Occurrence of Pleural/Pericardial Effusions in Ph+ CML Patients Failing Prior Tyrosine Kinase Inhibitors (TKI) Before Starting Nilotinib – Retrospective Analysis upon Entry into the Nilotinib Compassionate Use Program

Background: Imatinib, nilotinib, and dasatinib are BCR-ABL tyrosine kinase inhibitors (TKIs), with different selectivity profiles, approved for the treatment of patients (pts) with Philadelphia positive chronic myeloid leukemia (Ph+ CML). Given the differences in their kinase selectivity profiles, the safety profiles of these agents also differ, particularly with regard to episodes of fluid retention. The incidence of pleural/pericardial effusions in resistant or intolerant CML pts who failed imatinib, or both imatinib and dasatinib, therapy was evaluated.

Methods: The occurrence of pleural/pericardial effusions in resistant or intolerant CML pts following therapy with imatinib, or imatinib and dasatinib sequentially, was evaluated in 915 pts with Ph+ CML in chronic phase (CML-CP, 60%), accelerated phase (CML-AP, 23%), and blast crisis (CML-BC 17%) who entered the nilotinib compassionate use program between June 2006 and April 2008. At the time of medical review for compassionate use approval, safety information including the presence of or the history of pleural/pericardial effusions was collected along with dosing information for imatinib and dasatinib. Nearly all pts analyzed (94%) had not received nilotinib therapy prior to inclusion in the compassionate use program. Resistance and intolerance as well as CML phase were defined using similar criteria as previously reported in the nilotinib pivotal phase I/II study.

Results: The median age was 52 years (range: 11 – 87 years); 22 pts (2%) were 18 years old or younger. Most pts (734; 80%) had received prior imatinib only (64% discontinued due to resistance, 20% with resistance and intolerance and 16% due to intolerance) and 170 pts received both imatinib and dasatinib (29% resistant; 17% with resistance and intolerance, 54% intolerant), with most dasatinib failures being due to toxicity. Information on past treatment is currently unavailable for 11 pts. Of pts who were pretreated with imatinib alone, less than 2% of pts (n = 11) had pleural and/or pericardial effusions reported. Among those pts pretreated with both imatinib and dasatinib, 51 pts (30%) had pleural and/or pericardial effusions, with 50 (98%) having pleural effusions, 10 of which were bilateral. Fifty-five percent of pts with pleural and/or pericardial effusions were in chronic phase. Of the pts with dasatinib-associated pleural/pericardial effusions; 11% were noted on daily doses > 140 mg, 29% on doses of 140 mg, 20% on doses of 100 mg, and 10% on doses of < 100 mg. There were 14 pts who developed pleural and/or pericardial effusions in which the dasatinib dose was not available. Of the 33 pts with pleural and/or pericardial effusions on daily 140 mg dasatinib, 16 pts (48%) discontinued dasatinib due to pleural effusion and 6 pts exhibited persistent pleural effusions despite dasatinib dose reductions. One pediatric patient (age 11 years) had a pleural effusion with once daily 80 mg dasatinib. Pleural/pericardial effusions occurred in all age groups: >50 years old – 6 pts, 51–60 years old – 10 pts; 61–70 years old – 13 pts; 71–80 years old – 16 pts and >81 years old – 4 pts (2 of unknown age). No pts who developed dasatinib-associated pleural/pericardial effusions had a history of pleural/pericardial effusions during imatinib therapy.

Conclusions: This large dataset supports earlier reports that pleural/pericardial effusions are frequently reported among CML pts treated with dasatinib compared with imatinib. Furthermore, the occurrence of dasatinib-associated pleural/pericardial effusions may occur at any dose, even below the standard 140 mg/day dose and in some cases with doses less than 100 mg/day.