Is initial treatment with dasatinib for newly diagnosed chronic Phase chronic myeloid leukemia, followed by switching to imatinib for those that achieve MR3.0 at 12 months, an effective strategy? Results of the Phase 2 kinase inhibition with sprycel startup study Free

Introduction Frontline treatment of chronic phase chronic myeloid leukemia (CP-CML) with the second-generation tyrosine kinase inhibitors (2G-TKI) results in a more rapid and deeper molecular response than with imatinib (IM), but is associated with an increased risk of significant long term side effects. The aim of the KISS study was to evaluate the efficacy and safety of initial therapy with the 2G-TKI dasatinib (DAS), followed by a switch to IM for those that achieved MR^3.0 after 12 months of therapy.

Methods A multicenter, prospective, open-label, single arm phase II trial of DAS, followed by IM in previously untreated participants (ppts) with CP-CML was conducted. Participants with CP-CML were commenced on DAS 100mg daily. Those achieving Major Molecular Response (MR^3.0; BCR: ABL1 ≤0.1%) at 12 months, confirmed on repeat testing at 13 months, were eligible to switch to IM 400mg daily with a further two years of follow up. The primary outcome was maintenance of MR^3.0 for 2 years after the switch to IM. Secondary outcomes included: progression free survival (PFS); failure free survival (FFS); overall survival (OS); the proportion of ppts who regain MR^3.0 on DAS or other TKI therapy after having a confirmed loss of MR^3.0 on IM; time to MR^3.0, MR^4.0 and MR^4.5; adverse events (AEs); and quality of life (QoL). Proportions and 95% confidence intervals (CI) for time to event outcomes were calculated using Kaplan-Meier methods.

Results Ninety-six ppts were recruited between 17 July 2017 and 14 April 2022 across 9 New Zealand sites. Three ppts were ineligible due to variant transcript or baseline comorbidities and excluded. Baseline characteristics (n= 93) were: median age 53 years (range 19-79), 56% male, ELTS score 67% low, 27% medium and 5% high. Ten ppts (11%) had additional chromosomal abnormalities detected and 36 (39%) had b2a2 transcripts, 49 (53%) b3a2, and for 8 (9%) it was not determined.

At 12 months, 79 ppts were assessed for eligibility to switch to IM; 14 ppts had discontinued DAS (ten due to toxicity, two due to ppt choice, one developed blast crisis and one developed glioblastoma). Of the 79 ppts, 56 (71%) achieved confirmed MR^3.0, 3 had unconfirmed MR^3.0 and 20 had not achieved MR^3.0. Fifty of the 56 ppts who had achieved a confirmed MR^3.0 consented to switch to IM.

During the 2 years after switching to IM, 43 of the 50 (86%, 95% CI=73 to 94) retained MR^3.0. Of the 7 who lost MR^3.0; 5 regained it (4 switched back to DAS and 1 remained on IM due to prior non-adherence). Of the 2 who did not regain MR^3.0, 1 stayed on IM and 1 switched back to DAS and then had disease progression at month 36. On commencing IM, 12/50 (24%) of ppts were in MR^4.0 and 25/50 (50%) were in MR^4.5. At the end of follow-up (24 months after starting IM) 3/46 (7%) were in MR^4.0and36/46 (78%) ppts were in MR^4.5. Four ppts withdrew before the last study visit; their last MR level was MR^3.0 for 2 ppts and MR^4.5for 2 ppts. Among the 50 who switched to IM 1 ppt had disease progression, 7 treatment failure, and 0 died, giving PFS, FFS and OS at 3 years from start of DAS of 98%, (95%CI=89 to 100), 86%, (95%CI=73 to 94) and 100%, (95%CI=93 to100) respectively.

For the 50 ppts who switched to IM, 24% reported a severe symptom burden as per QoL score at 12 months (after 12 months of DAS), whilst 8% reported a severe symptom burden at 36 months (after 24 months of IM; missing for 7 ppts). Grade 3 or greater AEs were reported for 26% of these ppts in the first 12 months of DAS, and 36% of ppts throughout the 24 months of IM. For the total cohort (93 ppts) the proportion with Grade 3+ adverse events in the first 12 months of DAS was 39%.

Conclusion This clinical trial investigated the efficacy of initial DAS with a planned switch to IM at 12 months for those achieving MR^3.0. IM was well tolerated and effective in maintaining a molecular response in ppts that were in MMR after an initial 12 months of DAS therapy. This should be considered as a treatment strategy for inducing a deep and rapid molecular response but avoiding long term toxicity in patients with newly diagnosed CP-CML