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Rarely, immunotherapy makes the immune system attack blood cells, causing low platelets (easy bruising or bleeding), destruction of red cells (tiredness, breathlessness, yellow skin, dark urine) or low white cells (infections). These are found on blood tests and treated with steroids and other medicines, usually with a haematologist involved.
Uncommon (under 1% in one series of 745 patients on PD-(L)1 inhibitors) but potentially life-threatening (SITC 2021). The commonest are immune thrombocytopenia (median onset 41 days) and autoimmune haemolytic anaemia (median 50 days, more frequent on PD-(L)1 than CTLA-4 inhibitors). Neutropenia appears at a median of 10.5 weeks; aplastic anaemia is rare, hard to treat and often does not resolve; HLH (median 26 days) is the most dangerous. In a small series, 43% of patients rechallenged after a haematological irAE had a recurrence.
SITC 2021: work up each with a blood count, film and the relevant tests (clotting and LDH for thrombocytopenia; reticulocytes, Coombs test, LDH and ADAMTS13 for haemolysis; ferritin and soluble IL-2 receptor for HLH), separate immune causes from chemotherapy, and treat by haematological standard of care: prednisone 1 mg/kg for ITP (LE: 1) with IVIG for severe ITP (LE: 1) and rituximab as an option (LE: 2); prednisone 1 mg/kg for haemolysis (LE: 3) with IVIG if refractory (LE: 3); prednisone with G-CSF for immune neutropenia (LE: 3); ciclosporin or ATG for aplastic anaemia (LE: 4); steroids with etoposide or tocilizumab for HLH, under haematology (LE: 3). ASCO 2021 (abstract) makes haematological toxicity an exception to continuing treatment at grade 1.
Why: Cancer and other treatments often lower platelets, so a baseline makes a new immune drop easier to see.
“Because patients may already be experiencing thrombocytopenia as a result of cancer or due to a number of oncological treatment regimens, it may be prudent to establish a baseline platelet count and monitor for additional drops below this value when beginning ICI therapy.”
Why: These separate immune destruction from clotting disorders such as DIC.
“Diagnostic workup for patients with possible ICI-related ITP should include CBC with differential, blood smear evaluation, DIC labs (PT/partial thromboplastin time (PTT)/fibrinogen/d-dimer), and LDH.”
Why: Steroids stop the immune system destroying platelets.
“For patients with ICI-related ITP, treatment should follow hematological standard of care. Typically, this includes steroids (prednisone dose of 1 mg/kg oral or equivalent”
Why: These confirm red cells are being destroyed and exclude a clotting-related cause that needs different treatment.
“Diagnostic workup for patients with possible ICI-related HA should include CBC with differential, reticulocyte count, blood smear evaluation, direct antiglobulin test (Coomb’s), and LDH with ADAMTS13 level.”
Why: Steroids are the standard first treatment for immune haemolysis.
“For patients with ICI-related AIHA, treatment should follow hematological standard of care. Typically, this includes steroids (prednisone dose of 1 mg/kg oral or equivalent)”
Why: The treatments differ: immune neutropenia needs steroids, chemotherapy neutropenia does not.
“For patients being treated with chemo-immunotherapy who develop neutropenia, it is important to differentiate between immune-related neutropenia and chemotherapy-induced myelosuppression.”
Why: Steroids stop the immune attack and G-CSF lifts the white cell count to lower infection risk.
“For patients with immune-related neutropenia, treatment should follow hematological standard of care. Typically, this includes steroids (prednisone 1 mg/kg oral or equivalent) with G-CSF”
Why: Immune marrow failure rarely responds to steroids alone.
“For patients with ICI-related AA, additional immunosuppressive therapies beyond steroids should be used, such as cyclosporine.”
Why: HLH is life-threatening and needs specialist treatment such as etoposide or tocilizumab with steroids.
“Diagnostic workup for patients with possible ICI-related HLH should include CBC with differential, blood smear evaluation, ferritin, and soluble IL-2 receptor. Because this condition is life-threatening, it should be suspected when symptoms arise and warrants early consultation with a specialist.”
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
SITC 2021 is the only guideline read in full with a haematological section, and its rule is to treat each condition by the haematological standard of care for the same disease without immunotherapy: prednisone 1 mg/kg for immune thrombocytopenia (LE: 1) with IVIG for severe cases (LE: 1) and rituximab as an option (LE: 2); prednisone 1 mg/kg for haemolysis (LE: 3) with IVIG if refractory (LE: 3); prednisone with G-CSF for immune neutropenia (LE: 3); ciclosporin or ATG for aplastic anaemia (LE: 4); and steroids with etoposide or tocilizumab for HLH (LE: 3). The higher grades come from the evidence in the non-immunotherapy diseases. ASCO 2021 (abstract) agrees that haematological toxicity is an exception to continuing treatment at grade 1. ESMO 2022 could not be read.
SITC, Journal for ImmunoTherapy of Cancer 2021 · ASCO, Journal of Clinical Oncology 2021 · ESMO, Annals of Oncology 2022
| Recommendation | Grade, as printed | Source |
|---|---|---|
| Immune thrombocytopenia: prednisone 1 mg/kg | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Severe immune thrombocytopenia: IVIG 0.5 g/kg/day for 5 days with steroids; rituximab may be considered | LE: 1 (IVIG); LE: 2 (rituximab) | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Autoimmune haemolytic anaemia: prednisone 1 mg/kg; IVIG if steroid-refractory “For patients with severe ICI-related AIHA that do not respond to steroids, IVIG (0.5 g/kg/day for 5 days)” | LE: 3 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Immune neutropenia: prednisone 1 mg/kg with G-CSF | LE: 3 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Aplastic anaemia: ciclosporin; ATG may be considered | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| HLH: steroids and immunosuppressives such as etoposide or tocilizumab, with haematology “For patients with ICI-related secondary HLH, hematological consultation is required as this is a challenging condition to manage. Standard of care treatment typically involves steroids and immunosuppressives, such as etoposide or tocilizumab” | LE: 3 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Haematological toxicity is an exception to continuing treatment at grade 1 | expert consensus | ASCO, Journal of Clinical Oncology 2021 |
Shares Human normal immunoglobulin (IVIg), Tocilizumab, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer and the tags protocol, irae.
Shares Restarting a checkpoint inhibitor after an immune-related side effect, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab and the tags protocol, irae.
Shares Restarting a checkpoint inhibitor after an immune-related side effect, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab and the tags protocol, irae.
Shares Human normal immunoglobulin (IVIg), Restarting a checkpoint inhibitor after an immune-related side effect, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer and the tags protocol, irae.
Shares Society for Immunotherapy of Cancer, Avelumab, Tremelimumab, Dostarlimab and the tags protocol, irae.
Shares Restarting a checkpoint inhibitor after an immune-related side effect, Tocilizumab, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer and the tags protocol, irae.
Shares ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab, Tremelimumab and the tags protocol, irae.
Shares Restarting a checkpoint inhibitor after an immune-related side effect, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab and the tags protocol, irae.