Proactive dasatinib dose reduction in the allg cml 12 direct study based on trough levels minimise toxicity and preserve efficacy.

Abstract

Background: Dasatinib treatment leads to excellent molecular responses in chronic phase chronic myeloid leukemia (CP-CML) but at 100mg leads to a substantial risk of pleural effusions, which may be higher in the elderly. Rousselot et al (BJH 2021) suggested this risk may be mitigated through dose modifications as guided by trough levels (Cmin). Aim(s): The CML12 (DIRECT) study, run by the ALLG, is a single arm phase II study, aiming to minimise dasatinib related toxicity whilst preserving efficacy, through dose adaptation as guided by dasatinib trough levels. We report here the primary end point -cumulative incidence of pleural effusion (PEf) at 24 months (mos) and key efficacy secondary end points. Method(s): DIRECT enrolled newly diagnosed CP-CML pts. The first 34 patients (pts) were aged >60 years (yrs), after which the protocol was amended to include pts aged >18 yrs at the recommendation of the trial management committee. All pts started on dasatinib 100mg QD, with Cmin taken at 7, 28, 56 & 90 days, then every 3 mos hence. Pts sequentially dose reduced to 70mg, then to 50mg QD, for Cmin >3nM, within the first 2 mos, prior to assessment of early molecular response at 3 mos. Doses <50mg QD were permitted temporarily only for toxicity management. Chest x-ray and transthoracic echocardiograms were performed at baseline & 24 mos. Result(s): Eighty pts were enrolled from 14 centres, with a median follow up of 36 mos (range 24-60). Median age was 64 yrs (range 21-86) and 46% were female. The ELTS score was low and intermediate in 54% and 34% respectively, high in 5% and missing in 8%. Cmin and treatment assigned at various timepoints are detailed in Table 1. Older patients had higher Cmin, particularly prior to dose adjustments. The majority of pts were dose reduced to 50mg QD. Fifteen cases of pleural effusion (PEf) occurred, 5 within the first mo, and 12 in total by 24 mos; 3 were asymptomatically detected on chest x-ray. The cumulative incidence of PEf by 24 mos was 15% overall (95% CI 8-25%, Fig 1); with values of 7.6%, 14.3% and 45.5% respectively in patients <60 yrs, 60-75 yrs and >=75 yrs. The Cmin prior to the PEf was >3nM in 8/15 pts. At 24 mos, 59 (74%) of pts remained on dasatinib. Reasons for discontinuation were intolerance / adverse events (AE) (n=15, 19%); treatment failure (n=4, 5%); death (n=1, 1%) and consent withdrawn (n=1, 1%). AEs leading to discontinuation were PEf (n=6, 7.5%) pulmonary hypertension (n=4, 5%; 2 reported as SAEs), pericardial effusion (n=2, 2.5%) and cardiac failure (n=2, 2.5%). There were no cases of peripheral vascular disease or strokes. An early molecular response (BCR