Intravenous Busulfan Plus Melphalan Is a Highly Effective, Well-Tolerated Preparative Regimen for Autologous Stem Cell Transplantation in Patients with Advanced Lymphoid Malignancies

Abstract

We investigated the administration of intravenous (i.v.) busulfan (Bu) combined with melphalan (Mel) in patients with advanced lymphoid malignancies undergoing autologous SCT. Bu 130 mg/m2 was infused daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5,000 uMol-min, determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high dose regimen, followed by a rest day, followed by two daily doses of Mel at 70mg/m2. Stem cells were infused the following day. 80 patients had i.v. Bu delivered per test dose guidance. The median daily systemic Bu exposure was 4867 uMol-min. 102 patients [Hodgkin's Lymphoma (HL) n=49, Non Hodgkin's Lymphoma (NHL) n=12, Multiple Myeloma (MM) =41] with median age 44 years (range 19 to 65 years) were treated. 2-year overall survival (OS) and progression-free survival (PFS) rates were 85% and 57%, respectively, for patients with HL, 67% and 64%, respectively, for patients with NHL, and 82% and 42%, respectively, for patients with MM. The regimen was very well-tolerated with treatment-related mortality at 100 days, 1 year, and 2 years of 1%, 3%, and 3%, respectively. Intravenous Bu-Mel is well-tolerated. Disease control is encouraging, and should be explored in larger phase II studies.

Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

“…We previously explored Bu-Mel as an alternative to BuCy2 (Bu 16 mg/kg and Cy 120 mg/kg) in lymphoid malignancies. However, the double alkylator regimen had similarly high NRM and GVHD rates compared with standard TBI-based regimens (7). The replacement of Cy with the NA Flu has shown good efficacy with reduced toxicity.…”

“…The administration of PK-guided busulfan allows for accurate dose delivery within a tighter range in systemic drug exposure (7), and contributed to the low toxicity profile of the regimen. Transient transaminitis was common, as was also reported by Magenau and colleagues(39).…”

“…Bu dose targeted an average daily AUC of 5,500 microMol-min for patients less than 60 years of age or 4,000 microMol-min for patients older than 59 years. Collection of blood and methods for PK analyses were performed as previously reported (7, 19). …”

“…In attempts to limit the toxicities associated with TBI-based, myeloablative regimens, we replaced radiation with a chemotherapy-only, double alkylator regimen consisting of intravenous (i.v. ), pharmacokinetically (PK)-dosed busulfan (Bu), and melphalan (Mel)(7). We showed comparable disease control to radiation-based regimens, while decreasing acute regimen-related toxicities, but long-term NRM, primarily related to graft versus host disease (GVHD), remained substantial (55% at 2 years for patients older than 40 years(7).…”

Fifty Years of Melphalan Use in Hematopoietic Stem Cell Transplantation

“…First, Srivastava and colleagues demonstrated the feasibility of melphalan in combination with oral busulfan in 24 patients with a variety of malignancies(132). Recently, our group reported the results from a phase II trial of pharmacokinetics-guided intravenous busulfan and melphalan conditioning prior to ASCT for patients with advanced lymphoid malignancies(133). No grade IV regimen-related toxicity was observed.…”