A Phase II Study of Bortezomib-GIFOX (Gemcitabine, Ifosfamide, Oxaliplatin) in Patients with Newly Diagnosed Natural-Killer/T-Cell Lymphoma

Background:

Natural-killer/T-cell lymphoma (NKTL) is a subtype of non-Hodgkin's lymphoma with poor response to conventional chemotherapy. Gene expression profiling of NKTL revealed overexpression of NF-kB. Bortezomib (B) is a potent and reversible proteasome inhibitor which has shown single agent activity in preclinical models of NKTL in vitro and in vivo. Further, drug testing in mouse NKTL xenograft suggest gemcitabine (G), oxaliplatin (ox) and ifosfamide (if) were effective in inducing tumor regression. We have also previously published a patient with relapsed NKTL that was successfully treated with GIFOX therapy. Hence we conducted a study to evaluate the clinical efficacy of B-GIFOX in patients with newly diagnosed NKTL.

Methods:

This was an open-labelled prospective phase II study approved by the institutional review board. Patients with histologically confirmed NKTL with stage IB or bulky(X) and stage II-IV disease were included. Patients with stage IB/IX or II were treated with 4 cycles of B-GIFOX followed by radiotherapy. Patients with advanced stage disease were treated with 6 cycles of B-GIFOX. Intravenous B was dosed at 1.3mg/m2 on days 1, 4, 8, and 11 every 21 days. Dose and schedule of G, If and Ox were 1000mg/m2 on day 1, 5g/m2 on day 2 and 85mg/m2 on day 2 respectively. The primary objective was to estimate the overall response rates (ORR) and the secondary objectives were to estimate the progression free survival (PFS), overall survival (OS) and toxicities of this regimen. PFS was calculated from the start of treatment to the date of progression or last follow-up. OS was calculated from the start of treatment to the date of death or last follow-up. Both median PFS and OS were estimated using Kaplan-meier curves.

Results:

There were 7 patients recruited into the study; 3 had stage II disease and 4 had stage IV disease. The median age was 50 years (range: 34-61) and 5 (71.4%) were male. Four patients had B symptoms and all but one patient had elevated LDH at diagnosis. Six patients completed their planned treatment and one patient had disease progression through the first cycle of chemotherapy. The ORR was 42.8%; one patient had a complete response, two had partial responses and 4 had progressive disease. The median PFS was 4.3months (95% confidence interval [CI] 4.0-4.6 months) and the median OS was 14.9months (95% CI 0.6-29.2 months). The following grade 1-2 toxicities were seen in at least 1 patient: anemia (7), thrombocytopenia (5), fever (3), ALT increase (3), nausea (2), vomiting (2), ALP increase (2), AST increase (1), alopecia (1), fatigue (1), and body ache (1). The following grade 3-4 toxicities were seen in at least 1 patient: thrombocytopenia (2), and tumor lysis syndrome (1).

Conclusion:

This study showed that B-GIFOX induced an ORR of 43% in patients with newly diagnosed NKTL however the median PFS was short at around 4months.