Research from ASH ’ s newest peer-reviewed journal , Blood Advances in a Different Vein
Managing Toxicities of Dasatinib in Patients With CP-CML
In randomized studies , the secondgeneration tyrosine kinase inhibitor dasatinib demonstrated deeper and more rapid major molecular responses ( MRs ) in patients with newly diagnosed chronicphase chronic myeloid leukemia ( CP- CML ), compared with imatinib . However , the significant toxicities associated with dasatinib , including pleural effusion , may offset these advantages and complicate treatment decisions .
In a retrospective , real-world study published in Blood Advances , Lucy C . Fox , MBBS , from the Austin Hospital in Melbourne , Australia , and co-authors confirmed that the majority of patients treated with dasatinib required dose modifications or treatment cessation because of adverse events ( AEs ), but this had little impact on MR rates .
“ Our data suggest that the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients ,” Dr . Fox told ASH Clinical News .
The researchers surveyed 212 patients ( median age = 53 years ; range = 20-86 years ) receiving dasatinib at any therapy stage for CP-CML at 17 Australian institutions between February 1 , 2005 , and June 30 , 2015 . This was secondline therapy for more than half of the patients ( n = 125 ; 59 %), and most patients ( n = 177 ; 83 %) received dasatinib 100 mg as a starting dose .
After a median follow-up of 27 months ( range = 4-116 months ), more than half of patients ( 55 %; n = 116 ) had at least one AE , the most common of which was pleural effusion ( 25 %; n = 53 ).
The incidence of pleural effusion appeared to be dose-dependent . At dasatinib 100 mg , 21 percent of patients ( n = 37 / 177 ) experienced pleural effusion , compared with 43 percent of patients receiving dasatinib 140 mg ( n = 9 / 21 ; p value not provided ). A Kaplan-Meier analysis suggested a tendency for pleural effusion to occur early with both the 100 and 140 mg doses , but pleural effusion was more common and occurred earlier at the 140 mg dose level ( p = 0.056 ).
Overall , advanced age ( p < 0.01 ) and higher dose ( p = 0.047 ) were independent risk factors for pleural effusion across all dose levels , whereas sex ( p = 0.54 ) and line of therapy ( p = 0.22 ) were not .
Management of effusions “ varied substantially among institutions , reflecting a lack of consensus approach to this AE ,” the authors wrote . For example , of the 37 patients in the 100 mg group who developed pleural effusions , the investigators identified five treatment patterns :
• immediate cessation of dasatinib ( n = 8 )
• continuation of dasatinib 100 mg ( n = 4 )
• temporary withholding of dasatinib and resuming at 100 mg within 6 weeks ( n = 8 )
• continuation of therapy at a reduced dose ( n = 5 )
• temporary withholding of dasatinib and resuming at a lower dose ( n = 12 )
Decreasing the dasatinib dose “ reduced but did not abolish ” the risk of pleural
effusion recurrence , the authors noted , with pleural effusion reccurring after a median of 20 weeks ( range = 3-157 weeks ) in the 29 patients who continued taking dasatinib . The risk of recurrence was significantly higher in patients who did not immediately cease dasatinib , compared with those who did ( p < 0.001 ). Recurrence was also more common in patients who continued receiving dasatinib 100 mg ( n = 12 ), compared with those who received a reduced dose ( n = 17 ; p = 0.041 ).
Patients receiving dasatinib 100 mg who developed pleural effusion were more likely to have achieved MR4.5 ( defined as BCR-ABL1 transcript levels ≤0.0032 %) after six months , compared with those who did not ( p = 0.008 ).
Other common AEs included grade 3 / 4 thrombocytopenia ( n = 11 ), grade 3 / 4 bleeding ( n = 7 ; 2 of which were clinically significant ), and clinically significant infection ( n = 12 ). Also , five percent of patients who underwent echocardiography experienced pulmonary hypertension . “ Prior to initiation of therapy , a screening echocardiogram may be useful in identifying early pulmonary hypertension , which is probably an indication not to use this drug ,” the authors suggested . “ While we noted that overall serious bleeding rates are low , caution is warranted when prescribing concurrent antiplatelet agents .”
“ Using lower doses of dasatinib in older patients , perhaps with adjustments according to molecular response , may lower the incidence of pleural effusion .”
– LUCY C . FOX , MBBS
Seventy-nine patients discontinued dasatinib ( 37 %), most often because of AEs ( n = 51 ; 24 %), after a median of 16 months ( range = 0.1-55 months ). Twentyone of those patients ( 10 %) ceased treatment immediately , and 41 patients ( 80 %) first reduced or temporarily ceased the dose prior to permanent cessation .
Sixteen patients died during study follow-up ; 11 deaths occurred while patients were receiving dasatinib or within four months of the last dose . Causes of death were blast crisis CML ( n = 5 ), sepsis ( n = 1 ), suicide ( n = 1 ), intracerebral hemorrhage ( n = 1 ), cardiac event ( n = 1 ), and unknown ( n = 2 ).
“ We suggest that a reasonable approach to the management of symptomatic effusions includes temporary drug cessation and gentle diuretic therapy ( albeit of uncertain benefit ) until complete resolution ,” the authors concluded .
“ Using lower doses of dasatinib in older patients , perhaps with adjustments according to MR , may lower the incidence of pleural effusion ,” Dr . Fox added .
The study is limited by its retrospective design , as well as the variations in patient management . ●
Contributing authors reported financial relationships with Bristol-Myers Squibb .
REFERENCE
Fox LC , Cummins KD , Costello B , et al . The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia . Blood Adv . 2017 ; 1:802-11 .
24 ASH Clinical News August 2017