Stanford and City of Hope (COH) groups first evaluated a conditioning regimen consisting of fractionated TBI to a total dose 1320 cGy in 11 fractions on day -7 through day -4 administered erect and with lung shielding together with IV etoposide at 60 mg/kg administered over 4 hours on day -3. This group subsequently demonstrated considerable activity of this regimen in patients with advanced acute leukaemia in a randomised prospective SWOG trial versus Bu/Cy conditioning.r A German study using the same regimen reported 64% DFS at 18 months in 17 high-risk patients (10 were not in remission at transplantation).r In less advanced disease, these groups reported cumulative probabilities of disease-free survival and relapse at 3 years of 61% and 12%, respectively, for 61 patients with AML and 64% and 12%, respectively, for 34 patients with ALL.r Given these initial results the Medical Research Council UKALL12/Eastern Cooperative Oncology Group study adopted this conditioning regimen as standard in 1993. This study reported a 5-year DFS of 54% in 170 patients with Philadelphia-negative ALL conditioned with etoposide-TBI. However, the 100-day transplant-related mortality (TRM) in the multicenter, multinational setting was 21%.r The Stanford and COH groups found that the etoposide-TBI regimen caused considerable mucosal and dermatologic toxicity but with NRM reported as 28%.r
Marks et al, reported a registry based comparison of the outcome of 500 adult and paediatric patients with ALL in CR1 or CR2 who received either Cy-TBI or etoposide-TBI prior to a HLA matched sibling transplantation.r Cy doses ranged from 100 to 130 mg/kg, and etoposide doses ranged from 40 to 60 mg/kg. 217 patients received Cy-TBI less than 13 Gy, 81 patients received Cy-TBI greater than or equal to 13 Gy, 53 patients received etoposide-TBI less than 13 Gy, and 151 received etoposide-TBI greater than or equal to 13 Gy. COH provided data as a single institution for 75 patients who received etoposide-TBI greater than or equal to 13 Gy as their conditioning regimen. The median follow-up of survivors was 67 months (range, 8-156 months).
Transplant-related mortality did not differ by conditioning regimen but was significantly associated with age greater than or equal to 20, and receiving PBSC vs. BM. In CR1, there were also no significant differences in relapse, LFS, or survival by conditioning regimen. In CR2, these outcomes differed among conditioning groups. In comparison with Cy-TBI less than 13 Gy, the risks of relapse, treatment failure and mortality tended to be lower with etoposide (regardless of TBI dose) or with TBI doses greater than13 Gy (p=0.0016). Relapse risk was also significantly correlated with age greater than or equal to 20, and presence of cytogenetic abnormalities. For both CR1 and CR2 transplantations, causes of death were similar among the groups; disease recurrence accounted for 47% of deaths.
Efficacy
Relapse:

Cumulative incidence of relapse after HLA-identical sibling transplantations for ALL in first (A) or second (B) complete remission, according to the pre transplantation conditioning regimen (pointwise P value at 5 years for CR1 patients: etoposide-TBI versus Cy-TBI less than 13 Gy, P = .23; etoposide-TBI versus Cy-TBI greater than or equal to 13 Gy, P = .78; Cy-TBI less than 13 Gy versus Cy-TBI greater than or equal to 13 Gy, P = .60; pointwise P value at 5 years for CR2 patients: etoposide-TBI versus Cy-TBI less than13 Gy, P = .22; etoposide-TBI versus Cy-TBI greater than or equal to 13 Gy, P = .033; Cy-TBI less than 13 Gy versus Cy-TBI greater than or equal to 13 Gy, P = .001). Vp16 indicates etoposide.
© American Society for Blood and Marrow Transplantation 2006

© American Society for Blood and Marrow Transplantation 2006
Overall Survival:r

Adjusted probability (derived from multivariate regression models) of LFS after HLA-identical sibling transplantations for ALL in first (A) or second (B) complete remission, according to the pre transplantation conditioning regimen (pointwise P value at 5 years for CR1 patients: etoposide-TBI versus Cy-TBI less than 13 Gy, P = .21; etoposide-TBI versus Cy-TBI greater than or equal to 13 Gy, P = .17; Cy-TBI less than 13 Gy versus Cy-TBI greater than or equal to 13 Gy, P = .59; pointwise P value at 5 years for CR2 patients: etoposide-TBI versus Cy-TBI less than 13 Gy, P = .002; etoposide-TBI versus Cy-TBI greater than or equal to 13 Gy, P = .23; Cy-TBI less than 13 Gy versus Cy-TBI greater than or equal to 13 Gy, P < .001). Vp16 indicates etoposide.
© American Society for Blood and Marrow Transplantation 2006

© American Society for Blood and Marrow Transplantation 2006
Toxicity
Toxicity data by pre-transplantation conditioning regimen is presented below.r The major single cause of death was recurrence of disease. Overall, the causes of death were similar in the 4 groups. GVHD, infection, interstitial pneumonia, and organ failure were the other major causes of treatment failure.

© American Society for Blood and Marrow Transplantation 2006
Philadelphia-positive ALL
Laport et al, reviewed the 20 year Stanford and COH experience of VP16+TBI regimen in Ph+ ALL.r 67 pts received VP16+TBI, 11 pts received VP16+Cy+TBI and 1 pt received VP16+Bu+TBI. All pts received an HLA matched sibling allograft. 62% CR1, 38% greater than CR1. 10 yr OS for CR1 54% and greater than CR1, 29% (p=0.01) with no increase in relapse between the groups (28% vs. 41%, p=0.28) but a substantial increase in TRM for the greater than CR1 group (31% vs 54%, p=0.03). Multivariate analysis of outcomes for OS and EFS are presented below.

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