A retrospective analysis of 1,230 patients with acute myeloid leukemia (AML) who underwent bone marrow transplantation found that treatment with intravenous busulfan (Bu) and cyclophosphamide (Cy) produced higher survival rates compared with cyclophosphamide and total body irradiation (TBI).
The multi-institutional study, published in Blood (2013;122:3863-3870), and led by Edward A. Copelan, MD, Chair of the Department of Hematologic Oncology and Blood Disorders at the Levine Cancer Institute, in Charlotte, NC, used data from the Center for International Bone Marrow Transplant Research (CIBMTR) and found significantly less non-relapse mortality (relative risk [RR] of 0.58) and relapse after one year (RR 0.23) in patients treated with IV BuCy compared with Cy/TBI, and increased leukemia-free survival (RR 0.70) and overall survival (RR 0.68).
“I think that treatment is already evolving in this direction,” Copelan said in an interview. “Hopefully this study will help accelerate this change. Many patients are still receiving combined treatment with Cy and TBI, but over the last six years more and more are instead being treated with IV Bu.”
Results from another prospective study of patients transplanted for myeloid malignancies, published in Blood one week after the first study came out online (doi: 10.1182/blood-2013-08-519009), also found better outcomes with intravenous Bu.
In that study, Christopher Bredeson, MD, and colleagues at the Ottawa Hospital Blood and Marrow Transplant Program and the Ottawa Hospital Research Institute compared survival rates among 1,484 patients with myeloid malignancies who were treated with IV Bu or other combined TBI-based regimens.
Patients' two-year probability of survival was found to be 56 percent with IV Bu compared with 48 percent with TBI regimens. “Compared with TBI, IV Bu resulted in superior survival with no increased risk of relapse or treatment-related mortality,” the researchers reported. “These results support the use of myeloablative IV Bu over TBI-based conditioning regimens for treatment of myeloid malignancies.”
Researchers have been comparing the treatment approaches for more than two decades, Copelan noted. Early studies found that patients treated with Bu/Cy had comparable survival rates to Cy/TBI, but with higher rates of treatment-related mortality and a greater risk of veno-occlusive liver disease or hemorrhagic cystitis. However, these studies relied on oral rather than IV Bu delivery.
“Many hospitals do not have the experience or ability to monitor drug levels in each patient treated orally, so there can be significant side effects. Our study pushes IV Bu further because we found fewer of these problems,” Copelan said.
Asked for his opinion, Navneet Majhail, MD, Director of the Blood and Bone Marrow Transplant Program at Cleveland Clinic's Taussig Cancer Institute, agreed that the study should encourage more centers to switch to IV Bu. “I think that this is a practice-changing study for transplantation in this field. Patients need this because most of them are still receiving total body irradiation despite the fact that it is associated with more complications and side effects. My guess is that a lot more cancer treatment centers will start using IV Bu and cut down on TBI, at least in patients with AML.”
The main limitation of the first study was that it was retrospective he said. “They used data submitted by cancer centers, which reflects each center's experience with patients treated with IV Bu. But I think that this study shows that the results can be generalized to the AML patient population as a whole.”
He too agreed that the challenge has always been monitoring drug levels in patients pretreated with myeloablative otal dosing regimens. “Some centers are not equipped to do this or they lack the ability to properly monitor levels of either oral or IV Bu, but the fact is that today this is not that difficult,” Majhail said.
Practice Paths Diverge
TBI or busulfan in combination with cyclophosphamide are the most commonly used myeloablative regimens for patients preparing to receive allogeneic transplantation, and early studies of the two drugs occurred “largely in parallel,” Copelan and his co-researchers noted.
In 1977, one group reported “curing” some patients with advanced acute leukemia using Cy/TBI in transplants using cells from human leukocyte-antigen (HLA)-identical siblings, and later demonstrated sustained leukemia-free survival in more than 50 percent of AML patients transplanted in first complete remission.
In these early trials, 120 mg/kg Cy with TBI delivered in six fractions of 2 Gy was better than a single dose of 10 Gy3, and equivalent survival with lower non-relapse mortality was found using 12 Gy compared with 15.75 Gy in seven divided fractions. But in 1983, researchers reported that a pre-transplant regimen of 16 mg/kg oral Bu and 200mg/kg Cy was associated with very low relapse rates, but a high incidence of non-relapse mortality. Others reported less toxicity using a lower Cy dose of 120 mg/kg given over two days.
In 1991, a multi-institutional international study of AML in first complete remission, also led by Copelan, estimated a three-year leukemia-free survival rate of 63 percent in patients treated with Bu/Cy after being transplanted with cells from identical HLA-matched siblings. However, a randomized study published in 1992 reported better outcomes with Cy/TBI compared with Bu/Cy.
Over the following decade, prospective and retrospective studies as well as meta-analyses performed raised questions regarding the superiority of Cy/TBI over Bu/Cy, but generally indicated that there were lower relapse rates after TBI. However all of the studies used fixed doses of oral Bu, and lower blood levels of Bu were associated with higher rates of relapse and rejection.
“Therapeutic monitoring and dose adjustment of IV Bu reduces variability in levels in plasma,” Copelan said, “and while molecular HLA-typing and supportive care have both helped improve post-transplant survival, in general, over the past two decades, improvement in its administration appears to differentially improve results with Bu.”