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| Type of toxicity | Management of adverse effects |
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| Cutaneous | Rash/inflammatory dermatitis | Rashes that can be controlled through topical treatments and oral antihistamines do not require stopping the immune therapy, but in the case of severe or unmanageable rashes, it is necessary to hold the therapy until the resolution of skin toxicity. |
| Bullous dermatoses | If the blisters cover more or less than 10% of body surface area and do not affect the quality of life, the recommended treatment is topical corticosteroids. If the surface involved is more than 10%, the mucosal membranes are involved, and the lesions affect the quality of life, the immune therapy must be halted and continued only after skin resolution. |
| Severe cutaneous adverse reactions (Stevens-Johnson epidermal necrolysis, acute generalized exanthematous pustulosis) | In case of maculopapular exanthem covering 10–30% of BSA (body surface area) in association with systemic symptoms, lymphadenopathy, or facial swelling, it is recommended to hold the checkpoint inhibitor therapy and give topical emollients, oral antihistamines, and topical corticosteroids with medium to high potency. |
| Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DHIS/DRESS) | |
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| Pulmonary | Pneumonitis (identified on CT imaging as focal or diffuse inflammation of the lung parenchyma) | If the inflammation involves more than one lobe, but is less than 50% of the total parenchyma, the therapy is withheld until the resolution of symptoms, and prednisone 1–2 mg/kg/day is administered.
If the inflammation involves more than 50% of the lung parenchyma or severe symptoms are present, the treatment will be permanently discontinued and antibiotics and systemic corticosteroids will be administered. |
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| Renal | Nephritis | In case of G1 toxicity (creatinine 1.5–2 times over the baseline), only monitorisation is required. G2 toxicity (creatinine 2–3 times above baseline) leads to the hold of therapy, and if no improvement is observed, systemic corticosteroids will be administered (prednisone 1–2 mg/kg/day or equivalents). Grade 3 toxicity (creatinine > 3x baseline) leads to permanent discontinuation of therapy. Grade 4 toxicity has indication for dialysis and also administration of corticosteroids. |
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| Hematologic | Autoimmune hemolytic anemia | Grade 1 toxicity allows continuation of therapy and a close clinical check-up. Grade 2 needs holding therapy and also administration of 0.5–1 mg/kg/d prednisone. Grade 3 or 4 requires permanent discontinuation, with administration of prednisone 1–2 mg/kg/d and supplementation with folic acid 1 mg daily. In case of grade 4 toxicity, if no improvement is observed, initiation of immunosuppressive drugs is required (rituximab, IVIG, cyclosporin A, mycophenolate mofetil). |
| Acquired thrombotic thrombocytopenic purpura | All grades need therapy holding and hematology consult. G1 and G2 require the administration of 0.5–1 mg/kg/d prednisone, while grade 3 or 4 needs administration of methylprednisolone 1 g iv daily for 3 days, taking into consideration rituximab. |
| Hemolytic uremic syndrome | Grades 1 and 2 does not require stopping the therapy, while grades 3 and 4 require the stop and initiation of exulizumab therapy 900 mg weekly for 4 doses, 1200 mg week5, then 1200 mg every 2 weeks. |
| Aplastic anemia | Grade 1 requires therapy hold and administration of growth factor with close clinical observation. In case of grade 2 toxicity, it is added ATG (antithymocyte globulin) and cyclosporine administration to the protocol for grade 1. Patients with grade 3 or 4 have the same management as those with grade 2. If no response is observed, it is needed to repeat immunosuppression with ATG, cyclosporine, and cyclophosphamide. In the case of refractory patients, eltrombag needs to be taken into consideration. |
| Lymphopenia | The only situation that requires holding therapy is a grade 4 toxicity (<250 PB lymphocyte count). In this case, it has to be initiated mycobacterium avium complex prophylaxis and Pneumocystis jirovecii prophylaxis and also cytomegalovirus (CMV)/human immunodeficiency virus (HIV)/hepatitis screening. |
| Immune thrombocytopenia | Patients with a platelet count < 100/mcL (grade 1) need to continue the therapy with close clinical and laboratory evaluation. A count less than 75/mcL requires therapy holding with administration of oral prednisone 1 mg/kg/day 2–4 weeks, with taper over 4–6 weeks and also IVIG in case a faster increase in the platelet count is needed. Grade 4, meaning a platelet count < 25/mcL, is treated with prednisone 1–2 mg/kg/day and association with IGIV. In case of no response, rituximab or thrombopoietin receptor agonist can be used. |
| Acquired hemophilia | G1 toxicity (5–40% of normal factor activity in the blood) needs holding of therapy and administration of 0.5–1 mg/kg/day prednisone. G2 toxicity (1–5% of normal factor activity in the blood) requires holding the therapy, administration of factor replacement, and administration of 1 mg/kg/d prednisone and 375 mg/m2 rituximab weekly for 4 weeks and/or cyclophosphamide 1–2 mg/kg/day. In case of severe symptoms (G3 or 4, <1% of normal factor activity in the blood), permanent discontinuation of therapy is required, in association with administration of bypassing agents (factor VII, factor VIII inhibitor bypass activity) and also administration of 1 mg/kg/d prednisone and 375 mg/m2 rituximab weekly for 4 weeks and/or cyclophosphamide 1–2 mg/kg/day. In case of bleeding, transfusions are needed. |
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