Granulocyte Colony-Stimulating Factor Is Safe and Well Tolerated Following Allogeneic Transplantation in Patients with Sickle Cell Disease
Bibliographic record
Abstract
Background: Granulocyte colony-stimulating factor (G-CSF) is used after hematopoietic cell transplantation (HCT) to enhance neutrophil recovery in patients rendered neutropenic by the agents used in the preparative regimen (PMID: 9187067). G-CSF is contraindicated in patients with sickle cell disease (SCD) due to reported life-threatening complications ascribed to sickle vasculopathy, presumably secondary to leukocytosis and granulocyte activation (PMID: 11880644). Complications include severe vaso-occlusive pain crises, splenic engorgement, rupture, and death (PMID: 19513902). Individuals with sickle trait tolerate G-CSF without toxicity (PMID: 29743574, PMID: 27167356).The safety/toxicity of using G-CSF to enhance neutrophil recovery following HCT for SCD has not been previously described in the context of vasculopathy that is present in recipients but whose hematologic milieu is altered by transfusions and donor product infusion. Aim/Method: The hypothesis that G-CSF use would be safe in SCD patients following HCT was tested in a multicenter trial (NCT 03128996). Patients underwent HCT from matched or one-antigen mismatched (at HLA-A, -B, -C, -DRB1 if marrow; -A, -B, -DRB1 loci if cord) related or unrelated donor products between 2004 and 2019 following reduced intensity conditioning (RIC) which included hydroxyurea, alemtuzumab, fludarabine, melphalan +/- thiotepa. The regimen results in short-term marrow suppression followed by recovery. GVHD prophylaxis included tacrolimus, short-course methotrexate or mycophenolate or prednisone, and since 2018, abatacept. All patients underwent transfusions prior to commencing conditioning to reduce Hemoglobin S (Hb S) levels to <45%. G-CSF was commenced on day +7 post-HCT and continued until the absolute neutrophil count (ANC) was >1.5x103 cells/mL on 3 successive days. The clinical course, outcomes, and toxicities in the first 100 days post-HCT were evaluated as best representing the period of G-CSF influence on SCD recipients. Results: Sixty-four patients with SCD were evaluated post-HCT. The median age at HCT was 10.67 years (range, 1-21). HCT was performed for stroke/increased transcranial doppler velocity (N=32), acute chest syndrome (N=24) and vaso-occlusive episodes (VOE) (N=38). Twenty-nine and 35 patients received related and unrelated donor HCT respectively; 24 were mismatched at one antigen or allele locus. Graft sources included marrow (46), cord (12), peripheral blood (3), marrow + cord (2) and CD34 selected graft with T cell add-back (1). G-CSF was administered for a median of 9.4 days (range 6-33 days) post HCT. Neutrophil engraftment occurred at a median of 14.35 days (range 10-38), platelets at median of 25.2 days (range 12-89). Three patients recovered platelets beyond day 100. Seven patients had primary graft rejection and autologous reconstitution of hematopoiesis. Chimerism analysis in the remaining patients included a median of 93% (range 41-100% in the myeloid lineage; N=30), 89% (range 26-100% in the lymphoid lineage; N=36) and 93% (range 48-100% in whole blood; N=45) on day 100. The incidence of grade I-II and III-IV acute GVHD was 23.4% and 17% respectively during first 100 days. A total of 23 episodes of bloodstream and 7 non-bloodstream sites of bacterial infection were observed in 22 patients. No patient developed SCD related symptoms following post-HCT G-CSF administration. Organ toxicities noted in 17 of the 64 patients were variable [most common were hypertension (4), posterior reversible encephalopathy (3), and renal dysfunction (3)] and expected as part of the transplant process. Conclusion: In this cohort of SCD patients who underwent HCT from different donor sources following RIC and G-CSF to enhance neutrophil recovery, we noted no toxicities attributable to G-CSF. Specifically, no SCD related symptoms or extended hospitalization were encountered in any patient attributable to G-CSF administration. Commencing conditioning at a Hb S level <45% (the pre-alemtuzumab level) and chemotherapy induced destruction of native sickle hematopoiesis may be important factors in mitigating G-CSF related SCD complications post-HCT despite persistent vasculopathy and an inflammatory state. In this setting, G-CSF can be safely administered to SCD patients post-HCT. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".