SAFETY AND TOLERABILITY OF DASATINIB IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) AND PHILADELPHIA CHROMOSOME–POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH+ ALL): POOLED ANALYSIS OF OVER 2400 PATIENTS

ABSSUB-5356

Background: CML has become a manageable chronic disease for the majority of patients (pts). However, several rare, severe, and irreversible adverse events (AEs) have been reported in tyrosine kinase inhibitor (TKI)-treated populations. To better understand the incidence of such events previously reported in the context of individual trials, a large pooled dataset from Ph+ leukemic pts treated with dasatinib was interrogated for the incidence of reversible or irreversible nonhematologic AEs.

Aims: The objective of this analysis is to report clinical safety data from a large adult population of dasatinib-treated pts (n=2440) derived from 9 single-arm or comparative clinical trials of CML or Ph+ ALL resistant or intolerant to imatinib (IM; n=2182) or newly diagnosed CML in chronic phase (CML-CP; n=258).

Methods: All pts who received ≥1 dose of dasatinib 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily are included. Duration of treatment was defined as the interval from the first to the last dose of study drug and may include intermittent dose interruptions. AEs were graded using NCI CTCAE Version 3.0, and investigator AE terms were coded and grouped by System Organ Class using MedDRA Version 12.1. AEs that were determined by the investigator to have a certain, probable, or possible relationship to the study drug were defined as drug-related. Very common AEs (frequency ≥10%) and AEs of interest (eg, AEs with known association with dasatinib or other TKIs, clinical significance warranting evaluation, or nonclinical data suggesting an association) were analyzed.

Results: The median duration of therapy was 37 months (range <1 to 50 months) in pts with newly diagnosed CML-CP (n=258) and 15 months (range 0 to 65.6 months) in pts with IM-resistant or ‑intolerant CML or Ph+ ALL (n=2182). In this pooled analysis, minimum follow-up was 3 years and 5 years in the first-line DASISION (n=258) and second-line CA180-034 (n=662) CML-CP trials, respectively. On-study drug-related AEs with frequency ≥10% (any grade; n=2440) were diarrhea, pleural effusion, headache, dyspnea, rash, fatigue, nausea, peripheral edema, musculoskeletal pain, hemorrhage, pyrexia, vomiting, abdominal pain, infection, and cough. Drug-related AEs, such as pleural effusion, thrombocytopenia, or neutropenia, led to discontinuation in 16% of the 2440 pts. Fluid-related AEs (drug-related, any grade) were reported in 44% of pts and included: pleural effusion (30%), superficial edema (22%), pericardial effusion (5%), generalized edema (4%), congestive heart failure/cardiac dysfunction (3%), pulmonary edema (2%), pulmonary hypertension (1%), and ascites (0.5%). The single pulmonary arterial hypertension AE reported was not considered drug-related. Cardiac AEs, including ischemic AEs, rhythm abnormalities, and congestion were infrequent (Table), as were other AEs that may be related to vascular thrombosis. All-cause cerebrovascular accidents and transient ischemic attacks (TIAs) were reported in 0.6% and 0.4% of pts, respectively, and were rarely drug-related. Peripheral arterial occlusive disease (PAOD) and PAOD-related AEs have been reported (le Coutre Blood 2013;122:1489) in 0.3% of pts in a larger, 11-study dataset (n=2705).

Summary/Conclusion: Analysis of a large pooled dataset from dasatinib clinical trials did not identify new safety signals. Although pleural effusions are considered common (frequency >10%), they are generally reversible. AEs that are potentially irreversible, including vascular occlusive AEs, were rarely reported in dasatinib-treated pts.

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