Clinical approach to immune checkpoint inhibitor-associated hematologic toxicities
| Toxicity . | Putative mechanisms . | Diagnostic evaluation . | Therapy after stopping ICI# . | Expected outcome . | Retreatment strategy . | Recurrence after restarting ICI* . |
|---|---|---|---|---|---|---|
| Anemia | Autoantibodies? Cytotoxic T lymphocytes? | CBC, blood smear, reticulocyte count, Coombs testing, cold agglutinins, LDH, indirect bilirubin, haptoglobin, bone marrow aspirate and biopsy when pure red cell aplasia is suspected | Hgb decrease of 2 g/dL: 1. Corticosteroids with or without rituximab 2. High-dose IVIg 3. Calcineurin inhibitor 4. Mycophenolic acid | About two-thirds recover within 1 month. | Consider restarting ICI when hemolysis parameters stabilize, including during active or tapering immunosuppression. | 50% |
| Thrombocytopenia | Autoantibodies? Cytotoxic T lymphocytes? | CBC, blood smear, consider bone marrow aspirate and biopsy† | Platelets <30 000/µL: 1. Corticosteroids 2. Thrombopoietic agent 3. Rituximab 4. Calcineurin inhibitor | About two-thirds recover within 1 month | Consider restarting ICI when platelet recovery stabilizes, including during active or tapering immunosuppression | 33% |
| Neutropenia | Autoantibodies? Cytotoxic T lymphocytes? NK cells? | CBC, blood smear, bone marrow aspirate and biopsy†; consider vitamin and mineral measurements | ANC <1000/µL: 1. Leukocyte growth factor and corticosteroids 2. IVIg 3. Rituximab 4. Calcineurin inhibitor | About two-thirds recover within 1 month | Consider restarting ICI when ANC stabilizes at >1000/µL, including during active or tapering immunosuppression | 66% |
| Bone marrow failure | Cytotoxic T lymphocytes? NK cells? | CBC, blood smear, reticulocyte count, bone marrow aspirate and biopsy†; consider vitamin and mineral measurements | Cellularity <25%, ANC <500/µL, platelets <20 000/µL, and reticulocytes <20 000/µL: 1. Corticosteroids, transfusions, leukocyte growth factor 2. Antithymocyte globulin plus cyclosporine with or without eltrombopag 3. High-dose IVIg | About one-half recover within 2 months | Consider restarting ICI when ANC stabilizes at >1000/µL, Hgb >7 g/dL, and platelets >30 000/µL, including during active or tapering immunosuppression | Unknown |
| HLH | Macrophage secretion of IL-6? | CBC, reticulocyte count, blood smear, ferritin, fibrinogen, soluble CD25, triglycerides, bone marrow aspirate, and biopsy‡ | 1. Corticosteroids with or without tocilizumab 2. Etoposide | About three-quarters recover within unknown time frames | Consider restarting ICI when clinical and laboratory parameters stabilize, including during active or tapering immunosuppression | 0 |
| VTE | Macrophage secretion of IL-8? | Ultrasound Doppler and/or CT angiogram | Therapeutic anticoagulation | ∼9% recurrences and ∼5% major bleeding over a median of 8.5 months§ | ICI should not be discontinued | ICI should not be discontinued |
| Toxicity . | Putative mechanisms . | Diagnostic evaluation . | Therapy after stopping ICI# . | Expected outcome . | Retreatment strategy . | Recurrence after restarting ICI* . |
|---|---|---|---|---|---|---|
| Anemia | Autoantibodies? Cytotoxic T lymphocytes? | CBC, blood smear, reticulocyte count, Coombs testing, cold agglutinins, LDH, indirect bilirubin, haptoglobin, bone marrow aspirate and biopsy when pure red cell aplasia is suspected | Hgb decrease of 2 g/dL: 1. Corticosteroids with or without rituximab 2. High-dose IVIg 3. Calcineurin inhibitor 4. Mycophenolic acid | About two-thirds recover within 1 month. | Consider restarting ICI when hemolysis parameters stabilize, including during active or tapering immunosuppression. | 50% |
| Thrombocytopenia | Autoantibodies? Cytotoxic T lymphocytes? | CBC, blood smear, consider bone marrow aspirate and biopsy† | Platelets <30 000/µL: 1. Corticosteroids 2. Thrombopoietic agent 3. Rituximab 4. Calcineurin inhibitor | About two-thirds recover within 1 month | Consider restarting ICI when platelet recovery stabilizes, including during active or tapering immunosuppression | 33% |
| Neutropenia | Autoantibodies? Cytotoxic T lymphocytes? NK cells? | CBC, blood smear, bone marrow aspirate and biopsy†; consider vitamin and mineral measurements | ANC <1000/µL: 1. Leukocyte growth factor and corticosteroids 2. IVIg 3. Rituximab 4. Calcineurin inhibitor | About two-thirds recover within 1 month | Consider restarting ICI when ANC stabilizes at >1000/µL, including during active or tapering immunosuppression | 66% |
| Bone marrow failure | Cytotoxic T lymphocytes? NK cells? | CBC, blood smear, reticulocyte count, bone marrow aspirate and biopsy†; consider vitamin and mineral measurements | Cellularity <25%, ANC <500/µL, platelets <20 000/µL, and reticulocytes <20 000/µL: 1. Corticosteroids, transfusions, leukocyte growth factor 2. Antithymocyte globulin plus cyclosporine with or without eltrombopag 3. High-dose IVIg | About one-half recover within 2 months | Consider restarting ICI when ANC stabilizes at >1000/µL, Hgb >7 g/dL, and platelets >30 000/µL, including during active or tapering immunosuppression | Unknown |
| HLH | Macrophage secretion of IL-6? | CBC, reticulocyte count, blood smear, ferritin, fibrinogen, soluble CD25, triglycerides, bone marrow aspirate, and biopsy‡ | 1. Corticosteroids with or without tocilizumab 2. Etoposide | About three-quarters recover within unknown time frames | Consider restarting ICI when clinical and laboratory parameters stabilize, including during active or tapering immunosuppression | 0 |
| VTE | Macrophage secretion of IL-8? | Ultrasound Doppler and/or CT angiogram | Therapeutic anticoagulation | ∼9% recurrences and ∼5% major bleeding over a median of 8.5 months§ | ICI should not be discontinued | ICI should not be discontinued |
CBC, complete blood cell count; CT, computed tomography; Hgb, hemoglobin; LDH, lactate dehydrogenase.
Based on small case series.18-21
Including cytogenetics, flow cytometry, T-cell receptor rearrangements, and related molecular profiling by next-generation sequencing.
Direct identification of hemophagocytosis.
Major bleeding based on International Society of Thrombosis and Haemostasis criteria.23