Long-Term Follow-Up of IV Busulfan (Bu) with Fludarabine (Flu) vs IV Bu with Cyclophosphamide (Cy) as Pre (Allogeneic) Transplant Conditioning Therapy for AML/MDS.
Authors: De Lima Marcos , Wang X. , Thall P.F. , Couriel D. , Jones R.B. , Shpall E.J. , Popat U. , Giralt S. , Korbling M. , Champlin R. , Andersson B.S. 
Published: October 2019

Abstract
We previously demonstrated early safety and efficacy of fixed-dose IV BuFlu. Here we compare IV BuFlu and IV BuCy2, with long follow-up in a large number of pts. Since pts were treated on consecutive, not randomized programs, we used pts receiving Flu-Melphalan (M) in a program spanning the time of the IV Bu-based studies to estimate/correct for this non-randomized “period” effect.
Methods: 293 pts received Bu 130 mg/m2, Flu 40 mg/m2 (after April 2001; n=148); Bu 0.8 mg/kg × 16, Cy 60 mg/kg × 2 (before April 2001; n=67); Flu 30mg/m2 × 4, M 140–180 mg/m2 (FM; before and after April 2001; n=78). Patients received FM mainly based on higher age and coorbidities. Graft-vs-host dx (GVHD) prophylaxis was tacrolimus-based. Bayesian log-normal regression models were used to assess covariate- and treatment effects on survival, non-relapse mortality (NRM) and time to progressive disease (TPD). Covariates and survival model are shown in the table. The model accounts for the “period” effect, the effects of Bu-vs-FM, and Flu-vs-Cy within IV Bu pts. Patient and treatment characteristics were (BuFlu, BuCy2 and FM): median age 46 (19–66), 39 (13–64) and 54 (22–74) years. At HSCT 47%, 48% and 21% of the patients were in CR1-3. Donors were HLA-identical siblings in 53%, 79% and 41%. 30% of the Bu groups and 47% of FM had poor prognosis cytogenetics. Results: Median follow-up in months (BuFlu, BuCy2 and FM; alive pts): 30 (9–56; n=80; all but 2 pts followed for at least 1 yr), 69 (24–102; n=23) and 48 (17–89, n=25). 100-day NRM for pts in CR at HSCT was 2% and 9% after Bu-Flu and BuCy2, while 1 yr-NRM was 7% and 18%. BuFlu produced significantly better EFS (P=0.04) and overall NRM (P=0.02) than BuCy2, but TPD was similar (P=0.34). 2-yr actuarial survival (CR pts): 75% (BuFlu) vs. 50% (BuCy), P=0.01.
Conclusion: After accounting for covariate and treatment period effects, there was a significant benefit to being treated with BuFlu compared to BuCy2 in spite of a higher median age and proportion of MUDs. The benefit was most evident for CR-pts due to a significant reduction in NRM, without loss of antileukemic activity due to exchanging Cy with Flu.
Fitted Bayesian log-normal overall survival model Variable Mean SD Posterior 95% credible interval 2.5% 97.5%* Probability of beneficial effect *1=beneficial effect; 0=low likelihood of beneficial effect Cytogenetics −0.85 0.4 −1.652 −0.045 0.017 Disease status (CR vs other) 1.12 0.55 0.019 2.15 0.975 Donor (sibling vs other) 0.606 0.237 0.149 1.056 0.992 Age −0.022 0.010 −0.041 −0.003 0.017 Circulating blasts (0 vs >0) 0.951 0.268 0.454 1.463 1 Platelet count 0.002 0.001 0.000 0.004 0.967 Period effect −0.914 0.458 −1.795 0.041 0.029 IV Bu (vs FM) −0.513 0.481 −1.455 0.420 0.148 BuFlu (vs Bucy2) 1.476 0.544 0.406 2.555 0.995 Survival – patients in CR at transplant Survival – patients in CR at transplant