Pilot study of tandem high-dose chemotherapy and autologous stem cell transplantation with a novel combination of regimens in patients with poor risk lymphoma

Abstract

Summary:In an effort to improve the outcome of poor-risk lymphoma patients, we evaluated a novel regimen of tandem high-dose chemotherapy (THDC) with autologous stem cell transplantation. A total of 41 patients (median age 40 years, range 15-68 years) with poor-risk nonHodgkin's lymphoma and Hodgkin's disease were enrolled. THDC consisted of melphalan (180 mg/m 2 ) and escalating dose mitoxantrone (30-50 mg/m 2 ) (MMt) for the first conditioning regimen, and thiotepa (500 mg/m 2 ), carboplatin (800 mg/m 2 ), and escalating dose etoposide phosphate (400-850 mg/m 2 ), (ETCb) as the second regimen. In all, 31 patients (76%) completed both transplants, with a median time between transplants of 55 days (range 26-120). The maximum tolerated dose was determined as 40 mg/m 2 for mitoxantrone and 550 mg/m 2 for etoposide phosphate. The overall toxic death rate was 12%. Following high-dose chemotherapy, 10 of 24 evaluable patients (42%) were in CR. The two-year overall survival and event-free survival is 67% (95% CI, 52-81%) and 45%, (95% CI, 29-61%) for the 41 patients enrolled; and 69% (95% CI, 525-586%) and 48% (95% CI, 30-67%) for the 31 patients completing both transplants. This THDC regimen is feasible but with notable toxicity in heavily pretreated patients; its role in the current treatment of high-risk lymphoma remains to be determined. The majority of poor-risk lymphoma patients are not cured with conventional chemotherapy. High-dose chemotherapy (HDC) with peripheral blood progenitor cell support (PBPC) offers a survival advantage in such patients, but many still die from recurrent disease. 1 Strategies to improve survival in patients with poor risk, relapsed, or chemotherapy-resistant disease include intensified induction followed by HDC with PBPC support, 2-5 HDC with autografting and immunotherapy, 6 tandem HDC and autografting, [7][8][9][10][11][12] or sequential autologous and nonmyeloablative allogeneic transplantation.Tandem transplantation as a strategy to improve efficacy was demonstrated in myeloma by Barlogie et al 13 and Attal et al. 14 In an attempt to improve outcome in patients with high-risk lymphoma, our group examined the tolerability and efficacy of two regimens, first, mitoxantrone and melphalan (MMt) and second, etoposide, thiotepa, and carboplatin (ETCb), given in sequence with PBPC support in a program of tandem autologous transplantation. As first-line therapy for newly diagnosed poor-risk lymphoma, Corradini et al 15 reported favorable results using myeloablative doses of melphalan and mitoxantrone followed by autografting. Based on this report, we studied the utility and determined the maximum tolerated dose (MTD) of MMt given before the first transplant performed in our tandem autografting protocol for patients with poor-risk, resistant or relapsed disease.For our second autograft procedure, we devised a myeloablative conditioning regimen of ETCb. This combination derived from our experience with the high-dose combinations of cyclophosphamide, thiotepa, and carboplatin that we and o...

Unexpected acute renal injury after high‐dose etoposide phosphate and total body irradiation in children undergoing hematopoietic stem cell transplantation

“…However, to our knowledge, RFI has never been described in the literature, regardless of dosage. 7,8 We speculate that our unexpected cases of RFI when using etoposide phosphate may be explained by its formulation with dextran 40 (300 mg/100 mg of etoposide phosphate). This component is known to induce RFI, via an accumulation of proximal tubular lysosomes, called "osmotic nephrosis," when administered in high doses (from TA B L E 1 Bivariate analysis of disease, treatment, and patient characteristics in patients with and without renal function injury 50 to 1,000 g).…”

“…Both total dose and the time over which exposure occurs appeared relevant to define the maximum tolerated dose. However, to our knowledge, RFI has never been described in the literature, regardless of dosage …”

Impact of intensive PBSC mobilization therapy on outcomes following auto-SCT for non-Hodgkin's lymphoma

“…22,24 In contrast, 100% of our intensely mobilized patients were able to undergo ASCT. Significant complications of tandem ASCT include a treatment-related mortality rate of 8–16% 22–24 and, in one study, a veno-occlusive disease of liver rate of 13%. 18 We had a total treatment-related mortality of 4% (all after ASCT)and no veno-occlusive disease of liver.…”

“…18–24 These studies mostly involve NHL mixed with Hodgkin’s lymphoma patients whose disease status ranges from primary refractory to sensitive or refractory relapse to high-risk first complete remission. A total of 74–76% of patients completed both transplants.…”