Perspectives on the Use of a Medium-Dose Etoposide, Cyclophosphamide, and Total Body Irradiation Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation: The Japanese Experience from 1993 to Present.

Masahiro Imamura,Akio Shigematsu

doi:10.3390/jcm8050569

Masahiro Imamura, Akio Shigematsu

Open Access

https://doi.org/10.3390/jcm8050569

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Abstract

The outcome for adults with acute lymphoblastic leukemia (ALL) treated with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) is poor. Therefore, allogeneic HSCT (allo HSCT) for adults aged less than 50 years with ALL is performed with myeloablative conditioning (MAC) regimens. Among the several MAC regimens, a conditioning regimen of 120 mg/kg (60mg/kg for two days) cyclophosphamide (CY) and 12 gray fractionated (12 gray in six fractions for three days) total body irradiation (TBI) is commonly used, resulting in a long term survival rate of approximately 50% when transplanted at the first complete remission. The addition of 30 mg/kg (15 mg/kg for two days) etoposide (ETP) to the CY/TBI regimen revealed an excellent outcome (a long-term survival rate of approximately 80%) in adults with ALL, showing lower relapse and non-relapse mortality rates. It is preferable to perform allo HSCT with a medium-dose ETP/CY/TBI conditioning regimen at the first complete remission in high-risk ALL patients and at the second complete remission (in addition to the first complete remission) in standard-risk ALL patients. The ETP dose and administration schedule are important factors for reducing the relapse and non-relapse mortality rates, preserving a better outcome. The pharmacological study suggests that the prolonged administration of ETP at a reduced dose is a promising treatment.

Highlights

The outcome for adults with acute lymphoblastic leukemia (ALL) treated with chemotherapy or autologous hematopoietic stem cell transplantation is poor [1,2,3], given that the long-term survival rate is approximately 30% with a high incidence of relapse; allogeneic hematopoietic stem cell transplantation is utilized as an essential treatment modality for such patients
The medium-dose ETP added to a 120 mg/kg CY plus 12 Gy total body irradiation (TBI) conditioning regimen appears to be promising for allo hematopoietic stem cell transplantation (HSCT) in adults aged under 50 years with ALL when transplanted at CR1 and at CR2, showing an excellent outcome without increasing relapse and transplant-related mortality (TRM) rates [25,26,27,28,29]
We present the beneficial effect of a medium-dose ETP/CY/TBI conditioning regimen for adults with ALL who underwent allo HSCT at CR based on retrospective analysis mainly performed at the Hokkaido University Hospital, where a reduced-dose ETP/CY/TBI conditioning regimen has been utilized in allo HSCT for adults with various hematological malignancies since 1990, a retrospective analysis using a Japanese transplant registry database and a prospective multi-center phase II clinical trial in Japan

Summary

Introduction

The outcome for adults with acute lymphoblastic leukemia (ALL) treated with chemotherapy or autologous hematopoietic stem cell transplantation is poor [1,2,3], given that the long-term survival rate is approximately 30% with a high incidence of relapse; allogeneic hematopoietic stem cell transplantation (allo HSCT) is utilized as an essential treatment modality for such patients. The allogeneic bone marrow transplantation (allo BMT) for patients with advanced hematological malignancies including advanced leukemias using the high-dose (usually 60 to 70 mg/kg in a single dose) ETP/TBI conditioning regimens was reported by Blume et al [14] in 1987 using a 25 to 70 mg/kg ETP dose and by Schmitz et al [19] in 1988 using a 60 to 70 mg/kg ETP dose These studies showed some efficacy, and the maximum tolerated dose was shown to be 60 mg/kg [14]; severe toxicities were observed. We decided to use this regimen for only ALL patients rather than for patients with AML or other hematological malignancies at the Hokkaido University Hospital beginning in 2004

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