Immune-Mediated Hematologic Complications of Checkpoint Inhibitors: A Review of the Literature

Background:

The incidence and types of hematologic complications from immune check point inhibitors are not well known. We conducted this review to describe immune-mediated hematologic complications reported in clinical trials, case series, and case reports.

Methods:

A pre-defined comprehensive search strategy was used to identify case reports, case series, and clinical trials using PubMed. Any study that reported hematologic complications was included. Data were extracted for demographic characteristics and occurrence of immune-mediated hematologic complications. We pooled the data to calculate the frequency of immune-mediated hematologic adverse effects.

Results:

A total of 689 of studies were retrieved using the search criteria and 75 were included in the analysis (31 case reports and case series and 44 clinical trials). There were 44 patients reported having immune-mediated hematologic complications, 4 of them in clinical trials. The complications included aplastic anemia, autoimmune hemolytic anemia, cryoglobulinemia, graft versus host disease, hemophilia A (acquired), immune neutropenia, immune thrombocytopenia, macrophage activation syndrome, myelodysplastic syndrome, pure red cell aplasia, and thrombotic thrombocytopenic purpura. However, the overall rates were very low, ranging from 1-2.2% in clinical trials. Immune thrombocytopenia was the most common (29.5%), followed by autoimmune hemolytic anemia (15.9%), and immune neutropenia (13.6%). Immune-mediated hematologic complications were reported in all classes of checkpoint inhibitors including anti-programmed cell death protein 1 (nivolumab and pembrolizumab), anti-programmed death ligand 1 (avelumab and durvalumab), and anti-cytotoxic T-lymphocyte-associated protein 4 inhibitors (ipilimumab and tremelimumab). Among patients reported in case reports and case series, the median age was 57 years (range, 29-85) and most were males (52.9%). The majority of the complications occurred in patients treated with ipilimumab (38.8%), nivolumab (27.7%) and pembrolizumab (16.0%). The onset was usually within the first week of receiving the first dose but could occur up to 17 months after drug initiation. Indefinite discontinuation of the immunotherapy was the mainstay of treatment resulting in resolution of complications in the majority (74.5%) of the patients. Two patients were re-challenged with the same checkpoint inhibitor and one experienced a relapse of immune cytopenia (autoimmune hemolytic anemia).

Conclusion:

Immune-mediated hematologic complications associated with checkpoint inhibitors are rare. They are usually reversible after discontinuation of such treatment. Relapses may occur with re-challenge.

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