Conditioning With IV Busulfan Key to Improving AML Survival

Neil Osterweil

October 28, 2013

A retrospective study supports what many leukemia transplant specialists have come to believe: a pretransplant conditioning regimen of cyclophosphamide and intravenous (IV) busulfan offers patients with acute myeloid leukemia a better chance at survival than cyclophosphamide and total body irradiation.

The study of 1230 patients with acute myeloid leukemia (AML) in first complete remission after allogeneic hematopoietic cell transplant (HCT) showed that those who had undergone conditioning with cyclophosphamide and IV busulfan (CTX/IV Bu) had better overall and leukemia-free survival and a lower risk for nonrelapse death than patients who had received CTX and total body irradiation (TBI) as the conditioning regimen.

The relative risk (RR) for nonrelapse mortality 1-year post-transplant for patients who had undergone conditioning with CTX/IV Bu was 0.58 (95% confidence interval [CI], 0.39 - 0.86; P = .007) compared with patients who had undergone CTX/TBI, report Edward A. Copelan, MD, from the Levine Cancer Institute, at Carolinas HealthCare System, in Charlotte North Carolina, and colleagues in the Center for International Bone Marrow Transplant Research.

Using an IV form of busulfan is the key to the success of the chemotherapy regimen. The investigators report that conditioning with oral — rather than IV — busulfan plus CTX was not superior to CTX/TBI. Their study appears online in Blood ( doi:10.1182/blood-2013-07-514448 )

In an interview with Medscape Medical News, Dr. Copelan noted that earlier studies comparing busulfan with TBI in conditioning regimens used fixed oral doses of busulfan, and were therefore unable to account for differences in metabolism of busulfan among patients.

He and his colleagues point out that there is a therapeutic middle ground to be sought out between low steady-state levels of busulfan, which are associated with relapse and transplant rejection, and high levels, which are associated with serious toxicities such as hepatic veno-occlusive disease.

"One of the modern improvements is that you can do pharmacokinetics after you give an oral or an IV dose, and adjust further doses based on first-dose kinetics, because people are so varied in their absorption and metabolism of busulfan," he told Medscape Medical News.

To see how the 2 conditioning approaches stack up when applied in contemporary practice, the authors looked at data on 1230 patients with AML receiving a first HCT with cells donated from a human-leukocyte antigen (HLA)-matched sibling or unrelated donor after conditioning with either CTX/TBI or CTX/Bu.

The patients were treated from 2000 through 2006 with CTX with TBI either in a nonfractionated dose of 5.5 Gy or higher, or fractionated dose of 9 Gy or higher, or with CTX/Bu at a dose of 9 mg/kg with no additional chemotherapy agents.

In addition to the lower risk for nonrelapse mortality noted before, the investigators found that in multivariate analysis, CTX plus IV Bu was associated with a markedly lower incidence of relapse after 1 year post-transplant (RR = 0.23; 95% CI, 0.08 - 0.65; P = .006) There were no significant differences in relapse incidence during the first post-transplant year, however. The variables controlled for in the analysis included age, sex, Karnofsky performance scores at transplant, interval from diagnosis to transplant, cytogenetic risk, and transplant-related factors.

In addition, IV busulfan plus CTX was associated with better leukemia-free survival (RR = 0.70; 95% CI, 0.55 - 0.88; P = .003) and overall survival (RR = 0.68; 95% CI, 0.52 - 0.88; P = .003) than persons receiving CTX/TBI.

A transplant specialist who was not involved in the study says that the results reflect a growing trend in practice toward conditioning with CTX and IV rather than oral busulfan, and away from TBI.

"It confirms what was suspected, which is that IV is better than oral, and that busulfan is certainly easier to tolerate than total body irradiation," said Eyal C. Attar, MD, assistant professor of medicine at Harvard Medical School, and a hematologist/oncologist at Massachusetts General Hospital, both in Boston… He was not involved with the study.

The study results also hint that busulfan may have an effect on noncycling cells — including primitive hematopoietic progenitor cells — that can elude conventional chemotherapy agents, Dr. Attar said.

"Leukemia stem cells do not cycle rapidly, we do need more effective strategies to target them, and the fact that there is a decreased beyond 1 year leukemia relapse with the busulfan strategy suggests that it may target a quiescent population of cells," he added.

Dr. Copelan and colleagues speculate that "[r]elapse beyond a year after transplantation may result from the recovery of injured quiescent primitive leukemic cells. By reducing the variability in drug exposure, intravenous administration may more effectively eradicate these primitive, quiescent, drug-resistant leukemic precursors."

The study was supported b y the National Institutes of Health and grants from Allos, Inc.; Amgen, Inc.; Angioblast; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius Biotech North America, Inc.; Gamida Cell-Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; Swedish Orphan Biovitrum; THERAKOS, Inc.; and Wellpoint, Inc.

The authors and Dr. Attar have disclosed no relevant financial relationships.

Blood. 2013-07-514448; published ahead of print September 24, 2013, doi:10.1182/blood-2013-07-514448.

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