Memory Impairment in Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) Treated with Dasatinib Tyrosine Kinase Inhibitor (TKI) Therapy,

In some pts taking dasatinib, a dual ABL and SRC inhibitor, we have observed a variety of memory impairments, and little is known about this phenomenon. We examined this phenomenon by analyzing data from a phase II trial to study of frontline dasatinib in pts with previously untreated CML-CP.

To describe the incidence of memory impairment in pts with CML-CP treated with frontline dasatinib.

We reviewed pts enrolled on our frontline dasatinib prospective study for treatment of early CP-CML, which randomized newly diagnosed CML-CP pts to receive dasatinib, 50 mg twice daily (BID) or 100 mg once daily (QD). After 66 pts were accrued the BID arm was closed and all subsequent pts received 100 mg QD. Data was gathered from clinic progress notes, pt self-reported study medication and adverse event diaries. Memory changes graded according to CTCAE v 3 (0=no memory change, 1=mild, 2=moderate, interferes with function but not with daily activities, 3=severe, interferes with daily activities, 4=amnesia). In the memory change group, we included pts with new-onset memory impairment, defined as those who had documentation of no memory impairment at the beginning of study and then developed while on the study, as well as pts with worsening memory impairment, defined as those who had memory impairment at baseline, but exacerbated while on study either by grade or frequency. We excluded pts from memory change group if they had other significant medical, neurologic or psychiatric medical conditions which are known to cause or exacerbate memory impairment, including pts with hypothyroidism, depression, anxiety, attention deficit disorder, adjustment disorder. Pts with memory changes reported less than 7 days after the start of dasatinib were also not included in the memory change group.

19 of 99 pts (19%), all of whom had no prior history of neuro-psychiatric disorder, experienced a memory-related change while taking dasatinib. Median age was 47 years (yrs) (range 18–82) for those without a memory change, compared to 50 yrs (29–63) for those who did develop a memory change (p -value, median age difference between the two groups, 0.721). 10 pts (53%) were female. 17 pts reported a new memory change; 2 reported having worsening memory impairment compared to baseline. 12 (63%), 3 (16%), 4 (21%) experienced grades 1, 2, 3 of memory impairment, respectively. None developed grade 4 toxicity. In the clinic, symptoms of memory changes were referred to as short-term memory loss, difficulty in word finding, forgetfulness and trouble remembering appointments or numbers. Median dose of dasatinib at the time of these memory-related events was 100 mg/day (range 20–100 mg/day). Median amount of time from start of dasatinib to time of first report of memory-related event was 41 months (mo) (1–63 mo). In 11 pts, symptoms resolved or improved (1 pt had dasatinib interrupted for 45 days and then restarted at a lower dose; 2 pts did not interrupt the drug but had dose reduction, and the other 8 pts did not experience a dose reduction or treatment interruption). In 8 pts there was no resolution or improvement of symptoms (6 had only mentioned memory impairment in their medication diary, whereas 2 cases were discussed with the physician in the clinic but there was no change to treatment plan due to minimal symptoms).

Memory impairment of various degrees may occur among CML-CP pts treated with dasatinib. Because of the long-term nature of therapy with TKI, this effect may have long-term implications in the quality of life of pts. The main limitation of this study is its retrospective nature, which limits detailed information about the memory-related events. Prospective assessment of memory impairment with more objective tools will be required to more adequately assess the significance of this adverse event, occurrence with other TKI, and impact in overall quality of life and performance of daily activities at home and at work.

Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Ravandi:BMS: Honoraria, Research Funding. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.