Gemcitabine, ifosfamide, oxaliplatin and rituximab (R-GIFOX), a new effective cytoreductive/mobilizing salvage regimen for relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a pilot study.
BACKGROUND
The prognosis of patients with aggressive non-Hodgkin's lymphoma (NHL) relapsing or progressing after front-line therapy remains poor. Since high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) can cure a proportion of such patients, provided that a substantial tumor shrinkage is achieved, the development of more effective and less toxic salvage regimens remains a major challenge. We evaluated the clinical activity, toxicity and mobilizing capacity of a new salvage regimen, which combines gemcitabine and oxaliplatin with ifosfamide and rituximab (R-GIFOX) in patients with relapsed and refractory CD20(+) NHL.


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/m(2) on day 1), gemcitabine (1000 mg/m(2) on day 2), oxaliplatin (130 mg/m(2) on day 3) and ifosfamide (5 g/m(2) on day 3) as a 24-h single infusion in patients aged < or =65 years, or fractionated over 3 days (days 3-5) in patients aged >65 years. Treatment was given every 2 weeks with G-CSF support (5 microg/kg/day or 10 microg/kg/day at the end of the third course for stem cell mobilization). Responses were evaluated by the integrated FDG-PET/IWC criteria after the third course and at the end of the entire program.


RESULTS
Fourteen patients (median age 63 years, range 37-78 years) with relapsed (n = 9) or primary progressive (n = 5) aggressive (diffuse large cell, mantle cell, follicular G3), advanced (stage IV 71%), poor risk (IPI 3-5 50%) NHL were accrued in this pilot study. Patients had received a median of two previous treatment lines (range 1-4). The median number of R-GIFOX courses delivered was 4 (range 1-6). Thirteen patients completed at least three courses of therapy and were evaluable for response. The overall response rate assessed after three courses of R-GIFOX was 77%, with seven complete responses and three partial responses. Effective CD34(+) cell mobilization was obtained in four of six eligible patients and two had ASCT. Hematologic and extra-hematologic toxicity was tolerable. Failure-free survival was 79.6% at median follow-up of 6 months (range 2-12). Molecular remissions were documented in two patients with mantle cell NHL.


CONCLUSIONS
Based on the results of this pilot study, we conclude that the R-GIFOX regimen is feasible, tolerable, effective and able to mobilize peripheral stem cells in patients with relapsed and refractory aggressive NHL.
Corazzelli
G
G
Hematology-Oncology Unit, Istituto Nazionale Tumori, Fondazione G. Pascale, Naples, Italy.
Russo
F
F
Capobianco
G
G
Marcacci
G
G
Della Cioppa
P
P
Pinto
A
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D016393:Lymphoma, B-Cell / Q000473:pathology / Q000628:therapy*; D008224:Lymphoma, Follicular / Q000473:pathology / Q000628:therapy; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology / Q000628:therapy*; D020522:Lymphoma, Mantle-Cell / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000473:pathology / Q000628:therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010865:Pilot Projects; D012074:Remission Induction; D000069283:Rituximab; D016879:Salvage Therapy; D033581:Stem Cell Transplantation; D015996:Survival Rate; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069283:Rituximab; D007069:Ifosfamide; D000093542:Gemcitabine