A phase I dose escalation study of high-dose thiotepa, melphalan and carboplatin (TMCb) followed by autologous peripheral blood stem cell transplantation (PBSCT) in patients with solid tumors and hematologic malignancies

Abstract

Summary:The purpose of this study was to determine the maximum tolerated dose of carboplatin administered with 500 mg/m 2 thiotepa and 100 mg/m 2 melphalan followed by autologous peripheral blood stem cell (PBSC) infusion in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose thiotepa (500 mg/m 2 , melphalan (100 mg/m 2 ) and escalating doses of carboplatin 900-1500 mg/m 2 ) followed by infusion of cryopreserved autologous PBSCs. The maximum tolerated doses were determined to be 500 mg/m 2 thiotepa, 100 mg/m 2 melphalan and 1350 mg/m 2 carboplatin. Two consecutive patients receiving 1500 mg/m 2 carboplatin experienced grade 3 mucositis and colitis. Ten patients were enrolled at the maximum tolerated dose and none had grade 3-4 regimen-related toxicity and mortality. All patients at this level experienced grade 1-2 mucositis, 90% grade 1-2 gastrointestinal toxicity, 30% grade 1-2 cardiac and renal toxicity, and 10% experienced grade 1 hepatic toxicity. The median time to achieve a granulocyte count of 0.5 × 10 9 /l was 9 days (range 7-12 days) and platelet count of 20 × 10 9 /l was 10 days (range 7-15 days). Of eight patients with stage IV refractory breast cancer, even were evaluable for response, one patient on day 75 will be evaluated soon. Five of seven (71.5%) evaluable patients achieved a complete remission (CR) and two had no response. Of seven patients with non-Hodgkin's lymphoma (n = 4) or Hodgkin's disease (n = 3), five achieved a CR (71.5%). Thiotepa, melphalan and carboplatin can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy-sensitive malignancies are warranted. Bone Marrow Transplantation (2000) 25, 697-703.

The effect of post-transplant spironolactone on daily potassium requirements in patients undergoing autologous stem cell transplantation

“…[1][2][3] Nephrotoxic antibiotics which are commonly used in the post-transplant period may also cause hypokalemia. In general, the etiology of posttransplant hypokalemia is multi-factorial.…”

“…All patients received thiotepa 250 mg/m 2 /day (on days Ϫ9 and Ϫ8), melphalan 50 mg/m 2 /day (on days Ϫ7 and Ϫ6) and carboplatin 400 mg/m 2 /day (on days Ϫ5, Ϫ4 and Ϫ3) (TMCb regimen). 3 Patients rested on days Ϫ2 and Ϫ1 and PBSCs were infused on day 0.Two sequential groups of patients participated this study. The first 20 patients did not receive spironolactone and the second 20 patients received spironolactone 100 mg tablet twice daily per orum starting on day 0 and continuing up to post-transplant day +15.…”

“…All patients received thiotepa 250 mg/m 2 /day (on days Ϫ9 and Ϫ8), melphalan 50 mg/m 2 /day (on days Ϫ7 and Ϫ6) and carboplatin 400 mg/m 2 /day (on days Ϫ5, Ϫ4 and Ϫ3) (TMCb regimen). 3 Patients rested on days Ϫ2 and Ϫ1 and PBSCs were infused on day 0.…”

High-dose thiotepa, melphalan and carboplatin (TMCb) followed by autologous peripheral blood stem cell transplantation in patients with lymphoma – a retrospective evaluation

“…4 While considering the present literature data for carboplatin in the setting of autologous transplantation for solid tumors, we decided to combine carboplatin with thiotepa and melphalan in a previous phase-I study and developed a regimen of thiotepa, melphalan, and carboplatin (TMCb). 5 These drugs have marrow ablation as their dose-limiting toxicity, allowing significant dose escalation with the infusion of autologous hematopoietic stem cells. 5 The maximumtolerated dose (MTD) of carboplatin that could be added to fixed doses of thiotepa 500 mg/m 2 and melphalan 100 mg/m 2 was 1350 mg/m 2 , associated with a demonstrable activity in patients with breast cancer.…”

“…5 These drugs have marrow ablation as their dose-limiting toxicity, allowing significant dose escalation with the infusion of autologous hematopoietic stem cells. 5 The maximumtolerated dose (MTD) of carboplatin that could be added to fixed doses of thiotepa 500 mg/m 2 and melphalan 100 mg/m 2 was 1350 mg/m 2 , associated with a demonstrable activity in patients with breast cancer. 6 Upon observing intractable diarrhea at this dose level, we decided to use a cumulative carboplatin dose of 1200 mg/m 2 (one step down) in this regimen.…”