Peripheral blood progenitor cell mobilization practices vary significantly among institutions. Effective mobilization regimens include growth factor alone, chemotherapy and growth factor combined, and, more recently, incorporation of plerixafor with either approach. Many institutions have developed algorithms to improve stem cell mobilization success rates and cost-effectiveness. However, an optimal stem cell mobilization regimen has not been defined. Practical guidelines are needed to address important clinical questions, including which growth factor is optimal, what chemotherapy and dose is most effective, and when to initiate leukapheresis. We present recommendations, based on a comprehensive review of the literature, from the American Society of Blood and Marrow Transplantation.
Summary
Cytotoxic chemotherapy for acute myeloid leukemia (AML) usually produces only temporary remissions, at the cost of significant toxicity and risk for death. One fundamental reason for treatment failure is that it is designed to activate apoptosis genes (eg., TP53) that may be unavailable because of mutation or deletion. Unlike deletion of apoptosis genes, genes that mediate cell cycle exit by differentiation are present in myelodysplastic syndrome (MDS) and AML cells but are epigenetically repressed: MDS/AML cells express high levels of key lineage-specifying transcription factors (TF). Mutation in these TF (eg., CEBPA) or their cofactors (eg., RUNX1) affect transactivation function and produce epigenetic repression of late-differentiation genes that antagonize MYC. Importantly, this aberrant epigenetic repression can be redressed clinically by depleting DNA methyltransferase 1 (DNMT1, a central component of the epigenetic network that mediates transcription repression) using the deoxycytidine analogue decitabine (DAC) at non-cytotoxic concentrations. The DNMT1 depletion is sufficient to trigger upregulation of late-differentiation genes and irreversible cell cycle exit by p53-independent differentiation mechanisms. Fortuitously, the same treatment maintains or increases self-renewal of normal hematopoietic stem cells (HSC), which do not express high levels of lineage-specifying TF. The biological rationale for this approach to therapy appears to apply to cancers other than MDS/AML also. DAC or 5-azacytidine dose and schedule can be rationalized to emphasize this mechanism of action, as an alternative or complement to conventional apoptosis-based oncotherapy.
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