[A medical-pharmaceutical partnership model as a contributor to the success in conditioning regimen for allogenic hematopoietic stem cell transplantation in adults: a cross-reflection on our organizations]. / Modèle de coopération médico-pharmaceutique comme contributeur au succès du conditionnement de la greffe allogénique de cellules souches hématopoïétiques chez l'adulte : un regard croisé sur nos organisations.

Allogeneic hematopoietic stem-cell transplant (allo-SCT) remains the only cure for many hematological malignancies and some benign and congenital diseases. Busulfan, proposed in its injectable form, has quickly become a mainstay of pharmacological and myeloablative (or non-myeloablative) conditioning. This is following the outbreak in 2010 of a multicenter international clinical phase II trial, we tested the robustness and reliability of our organization in a complex model of organization and multifactorial partnership. In this type "BuCy2" protocol based on a classical treatment duration of 4 consecutive days, the administration of IV busulfan is given in one single daily infusion instead of the conventional 16 infusions, while keeping the same total dose. Under these conditions, the treatment is totally secured using a therapeutic drug monitoring of busulfan, applied in real-time. The process is technically complex and requires the very close cooperation of the teams involved. A strength, weakness, opportunity and threat (SWOT) analysis has been constructed; it fully supports continuous quality improvement to the triple benefit of the nursing chain, the patients and their environment. Several critical points were identified and corrected. The experiment strongly contributes to the safety and security of the medication circuit at the hospital and, improves the performance of allo-SCT. It also contributes to the protection of all actors in the health field and their working environment via a well-functioning quality management system.

Oxazaphosphorines: new therapeutic strategies for an old class of drugs.

IMPORTANCE OF THE FIELD: The oxazaphosphorines (cyclophosphamide, ifosfamide and trofosfamide) are widely used in clinical practice for their antitumor and immunomodulatory activities. However, their use is associated with toxicities. The metabolism of oxazaphosphorines involves cytochrome P450 biotransformations, leading to highly reactive metabolites such as acrolein and chloroacetaldehyde responsible for urotoxicity, neurotoxicity and nephrotoxicity. While the mechanisms behind these toxicities remain under investigation, some advances have been made, as exemplified by the use of mesna to limit acrolein related urotoxicity. AREAS COVERED IN THIS REVIEW: This review highlights potential strategies for limiting side effects commonly associated with the oxazaphosphorine drugs, through pharmacological or medicinal chemistry-based approaches. WHAT THE READER WILL GAIN: The readers will gain a comprehensive review of these approaches to treatment in terms of: i) pharmacology: use of antidotes and modification of metabolism through inhibition/induction of CYP enzymes or use of gene therapy; and ii) medicinal chemistry: the design of new drugs to target cancer cells and avoid CYP biotransformation with pre-activated prodrugs or with side-chain substituted analogues. TAKE HOME MESSAGE: An increased knowledge of oxazaphosphorines' metabolism and toxicity may allow the development of new anticancer drugs combined with drug delivery systems to circumvent drug toxicity, providing increased tumoral specificity and greater anticancer activity.