Allogeneic bone marrow transplantation for children with acute leukemia: cytoreduction with fractionated total body irradiation, high-dose etoposide and cyclophosphamide

Abstract

Summary:Marrow-ablative chemo-radiotherapy followed by hematopoietic stem cell rescue from an allogeneic source improves outcomes for children with high-risk acute leukemia. The first effective pre-transplant preparative regimens consisted of high-dose cyclophosphamide (CY) and total body irradiation (TBI). Subsequent attempts have been made to improve leukemia-free survival, by adding other chemotherapy agents to these agents. In previous clinical studies of total body irradiation, etoposide, cyclophosphamide (TBI-VP-16-Cy) in adult allogeneic bone marrow transplantation, there has been a high incidence of severe regimen-related toxicity. In this study, we investigated the safety and efficacy of this combination in 41 children who received TBI (12-14 Gy), VP-16 (30 mg/kg), and CY (60 mg/kg × 2) and then either matched sibling or alternative donor transplants for acute leukemia. There was only one case of fatal regimen-related toxicity. The estimated 3-year event-free survival for patients with early or intermediate stage disease was 68% (53-88%). The estimated event-free survival of patients with advanced disease was 17% (5-59%). TBI-VP16-CY is safe in pediatric transplantation, and it has good efficacy for transplant recipients with less advanced disease. outcomes for both adults and children by augmenting the anti-leukemic activity of this combination. Increasing the TBI dose led to decreased relapse rates, but this was offset by increased treatment-related mortality. 3 Alternatively, many investigators sought improved preparative regimen efficacy, by incorporating supplemental chemotherapy agents such as busulphan, 4 cytarabine, 5 or etoposide. [6][7][8] Previous clinical studies of one of these novel regimens, total body irradiation, etoposide and cyclophosphamide combined with allogeneic bone marrow transplantation for adults with acute leukemia have yielded mixed results. [6][7][8] To assess the safety and efficacy of this combination in pediatric patients, we evaluated the outcomes of 41 children and adolescents who received allogeneic bone marrow transplants for acute leukemia after total body irradiation, etoposide and cyclophosphamide. Patients and methods EligibilityThe pediatric bone marrow recipients included in this analysis were treated between September 1990 and October 1998 at the University of Rochester Medical Center. Patients were followed until 1 April 1999. During this time, all patients between the ages of 1 and 19 years who were receiving their first sibling or unrelated donor bone marrow transplant, and had acute lymphoblastic leukemia (FAB classification 1 or 2) or acute undifferentiated leukemia, were treated with this regimen. Patients with AML in undelayed first remission with matched sibling donors were treated on Pediatric Oncology Group protocols and not included in this analysis. All other pediatric patients who received allogeneic bone marrow transplants for AML were treated with this regimen. Two patients receiving second transplants received this preparative regimen; differen...

TBI and melphalan followed by allogeneic hematopoietic SCT in children with advanced hematological malignancies

“…As a result, a probability of approximately 40% DFS was compared favorably with the outcomes previously reported for HSCT in pediatric advanced disease. [4][5][6] This study showed that the cumulative incidence of RP was 47.6%, which may be relatively high. In this study, however, approximately half of the patients were in non-remission status at HSCT.…”

“…1,2 In addition, the risk for TRM increases as the disease status at HSCT is advanced. [2][3][4] Although investigators have attempted to intensify the anti-leukemic effect by adding etoposide or thiotepa to conventional preparative conditioning regimens, such as TBI and CY or BU and CY, the disease-free survival (DFS) rates still do not significantly improve in patients with advanced disease. [3][4][5][6] The incidence of RP after HSCT still remains high.…”

Fludarabine, amsacrine, high-dose cytarabine and 12 Gy total body irradiation followed by allogeneic hematopoietic stem cell transplantation is effective in patients with relapsed or high-risk acute lymphoblastic leukemia

“…Time to leukocyte engraftment was 18 days (median, range, 13-34 days) and thereby comparable with other intensified conditioning regimens such as cyclophosphamide/TBI/ Ara-C 32 and cyclophosphamide/TBI/VP-16. 32,39,40 With 60% patients suffering from grade III/IV (6 III, 3 IV) infectious complications during aplasia, infections were the main risks for our patients within the early post transplant phase. But, there was no case of TRM due to infectious complications.…”

“…Grades III-IV nausea/vomiting was seen in 33%, grades III-IV mucositis in 46% and grades III-IV diarrhea in 33%, which was higher than in earlier studies with cyclophosphamide/TBI/ Ara-C or cyclophosphamide/TBI/VP-16. 32,39,40 However, no patient required preventive intubation or experienced aspiration pneumonia. Life-threatening toxicities other than infections did not accumulate.…”

Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens

“…[7][8][9] Furthermore, some protocols have added VP16 to the cyclophosphamide and TBI preparative regimens for patients with very highrisk acute leukemias in an attempt to improve survival. [10][11][12] Therefore, we conducted this retrospective study to compare the outcome of HSCT in pediatric ALL conditioned with two different regimens: (1) single dose of VP16 (60 mg/kg over 4 h) and fractionated TBI (1200 cGy in six fractions over 3 days) (VP16/TBI) and (2) Cyclophosphamide 50 mg/kg over 1 h daily for 4 days followed by the same fractionated TBI (CY/TBI).…”