Real-world burden and risk analysis of hematologic iraes in patients treated with immune checkpoint inhibitors: 5-year cohort study

Abstract Introduction Immune checkpoint inhibitors (ICIs) have revolutionized the treatment and prognosis of multiple solid tumors like melanoma, renal cell carcinoma, and others. However, exaggerated immune activation can lead to immune-related adverse events (irAEs), among which hematologic irAEs remain poorly characterized. Robust incidence data and clinically relevant predictors are required to guide monitoring and early intervention. Hence, we evaluated the frequency, spectrum, and risk factors of hematologic irAEs in patients with melanoma, renal cell carcinoma, or urothelial carcinoma treated with ICIs at a tertiary cancer center. Methods We conducted a single-center, retrospective cohort study at the American University of Beirut Medical Center (AUBMC), including adult patients (N = 116) who received at least one dose of ipilimumab, nivolumab, pembrolizumab, atezolizumab, or durvalumab between January 1, 2019, and January 31, 2024. Patients' electronic medical records were retrospectively reviewed for their ICI regimen, demographics, comorbidities, tumor characteristics, prior chemo-/radiotherapy, and baseline complete blood count(CBC) and laboratory values. Collected hematologic toxicities included anemia, thrombocytopenia, neutropenia, pancytopenia, lineage number affected, time-to-onset, need for G-CSF or transfusion, and documented syndromes (HLH, autoimmune hemolysis, myelodysplasia). Binary logistic regressions assessed the relationships between potential predictors and development of hematologic irAES. The primary outcome of interest was the incidence of at least one hematological irAEs. Results We included 116 patients (median age 68.5 years, 68.1% male, mean BMI 27.3 ±4.9 kg/m²) receiving ICIs for melanoma (28.9%), renal cell carcinoma (28.1%), or urothelial carcinoma (43.0%). Most patients (98%) scored between 0 to 1 on ECOG performance status, while 62.1% had a history of smoking, and 4.3% had a preexisting autoimmune disorder. Pembrolizumab (50.0%) and nivolumab (22.4%) were the most used ICIs, with 24.1% receiving combination therapy. The mean duration of ICI treatment was 13.9 ±18.5 months. 30.2% of patients received prior chemotherapy and 79.3% underwent surgery. None had hematological malignancies at baseline. Initially, 45.7% of patients had pre-treatment anemia (mostly grade 1), while thrombocytopenia was rare (5.2%, all grade 1), and no patients had neutropenia. Following initiation with ICIs, 62.9% (73/116) experienced at least one new-onset or worsening hematologic- irAE. Anemia was the most common irAE (44.8%), followed by thrombocytopenia (28.4%) and neutropenia (25.8%). Pancytopenia occurred in 14.7% and bi-cytopenia in 16.4%. Median time to first hematologic disturbance was 1.41 months (mean 4.72 months), or approximately 5.9 cycles. Most hematologic irAEs were mild, with grade 1 (70.7%) being more common than grades 2 (19.8%) and 3 (9.5%). There were no grade 4 or 5 events and no hematology-related fatalities. Isolated autoimmune syndromes like autoimmune hemolytic anemia were uncommon, with no reported cases of hemophagocytic lymph histiocytosis or myelodysplastic syndrome. Supportive treatment included transfusions in 18.9% and G-CSF administration in 11.2%; no patient required steroids, IVIG, or treatment discontinuation due to hematologic irAEs. Hematological abnormalities generally resolved to baseline with supportive care alone. Regression analysis revealed confidence intervals for hazard ratios that were narrow and hazard effect ratios that were close to 1, with none achieving statistical significance as predictors of hematologic irAEs. Immunotherapy-associated hematologic irAEs were common but largely mild, manageable, and rarely required any significant clinical interventions or treatment interruption. These irAEs emerged early (median ~6 weeks) in the treatment course, highlighting the importance of early surveillance and rapid supportive management when using ICIs. Conclusion: Although usually rare in literature, we found hematologic irAEs to be common but mild and manageable with ICIs. No significant predictors were identified. Early monitoring and supportive care are key.