Hematological Adverse Events with Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia: A Systematic Review with Meta-Analysis

SIMPLE SUMMARY: Tyrosine kinase inhibitors (TKIs) are the main class of drugs used to treat chronic myeloid leukemia. Because most CML patients must remain on TKIs indefinitely, it is important to understand and monitor adverse events (AEs). Changes to blood cells, or hematological adverse events, are often attributed to CML, itself. However, once the disease is stabilized, changes in red blood cells, white blood cells, or platelets, may be due to the TKI therapy. This study reports the frequency of hematological AEs in CML patients treated with TKIs, which has implications in TKI selection and patient monitoring. ABSTRACT: Chronic myeloid leukemia (CML) is treated with tyrosine kinase inhibitors (TKI) that target the pathological BCR-ABL1 fusion oncogene. The objective of this statistical meta-analysis was to assess the prevalence of other hematological adverse events (AEs) that occur during or after predominantly first-line treatment with TKIs. Data from seventy peer-reviewed, published studies were included in the analysis. Hematological AEs were assessed as a function of TKI drug type (dasatinib, imatinib, bosutinib, nilotinib) and CML phase (chronic, accelerated, blast). AE prevalence aggregated across all severities and phases was significantly different between each TKI (p < 0.05) for anemia—dasatinib (54.5%), bosutinib (44.0%), imatinib (32.8%), nilotinib (11.2%); neutropenia—dasatinib (51.2%), imatinib (29.8%), bosutinib (14.1%), nilotinib (14.1%); thrombocytopenia—dasatinib (62.2%), imatinib (30.4%), bosutinib (35.3%), nilotinib (22.3%). AE prevalence aggregated across all severities and TKIs was significantly (p < 0.05) different between CML phases for anemia—chronic (28.4%), accelerated (66.9%), blast (55.8%); neutropenia—chronic (26.7%), accelerated (63.8%), blast (36.4%); thrombocytopenia—chronic (33.3%), accelerated (65.6%), blast (37.9%). An odds ratio (OR) with 95% confidence interval was used to compare hematological AE prevalence of each TKI compared to the most common first-line TKI therapy, imatinib. For anemia, dasatinib OR = 1.65, [1.51, 1.83]; bosutinib OR = 1.34, [1.16, 1.54]; nilotinib OR = 0.34, [0.30, 0.39]. For neutropenia, dasatinib OR = 1.72, [1.53, 1.92]; bosutinib OR = 0.47, [0.38, 0.58]; nilotinib OR = 0.47, [0.42, 0.54]. For thrombocytopenia, dasatinib OR = 2.04, [1.82, 2.30]; bosutinib OR = 1.16, [0.97, 1.39]; nilotinib OR = 0.73, [0.65, 0.82]. Nilotinib had the greatest fraction of severe (grade 3/4) hematological AEs (30%). In conclusion, the overall prevalence of hematological AEs by TKI type was: dasatinib > bosutinib > imatinib > nilotinib. Study limitations include inability to normalize for dosage and treatment duration.