Table 8.

Management of Hematologic irAEs in Patients Treated With ICPis

8.0 Hematologic Toxicities
8.1 Autoimmune hemolytic anemia
Definition:A condition in which RBCs are destroyed and removed from the blood stream before their normal lifespan is over. Symptoms includeweakness, paleness, jaundice, dark-colored urine, fever, inability to do physical activity, and heart murmur.
Diagnostic work-up  History and physical examination (with special consideration of history of new drugs and insect, spider, or snake bites)  Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on peripheral smear; LDH, haptoglobin, bilirubin, reticulocyte count, free Hgb DIC panel, which could include PTINR infectious causes  Autoimmune serology  Paroxysmal nocturnal hemoglobinuria screening  Direct and indirect bilirubin; LDH; direct agglutinin test; and if no obvious cause, bone marrow analysis, cytogenetic analysis to evaluate for myelodysplastic syndromes  Evaluation for viral/bacterial (mycoplasma, etc) causes of hemolysis studies  Protein electrophoresis, cryoglobulin analysis  Work-up for bone marrow failure syndrome if refractory, including B12, folate, copper, parvovirus, FE, thyroid, infection  Glucose-6-phosphate dehydrogenase  Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, quinine/quinidine, fludarabine, ciprofloxacin, lorazepam, diclofenac, etc)  Assessment of methemoglobinemia
Grading	Management
G1: Hgb < LLN to 10.0 g/dL; < LLN to 6.2 mmol/L; < LLN to 100 g/L	Continue ICPi with close clinical follow-up and laboratory evaluation
G2: Hgb < 10.0 to 8.0 g/dL; < 6.2 to 4.9 mmol/L; < 100 to 80 g/L	Hold ICPi and strongly consider permanent discontinuation  Administer 0.5–1 mg/kg/d prednisone equivalents
G3: Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L; transfusion indicated	Permanently discontinue ICPi  Should use clinical judgment and consider admitting the patient  Hematology consult  Prednisone 1–2 mg/kg/d (oral or IV depending on symptoms/speed of development)  If worsening or no improvement, 1–2 mg/kg/d prednisone equivalents and permanently discontinue ICPi treatment  Consider RBC transfusion per existing guidelines; do not transfuse more than the minimum number of RBC units necessary to relieve symptoms of anemia or to return a patient to a safe  Hgb range (7–8 g/dL in stable, noncardiac inpatients)  Should offer patients supplementation with folic acid 1 mg once daily
G4: Life-threatening consequences, urgent intervention indicated	Permanently discontinue ICPi  Admit patient  Hematology consult  IV prednisone corticosteroids 1–2 mg/kg/d  If no improvement or if worsening while on corticosteroids or severe symptoms on presentation, initiate other immunosuppressive drugs, such as rituximab, IVIG, cyclosporin A, and mycophenolate mofetil  RBC transfusion per existing guidelines; discuss with blood bank team prior to transfusions that a patient with possible ICPi serious AE is in house.
Additional considerations: Monitor Hgb levels on a weekly basis until the corticosteroid tapering process is complete; thereafter, less-frequent testing is needed164
8.2 Acquired TTP
Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities, and neurologic abnormalities, such as seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition.
Diagnostic work-up  History with specific questions related to drug exposure (eg, chemotherapy, sirolimus, tacrolimus, opana ER antibiotics, quinine)  Physical examination, peripheral smear  ADAMTS13 activity level and inhibitor titer  LDH, haptoglobin, reticulocyte count, bilirubin, urinalysis to rule out other causes  PT, activated PTT, fibrinogen  Blood group and antibody screen, direct antiglobulin test, CMV serology  Consider CT/MRI brain, echocardiogram, ECG  Viral studies  Note: This disorder is usually associated with a severe drop in platelets and hemolysis/anemia precipitously
Grading	Management
All grades	The first step in the management of TTP is a high index of suspicion for the diagnosis and timely recognition; hematology consult should immediately be called, as delay in identification is associated with increased mortality/morbidity.  Initially, the patient should be stabilized and any critical organ dysfunction stabilized
G1: Evidence of RBC destruction (schistocytosis) without anemia, renal insufficiency, or thrombocytopenia clinically G2: Evidence of RBC destruction (schistocytosis) without clinical consequence with G2 anemia and thrombocytopenia G3: Laboratory findings with clinical consequences (G3 thrombocytopenia, anemia, renal insufficiency > 2) G4: Life-threatening consequences (eg, CNS hemorrhage or thrombosis/embolism or renal failure)	Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits, noting that there are currently no data to recommend restarting ICPi therapy  Hematology consult  Administer 0.5–1 mg/kg/d prednisone Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits, noting that there are currently no data to recommend restarting ICPi therapy Hematology consult  In conjunction with hematology, initiate PEX according to existing guidelines with further PEX dependent on clinical progress94–96  Administer methylprednisolone 1 g IV daily for 3 days, with the first dose typically administered immediately after the first PEX  May offer rituximab
8.3 Hemolytic uremic syndrome
Definition: Adisorder characterized byaform ofthrombotic microangiopathywith renal failure, hemolytic anemia, and severe thrombocytopenia. Signs and symptoms of hemolytic uremic syndrome can include:  Bloody diarrhea  Decreased urination or blood in the urine  Abdominal pain, vomiting, and occasionally fever  Pallor  Small, unexplained bruises or bleeding from the nose and mouth  Fatigue and irritability  Confusion or seizures  High blood pressure  Swelling of the face, hands, feet, or entire body
Diagnostic work-up  History and physical examination (special consideration for new history of high-risk drugs, hypertension, or cardiac causes)  CBC with indices  Blood smear morphology. Note that the presence of schistocytes on smear is critical for diagnosis.  Serum creatinine  ADAMTS13 (to rule out TTP)  Homocysteine/methylmalonic acid  Complement testing C3, C4, CH50 (complement inhibitory antibodies for suspected familial)  Evaluate reticulocyte count and mean corpuscular volume  Evaluation of infectious cause, including screening for EBV, CMV, HHV6  Evaluation for nutritional causes of macrocytosis (B12 and folate)  Pancreatic enzymes  Evaluation for diarrheal causes, shiga toxin, Escherichia coli 0157, etc  Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia  Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, sirolimus, etc)  Evaluation for concurrent confusion
Grading	Management
G1–2: Evidence of RBC destruction (schistocytosis) without clinical consequences ofanemia, thrombocytopenia grade 2 G3: Laboratory findings with clinical consequences (eg, renal insufficiency, petechiae) G4: Life-threatening consequences (eg, CNS thrombosis/ embolism or renal failure)	Continue ICPi with close clinical follow-up and laboratory evaluation  Supportive care Permanently discontinue ICPi  Begin therapy with eculizumab therapy 900 mg weekly for four doses, 1,200 mg week 5, then 1,200 mg every 2 weeks  Red blood transfusion according to existing guidelines
8.4 Aplastic anemia
Definition: Condition in which the body stops producing enough new blood cells
Diagnostic work-up  History and physical examination (close attention to medications, exposure to radiation, toxins, recent viral infections)  CBC, smear, reticulocyte count  Viral studies, including CMV, HHV6, EBV, parvovirus  Nutritional assessments including B12, folate, iron, copper, ceruloplasmin, vitamin D  Serum LDH, renal function  Work-up for infectious causes  Identify marrow hypo/aplasia  Bone marrow biopsy and aspirate analysis  Peripheral blood analysis, including neutrophil count, proportion of GPI-negative cells by flow for PNH  Flow cytometry to evaluate loss of GPI-anchored proteins  Type and screen patient for transfusions and notify blood bank that all transfusions need to be irradiated and filtered
Grading	Management
G1: Nonsevere, > 0.5 polymorphonuclear cells × 109/L hypocellular marrow, with marrow cellularity < 25%, peripheral platelet count > 20,000, reticulocyte count > 20,000	Hold ICPi and provide growth factorsupport and close clinical follow-up, and laboratoryevaluation Supportive transfusions as per local guidelines
G2: Severe, hypocellular marrow < 25% and two of the following: ANC < 500, peripheral platelet < 20,000, and reticulocyte < 20,000	Hold ICPi and provide growth factor support and close clinical laboratory evaluations daily Administer ATG + cyclosporine; HLA typing and evaluation for bone marrow transplantation if patient is candidate; all blood products should be irradiated and filtered Supportive care with granulocyte colony-stimulating factor may be added in addition
G3–4: Very severe, ANC < 200, platelet count < 20,000, reticulocyte count < 20,000, plus hypocellular marrow < 25%	Hold ICPi and monitor weekly for improvement; if not resolved, discontinue treatment until AE has reverted to G1  Hematology consult, growth factor support  Horse ATG plus cyclosporine  If no response, repeat immunosuppression with rabbit ATG plus cyclosporine, cyclophosphamide  For refractory patients, consider eltrombopag plus supportive care
8.5 Lymphopenia
Definition: An abnormally low level of lymphocytes in PB; for adults, counts of < 1,500/mm3
Diagnostic work-up  History and physical examination (special attention for lymphocyte-depleting therapy such as fludarabine, ATG, corticosteroids, cytotoxic chemotherapy, radiation exposure, etc, as well as history of autoimmune disease, family history of autoimmune disease)  Evaluation of nutritional state as cause  Spleen size  CBC with differential, peripheral smear and reticulocyte counts  CXR for evaluation of presence of thymoma  Bacterial cultures and evaluation for infection (fungal, viral, bacterial specifically CMV/HIV)
Grading	Management
G1–2: 500–1,000 PB lymphocyte count	Continue ICPi
G3: 250–499 PB lymphocyte count	Continue ICPi, checking CBC weekly for monitoring, initiation of CMV screening
G4: < 250 PB lymphocyte count	Consider holding ICPi  Initiate Mycobacterium avium complex prophylaxis and Pneumocystis jirovecii prophylaxis, CMV screening. HIV/hepatitis screening if not already done  May consider EBV testing if evidence of lymphadenopathy/hepatitis, fevers, hemolysis consistent with lymphoproliferative disease
8.6 Immune thrombocytopenia
Definition: An autoimmune disorder characterized by immunologic destruction of otherwise normal platelets
Diagnostic work-up  History and physical examination (special attention for lymphocyte-depleting therapy, such as fludarabine, ATG, corticosteroids, cytotoxic therapy)  Family history of autoimmunity or personal history of autoimmune disease  History of viral illness  CBC  Peripheral blood smear, reticulocyte count  Bone marrow evaluation only if abnormalities in the above test results and further investigation is necessary for a diagnosis  Patients with newly diagnosed immune thrombocytopenia should undergo testing for HIV, hepatitis C virus, hepatitis B virus, and Helicobacter pylori  Direct antigen test should be checked to rule out concurrent Evan syndrome  Nutritional evaluation  Bone marrow evaluation if other cell lines affected and concern for aplastic anemia
Grading	Management
G1: Platelet count < 100/μL	Continue ICPi with close clinical follow up and laboratory evaluation
G2: Platelet count < 75/μL	Hold ICPi but monitor for improvement; if not resolved, interrupt treatment until AE has reverted to G1  Administer prednisone 1 mg/kg/d (dosage range, 0.5–2 mg/kg/d) orally for 2–4 weeks after which time this medication should be tapered over 4–6 weeks to the lowest effective dose IVIG may be used in conjunction with corticosteroids ifa more-rapid increase in plateletcount is required.
G3: Platelet count < 50/μL G4: Platelet count < 25/μL	Hold ICPi but monitor for improvement; if not resolved, interrupt treatment until AE has reverted to G1 Hematology consult  Prednisone 1–2 mg/kg/d (oral or IV depending on symptoms)  If worsening or no improvement, 1–2 mg/kg/d prednisone equivalents and permanently discontinue treatment  IVIG used with corticosteroids when a more-rapid increase in platelet count is required  If IVIG is used, the dose should initially be 1 g/kg as a one-time dose. This dosage may be repeated if necessary  If previous treatment with corticosteroids and/or IVIG unsuccessful, subsequent treatment may include rituximab, thrombopoietin receptor agonists, or more-potent immunosuppression (From American Society of Hematology guideline on immune thrombocytopenia97; consult for further details)
8.7 Acquired hemophilia
Definition: Disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors
Diagnostic work-up  Full blood count to assess platelet number, fibrinogen, PT, PTT, INR; the typical finding in patients with acquired hemophilia A is a prolonged activated PTT with a normal PT  MRI, CT, and ultrasonography may be indicated to localize, quantify, and serially monitor the location and response of bleeding  Medication review to assess for alternative causes  Determination of Bethesda unit level of inhibitor
Grading	Management
G1: Mild, 5%–40% ofnormal factoractivityin blood, 0.05–0.4 lU/mL of whole blood	Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits  Administer 0.5–1 mg/kg/d prednisone  Transfusion support as required  Treatment of bleeding disorders with hematology consult
G2: Moderate, 1%–5% of normal factor activity in blood, 0.01–.05 IU/mL of whole blood	Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits  Hematology consult  Administration of factor replacement (choice based on Bethesda unit of titer)  Administer 1 mg/kg/d prednisone ± rituximab (dose, 375 mg/m2 weekly for 4 weeks) and/or cyclophosphamide (dose, 1–2 mg/kg/d); choice of rituximab vcyclophosphamide is patient specific and should be done with assistance of hematology consult; prednisone, rituximab, and cyclophosphamide should be given for at least 5 weeks  Factors should be provided to increase level during bleeding episodes, with choice of factor based on presence or absence of inhibitor
G3–4: Severe, < 1% of normal factor activity in blood, < 0.01 IU/mL of whole blood	Permanently discontinue ICPi  Admit patient  Hematology consult  Administration of factor replacement, choice based on Bethesda unit level of inhibitor  Bypassing agents may be used (factor VII, factor VIII inhibitor bypass activity); caution should be taken in the elderly and those with coronary artery disease  Prednisone 1–2 mg/kg/d (oral or IV depending on symptoms) ± rituximab (dose, 375 mg/m2 weekly for 4 weeks) and/or cyclophosphamide (dose, 1–2 mg/kg/d).  Transfusion support as required for bleeding  If worsening or no improvement add cyclosporine or immunosuppression/immunoadsorption
Additional considerations: Acquired hemophilia A requires specialist clinical and laboratory expertise. Consult and/or transferto a specialist center is often appropriate.  If consultation with or transfer to a hemophilia center is not immediately possible, then investigation and treatment should be initiated while a liaison is being established.98
All recommendations are expert consensus based, with benefits outweighing harms, and strength of recommendations are moderate.

Abbreviations: AE, adverse event; ANC, antineutrophil cytoplasmic antibodies; ATG, antithymocyte globulin; CMV, cytomegalovirus; CT, computed tomography; DIC, disseminated intravascular coagulation; EBV, Epstein-Barr virus; G, grade; GPI, glycosylphosphatidylinositol; Hgb, hemoglobin; HHV6, human herpesvirus 6; ICPi, immune checkpoint inhibitor; INR, international normalized ratio; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; LLN, lower limit of normal; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; PB, peripheral blood; PEX, plasma exchange; PNH, paroxusmal nocturnal hemoglobinuria; PT, prothrombin time; PTT, partial thromboplastin time; TTP, thrombotic thrombocytopenic purpura.