When determining whether any intervention should be undertaken, careful consideration of the risks and benefits should be performed. Current approved indications for G-CSF usage include decreasing the incidence of infection in cancer patients receiving myelosuppressive chemotherapy, reducing the time to neutrophil recovery in patients receiving induction or consolidation chemotherapy for acute myeloid leukemia, reducing the duration of neutropenia in cancer patients receiving bone marrow transplantation, reducing the incidence and duration of sequelae of neutropenia in patients with severe chronic neutropenia, and collection of peripheral blood progenitor cells by apheresis [30
]. Though hospitalization duration is reduced with G-CSF usage in patients undergoing chemotherapy, a reduction in overall mortality has not been demonstrated. In a recent meta-analysis of 17 randomized controlled trials, including 3,493 patients with solid tumors and lymphomas [38
], G-CSF was demonstrated to decrease the incidence of febrile neutropenia from 39.5% to 22.4% (RR 0.54, p<0.0001) and early mortality from 5.7% to 3.4% (RR 0.6, p=0.002). However, decreased overall and event-free survival were not demonstrated. Another meta-analysis evaluated eight randomized controlled trials involving 1221 patients with malignancies who received antibiotics alone versus antibiotics plus G-CSF for treatment of established febrile neutropenia [39
]. Length of hospitalization decreased in patients that received G-CSF (HR 0.63, p=0.0006), but there was again no difference in overall mortality between the two groups. Thus, in the setting of chemotherapy, the benefit of G-CSF is shorter hospitalization duration. The risks of G-CSF use in SCD patients include severe adverse reactions in a significant number of cases (7 out of 11); these complications led to a significantly longer overall hospitalization due to VOC and even death. Since these risks clearly outweigh the benefit of G-CSF use, the routine use of G-CSF in SCD should be avoided. This assessment is supported by the package insert of G-CSF, which states that “severe sickle cell crises, in some cases resulting in death, have been associated with the use of Neupogen® (G-CSF) in patients with sickle cell disorders. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Neupogen® for such patients, and only after careful consideration of the potential risks and benefits” [40
]. Further, the National Marrow Donor Program continues to maintain a policy against the collection of HSCs through G-CSF mobilization from subjects with not only SCD, but also sickle cell trait (personal communication Dr. Willis Navarro, Medical Director, NMDP).
Regarding the usage of G-CSF for peripheral blood progenitor cell collection, a risk/benefit assessment for individuals with SCD is not even necessary. The existence of a safe and viable alternative to G-CSF mobilization proves that its use in SCD, and the unnecessary exposure to the ensuing risks, are not justified. Indeed, multiple studies have compared outcomes between recipients of G-CSF-mobilized peripheral blood and harvested bone marrow as the allogeneic HSC source. While most studies have found no difference in the rates of graft versus host disease (GVHD), overall survival, and disease-free survival [41
], in some settings, such as pediatric patients with severe aplastic anemia, bone marrow was found to be superior as a stem cell source due to an increased risk of GVHD and mortality with G-CSF-mobilized peripheral blood HSCs [44
]. Autologous transplantation studies also demonstrate similar long-term outcomes with bone marrow as the HSC source [47
]. With respect to gene therapy applications, we have previously demonstrated equivalent engraftment of genetically modified HSCs derived from bone marrow when compared to that from G-CSF mobilized peripheral blood in non-human primates [48
]. Though often used in bone marrow harvesting, the safety of general anesthesia in SCD patients undergoing surgical procedures has been optimized over the last 3 decades, and the morbidity and mortality has been significantly reduced [49
]. Furthermore, bone marrow harvesting can be safely performed under conscious sedation and local anesthesia [51
] or spinal anesthesia [53
]. Thus, bone marrow harvesting should be considered in any scenario when the risk of G-CSF mobilization in the donor is significant.
Another potential alternative to G-CSF mobilization is the CXCR4 antagonist, AMD-3100, which blocks the interaction between the CXCR4 receptor of HSC and the SDF-1 ligand on the bone marrow stroma, and releases HSCs into circulation allowing for collection by apheresis. However, AMD3100 also increases leukocyte counts, albeit to a lesser degree than G-CSF [54
], suggesting that similar related side effects might also be encountered.