Improved Outcomes of Autologous (Auto) Hematopoeitic Stem Cell Transplantation (HSCT) for Intermediate and High Risk (I/HR) Aggressive (AG) Non Hodgkin Lymphoma (NHL) with IV vs PO Busulfan (Bu) in a Bu, Cyclophosphamide (Cy) and Etoposide (E) Preparative Regimen.
Authors: Aggarwal Charu , Gupta Sameer , Salzman Donna E. , Dickey Amy G. , Vaughan William P. 
Published: October 2019

The BUCYE preparative regimen was originally developed for allogeneic HSCT for advanced hematological malignancy (BMT 4:489-495). We have been using it as high dose chemotherapy for auto-HSCT for malignant lymphoma patients (pt). We have now had the opportunity to review the results of this experience in 49 I/HR AG NHL pt transplanted between 8/94 and 9/03. Eighteen pt treated before 4/99 received CY 2.5 Gm/M2/d d −3 to −1 and E 1800 mg/M2 over 4 hr on d −3 following BU 1mg/Kg Q6h X 16 doses administered po beginning on d −7. Since 4/99, 31 pt have received the same regimen substituting iv BU using Pharmacokinetics (PK) guided dosing to target an area under the concentration*time curve (AUC) of 1000–1400μMol *min on the same Q6h X 16 dose schedule. Eleven of these pt, treated prior to 3/01, had dose 8 adjusted based on dose1 PK and the remaining 20 had dose 1 or 2 adjusted based upon a test dose. We hypothesized that reduced inter- and intra-pt variation in AUC due to PK guided iv BU would reduce the risk of over or under treatment with excess risk of toxicity or relapse as compared to po administered drug. The age range (18–69, med 53 for po pt; 19–68, med 51 for iv pt), HR ratio (7/18, 39% for po pt; 14/31, 45% for iv pt), and number of prior chemotherapy regimens (1–3, med 2 for both) were the same for both the iv and po groups. The distribution of histological sub-classifications was also not different. The iv group consisted of 23 Diffuse Large B-Cell, 1 Burkitt, 2 Mantle Cell, 2 T cell and 3 others. The po group contained 16 Diffuse Large B-Cell, 2 Mantle Cell, 1 T cell and 4 others. The non-relapse mortality for the po BU pt was 5/13 (28%) and for the iv BU pt was 1/31 (3%) (p = 0.01 chi square). The overall survival (OS) for the po pt is currently 28% with no deaths beyond 4 yr and med follow up of survivors of 7 yr (range 4–10); in contrast the OS is 63% for the iv pt with no deaths beyond 2 yr and median follow up of survivors of 2 yr (range 4 mo to 4.5 yr), (p = 0.012 log rank). The progression free survival (PFS) is 22% for the po pt and 55% for the iv pt (p = 0.013 log rank). During the same time period we treated 48 Hodgkin’s disease (HD) pt with the same regimen (17 po, 31 iv). There was no significant difference in any outcome parameter between iv and po regimens in this significantly younger (19–63 yr, med 31) and otherwise lower risk population. With follow up of survivors from 18 to 90 mo (med 36), OS is 60% at median follow up and PFS is 50%. Overall, the results of the use of the BUCYE regimen in auto HSCT for both HD and NHL are excellent. The substitution of PK guided iv BU for the more erratic po administration in the BUCYE regimen appeared to be responsible for reduced relapse rate and non-relapse mortality with improved OS and PFS. These results are especially dramatic in the I/HR AG NHL pt, the group at highest risk for relapse and regimen related mortality.