Neutropenia secondary to ICIs and CAR T-cells with correlation to known immune disorders
| Treatment . | irAE . | Proposed mechanism . | Treatment of cytopenias in irAE . | Correlate to known immune disorders . | Treatment of cytopenias in IEI . |
|---|---|---|---|---|---|
| ICI (PD-1/PD-L1 and CTLA-4 blockade) | Hypoplastic neutropenia/aplastic anemia | T-cell infiltration of the bone marrow with subsequent destruction of hematopoietic precursors26 | Corticosteroids Cyclosporine ATG G-CSF | Immune-mediated aplastic anemia67 | Cyclosporine ATG |
| Immune-mediated dysfunction of HSC maturation and proliferation68 | Corticosteroids G-CSF | HSC dysfunction in ADA2 deficiency69 | TNF inhibition15 | ||
| Hyperplastic/peripheral neutropenia | Peripheral destruction of neutrophils mediated by autoantibodies31 | Corticosteroids IVIG G-CSF | Fas/Fas ligand deficiency and development of autoimmune cytopenias70 | Corticosteroids Rapamycin Mycophenolate Mofetil | |
| HLH | T-cell and macrophage activation, perhaps from immune cell tumor invasion and malignant cell apoptosis71 | Corticosteroids Etoposide | HLH and MAS disorders with normal phagocytic and cytotoxic function; malignancy-associated HLH72 | Corticosteroids Etoposide IFNG antibody IL-1 antibody IL-6R antibody Jak inhibitors | |
| ICI CTLA-4 blockade | Multiple irAE, including neutropenia | Regulatory T-cell inhibition and/or depletion73,74 | Corticosteroids (to suppress expanded effector T cells) G-CSF | CTLA-4 haploinsufficiency LRBA deficiency IPEX syndrome (FOXP3 deficiency) CD25 deficiency | Corticosteroids CTLA-4-Ig Rapamycin Calcineurin inhibitors |
| CAR-T | Early neutropenia | Lymphodepleting therapy and CRS75 | IL-6R antibody Corticosteroids | HLH and MAS syndromes with normal phagocytic and cytotoxic function | Corticosteroids Etoposide IFNG antibody IL-1 antibody IL-6R antibody Jak inhibitors |
| Late neutropenia | Disrupted CXCL12 bone marrow gradient inhibiting neutrophil egress46 | G-CSF | WHIM syndrome (CXCR4-GOF) Late-onset neutropenia secondary to rituximab48 | G-CSF CXCR4 inhibition |
| Treatment . | irAE . | Proposed mechanism . | Treatment of cytopenias in irAE . | Correlate to known immune disorders . | Treatment of cytopenias in IEI . |
|---|---|---|---|---|---|
| ICI (PD-1/PD-L1 and CTLA-4 blockade) | Hypoplastic neutropenia/aplastic anemia | T-cell infiltration of the bone marrow with subsequent destruction of hematopoietic precursors26 | Corticosteroids Cyclosporine ATG G-CSF | Immune-mediated aplastic anemia67 | Cyclosporine ATG |
| Immune-mediated dysfunction of HSC maturation and proliferation68 | Corticosteroids G-CSF | HSC dysfunction in ADA2 deficiency69 | TNF inhibition15 | ||
| Hyperplastic/peripheral neutropenia | Peripheral destruction of neutrophils mediated by autoantibodies31 | Corticosteroids IVIG G-CSF | Fas/Fas ligand deficiency and development of autoimmune cytopenias70 | Corticosteroids Rapamycin Mycophenolate Mofetil | |
| HLH | T-cell and macrophage activation, perhaps from immune cell tumor invasion and malignant cell apoptosis71 | Corticosteroids Etoposide | HLH and MAS disorders with normal phagocytic and cytotoxic function; malignancy-associated HLH72 | Corticosteroids Etoposide IFNG antibody IL-1 antibody IL-6R antibody Jak inhibitors | |
| ICI CTLA-4 blockade | Multiple irAE, including neutropenia | Regulatory T-cell inhibition and/or depletion73,74 | Corticosteroids (to suppress expanded effector T cells) G-CSF | CTLA-4 haploinsufficiency LRBA deficiency IPEX syndrome (FOXP3 deficiency) CD25 deficiency | Corticosteroids CTLA-4-Ig Rapamycin Calcineurin inhibitors |
| CAR-T | Early neutropenia | Lymphodepleting therapy and CRS75 | IL-6R antibody Corticosteroids | HLH and MAS syndromes with normal phagocytic and cytotoxic function | Corticosteroids Etoposide IFNG antibody IL-1 antibody IL-6R antibody Jak inhibitors |
| Late neutropenia | Disrupted CXCL12 bone marrow gradient inhibiting neutrophil egress46 | G-CSF | WHIM syndrome (CXCR4-GOF) Late-onset neutropenia secondary to rituximab48 | G-CSF CXCR4 inhibition |
ATG, antithymocyte globulin; GOF, gain-of-function; IFNG, interferon gamma; Ig, immunoglobulin; IPEX, immunodysregulation, polyendocrinopathy, and enteropathy, X-linked; MAS, macrophage activation syndrome.