There is evidence for the use of the second-generation tyrosine kinase inhibitor (TKI) dasatinib in chronic, accelerated and blast phases of chronic myeloid leukaemia (CML).
CHRONIC PHASE (CP)
Kantarjian and colleagues first published the results of the DASISION Trial (‘Dasatinib vs Imatinib in treatment-naïve CML patients) in 2010.r In this open label, phase 3 multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100mg once daily (n=259) or imatinib at a dose of 400mg once daily (n=260). Prior treatment with anagrelide or hydroxyurea was permitted. Notable exclusions include ECOG>2, QTc>450ms and pleural effusion at baseline. The primary end point was complete cytogenetic response (CCyR) by 12 months, confirmed on two consecutive assessments at least 28 days apart. Marrow samples were collected at 6 weeks and then every 3 months thereafter. Minimum follow up was 12 months.
Confirmed CCyR was higher with dasatinib than with imatinib (77% vs. 66%, P = 0.007), as was the rate of CCyR observed on at least one assessment (83% vs. 72%, P = 0.001). The rate of major molecular response (MMR) was also higher with dasatinib than with imatinib (46% vs. 28%, p<0.0001), and responses were achieved in a shorter time with dasatinib (p<0.0001) (see figure below). Progression to accelerated or blast phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%).
Safety profiles of the two treatments were similar (see Toxicity section below). Median dose of dasatinib delivered was 99mg/day (21-136mg), and for imatinib was 400mg/day (125-657mg), with 84% and 81% of patients respectively remaining on study treatment at end of the trial.
A 5-year follow up of the DASISION trial was published in 2016.r The cumulative 5 year MMR rate in the dasatinib group was 76% and imatinib, 64% (P = 0.0022). The rate of achieving MR4.5 (molecular response with a 4.5-log reduction from a standardized baseline) was also significantly higher in those on dasatinib (42% vs 33%; P = 0.0251). At the end of the study, the response rates for the dasatinib vs imatinib arms were, respectively: 52% and 49% for MMR, and 25% and 18% for MR4.5.
The 5-year progression free and overall survival of the two groups was not significantly different (5yr PFS 85% vs 86%, 5yr OS 91% vs 90%, for dasatinib and imatinib, respectively). Notably, the life expectancy of patients on the study approached that of the non-CML population.
In both arms of the study, patients who achieved early molecular responses had better outcomes.r Those with a BCR-ABL transcript level <10% at 3 months more often reached CCyR, MMR, and MR4.5 by 5 years (see “Table 2” below). They also had a higher probability of progression free (94-95% vs 80%) and overall survival (89-93% vs 72%) at 5 years and had a lower transformation rate (3% vs 14-15%).
Dasatinib has also shown to be effective in patients who failed imatinib therapy.r
© NEJM 2010
ACCELERATED PHASE (AP)
Patients may present with CML in accelerated phase (CML-AP) or may progress to AP from chronic phase due to the development of resistance to therapy. In either case, the initial aim of treatment is to return the patient to chronic phase using a TKI, proceeding to allogeneic stem cell transplant where possible. The choice of TKI should ideally be guided by the results of resistance testing. For example, the BCR-ABL mutations Y253H, E255K/V and F359V/C confer resistance to imatinib and nilotinib whilst retaining sensitivity to dasatinib.r
Apperley et alr reported the result of the ‘START A Trial’ in 2009. Patients with imatinib resistant (n=161) or intolerant (n=13) CML-AP were given dasatinib 70 mg twice daily. Median follow up duration was 14.1 months (0.1-21.7 months). Major and complete haematologic responses were attained by 64% and 45% of patients, respectively. Major and complete cytogenetic responses were achieved in 39% and 32% of patients. Responses were seen irrespective of imatinib status, prior stem cell transplantation, or the presence of prior bcr-abl mutations (except T315I, F317L and E225K). The 12-month progression free survival and overall survival rates were 62% and 82% respectively. Pleural effusion was seen in 27% of patients (grade 3 - 4 in 5%). Common adverse events were diarrhoea (52%, grade 3-4 in 8%), grade 3-4 neutropenia in 76% and thrombocytopenia 82%. Dose reductions were required by 65% of patients, in 30% of cases due to haematologic toxicities. Treatment was discontinued in 90 patients (52%), most commonly due to disease progression; six patients (3%) underwent stem cell transplantation after discontinuing dasatinib.
In a separate study, Kantarjian et al reportedr that dasatinib 140 mg once daily was as effective as 70 mg twice daily in CML-AP. The comparison between the once-daily cohort (n=158) and the twice-daily cohort (n=159) showed: major hematologic response 66% vs 68%, major cytogenetic response 39 vs 43%, progression free survival at 24 months 51 vs 55%, overall survival 63% vs 72% respectively. Significantly fewer patients in the once-daily group experienced a pleural effusion (all grades, 20% vs 39%, p<0.001).
BLAST PHASE (BP)
Hehlmann in a review articler cited three studies reporting on the efficacy of dasatinib in 400 CML in blast phase (CML-BP) patients pretreated with imatinib, including 119 with lymphoid blast crisis (BC). These showed haematologic remission rates of 33% to 61% (lymphoid BC 36%-80%), major cytogenetic remission rates of 35% to 56%, and a median survival of 8 to 11 months (2–year survival of 20-30%). The largest of these, a randomised open-label phase 3 studyr on 214 patients of patients with 61 in lymphoid BC, examined dasatinib 140mg once daily vs the 70mg twice daily schedule. It yielded similar efficacy data and improved tolerability for the once-daily regimen. Pleural effusion can be seen in as much as 1/3 of such patients and may necessitate dose reduction, diuretics and in some cases, corticosteroids.
In addition, dasatinib crosses the blood-brain barrier and shows long lasting responses in Ph+ CNS disease. Dasatinib maintenance is recommended in responders not suitable for allogeneic stem cell transplantation.
In the intial report of the DASISION trial of dasatinib vs imatinib in CP-CML, drug related adverse events (AEs) in both arms were mainly low grade (1/2).r Grade 3/4 neutropenia occurred with similar frequency on dasatinib (21%) and imatinib (20%) whilst grade 3/4 thrombocytopenia occurred in 19% of patients on dasatinib compared with 10% on imatinib. Several non-haematologic adverse events were more common with imatinib than with dasatinib (eg, fluid retention, which occurred in 19% of the patients in the dasatinib group and in 42% of those in the imatinib group). Episodes of pleural effusion, which were reported in 26 (10%) of dasatinib-treated patients, were all grade 1 or 2 and were managed by dose modifications or medical interventions. Treatment was interrupted in 19 patients and the dose of dasatinib reduced in 8.r
The drug related adverse events that occurred in at least 10% of treated patients in the first year of the DASISION trialr are summarised below:
© NEJM 2010
Over five years of follow up of the DASISION trial, the majority of adverse events (AEs) were grade 1/2, with 15% of patients on dasatinib and 11% on imatinib, experiencing a grade 3/4 AE.r Drug discontinuation due to an adverse event occurred in 16% on dasatinib and 7% on imatinib. Of note, the incidence of pleural effusions continued to increase, with 28% of patients on dasatinib affected (26% grade 1/2, 3% grade 3/4) and 0.8% on imatinib. Pleural effusions affected 8% of patients in the first year on dasatinib and the annual rate was comparable thereafter (6-9% per year).r Pleural effusion resulted in drug discontinuation in 6% of the patients on dasatinib.
An Australian retrospective analysis of 212 CML-CP patients demonstrated that pleural effusions were common (25%) and were the predominant cause of permanent drug cessation. Age and dose were identified as risk factors for pleural effusion. Dose reduction and temporary cessations had minimal impact on MR rates, leading to the authors to advise that using lowest effective dose in older patients minimise the effusion risk and the necessity for permanent dasatinib cessation.r
Pulmonary hypertension was reported in 14 (5.4%) patients on dasatinib vs 1 (0.4%) on imatinib in the DASISION study, which is consistent with the Australian retrospective analysis (also 5%). Nine of the patients with pulmonary hypertension had pleural effusions. Overall, the rates of PAH vary between 0.45% up to 25% in registry data and small retrospective analysis.r