High-dose VP-16-213 and autologous bone marrow transplantation for refractory malignancies: a phase I study.

Abstract

VP-16-213, a congener of epipodophyllotoxin, is a useful chemotherapeutic agent especially against small-cell carcinoma of the lung, germ cell carcinoma, and lymphoma. The standard dose of this drug is limited by myelosuppression. Autologous transplantation of cryopreserved bone marrow assures the restoration of hematopoiesis after marrow ablative cytotoxic therapy. By using this technique, VP-16-213 was dose-escalated using a Fibonacci scheme from the previous highest dose administered to humans (1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for three consecutive days). At 2,700 mg/m2, severe extramedullary toxicity of the mucous membranes was observed in three of three courses. At the next highest dose (2,400 mg/m2), two of 18 courses (11%, p less than 0.01) resulted in severe mucositis, thus defining this dose as the maximally tolerated dose based on extramedullary toxicities. As anticipated, myelotoxicity was severe but based on the kinetics of marrow recovery, VP-16-213 in these doses appeared not to be marrow ablative. Based on responses observed in this study, high-dose VP-16-213 should be explored in phase II studies or used in combination chemotherapy.

Dose-dependent effect of etoposide in combination with busulfan plus cyclophosphamide as conditioning for stem cell transplantation in patients with acute myeloid leukemia

“…Other side-effects are hepatic and pulmonary toxicity, especially in extensively pretreated patients. [15][16][17][18] …”

“…The efficacy of high-dose etoposide in advanced hematological malignancies has been confirmed in several studies. [15][16][17] In combination with TBI, high-dose etoposide followed by allogeneic stem cell transplantation resulted in a disease-free survival of 43% and a relapse rate of 32% in patients with advanced leukemia. 28,29 In a comparative study of AML beyond first CR, Bu/Cy showed an advantage without significance in terms of survival, but the TBI/etoposide regimen resulted in less VOD and GVHD.…”

Allo-SCT using BU, CY and melphalan for children with AML in second CR

“…12,17 Where thiotepa and Mel are strongly myeloablative even as single agents, this is not the case for etoposide. [18][19][20] In the late 70's, etoposide was shown to be able to induce remission in 15-25% of patients with AML who had failed to remit after standard regimens used at that time. 21 These experiences led to the incorporation of this drug into the standard induction courses for newly diagnosed AML.…”

Autologous transplantation in poor risk Hodgkin's disease using high dose melphalan/etoposide conditioning with non-cryopreserved marrow rescue

“…The choice of preconditioning for HD was based on our experience with melphalan in high grade non-Hodgkin's lymphoma autotransplants and the fact that it had been shown to have value in other series of ABMT in HD (Russell et al, 1989;Zulian et al, 1989). It was considered that VP16, known to be an active agent in HD, used at high dose would be of benefit Wolff et al, 1983;Blume et al, 1987;Jagannath et al, 1986;Stewart et al, 1991). All agents for this procedure needed a short half-life if our policy of using non-cryopreserved marrow, which is associated with rapid engraftment and lack of procedural mortality (Carey et al, 1991) (range 19-46).…”