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The article by Arcioni et al. describes the use of combined plerixafor and filgrastim (granulocyte colony-stimulating factor [G-CSF]) to mobilize CD34+ cells in five individuals with sickle cell disease (SCD) for whom collections with plerixafor alone had been inadequate [1]. We commend the authors for transparently reporting their experience. The reported outcomes provide a thought-provoking pilot experience, and the authors appropriately suggest the need for prospective studies to validate their findings. However, as clinicians and investigators with longstanding involvement in hematopoietic stem cell (HSC) mobilization and gene therapy for SCD, we are deeply concerned that normalizing or encouraging more widespread G-CSF use in individuals with SCD based on such limited data could lead to adverse outcomes, given the substantial literature documenting serious and potentially fatal toxicities with G-CSF [2-6]. It is critical to re-emphasize why G-CSF–based mobilization should remain contraindicated in SCD outside of the most exceptional circumstances, unless it is studied rigorously in a well-designed clinical trial or with great caution at an experienced center, especially as safer alternatives are now available. Across the published literature, of 11 individuals with SCD who received G-CSF for mobilization, seven developed severe, life-threatening complications, including vaso-occlusive crises (VOCs), acute chest syndrome (ACS), multi-organ failure, and death [2]. This translates to a complication rate of approximately 64% [2], an unacceptably high figure for any elective intervention. These adverse events occurred despite multiple precautions, including reduced or divided G-CSF dosing, aggressive hydration, anticoagulation, and red blood cell transfusions or exchange transfusions to lower HbS levels [2]. Accordingly, a moratorium on G-CSF use in SCD was recommended more than a decade ago, and it has never been reversed [2]. Current exagamglogene autotemcel and lovotibeglogene autotemcel FDA labels warn explicitly about the risk of sickle cell crises prohibiting the use of G-CSF for mobilization or within 21 days of infusion of the drug product, underscoring that this risk remains recognized by regulators and manufacturers. The generally “tolerable” safety profile of G-CSF in other populations should not be extrapolated to the SCD population, which at baseline has an inflammatory milieu and vasculopathy inherently sensitive to blood viscosity. In contrast, plerixafor has now emerged as a safe and effective standard of care in the gene therapy space for HSC mobilization in SCD, that has been validated in multicenter, prospective studies [7-9]. Contemporary gene therapy protocols [10-12] uniformly employ single-agent plerixafor while explicitly avoiding G-CSF. Multiple clinical trials have demonstrated that, when administered after exchange transfusion to reduce HbS levels below approximately 30%, plerixafor enables rapid, predictable, and safe mobilization of CD34+ cells [7, 9, 13]. Arcioni et al. described five highly selected patients treated at specialized centers with intensive exchange transfusion (often over months), prophylactic anticoagulation or antiplatelet therapy, and extremely close monitoring [1]. Although it is reassuring that no acute complications were observed, the absence of toxicity in five patients cannot override or negate the cumulative evidence from the broader literature. Case series are inherently subject to selection bias and are underpowered to detect infrequent but catastrophic events. Moreover, negative outcomes are historically underreported, particularly with off-label interventions. There is danger in extrapolating from a small-scale, favorable experience to routine clinical practice, in which intensive resources, expertise, and monitoring may be unavailable. The authors acknowledge that G-CSF has been historically contraindicated in SCD, yet their conclusion suggests that “controlled” use with preventive measures may mitigate the risk. This warrants caution. The literature clearly demonstrates that similar preventive strategies, including aggressive transfusion to reduce HbS, minimizing peak white blood cell counts, and dose modification, have not reliably prevented severe complications [2]. Critically, no predictive factors distinguish patients who will tolerate G-CSF from those who will develop life-threatening events. In other words, there is currently no reliable way to identify a “safe” scenario for a patient with SCD for G-CSF exposure before gene therapy or allogeneic hematopoietic cell transplantation (alloHCT). Mechanistically, the risk is biologically plausible and consistent with current knowledge of SCD pathophysiology. Leukocyte-mediated vaso-occlusion appears central to G-CSF toxicity. SCD is characterized by chronic inflammation, with elevated pro-inflammatory cytokines and complex interactions between sickled red cells, activated neutrophils, platelets, and the endothelium through adhesion molecules [14, 15]. G-CSF induces marked leukocytosis (predominantly neutrophilia), leukocyte activation, and cytokine release and augments leukocyte–endothelial cell adhesion, thereby potentially amplifying a cascade of endothelial activation, microvascular occlusion, and thrombo-inflammation that can precipitate VOCs or ACS. Supporting this, endogenous G-CSF is elevated during acute SCD complications: increased concentrations have been detected in bronchoalveolar lavage fluid during ACS, and serum G-CSF increases during VOCs alongside other inflammatory mediators such as IL-8 [16, 17]. Blocking G-CSF receptors mitigates some of these effects in animal models [18]. These observations suggest that G-CSF itself is part of the inflammatory cascade driving SCD morbidity, raising concern that exogenous administration could exacerbate an already primed system. Notably, current practice is to withhold hydroxyurea during the months prior to autologous HSC collection, further compounding the risk of complications. It is critical to distinguish this context from the post-alloHCT setting. G-CSF has been used safely after allogeneic HCT in at least 62 patients with SCD to accelerate neutrophil recovery, without reported SCD-related complications [19]. After conditioning and alloHCT, patients exhibit markedly reduced or absent HbS-producing erythropoiesis and profound leukopenia, which fundamentally alters the disease biology. Furthermore, G-CSF is dosed to normalize the neutrophil count and shorten the duration of neutropenia, unlike neutrophilia encountered during mobilization. Safety in this context should not be interpreted as supporting G-CSF use before alloHCT or gene therapy, when the underlying pathophysiology of SCD remains fully active and is not mitigated by measures such as transfusion therapy. We are also concerned about the broader implications of suggesting G-CSF as a “salvage” strategy after plerixafor failure. HSC mobilization depends on complex interactions between several factors and on external variables, including expertise in apheresis collection in individuals with SCD, the number of consecutive days of mobilization, and patient characteristics such as age, recent history of VOCs, etc. Many of these variables are not insurmountable. Framing G-CSF as the only remaining option risks creating pressure—on clinicians and patients alike—to accept disproportionate risk in pursuing higher CD34+ yields, particularly in adults who may be at higher risk for poor mobilization and for SCD-related complications. We recognize the need for alternative mobilization strategies to support “poorly mobilizing” individuals, and we support ongoing scientific exploration of alternative protocols and therapeutics. Optimizing plerixafor timing and dosing, refining apheresis techniques, and alternative mobilization agents such as the second-generation long-acting CXCR4 antagonist motixafortide are under investigation. Both motixafortide and plerixafor block the binding of stromal-derived factor 1α (SDF-1α/CXCL12) to the CXCR4 receptor, thereby disrupting the CXCL12–CXCR4 axis that anchors HSCs to the bone marrow matrix. This inhibition leads to HSCs being mobilized into the peripheral circulation without immune cell activation or cytokine release and is, therefore, probably much safer than G-CSF. Importantly, the threshold for acceptable risk and explorative interventions in a disease without an obligatory transplant indication, such as SCD, especially in the era of multiple emerging disease-modifying and curative options, must remain high and should certainly not be mitigated by anecdotal experience in a few patients. In summary, although the experience reported by Arcioni et al. is informative, it should not be interpreted as evidence that G-CSF is safe for routine mobilization in individuals with SCD. The weight of evidence demonstrates a high incidence of severe, unpredictable, and potentially fatal complications with no reliable mitigation strategies or predictive markers. Plerixafor-based mobilization remains the established and validated standard for gene therapy in SCD, and deviating from this approach should be considered only in the context of a rigorously designed clinical trial with full risk disclosure. Although this report suggests that G-CSF may be safe in SCD, adopting this therapy without robust clinical trials with primary safety outcomes and meaningful community engagement could undermine trust within this vulnerable patient population. We urge the hematology and HCT providers to exercise caution in interpreting small case series and to avoid broad extrapolation that could place patients at significant risk. Severe complications or fatalities resulting from G-CSF use in patients with SCD could undo years of progress in building confidence and improving care for this population, who are appropriately cautious in light of recent clinical trial failures, clonal expansion adverse events in recent gene therapy clinical trials, and market withdrawal of drugs [20]. As the success of gene therapy becomes more widely recognized, more patients and caregivers will seek gene and cellular therapy. Hematologists and transplanters should remember that patient safety must remain paramount as we expand access to transformative therapies for SCD. Akshay Sharma wrote the first draft of the manuscript and then revised it after input from all other co-authors. All authors provided critical input to the review, analysis, and interpretation of the data. All authors are responsible for all aspects of the article from conception to completion. The authors thank Keith A. Laycock, PhD, ELS, a senior scientific editor employed by St. Jude Children's Research Hospital, for scientific editing of the manuscript. Akshay Sharma acknowledges support from the American Lebanese Syrian Associated Charities (ALSAC) for his work at St. Jude Children's Research Hospital, as well as grant support (1U01HL163983) from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI). This work was supported (in part) by the Intramural Research Program of the NIH. The contributions of the NIH author were made as part of her official duties as an NIH federal employee, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. Akshay Sharma has received consultant fees from Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, Sangamo Therapeutics, Editas Medicine, Pfizer, BioLineRx, Gamida Cell, RGenta Therapeutics, and Bristol Myers Squibb. He is a medical monitor for an RCI BMT CSIDE clinical trial for which he receives financial compensation. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education and Blackwood CME. Dr. Sharma is the St. Jude Children's Research Hospital site principal investigator for clinical trials of genome editing for sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907), and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which includes salary support paid to Dr. Sharma's institution. Dr. Sharma has no direct financial interest in these therapies. These conflicts are managed through the Compliance Office at St. Jude Children's Research Hospital, in accordance with their conflict-of-interest policy. Sonali Chaudhury has received consultant and advisory fees from Vertex Pharmaceuticals, Genetix, Alexion, and AbbVie. Gregory M. T. Guilcher is the principal investigator of Project Sickle Cure, a Sickle Cell Transplant Advocacy and Research Alliance study partially funded by Genetix Biotherapeutics (previously bluebird bio). Ashish Gupta has received consultancy for Vertex Pharmaceuticals. He is also on the Speakers bureau for Emerging Therapies Solutions. Dr. Gupta has received research funding from Jazz Pharmaceuticals for the investigator-initiated trial. He is also the site principal investigator at University of Minnesota for the base editing gene therapy trial sponsored by BEAM Therapeutics (NCT05456880), the lentiviral gene therapy trial for sickle cell disease sponsored by Genetix Biotherapeutics (NCT04293185, NCT04628585), and the lentiviral gene therapy trial for Hurler syndrome sponsored by Orchard Therapeutics (NCT06149403). Matthew Heeney has received consultant fee for Novartis, Beam Therapeutics, Agios, and Octapharma. He is also a site principal investigator for a base editing gene therapy trial sponsored by BEAM Therapeutics (NCT05456880). Tami John has participated as an advisory board member and has received consulting fees from bluebird bio, Vertex Pharmaceuticals, and BioLineRx. She is a medical monitor for the BMT CTN 2001 GRASP study and for BMT CTN CRISPR_SCD001, for which she receives compensation. Dr. John is the Stanford site principal investigator for clinical trials of genome editing sponsored by Beam Therapeutics (NCT05456880) but has no direct financial interest in this therapy. James L. LaBelle has received consultant and advisory fees from Vertex Pharmaceuticals, Pfizer, and AbbVie. Dr. LaBelle is the site principal investigator for Novartis Pharmaceuticals (NCT04443907). Hemalatha G. Rangarajan has received consultant fees from Medexus Inc. and Vertex Pharmaceuticals. Crawford Strunk has received consultant and advisory fees from Pfizer and Spark HealthCare. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.