The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukaemia.

Abstract

Background: Dasatinib (DAS) has shown superiority over imatinib in achieving cytogenetic and molecular responses in chronic phase (CP) CML but with a different toxicity profile, which may impact on its overall benefit. Reported tox- icities from the DASISION trial at 5 years include pleural effusions (PE) (29%), pulmonary hypertension (PHTN) (5%), and low rates of arterial ischemic events. While the literature well describes the incidence of these events, the response to therapy and the impact of subsequent dose modifications on the outcome of the toxicity have generally not been comprehensively characterised. Aim(s): To review the incidence of these side-effects in a snapshot survey of Australian patients (pts) receiving DAS, either as first or subsequent line of therapy for CML-CP, with a focus on risk factors and the response of the toxicity to therapeutic changes. Method(s): Retrospective study of all eligible pts (received DAS for CML-CP and access to sufficient data) at 17 Australian institutions. Each pt's history was tracked in detail to identify any complications potentially attributable to DAS, and the treatment and outcome of these complications in response to cessation or alterations in DAS dose or schedule. Result(s): 221 pts were evaluable, with a median age at DAS commencement of 53 years (range 20 - 86) and median starting dose of 100mg (20-140). 51 (23%) received DAS as 1st line therapy, 133 (60%) 2nd line and 37 (17%) 3rd line. The median follow up from DAS commencement was 27 months (4 -116 months). No side effects were reported in 105 (48%) pts. Of the 116 (52%) pts with side-effects, the most common side effect was PE, observed in 53 (24%) pts with a median age of 65 years (41-86 years) and with median time to onset of 11 months (0.5-59 months). Most (40 pts, 76%) were receiving DAS as 2nd line therapy. DAS dose at PE onset was 100mg in 37 pts (70%), 140mg in 9 pts (17% PEs; notably 38% of pts on this dose developed PE), 70mg in 4 pts, 80mg in 2 pts and 50mg in 2 pts. The Figure 1 documents outcomes in pts with PE at 100mg dose with the key findings being a very high risk of recurrence in the absence of dose reduction and a substantial risk despite dose modifications. Evaluation of the CML status in these patients 6 months after changes in DAS dose and schedule is currently underway. Additional management of PE included diuretics (79%), thoracocentesis (43%), and steroids (47%). Only 1 of 7 pts given maintenance low dose steroids developed recurrence. Other side-effects included Grade 3-4 haemorrhage in 8 pts (4%), 3 of whom had platelets <50 x109/L and fatal intracerebral haemorrhage in a pt with a normal count. Ten (5%) pts had elevated pulmonary artery pressures meeting criteria for PHTN (RVSP >36mmHg) [median DAS dose 100mg (100-140)]; all described dyspnoea, although notably 8 had either concurrent PE or developed PE within 6 months. Of 5 PHTN pts with available follow up data, RVSP normalised in 4 post DAS cessation. The two episodes of peripheral vascular disease requiring intervention occurred in pts previously treated with nilotininb. There were no atypical infections apart from one pt with an empyema. Two pts had benign cervical lymphadenopathy. There were no deaths clearly attributable to DAS. Side-effects led to permanent DAS cessation in 51 pts (23%). (Figure Presented) Summary/Conclusions: The incidence of common DAS side effects (PE, PHTN) were similar to those seen in the DASISION study. Other side-effects were uncommon. Age and dose were risk factors for PE. In pts with PE on 100mg, recurrence was very high in the absence of dose reduction, and was still high despite reduction but appeared to be reduced by maintenance low dose steroids. These findings support the results of Porrini (ASH 2011) who found DAS at lower doses is effective in the elderly. With dosing appropriate for age, possibly supported by titration according to DAS levels and molecular response, severe side effects of DAS requiring permanent drug cessation are likely to be rare.