Allogeneic Bone Marrow Transplantation after Hyperfractionated Total-Body Irradiation and Cyclophosphamide in Children with Acute Leukemia

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...

Section: Discussionsupporting

confidence: 85%

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

Duerst

Horan

Liesveld

et al. 2000

“…3,4 There exists controversy with regard to what length of time defines a late relapse after which point an HSCT may have no advantage over chemotherapy. In analyzing 287 patients with ALL in CR2, Uderzo reported no advantage of matched-sibling HSCT over chemotherapy for patients who relapsed more than 30 months from diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Hematopoietic stem cell transplantation (HSCT) has been commonly employed for patients with relapse or high-risk features. 3,4 While most children with recurrent or high-risk ALL can achieve a remission with intensified therapy, the most appropriate management strategy to employ once remission has been achieved remains controversial. Some transplant centers base that decision on whether a matched related donor is available.…”

mentioning

confidence: 99%

Outcomes of unrelated cord blood transplants and allogeneic-related hematopoietic stem cell transplants in children with high-risk acute lymphocytic leukemia

Jacobsohn

Hewlett

Ranalli

et al. 2004

Summary:Acute lymphocytic leukemia (ALL) is a common indication for hematopoietic stem cell transplantation (HSCT) in children. Use of unrelated cord blood (UCB) has become increasingly popular as a stem cell source, given the rapid availability and decreased GVHD potential. Publications describing outcomes of children with leukemia who underwent UCB transplants have compared them to those having received unrelated donor marrow transplants. Results are similar. We compared our outcomes using UCB vs allogeneic-related hematopoietic stem cells in pediatric ALL patients since 1992. A total of 49 patients were analyzed. All patients were either in CR1 with high-risk features (n ¼ 21) or in CR2 (n ¼ 28) with initial remission less than 36 months. Patients received myeloablation with fractionated total body irradiation, cyclophosphamide, and etoposide and GVHD prophylaxis with cyclosporine and methotrexate. Antithymocyte globulin was added for UCB recipients to address the HLA differences. In all, 23 patients underwent allogeneic -related HSCT and 26 underwent UCB transplantation. Other than increased time to engraftment for UCB recipients, results are equivalent. The 3-year overall survival is 64% and 3-year event-free survival is 60% for both groups. Rates of GVHD and transplant-related mortality are also equivalent. UCB is a reasonable option for children with ALL who are referred for HSCT. Although the majority of children with acute lymphocytic leukemia (ALL) enjoy excellent outcomes with conventional multiagent chemotherapy, the outlook for those patients who develop recurrent disease, particularly within the first 2 years of therapy, is far less favorable. Patients who relapse within 24 months of diagnosis and are treated with chemotherapy alone have less than 20% survival. 1,2 Hematopoietic stem cell transplantation (HSCT) has been commonly employed for patients with relapse or high-risk features. 3,4 While most children with recurrent or high-risk ALL can achieve a remission with intensified therapy, the most appropriate management strategy to employ once remission has been achieved remains controversial. Some transplant centers base that decision on whether a matched related donor is available.For patients with relapse, HSCT with HLA-matched related donors during the second complete remission (CR2) has provided leukemia-free survival (LFS) rates in the range of 40-50% at 2-5 years. 3,4 There exists controversy with regard to what length of time defines a late relapse after which point an HSCT may have no advantage over chemotherapy. In analyzing 287 patients with ALL in CR2, Uderzo reported no advantage of matched-sibling HSCT over chemotherapy for patients who relapsed more than 30 months from diagnosis. 5 With unrelated cord blood transplantation (UCBT) for ALL and AML, a relapse on therapy prior to transplant confers a worse LFS (22% on therapy vs 48% off therapy). 6 UCB can be an attractive alternative stem cell source for a variety of reasons. Cells are rapidly available, HLAmatching can be considerably...

“…All individuals in this study received hyperfractionated TBI as part of their conditioning regimen. 12 TBI was delivered via a linear accelerator in 11 or 12 fractions of 125 cGy each at a dose rate of 8-20 cGy/min. The doses were administered three times daily for 3 days with two or three fractions on day 4 to a total dose of 1375 cGy (n ¼ 10) or 1500 cGy (n ¼ 20).…”

Section: Patientsmentioning

confidence: 99%

Final height in pediatric patients after hyperfractionated total body irradiation and stem cell transplantation

Chemaitilly

Boulad

Heller

et al. 2007

Impaired linear growth has been shown to occur in individuals treated during childhood with single-dose and fractionated total body irradiation (TBI) before stem cell transplantation. Our objective was to describe the final heights attained and patient/treatment factors correlating with final height in a cohort of childhood cancer survivors treated with hyperfractionated TBI (total dose 1375 or 1500 cGy). Thirty individuals (18 men In conclusion, treatment with hyperfractionated TBI is associated with a reduction in standing height and an even greater reduction in sitting height. Final height after hyperfractionated TBI was similar to that reported after fractionated TBI.