Results of 10-Year Single Center Experience with Pharmacokinetics Directed Intravenous Busulfan, Cyclophosphamide and Etoposide Preparative Regimen in Autologous Hematopoietic Stem Cell Transplantation for Intermediate and High Grade Non-Hodgkin Lymphoma

Introduction: High dose chemotherapy followed by Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is indicated for patients with Non-Hodgkin Lymphoma (NHL) recurring after or resistant to primary therapy. Busulfan based conditioning regimens are commonly used.  Since the approval of the intravenous formulation of busulfan in March of 1999, AHSCT patients at UAB have been treated with a regimen of pharmacokinetics directed (PK) busulfan together with cyclophosphamide and etoposide (BuCyE). We sought to evaluate the long term outcomes of this PK directed dosing scheme.

Patients and Methods:  Between April 1999 and November 2009, 69 consecutive patients with intermediate and high risk NHL ranging in age from 19 to 74 with a median age of 54 at the time of transplant were treated with a Bu “test dose” of one 60 mg vial with adjustment of the remaining doses to achieve an exposure of 20,000 uMol-min total Bu AUC followed by Cy (2.5 g/m2) and E (1800 mg/m2).

	*DLBC (n=40)	*FL (n=15)	*MCL (n=14)
Age at Transplant	55 (19-74)	55 (26-70)	57 (30-73)
Gender:  Male	26 (65%)	10 (67%)	9 (64%)
Female	14 (35%)	5 (33%)	5 (36%)
Race:      White	33 (83%)	12 (80%)	14 (100%)
Black	6 (15%)	2 (13%)	0
Other	1 (2%)	1 (7%)	0
Status at Transplant:
Complete Remission 1-3	13 (33%)	1 (7%)	6 (44%)
Partial Response	5 (12%)	1 (7%)	3 (21%)
Relapse	17 (43%)	6 (40%)	2 (14%)
Primary Refractory	5 (12%)	7 (46%)	3 (21%)

*DLBC: Diffuse Large B-Cell Lymphoma, FL: Follicular Lymphoma, MCL: Mantle Cell Lymphoma

Results:  The average hospital stay was 25 days. There were 2 patient deaths prior to hospital discharge and 3 additional deaths within the 100 day post-transplant period.  At a minimum follow-up of 3 years the overall survival and disease free survival were 59% and 56%, respectively, for patients less than 54 years of age and 57% and 54%, respectively, for patients more than 54 years of age. The 100 day mortality, 1 year mortality, overall survival and relapse-free survival were similar in regardless of age (p value 0.5).

	DLBC (n=40)	FL (n=15)	MCL (n=14)
100 day Mortality*	2 (5%)	2 (13%)	1 (7%)
100 day - 1 year Mortality	8 (20%)	4 (26%)	1 (7%)
3 year Overall Survival	63%	47%	57%
3 year Relapse-free  Survival	60%	46%	50%
*Causes of 100 day Mortality	Intracranial hemorrhage Disease	Heart failure Sepsis	Sepsis

Conclusion:  This PK directed BuCyE regimen followed by AHSCT resulted in good overall and 3 year disease free survival in intermediate and high risk NHL patients. Survival outcomes were similar regardless of patient age at the time of transplant.