Choosing a Reduced-Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation, Fludarabine/Busulfan versus Fludarabine Melphalan: A Systematic Review and Meta-Analysis

Abstract

A B S T R A C T Fludarabine with busulfan (FB) or melphalan (FM) are 2 more commonly used reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (HCT).We present a systematic review and meta-analysis of studies comparing these 2 RIC regimens. We searched electronic databases from inception through November 1, 2017 for literature searches to identify relevant studies. A DerSimonian random effects model was used to measure efficacy outcomes; hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are reported. Seven studies, including a total of 1955 patients, met criteria for inclusion, of which 6 were included in the overall pooled analysis because of repetition of some patients in 2 studies. Three studies were included in the subgroup analysis of acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) and 2 in the subgroup analysis of lymphoid malignancies. Overall survival (OS) and progression-free survival were not statistically significantly different between the 2 RIC regimens in analysis of all studies. However, OS was better with FM in subgroup analysis of AML/MDS studies (HR, .83; 95% CI, .73 to .95). Nonrelapse mortality was lower with FB (HR, .64; 95% CI, .46 to .89), whereas relapse was lower with FM (HR, 1.52; 95% CI, 1.13 to 2.06) in the analysis of all studies. This meta-analysis shows that FB and FM are associated with a similar OS in patients undergoing HCT. Relapse rates are lower with FM but at the cost of higher nonrelapse mortality.

Effect of Primary and Secondary Beads of Carbon Enterosorbent on Haematological Parameters and Oxidative Stress Development Caused by Melphalan in Rats

“…The results of our experiment showed that Melphalan caused an increase in the values of pro-oxidant/antioxidant ratio, MDA levels, oxidative damage to plasma proteins and oxidative protein modification. This supports the results of previous studies, which demonstrated that cytotoxic effect of the drug is mediated through ROS-dependent cell death, in addition to alkylation of DNA and activation of the p53 pathway [36,37]. We observed only slight elevation of the other markers, which can be due to our experimental design: we assessed oxidative stress parameters on the 8th day after exposure to the alkylating agent, when the intensity of response has likely subsided.…”

“…It also evaluates a protective potential of two forms of oral carbon adsorbent: primary solid beads (AC1) and orally disintegrating micronized form (secondary granules, AC2). Cytotoxic drugs, including alkylating agents, are among the most effective agents for treating advanced ovarian and breast cancer, haematological malignancies such as leukaemia, multiple myeloma, and others; these drugs are also used for reduced-intensity conditioning regimens in allogeneic stem cell transplantation [4,35,36]. Myelosuppression is a dose-limiting factor for chemotherapy schemes [20,21,37] and thus control of such side-effects improves chemotherapeutic outcomes.…”

Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report

“…12 There have been several retrospective studies and a meta-analysis comparing the 2; however, these studies were limited by the inclusion of various age groups, disease-related factors, and graft-versus-host disease (GVHD) prophylaxis regimens. [14][15][16] In general, the results suggested a higher NRM but better disease control with FM RIC compared with FB and a variable effect on overall survival (OS). In the current study, we analyzed individual level data from a large cohort of AML transplantation patients from Center for International Blood and Marrow Transplant Research (CIBMTR) to compare the 2 RIC regimens.…”

Comparison of melphalan‐ And busulfan‐based myeloablative conditioning in children undergoing allogeneic transplantation for acute myeloid leukemia or myelodysplasia

“…Our results add to a growing body of literature supporting the use of a melphalan‐based conditioning approach in myeloid malignancies, both in the submyeloablative and myeloablative contexts. There are numerous reports comparing melphalan‐ and busulfan‐based RIC regimens for AML/MDS in adult patients, which were recently reviewed in a meta‐analysis . AML/MDS patients (N = 1271) had superior OS with fludarabine/melphalan conditioning compared to submyeloablative busulfan/fludarabine conditioning (HR 0.83; 95% confidence interval 0.73‐0.95).…”

“…Regimens that carry reduced toxicity yet are still myeloablative may offer a balance between the risks of relapse and TRM. Melphalan‐based conditioning is widely used in RIC protocols, particularly in adult patients with decreased tolerance of MAC, with outcomes that compare favorably to busulfan‐based RIC regimens . Melphalan‐based RTC regimens have not been fully evaluated in children.…”