Intravenous Busulfan Plus Melphalan Is a Highly Effective, Non-Toxic Preparative Regimen for Autologous Stem Cell Transplantation (ASCT) in Patients with Advanced Lymphoid Malignancies.
Authors: Kebriaei Partow , Madden Timothy , Kazerooni Reza , Shpall Elizabeth , Wang Xuemei , Thall Peter , Hosing Chitra , Qazilbash Muzaffar , Popat Uday , Ledesma Celina , Khouri Issa , Champlin Richard , Jones Roy , Andersson Borje S. 
Published: October 2019

Abstract
Abstract 3415
Poster Board III-303
High dose chemotherapy and SCT is an accepted treatment option for patients with relapsed lymphoid malignancies. Relapse remains a significant issue for patients with advanced disease. Predicting effective disease control with improved safety, we investigated the administration of intravenous (i.v.) busulfan (Bu) combined with melphalan (Mel) in patients with lymphoid malignancies undergoing ASCT.

Patients and Methods
Bu130 mg/m2 was infused daily for 4 days, either as a fixed dose per BSA (n=20), or to target an average daily AUC of 5,000 uMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high dose regimen (n=82), followed by a rest day, followed by two daily Mel doses at 70mg/m2. Stem cells were infused the following day. Dilantin was given for seizure prophylaxis.

Results
102 patients (38 F/64 M) with non-Hodgkin's lymphoma (n=12), Hodgkin's lymphoma (n=49) and multiple myeloma (n=41) with median age 44 years (range 19-66) have been enrolled to date. The median number of prior chemotherapy regimens was 3 (range 1-6). At time of study entry, 88% of patients were in relapse (sensitive relapse n=70, refractory relapse n=19) and 12% were in second remission. The median CD34+ cell dose infused was 5.2 × 106/kg (range 0.7-12.5). Median days to ANC ≥ 0.5 × 109/L and platelet count ≥ 20 × 109/L were 10 (range 8-44) and 9 (7-141), respectively. There was no grade IV or V toxicity. The most commonly observed toxicities were grade I or II nausea and vomiting (77%), mucositis (67%), and diarrhea (55%)., Reversible grade III liver enzyme abnormalities were observed in 4% of patients; one patient developed reversible VOD. With a median follow-up of 2.1 years (range 0.2-4.3), the cumulative incidence of treatment-related mortality (TRM) at 100 days, 1 year, and 2 years was 1.0%, 3.1%, and 4.3%, respectively. Among patients with non-Hodgkin's or Hodgkin's lymphoma, the overall response rate was 90%, with 1- and 2-year PFS rates of 63% and 58%, respectively; 1- and 2-year OS rates were 90% and 82% respectively (Figure 1). PFS was significantly better in patients with chemo-sensitive lymphoma, 61% vs. 42% at 2 years, p=.03. Among patients with multiple myeloma, the overall response rate was 58%, with 1- and 2-year PFS rates of 67% and 44%, respectively; 1- and 2-year OS rates were 90% and 82%, respectively. Survival rates were not significantly different between the chemo-sensitive and chemo-refractory multiple myeloma patients.

Conclusion
Intravenous busulfan-melphalan is well-tolerated, and the individualized PK-directed dosing of i.v. busulfan likely contributes to the low toxicity profile of this regimen. The high response rate and disease control in patients with advanced disease is encouraging, and should be explored in larger phase II studies.

Disclosures
Andersson: Otsuka Pharmaceuticals: Consultancy.