Risk Adapted Dose Intensive DICEP Salvage Chemotherapy Prior to Autologous Stem Cell Transplantation Yields Successful Outcomes in Chemotherapy Refractory Lymphoma.

Background: Previous reports have suggested that patients with aggressive histology lymphoma who fail to respond to standard-dose salvage chemotherapy are unlikely to become long-term survivors with high-dose therapy. Thus, chemotherapy-refractory disease has traditionally been considered a contraindication for autologous transplantation. Whether the use of dose-intensified salvage chemotherapy prior to transplantation will alter outcomes is unknown.

Patients and Methods: 207 patients with aggressive lymphoma (diffuse large cell B cell NHL n=137, Hodgkins Disease n=70) underwent autologous peripheral blood (n=192), bone marrow (n=7) or combined (n=8) transplantation at Hackensack University Medical Center between January 1997 and June 2004 using a regimen of BCNU 600 mg/m2, Etoposide 1600 mg/m2, Cytarabine 24 gms/m2 and Cyclophosphamide 90 mg/m2 (with dose attenuations for advanced age/poor performance status). All patients received a single cycle of DICE (Dexamethasone 160 mg, Ifosphamide 4 gm/m2, Cisplatin 100 mg/m2, Etoposide 400 mg/m2 in divided doses over 4 days) chemotherapy at the time of initial relapse. Restaging was performed and responding patients (n=142) received a second cycle of DICE prior to collection of stem cells. Patients not achieving at least a PR (>50% reduction in tumor bulk or only minimal residual for low volume disease) were considered to have chemotherapy refractory disease (n=65) and were given an intensified salvage regimen of DICEP (dose intensive Cyclophosphamide 5000 mg/m2, Etoposide 1500 mg/m2, Cisplatin 120 mg/m2 in divided doses over 3 days) prior to stem cell collection.

Results: Chemotherapy refractory patients receiving dose intensified DICEP prior to autologous transplantation were able to achieve long-term survival. The 3 and 7-year Kaplan-Meier survival rates for DICEP treated refractory patients were 43% and 39%, respectively. This compares favorably, although less than, chemosensistive lymphoma patients treated with DICE salvage (3-yr: 65%, 7-yr: 52%; versus DICEP log-rank p=0.004). This difference in survival between refractory/sensitive patients held in both non-Hodgkins (refractory 3-yr: 47%, 7-yr 47%; sensitive 3-yr 61%, 7-yr: 47%; p=0.017) and Hodgkins Disease (refractory 3-yr: 48%, 7-yr: 39%; sensitive 3-yr: 74%, 7-yr: 61%; p=0.07). The most significant difference in outcomes by chemosensitivity was noted among patients with 1st relapse, with 3 and 7-year survivals of 70% and 58% in DICE sensitive and 32% and 32% in refractory patients requiring DICEP (p=0.0016). Minimal differences (p=0.36) were noted in Primary Induction Failure patients (7 yr survivals of 47% in both). Early (<100 day) all-cause mortality was similar among refractory (21.5%) and sensitive (14%; z=1.15; p=0.25) patients, although early relapse death rates trended higher in the refractory patients (15% vs 7%; z=1.63; p=0.10).

Conclusions: Aggressive histology lymphoma patients not responding to standard-dose DICE salvage therapy may become long-term survivors with DICEP salvage followed by autologous transplantation, although outcomes are slightly inferior. A risk adapted strategy of dose intensified salvage in refractory lymphomas should be considered and transplant offered to chemotherapy refractory patients.