Comparison of reduced-toxicity conditioning protocols using fludarabine, melphalan combined with thiotepa or carmustine in allogeneic hematopoietic cell transplantation

Abstract

The age of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) has increased during the last decades, mainly due to improved reduced-intensity/toxicity conditioning protocols. A reduced-intensity conditioning based on fludarabin, carmustin/BCNU and melphalan (FBM) has been previously developed at our institution. Since we observed detrimental effects in individual patients with compromised lung function, efforts have been made in order to replace BCNU by thiotepa (FTM) to reduce toxicity. In this study, we retrospectively analyzed the outcome, GvHD incidence, lung function and organ toxicity of patients with a median age of 62 years (range 21-79) transplanted for malignant disease (96.7%, 62.3% in intermediate/advanced disease stage) at our institution after conditioning with FBM (n = 136) or FTM (n = 105) between 2013 and 2017. Median follow-up was 868 days (range 0-2615). In multivariate analysis for overall survival, no difference was detected between both conditioning protocols in the presence of impaired lung function, age, lower performance, and liver disease previous allo-HCT. In the subgroup analysis, FTM was not inferior to FBM in patients with pulmonary disease prior allo-HCT, lymphoid malignancies, and higher comorbidity index. In conclusion, the reduced-intensity FBM and FTM conditioning protocols show adequate antineoplastic efficacy and are suitable for patients with impaired lung function.

The impact of pulmonary function in patients undergoing autologous stem cell transplantation

“…34,35 In the allo-HSCT setting at our institution, we first reduced the dose of BCNU and later replaced it with thiotepa in reduced-intensity conditioning to decrease or eliminate the risk of lung toxicity. 36 De-escalation of the melphalan dose while maintaining the antitumor activity is a good alternative, especially for older and fragile patients with multiple myeloma. 37 The most suitable protocols for specific patients with advanced age, comorbidities, and/or impaired lung and cardiac function are important research questions that should be addressed in the future in the context of controlled randomized clinical trials.…”

Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation – a registry study on behalf of the EBMT Acute Leukemia Working Party.

“…Hence, our previous studies have shown that both conditioning protocols based on two alkylating agents (FBM or FTM) have adequate anti-leukemic activity and were suitable for older patients or those with co-morbidities including impaired lung function. Hence, both protocols were comparable regarding adjusted OS [14][15] .…”

“…In previous single-center-based studies, it was shown that FBM and FTM protocols are comparable after adjusting for variables in uencing mortality in multivariate analysis 15 . This was con rmed using EBMT registry-based data in a preliminary analysis of the present study and allowed us to include FBM-and FTM-treated patients in the same group.…”

Pulmonary microbiome and gene expression signatures differentiate lung function in pediatric hematopoietic cell transplant candidates

“…Although more than 7500 children receive this treatment annually in the United States and Europe, the success of this therapy is limited by a broad range of post-HCT pulmonary injuries that develop in 10 to 40% of pediatric recipients in response to chemotherapeutic toxicity, infection, and impaired or dysregulated immunity (1)(2)(3). Comprehensive assessment of pulmonary health before HCT conditioning is critical to identify high-risk patients who may benefit from modified conditioning chemotherapy regimens, closer surveillance, and risk-stratified treatments aimed at mitigating the development of irreversible pulmonary toxicity (4)(5)(6).…”