Immune-Related Hematologic Adverse Events in the Context of Checkpoint Inhibitors
Authors: Saliba Antoine , Xie Zhuoer , Higgins Ally , Andrade-Gonzalez Xavier A , Fuentes-Bayne Harry E , Hampel Paul J. , Kankeu Fonkoua Lionel , Childs Daniel , Rakshit Sagar , Bezerra Evandro D. , Lou Yanyan , Rivera Candido E. , Price Katharine , Yan Yiyi , Schwecke Anna , Block Matthew S. , Thanarajasingam Uma , Thanarajasingam Gita , Wolanskyj Alexandra P. , Marshall Ariela L. , Kottschade Lisa A , Go Ronald S. , Al-Kali Aref 
Published: February 2021

Introduction
Immune-mediated hematologic disorders are relatively rare but potentially life-threatening immune-related adverse events (irAE) with immune checkpoint inhibitor (ICI) therapy (Shiuan, Beckermann et al 2017). The management strategy often relies on systemic corticosteroids and other immunosuppressant agents in steroid-refractory cases (Brahmer, Lacchetti et al 2018). We hereby describe our institution's experience in diagnosing and managing immune-related hematologic adverse events (ir-h-AE).
Methods
We retrospectively searched the electronic health record for all ir-h-AE diagnosed by treating providers and confirmed by study authors between 2015 and 2020. The search included patients on ICI and the following conditions: immune-related neutropenia (IRN), autoimmune hemolytic anemia (AIHA), cold agglutinin disease (CAD), immune thrombocytopenia (ITP), immune-related pancytopenia, aplastic anemia (AA), and pure red cell aplasia (PRCA). For AIHA, PRCA, and CAD, partial response (PR) was defined as hemoglobin greater than 10 g/dL but &lt; 12 g/dL and 2 g/dL above the nadir without blood product transfusion. Complete response (CR) was defined as hemoglobin of ≥ 12 g/dL and 2 g/dL above the nadir without blood product transfusion (Peñalver, Alvarez-Larrán et al. 2010). For ITP, CR was defined as platelet count ≥ 100 × 109/L and absence of bleeding. PR was defined as platelet count ≥ 30 × 109/L and ≥ two-fold increase from the baseline count and absence of bleeding (Gómez-Almaguer, Tarín-Arzaga et al. 2013). For IRN, CR was defined as absolute neutrophil count (ANC) ≥ 1500/ mm3 on 2 consecutive measurements separated by 7 days; PR was defined as ANC ≥ 500/ mm3 sustained over 7 days. JMP® 14.1 was used for data analysis.
Results
Seventeen patients were identified, 9 (52.9%) of whom were female (table 1). Median age was 68 years (range 26-78). The most common pre-existing malignancies were melanoma (6 patients, 35.3%), non-small cell lung cancer (4 patients, 23.5%), and gastrointestinal cancer (3 patients, 17.6%). The ir-h-AE included 7 patients (41.2%) with warm AIHA, 4 (23.5%) with ITP (1 had immune-related pancytopenia that resolved with ITP persisting), 3 (17.6%) with IRN, 1 with AA, 1 with CAD, and 1 with PRCA and mild ITP. All patients had received an ICI dose within 60 days of diagnosis (range 3-52 days, median 18 days). Only 1 patient had a concomitant chronic autoimmune disorder (antinuclear antibody-positive arthritis). Four patients (23.5%) were receiving chemotherapy. Sixteen patients (94.1%) required treatment and received corticosteroids. Eight out of 15 evaluable patients (53.3%) responded to corticosteroids only. Another 4 responders (26.7%) required additional therapies including intravenous immunoglobulins (IVIG) (4, 23.5%) and/or rituximab (4, 23.5%). Overall response rate was 71.4% for AIHA and 100% for IRN. ITP was likely underrepresented in our cohort, and the response rate of 66.7% is likely lower than the response rate in clinical practice. This could be related to the fact that many mild thrombocytopenia cases are not further evaluated in clinical practice. None of our patients died from the sequelae of an ir-h-AE. Two patients (11.8%) died within 30 days of ir-h-AE diagnosis (disseminated intravascular coagulation likely due to the underlying malignancy and sepsis from bacterial pneumonia). At the time of ir-h-AE diagnosis, the malignancy was showing evidence of response in 9 patients (52.9%), progression in 6 patients (35.3%), and stability in 2 patients (11.8%). ICI therapy was permanently discontinued in 9 patients (52.9%) and temporarily held in 6 patients (35.3%). Three of the 5 patients (60%), who were rechallenged with ICI therapy, had recurrence of the same ir-h-AE (AIHA) with adequate response to therapy. Non-hematologic irAE (7 patients, 41.2%) included 3 patients with hepatitis, 2 with thyroiditis, 2 with pneumonitis, 1 with colitis, and 1 with dermatitis.
Conclusion
Our clinical experience with ir-h-AE highlights the importance of exercising vigilance in assessing the hematologic parameters of patients receiving ICI therapy. While relatively rare, ir-h-AE may impact the clinical course of patients with cancer and their eligibility for therapies that have the potential of offering durable control of the underlying malignancy. ir-h-AE respond to classical therapies including corticosteroids, IVIG, and rituximab.

Disclosures
Block: Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Marker Therapeutics: Research Funding; Transgene: Research Funding; Immune Design: Research Funding. Kottschade:Bristol-Myers Squibb: Consultancy, Research Funding.