ORLANDO, Fla.—The combination of rituximab plus vinorelbine, ifosfamide, mitoxantrone, and prednisone (R-NIMP) is well tolerated, yields a high complete response rate, and allows for successful mobilization of CD34+ cells in patients with diffuse large B-cell lymphoma (DLBCL) in first relapse, results of a phase 2 study have found.
Therefore, this regimen is a suitable salvage treatment for relapsed DLBCL prior to appropriate consolidation, and further investigation is warranted, reported Emmanuel Gyan, MD, PhD, of CHRU de Tours, Tours, France, and colleagues.
In patients with DLBCL, relapse prognosis is poor, and the optimal salvage treatment remains unknown. Previously, a pilot study utilizing NIMP without rituximab showed promising efficacy in the setting of relapsed DLBCL, which led to this multicenter, single-arm study, Dr. Gyan noted in a poster presentation during the 52nd American Society of Hematology Annual Meeting and Exposition.
Eligibility included age 18 to 75 years and CD20-positive DLBCL in first relapse, which was defined as having obtained at least a partial remission (PR) of >50% to an anthracycline-based front-line regimen that occurred >30 days after the last chemotherapy cycle or >1 year after an autologous stem cell transplantation (ASCT) in first line. Other inclusion criteria were ECOG performance status ≤2, absence of CNS involvement, and signed consent. Excluded were patients with evidence of transformation from indolent lymphoma, primary refractory disease, LVEF <50%, creatinine clearance <60 mL/min, transaminases >3N, mental deficiency, and previous history of cancer (except for in situ cervical carcinoma or non-invasive skin cancer).
Initial and relapse biopsies were centrally reviewed. Each patient received intravenous (IV) rituximab 375 mg/m2 day 1, ifosfamide 1,000 mg/m2 as a continuous infusion days 1 to 5, IV vinorelbine 25 mg/m2 day 1 and 15, IV mitoxantrone 10 mg/m2 day 1, MESNA 1,000 mg/m2 as a continuous infusion days 1 to 5, and oral prednisone 1 mg/kg days 1 to 5, repeated every 28 days for 3 cycles. Pegfilgrastim support (6 mg at day 7) or epoietin alfa 40,000 IU/week subcutaneously if Hb <11g/dL (with interruption) above 13g/dL was recommended. Primary end point was CR/CRu after 3 cycles, which was assessed by computed tomography according to the International Working Group criteria. Mobilization, consolidation, or subsequent salvage therapy was at investigator discretion. All monitoring and data management were performed by GOELAMS (Groupe Ouest-Est d’Etude des Leucémies Aiguës et Autre Maladies du Sang) clinical research assistants. The database was locked on July 27, 2010.
Between December 2004 and accrual closure in April 2010, 50 patients were enrolled in the study from 18 centers. Median age at study entry was 62.9 years (range, 34.8-75.6 years); 58% were male. Median time between first diagnosis of DLBCL and relapse was 18.0 months (range, 2.4-208 months). All patients received at least 1 cycle of R-NIMP.
Forty-five patients were available for central pathology review, toxicity, and response. Central review of all patient samples confirmed DLBCL histology. Overall response rate was 67.9%, with 20 CR/CRu (43.5%), 11 PR (24.4%), and 2 SD (4.4%); 12 patients (26.7%) progressed under therapy.
Toxicity information was available for 108 cycles of R-NIMP. Observed toxicities (all grades, ≥ grade 3 for all cycles) were anemia (90%, 9%), neutropenia (79%, 48%), thrombopenia (51%, 14%), elevated liver tests (12%, 0%), constipation (28%, 0%), kidney failure (7%, 0%), nausea (15%, 0%), vomiting (6%, 0%), allergic reactions (5%, 0%), and mucositis (4%, 0%). Twenty-nine infectious events (27%) were observed needing hospitalization in 9 cases.
Of 11 patients who received 3 additional cycles of R-NIMP, 3 remained in CR/CRu, 1 remained in PR, 4 converted from PR to CR/CRu, and 3 progressed. Among 11 patients who underwent ASCT, 9 were in CR at the end of the procedure, 1 patient had died of toxicity, and 1 had progressed. For 12 patients mobilized after a R-NIMP cycle, a median of 1 apheresis (range 1-4) was necessary to harvest a median of 3.85 x 106 CD34+ cells/kg.
Median time to second progression or relapse (TTP2) was 11.4 months, and median survival, 55.5 months. On multivariate analysis, the variable associated with a longer TTP2 was achievement of CR/CRu (RR 0.12; 95% CI, 0.03-0.39; P=0.0006. Time to first relapse or previous rituximab exposure did not affect TTP2 or overall survival, whereas relapse-IPI (International Prognostic Index, as a continuous variable, by 1 additional risk factor) was associated with a poor survival (RR 2.59; 95% CI, 1.51-4.45; P =0.0006).