Diagnosis and Management of Hematological Adverse Events Induced by Immune Checkpoint Inhibitors: A Systematic Review

Abstract

There has been less volume of literature focusing on the Immune-related Hematological Adverse Drug Events (Hem-irAEs) of Immune Checkpoint Inhibitors (ICPis) in cancer patients. Furthermore, there has been no consensus about the management of hematological toxicity from immunotherapy in the recently published practice guidelines by the European Society for Medical Oncology (ESMO). We conducted a systematic review of case reports/series to describe the diagnosis and management of potentially rare and unrecognized Hem-irAEs. We searched Medline, OVID, Web of Science for eligible articles. Data were extracted on patient characteristics, Hem-irAEs, and management strategies. We performed quality assessment using the Pierson-5 evaluation scheme and causality assessment using the Naranjo scale. Our search retrieved 49 articles that described 118 cases. The majority of patients had melanoma (57.6%) and lung cancer (26.3%). The most common Hem-irAEs reported with ICPis (such as nivolumab, ipilimumab, and pembrolizumab) were thrombocytopenia, hemolytic and aplastic anemias. Less reported adverse events included agranulocytosis and neutropenia. Steroids were commonly used to treat these adverse events with frequent success. Other used strategies included intravenous immunoglobulins (IVIG), rituximab, and transfusion of blood components. The findings of this review provide more insights into the diagnosis and management of the rarely reported Hem-irAEs of ICPis.

Safety of Immune Checkpoint Inhibitor Resumption after Interruption for Immune-Related Adverse Events, a Narrative Review

“…Several general or organ-specific recommendations have been published to help to manage irAEs [ 17 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. Generally, ICI should be continued with close monitoring for grade 1 irAEs, except for some neurologic, hematologic, and cardiac toxicities.…”

Understanding neutropenia secondary to intrinsic or iatrogenic immune dysregulation

“…Immune check point inhib i tors (ICIs) include agents that inhibit CTLA4, programmed cell death 1 pro tein (PD1), or programmed cell death 1 ligand 1 (PDL1) sig nal ing and are inte gral to the treat ment of many can cers. 26 The reported inci dence of all grade hema to logic irAEs is 0.4% to 8.3% with highgrade (grade 35) at 0% to 1.7%. 2729 Highgrade neutropenia in iso la tion or in con cert with addi tional cytopenias is reported at a fre quency of 0.2% to 0.94%.…”

“…27,29,33 The devel op ment of autoreactive T cells and B cells, the increased secre tion of cyto kine with the sub se quent infil tra tion of CD8+ T cells, and the immunemedi ated dys func tion of HSC mat u ra tion or pro lif er a tion have all been pos tu lated as gen eral mech a nisms of neutropenia. 26 It is prob a ble that dif fer ent mech a nisms exist, based on bone mar row biopsy find ings dem on strat ing that a minor ity of patients have gran u lo cytic hypo pla sia with lym pho cytic infil trate (a cen tral or hypo plas tic type), while the major ity of patients have nor mal or hyper plas tic bone mar row with or with out the iden ti fi ca tion of a neu tro phil anti body (periph eral or hyper plas tic type). 31 Patients on ICIs presenting with neutropenia should undergo bone mar row eval u a tion to dif fer en ti ate cen tral vs periph eral neutropenia and to rule out under ly ing malig nancy.…”

“…For grade 3 to 4 tox ic ity, ICIs should be discontinued and highdose cor ti co ste roids admin is tered with taper ing over 4 to 6 weeks for responding patients. 26,27 GCSF should be pre scribed to has ten recov ery for all grade 2 to 4 toxicities. IVIG is likely safe and may be more effec tive for the periph eral destruc tion of neu tro phils, 31 but there is no con sen sus in the lit er a ture regard ing whether it should be used as upfront ther apy or as sal vage for cor ti co ste roid non re spond ers.…”

Organ-specific Adverse Events of Immune Checkpoint Inhibitor Therapy, with Special Reference to Endocrinopathies

“…Commonly reported haematological manifestations of ICI toxicity are thrombocytopaenia, haemolytic anaemia and aplastic anaemia. 44 Agranulocytosis and neutropenia are less often described. Management is usually successful with corticosteroids; other therapeutic strategies, such as intravenous immunoglobulins, rituximab and transfusion of blood components are rarely needed.…”