteria, after the third course and at the end of the entire program.

Results: Fifteen patients (median age 36 years, range 24–64 years) with relapsed (n = 12) [post-ABMT (n=4), < 12 mo.s (n=6), > 12 mo.s (n=2)] or primary progressive (n = 3) Hodgkin Lymphoma, were accrued in this prospective study. Forty percent of them had received 2 or more previous treatment lines. Stage IV at recurrence was found in 9 patients (60%), B symptoms in 7 (46%). Sixty-two total courses were delivered (median 3, range, 3–6). Hematologic toxicity was tolerable, but CTCAE v3.0 G4 thrombocytopenia was found in 15% of courses and infection occurred in 9% of cycles. Ifosfamide was withdrawn in two patients; both aged 64 years, at the fourth course due to the occurrence of tachyarrhythmia and encephalopathy, respectively. Actual dose intensity of the first 3 courses was 84%, 87%, and 91% for Gemcitabine, Ifosfamide, and Oxaliplatin, respectively. All the patients completed at least 3 courses of therapy and were valuable for response. The overall response rate assessed after three courses of R-GIFOX was 87%, with 12 complete responses (CRs) (80%; CR=8, CRu=4) and 1 partial response. Interestingly 3 CRs were achieved among the four patients with post-ABMT relapses. Effective CD34+ cell mobilization was obtained in 6 out of 11 eligible patients and all of them proceeded to subsequent ASCT. The median number of collected CD34+ cells was 4,16 × 10⁶/kg body weight (range, 3.52–10.95) In all instances a single leukapheresis was performed. Among the five ‘bad mobilizers’, two patients had previously undergone radiation therapy and one had received immunoradiotherapy with Ibritumomab Tiuxetan. Failure Free Survival was 46% at 32 mo.s and Disease Free Survival 53% at 30 mo.s. with a median follow-up of complete responders of 11 mo.s.

Conclusions: The present study confirms the attractive therapeutic potential of Gemcitabine/Ifosfamide-based combination in the setting of recurrent Hodgkin Lymphoma and further suggests additional contribution from Rituximab and Oxaliplatin. R-GIFOX may represent a less toxic, cytoreductive, and stem cell mobilizing alternative to toxic cisplatin-based salvage regimes, useful for pre-ABMT cytoreduction but also for a full salvage treatment program to be safely delivered to patients unfit for high-dose procedures.