Improved prognosis with additional medium‐dose VP16 to CY/TBI in allogeneic transplantation for high risk ALL in adults

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) with the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen is an essential therapeutic strategy for acute lymphoblastic leukemia (ALL) in adults. Medium-dose etoposide (VP16, 30-40 mg/kg) can be added to intensify this CY/TBI regimen and reduce relapse; however, differences in prognosis between the VP16/CY/TBI and CY/TBI regimens have not yet been fully analyzed. We conducted a retrospective cohort study using a Japanese transplant registry database to compare the prognosis between the VP16/CY/TBI (VP16, total 30-40 mg/kg) (N = 376) and CY/TBI (N = 1178) regimens in adult patients with ALL transplanted at complete remission (CR) between January 1, 2000 and December 31, 2014. Our analyses indicated that VP16/CY/TBI significantly reduced relapse compared with CY/TBI (risk ratio, 0.75; 95% confidence interval [CI], 0.56-1.00; P = .05) with a corresponding improvement in leukemia-free survival (hazard ratio [HR], 0.76; 95%CI, 0.62-0.93; P = .01), particularly in patients transplanted at CR1 with advanced-risk (positive minimal residual disease, presence of poor-risk cytogenetics, or an initial elevated leukocyte count) (HR, 0.75; 95%CI, 0.56-1.00; P = .05) or those transplanted beyond CR2 (HR, 0.58; 95%CI, 0.39-0.88; P = .01). The addition of VP16 did not increase post-transplant complications or nonrelapse mortality (HR, 0.88; 95%CI, 0.65-1.18; P = .38). This study is the first to reveal the efficacy of the addition of medium-dose VP16 to CY/TBI in high-risk ALL. To establish new myeloablative conditioning regimens including VP16, a large-scale prospective study is necessary.

Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

“…Furthermore, according to the study by Marks et al [43], patients treated with alloHSCT in CR2 benefited from TBI dose ≥13 Gy as compared to <13 Gy, in terms of reduced risk of relapse and improved LFS. The Japanese group performed a retrospective study comparing 1178 ALL patients treated in first or subsequent CR with Cy/TBI and 376 ALL patients receiving Cy/TBI in combination with intermediate doses of etoposide (VP16, 30-40 mg/kg) [45]. The latter was associated with decreased risk of relapse (HR = 0.75, p = 0.05) and improved LFS (HR = 0.76, p = 0.01).…”

Safety of total body irradiation using intensity-modulated radiation therapy by helical tomotherapy in allogeneic hematopoietic stem cell transplantation: a prospective pilot study

“…In this study, two of the three patients who received intensified conditioning developed SOS. However, previous reports have shown that the addition of cytarabine or etoposide does not increase complication risk [ 16–19 ]. In fact, regimen-related toxicities other than SOS for these three patients were not serious and were comparable to the toxicities of the other seven patients.…”

“…The standard conditioning regimen consisted of cyclophosphamide (CY, 60 mg/kg/day) for 2 days and IMRT-TBI (12 Gy) for 3 days. As suggested by existing literature, additional cytarabine or etoposide administration was at the discretion of the attending physician [ 16–19 ]. Standard GVHD prophylaxis consisted of a calcineurin inhibitor (cyclosporine or tacrolimus) with short-term methotrexate or mycophenolate mofetil.…”

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

“…A retrospective cohort study was conducted using a Japanese transplant registry database to compare the prognosis between the medium-dose ETP/CY/TBI (ETP, total 30 to 40 mg/kg) ( n = 376) and CY/TBI ( n = 1178) conditioning regimens in adults with ALL transplanted at CR between January 1 2000 and December 31 2014 [29]. We are pleased with the fact that more than 300 adults with ALL underwent allo HSCT with the medium-dose ETP/CY/TBI conditioning regimen in the almost three years after enrollment in the prospective multi-center phase II clinical trial in Japan was completed.…”

“…Although the ETP-based regimens (usually 40–70 mg/kg as a single dose) showed efficacy to some extent, severe toxicities were often seen [24]. Among those regimens, the medium-dose (intravenous administration over three hours at a dose of 15 mg/kg once daily for two days) ETP added to a 120 mg/kg CY plus 12 Gy TBI conditioning regimen appears to be promising for allo HSCT in adults aged under 50 years with ALL when transplanted at CR1 and also at CR2, showing an excellent outcome without increasing relapse and transplant-related mortality (TRM) rates [25,26,27,28,29]. In contrast, RIC regimens have also been applied to adults with ALL and favorable outcomes have been obtained; however, relapse and TRM rates remain high [9,10,11,12,13].…”