Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial

Rambaldi, Alessandro; Grassi, Anna; Masciulli, Arianna; Boschini, Cristina; Micò, Maria Caterina; Busca, Alessandro; Bruno, Benedetto; Cavattoni, Irene; Santarone, Stella; Raimondi, Roberto; Montanari, Mauro; Milone, Giuseppe; Chiusolo, Patrizia; Pastore, Domenico; Guidi, Stefano; Patriarca, Francesca; Risitano, Antonio M.; Saporiti, Giorgia; Pini, Massimo; Terruzzi, Elisabetta; Arcese, William; Marotta, Giuseppe; Carella, Angelo Michele; Nagler, Arnon; Russo, Domenico; Corradini, Paolo; Alessandrino, Emilio Paolo; Torelli, Giovanni Fernando; Scimè, Rosanna; Mordini, Nicola; Oldani, Elena; Marfisi, Rosa Maria; Bacigalupo, Andrea; Bosi, Alberto

doi:10.1016/s1470-2045(15)00200-4

Cited by 147 publications

(132 citation statements)

References 32 publications

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“…The replacement of Cy with the NA Flu has shown good efficacy with reduced toxicity. We demonstrated excellent results with the Flu-Bu combination in patients undergoing transplant for AML(8), and our results were corroborated in prospective, multicenter, randomized studies of Flu-Bu vs. Bu- Cy(33)(13) in AML, in which the patients treated with Flu-Bu had a significantly lower rate of NRM rate compared with Bu-Cy2, with similar overall and disease-free survival in the two groups. The Flu-Bu combination has also been tested in ALL.…”

Section: Discussionsupporting

confidence: 66%

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

Kebriaei

Bassett

Lyons

et al. 2017

Biology of Blood and Marrow Transplantation

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We investigated the long-term safety and disease-control data obtained with intravenous busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (SCT). 107 patients with median age 38 years (range 19–64 years) received a matched sibling (n=52), or matched unrelated donor transplant (n=55) for ALL in first complete remission (n=62), second complete remission (n=28), or more advanced disease (n=17). Nearly half of the patients had high-risk cytogenetic profiles as defined by the presence of t(9;22) (n=34), t(4;11) (n=4), or complex cytogenetics (n=7). Clo 40 mg/m2 was given once daily, each dose followed by pharmacokinetically-dosed Bu infused over three hours daily for 4 days, followed by hematopoietic cell infusion after two rest days. The Bu dose was based upon the drug clearance determined by a test Bu dose, 32 mg/m2, given 48 hours prior to the high dose regimen. The target daily area under the curve (AUC) was 5,500 microMol-min for patients less than 60 years of age and 4000 microMol-min for patients older than 59 years of age. With a median follow-up of 3.3 years among surviving patients (1–5.8 years), the 2-year progression-free survival (PFS) rates for patients transplanted in CR1, CR2, or more advanced disease were 62%, 34%, and 35%, respectively. The regimen was well tolerated with non-relapse mortality (NRM) rates of 10% and 31% and at 100 days and 2 years, respectively. The incidence of grades II–IV and III–IV acute graft versus host disease (GVHD) were 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) rates for patients transplanted in CR1, CR2, or more advanced disease were 70%, 57%, and 35%, respectively. Among 11 patients older than 59 years treated with reduced dose Bu in CR1 (n=7) or CR2 (n=4), 4 remain alive and disease-free with a median follow up of 2.6 years (2–4.7 years). Only the presence of MRD at time of transplant was associated with significantly worse PFS and OS on multivariate analysis. The Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. Overall survival and NRM rates compare favorably with traditional myeloablative TBI-based conditioning regimens.

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Section: Discussionsupporting

confidence: 66%

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

Kebriaei

Bassett

Lyons

et al. 2017

Biology of Blood and Marrow Transplantation

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“…RIC potentially extends the curative graft-versus-leukemia effect to patients of older age or to young patients with significant comorbidities. [179][180][181][182] Conditioning intensity varies. For instance, busulfan/fludarabine is more dose-intense than fludarabine/low-dose total-body irradiation.…”

Section: -5977174177mentioning

confidence: 99%

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Döhner

Estey

Grimwade

et al. 2017

Blood

4,527

5,387

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The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease

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“…51 Finally, in the most recently reported study in AML patients aged 40-65 years, BuCy showed higher 1-year NRM versus BuFlu but no differences in 5-year DFS. 52 The results therefore supported improved safety with BuFlu compared with BuCy but this did not confer any real advantage in terms of survival. Another area of interest is the role of BuFlu as an alternative to RIC regimens in elderly patients, a population who would be suitable for both types of conditioning.…”

Section: Discussionmentioning

confidence: 74%

Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS

Serna

Sanz

Bermúdez

et al. 2016

Bone Marrow Transplant

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The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m 2 /day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19-74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2-4 and grade 3-4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with earlyand late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged o 50 years had better outcomes compared with older patients (DFS 64 vs 42%, P = 0.006; OS 73 vs 47%, P o 0.001, respectively).Bone Marrow Transplantation (2016) 51, 961-966;

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Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial

Cited by 147 publications

References 32 publications

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

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

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS

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