Neutropenia-driven Approach to G-CSF Use May Be Feasible With CAR T-Cell Therapy
Key findings
- This study examined how exposure to granulocyte colony-stimulating factor affected the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric receptor antigen T-cell therapy
- Among 197 patients with lymphoma, the 140 who received prophylactic granulocyte colony-stimulating factor (G-CSF) had increased risk of grade ≥2 CRS compared with controls (HR, 2.15; P=0.02), but the risk of grade ≥2 ICANS was similar between groups
- Prophylactic G-CSF was associated with significantly faster neutrophil recovery (3 vs. 4 days, P<0.01) but did not reduce the risk of recurrent neutropenia
- 17 patients had neutropenia treated with G-CSF after CAR T-cell therapy within seven days of developing grade ≥1 CRS and did not experience worsening toxicity
- Prospective trials should examine whether neutropenia-driven G-CSF administration could improve the safety of CAR T-cell therapy
The success of chimeric antigen receptor T-cell therapy (CAR T) in treating hematologic malignancies has been tempered by cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These toxicities involve activation of recipient myeloid cells and upregulation of myeloid-derived cytokines.
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There's justifiable hesitancy to use granulocyte colony-stimulating factor to treat neutropenia after CAR T, since stimulating myeloid progenitor cells could exacerbate CRS and ICANS. Lacking clear guidance from clinical trials, most institutions have created their own policies about granulocyte colony-stimulating factor (G-CSF) use in this setting.
Physicians at Mass General Brigham sometimes administer pegylated G-CSF prior to CAR T. Jeremy S. Abramson, MD, director of the Center for Lymphoma at the Massachusetts General Hospital Cancer Center, Elizabeth K. O'Donnell, MD, a medical oncologist at Brigham and Women's Hospital, Matthew J. Frigault, MD, administrative director of the Cellular Immunotherapy Program at the Cancer Center, and colleagues conducted the first study that stratified patients based on G-CSF exposure prior to CAR T.
In Nature Cancer they report prophylactic G-CSF was associated with increased risk of CRS, although not ICANS, in patients with lymphoma.
Methods
The retrospective cohort included 197 adults treated with anti-CD19 CAR T. Immediately prior, 140 patients received prophylactic G-CSF; the other 57 served as controls. Median follow-up was 30 months.
Results With Prophylactic G-CSF
Prophylactic G-CSF was associated in multivariate analysis with increased risk of grade ≥2 CRS (HR, 2.15; P=0.02) but not grade ≥2 ICANS.
There was a trend for G-CSF to be associated with decreased relative odds of severe neutropenia (OR, 0.33; P=0.05). Neutrophil recovery was significantly faster with G-CSF (3 vs. 4 days, P<0.01) but the clinical significance is questionable as infection rates didn't differ between groups.
The two groups were also similar in risk of severe thrombocytopenia or recurrent severe neutropenia, need for IV antibiotics or ICU admission, complete response rates and survival.
Results With Therapeutic G-CSF
Of the 57 patients who did not receive prophylactic G-CSF, 17 had neutropenia treated with G-CSF after CAR T-cell therapy within seven days of developing grade ≥1 CRS. There was no signal of significantly worsened CRS. The effect of G-CSF on ICANS couldn't be analyzed because of small sample size.
Conclusion
Using G-CSF after CAR T to treat severe neutropenia, rather than as prophylaxis, could be associated with less severe CRS. Future trials will need to examine the balance between that potential benefit and the risks of longer periods of early neutropenia.
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