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Highlights from

American Society of Hematology

Annual meeting 2018

San Diego 1-4 December 2018

SPIRIT 2: 5-year data released from the largest (n=814) study of imatinib and dasatinib in newly diagnosed CML

Take-home messages
  • There were no statistically significant differences in event-free survival or OS between the two treatment arms
  • Dasatinib demonstrated a higher molecular and cytogenetic response than imatinib
  • Patients receiving dasatinib had higher rates (36%) of pleural effusion compared with those receiving imatinib
Though second-generation TKIs, such as dasatinib, generally produce higher MMR rates than first-generation TKIs, there have been concerns about their long-term safety.

Long-term data on imatinib and dasatinib from SPIRIT 2, the largest study of its kind, were presented at the American Society of Hematology (ASH) 60th Annual Meeting 2018 by Professor Stephen O’Brien, Consultant Haematologist, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.

Imatinib, a first-generation tyrosine kinase inhibitor (TKI), is a commonly used first-line therapy in patients with chronic myeloid leukaemia (CML). Though second-generation TKIs, such as dasatinib, generally provide higher major molecular response (MMR) rates than first-generation TKIs, there have been concerns about their long-term safety.

SPIRIT 2 is a prospective, open-label, phase III trial, which has been ongoing for 5 years. A total of 814 patients with newly diagnosed, chronic phase CML were randomised in a 1:1 ratio to receive either imatinib (400 mg daily) and dasatinib (100 mg daily). Median age was 53.2, and 33.8% (n=275) of patients were >60 years old.

Professor O’Brien’s team found that there were no significant differences in the primary endpoint of 5-year event-free survival between the two treatment arms (dasatinib 91.0% vs imatinib 89.0%; hazard ratio (HR): 0.80; 95% CI: 0.51-1.25; p=0.319), intention-to-treat (ITT) analysis.

Considering some patients switched from randomised treatment to another TKI or other treatment, the team used exploratory per-protocol analyses to avoid data confounding, using the inverse probability of censoring weighting (IPCW) method. These data, released at ASH 2018, also found no significant difference between the treatment arms.

Similarly, there were no significant differences in overall survival in patients receiving dasatinib or imatinib (91.9% vs 91.2%, respectively; HR: 0.90; 95% CI: 0.56-1.47; p=0.690), a secondary endpoint of the study. Other secondary endpoints included: complete cytogenetic response (CCR), MMR (MR3/4: 3 and 4 log reduction), BCR-ABL1:ABL1 ratio<0.1%, toxicity, treatment failure rate, complete haematologic response and quality of life.

In the ITT population, 5-year cumulative incidence of MR3 in first-line therapy was significantly higher with dasatinib (83.0%) than with imatinib (63.0%; 20.0% difference; p<0.0001), as was MR4 (77.5% vs 57.2%, respectively; difference 20.3%; p<0.0001). CCR at 2 years (incomplete data, worst-case scenario) was 42.6% with dasatinib versus 31.8% with imatinib (10.8% difference; p=0.001).

The probability of treatment failure-free survival at 5 years was higher with dasatinib (60.9%) than with imatinib (52.9%; HR: 0.73; 95% CI: 0.59-0.90; p=0.004). More patients in the imatinib arm (7.6%) went on to transplant compared with the dasatinib arm (1.5%), the predominant reason for which, in imatinib patients, was disease progression and suboptimal molecular response.

Pleural effusion occurred at a higher rate in patients receiving dasatinib (36.0%) versus imatinib, with a higher incidence in older patients. Professor O’Brien pointed out, however, that a high percentage of patients in SPIRIT 2 were over the age of 60.

52.2% (n=424) patients completed the study on first-line treatment; 56.7% (n=230) on dasatinib and 47.8% (n=194) on imatinib. More patients switched due to suboptimal cytogenetic response in the imatinib versus the dasatinib arm (1.7% vs 17.4%, respectively), and more patients discontinued due to intolerance in the dasatinib versus the imatinib arm (30.3% vs 16.7%, respectively)

Professor O’Brien concluded by noting that imatinib is considered a highly effective first-line therapy, and that subgroup analyses have been planned to explore whether dasatinib has advantages over imatinib in specific clinical scenarios.

Based on O’Brien S, Cork L et al. SPIRIT 2: final 5 year analysis of the UK National Cancer Research Institute randomized study comparing imatinib with dasatinib in patients with newly diagnosed chronic phase CML (abstract 457). Presented on Sunday 2 December 2018.

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