Immune‐related hematologic adverse events in the context of immune checkpoint inhibitor therapy
Authors: Antoine N. Saliba, Zhuoer Xie, Alexandra S. Higgins, Xavier A. Andrade‐Gonzalez, Harry E. Fuentes‐Bayne, Paul J. Hampel, Lionel A. Kankeu Fonkoua, Daniel S. Childs, Sagar Rakshit, Evandro D. Bezerra, Anuhya Kommalapati, Yanyan Lou, Candido E. Rivera, Katharine A. Price, Ashish Chintakuntlawar, Yiyi Yan, Anna J. Schwecke, Matthew S. Block, Uma Thanarajasingam, Gita Thanarajasingam, Alexandra P. Wolanskyj‐Spinner, Ariela L. Marshall, Lisa A. Kottschade, Ronald S. Go, Aref Al‐Kali
Journal: American Journal of Hematology (2021)

To the Editor: Immune checkpoint inhibitors (ICI), such as antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1), are increasingly used in the treatment of many malignancies. Red cell aplasia, neutropenia, thrombocytopenia, warm autoimmune hemolytic anemia (AIHA), acquired hemophilia A, cryoglobulinemia, and other immune-mediated hematologic disorders are relatively rare, but potentially life-threatening immune-related adverse events with ICI therapy.1-3 The benefits of ICI therapy in terms of disease control may be diminished in the setting of treatment toxicity due to uninhibited T-cell activity. Additionally, ICI toxicity may delay the treatment of the primary malignancy. Hematologic complications can be particularly challenging to diagnose as both cancer and cancer-directed therapies (like chemotherapy or radiation) may be associated with cytopenias. The main approach to the management of these immune-related hematologic adverse events (ir-h-AE) often relies on systemic corticosteroid therapy as first-line therapy and the subsequent addition of other immunosuppressant agents in steroid-refractory cases.1 Our study describes the characteristics and outcomes of patients with ir-h-AE diagnosed and treated at our institution. After institutional review board approval, we retrospectively searched the electronic health record for all ir-h-AE diagnosed by a treating provider and confirmed by study authors (ANS and AA) between January 2015 and July 2020. The search included patients on ICI and the following conditions: immune-related neutropenia (IRN), 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 was defined as hemoglobin >10 g/dL but <12 g/dL and 2 g/dL above the nadir without blood product transfusion. Complete response was defined as hemoglobin of ≥12 g/dL and 2 g/dL above the nadir without blood product transfusion.4 For ITP, complete response was defined as platelet count ≥100 × 109/L and absence of bleeding. Partial response was defined as platelet count ≥30 × 109/L and at least two-fold increase from the baseline count and absence of bleeding.5 For IRN, complete response was defined as an absolute neutrophil count (ANC) of ≥1500/μL on two consecutive measurements separated by at least 7 days, and partial response was defined as an ANC of ≥500/ μL sustained over 7 days.6 Seventeen cases were identified between January 2015 and July 2020, nine (52.9%) of whom were female. Median age at diagnosis of ir-h-AEs was 68 years (range: 26–78). Reflecting diseases where ICI therapy is approved, the most common pre-existing malignancies were melanoma (six patients, 35.3%), non-small cell lung cancer (five patients, 29.4%), and gastrointestinal cancer (three patients, 17.6%). Fourteen patients were on pembrolizumab (82.4%) and three patients were on nivolumab (17.6%). The ir-h-AEs included: seven patients (41.2%) with warm AIHA, four (23.5%) with ITP (one had immune-related pancytopenia that resolved with ITP persisting), three (17.6%) with IRN, one with AA, one with CAD, and one with PRCA and mild ITP. All patients had received an ICI dose within 60 days of onset of the ir-h-AE (median time to ir-h-AE onset from the last dose of ICI was 20 days; range: 5–52 days). The median number of cycles of ICI therapy received before the onset of ir-h-AE was three cycles (range: 1–15) with four patients (23.5%) experiencing an ir-h-AE after one cycle of therapy. Only one patient had a history of a concomitant chronic autoimmune disorder (antinuclear antibody-positive arthritis). The ir-h-AEs in the four patients (23.5%), who were concomitantly receiving chemotherapy, were AIHA and AA. Sixteen patients (94.1%) required treatment and received corticosteroids at variable doses. Eight out of 15 evaluable patients (53.3%) responded to corticosteroids only. Another four responders (26.7% of the evaluable patients) required additional therapies including intravenous immunoglobulins (IVIG) (three patients; 20.0%) and/or rituximab (three patients; 20.0%). The overall response rate to therapy was 71.4% for AIHA and 100% for IRN. Immune thrombocytopenia was likely underrepresented in our cohort as mild cases were likely not further evaluated by the treating provider. The response rate was 66.7%. None of our patients died of the complications of an ir-h-AE. Two patients (11.8%) died within 30 days of diagnosis of the ir-h-AE with the causes of death being disseminated intravascular coagulation (likely due to the underlying malignancy) and sepsis from bacterial pneumonia. At the time of diagnosis of ir-h-AE, the malignancy was showing evidence of response in eight patients (47.1%), progression in seven patients (41.2%), and stability in two patients (11.8%). Immune checkpoint inhibitors therapy was continued in two patients (11.8%), permanently discontinued in nine patients (52.9%), and temporarily held in six patients (35.3%) as a result of the ir-h-AE. Three of the five patients (60.0%), who were rechallenged with ICI therapy after a temporary hold, had recurrence of the same ir-h-AE (warm AIHA) with an adequate response to subsequent immunosuppressive therapy. Non-hematologic ir-AE occurred in seven patients (41.2%) and included: three patients with hepatitis, two with thyroiditis, two with pneumonitis, one with colitis, and one with dermatitis. Table 1 summarizes the characteristics of our cohort. Ir-AEs affect various organs including the skin, the gastrointestinal tract, the endocrine glands, the liver, the lungs, and others. In this report, we specifically focus on the AEs involving the hematopoietic system.1 Ir-h-AEs have been reported at a variety of time points after the initiation of ICI. In a case series, Davis et al. reported that ir-h-AE occurred relatively early (median of 40 days after initiation of ICI therapy) while another series by Michot et al. reported a wide variation in the time from initiation of ICI to the diagnosis of ir-h-AEs.1, 2 In our series, the time of onset of ir-h-AEs ranged from one to 15 cycles, underscoring that in some patients ir-h-AEs can be delayed, similarly to non-hematologic ir-AEs. Despite the limited number of patients, our study suggests that rechallenge with ICI may be considered with caution depending of the clinical severity of the initial ir-h-AE and the expected continued benefit from ICI therapy. From this retrospective series, it is difficult to assess the relative effect of tapering of ir-h-AE-directed therapy vs rechallenge with ICI therapy on the recurrence of ir-h-AE. Our institutional series of ir-h-AEs highlights the importance of exercising vigilance in assessing the hematologic parameters of patients receiving ICI therapy. While relatively rare, ir-h-AEs may impact the clinical course of patients with cancer and their eligibility for therapies that carry the potential of offering durable control of the underlying malignancy. We acknowledge the limitations inherent to the use of retrospective data to understand the etiology of abnormal blood counts given other confounding factors. However, our series did not only rely on documented ir-h-AEs but also independently confirmed them through a review of the record and exclusion of other conditions, such as the effects of infection, other medications, and chemotherapy. In our experience, most patients experienced non-hematologic ir-AEs before or after the diagnosis of the ir-h-AE. About half of the patients with ir-h-AEs responded to corticosteroids. Rechallenging with ICI caused recurrent toxicity in most patients. Optimizing the study of ir-h-AEs will require a multi-institutional effort to achieve larger cohort sizes allowing the prospective identification of predictive factors of toxicity and trends in optimal management. The authors declare no conflict of interest. All authors contributed to performing the research. A.N.S., R.S.G., and A.A. analyzed the data and wrote the manuscript draft. A.N.S., R.S.G., and A.A. designed the research study, wrote, and reviewed the paper. All authors were involved in reviewing and editing the manuscript. All authors approved the final version. Part of this data was presented at the 62nd American Society of Hematology Annual Meeting December 2020. The data that support the findings of this study are available from the corresponding author upon reasonable request.