Phase II study of autologous transplantation with interleukin-2-incubated peripheral blood stem cells and posttransplantation interleukin-2 in relapsed or refractory non-Hodgkin lymphoma

Abstract

Previous work suggested that interleukin (IL)-2 can be used for eradicating residual disease in autologous grafts and for preventing recurrence. We report a phase II study of autologous peripheral blood stem cell transplantation with in vitro IL-2 incubation of peripheral blood stem cells and posttransplantation IL-2 in patients with recurrent or refractory non-Hodgkin lymphoma. Salvage chemotherapy consisted of ifosfamide and etoposide. Responding patients underwent autologous peripheral blood stem cell transplantation. IL-2incubated stem cells were infused on day 0. IL-2 1 mIU/m 2 was given from day 1 until day 28. Four monthly maintenance cycles of IL-2 4 mIU/m 2 subcutaneously twice daily days 1 to 5 and days 8 to 11 were administered thereafter. Eighty-four evaluable patients were enrolled, and 60 proceeded to transplantation, of which 56 received IL-2-incubated stem cells. The average received dose of posttransplantation IL-2 was 30% to 50% of planned. Only 42 patients received maintenance IL-2. The average received maintenance dose of IL-2 was also approximately 30% of planned. Most dose reductions were due to toxicity or patient refusal. Three-year survival and progression-free survival for all registered patients were 43% (95% confidence interval [CI], 33%-53%) and 31% (95% CI, 21%-41%), respectively. For the 60 patients undergoing transplantation, they were 59% (95% CI, 46%-72%) and 44% (95% CI, 31%-57%), respectively. There was no relation between the dose of IL-2 received and outcome. Survival and disease-free survival of the study group were similar to those of a previous study cohort that received unmanipulated stem cells and no systemic IL-2. Administration of IL-2-incubated peripheral blood stem cells and intensive posttransplantation IL-2 was associated with considerable but rapidly reversible toxicity. No effect on long-term outcome was observed.

Total body irradiation, etoposide, cyclophosphamide, and autologous peripheral blood stem-cell transplantation followed by randomization to therapy with interleukin-2 versus observation for patients with non-Hodgkin lymphoma: results of a phase 3 randomized trial by the Southwest Oncology Group (SWOG 9438)

“…It is possible that the relatively brief, intensive course of IL-2 therapy in this study may not have provided sufficient duration of immunostimulation. Other groups have investigated the use of prolonged, lower-dose IL-2 immunotherapy with or without IL-2-activated lymphocytes beginning immediately after transplantation, 19 or 1 to 2 months after transplantation. 20 Although immunostimulatory changes of potential antitumor significance were reported, these researchers did not observe beneficial effects on relapse or survival in comparison with historical controls.…”

Conditional power calculations for clinical trials with historical controls

“…Although this is a widely used method (e.g. References [15][16][17]), this substitution of a control-arm estimator in a conditional power formula has the same problems as in the normal-outcomes and binomial-outcomes cases. Instead, we recommend using the estimator of the unconditional power, P 1S ( ;ˆ C ).…”