“The biggest concern is relapse,” said Dr Schiffer, “and a sort of amazing thing is that it happens almost exclusively within the first 6 to 8 months with very few relapses thereafter, and frankly, we don’t understand the mechanism of either the fast relapse or, more importantly, of who stays disease free.”

In a study by the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA), published in the same issue of Haematologica, the investigators reported on 293 patients with cpCML who discontinued (first- and second-generation) TKI therapy. After a median follow-up duration of 34 months, the overall estimated treatment-free remission was 62% (95% CI, 56%-68%).4

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This result is higher than what was previously reported in the French imatinib discontinuation study: a molecular recurrence-free survival of 43% (95% CI, 33%-52%) at 6 months and 38% (95% CI, 29%-47%) at 60 months.5 Similarly, in a recent European-based TKI discontinuation study, molecular relapse-free survival was 61% (95% CI, 57%-64%) at 6 months and 50% (95% CI, 46%-54%) at 24 months.6

For patients who are discontinuing TKIs, relapse is defined as the loss of MR3, which must be documented at least twice due to variability in the assay. If a patient experiences relapse, they can resume TKI therapy.1 In the aforementioned studies, patients with longer TKI use tended to have lower relapse rates. Nearly all patients who experienced relapse reinitiated therapy with their original TKI or switched to another TKI and were able to achieve responses that were similar to their response prior to discontinuation.4-6

“I think everyone’s comforted by the fact that if patients recur, they’re essentially 100% treatable,” said Dr Schiffer.

Despite the positive outcomes from initial studies of TKI discontinuation, a majority of patients will need to remain on TKI therapy. Approximately 40% of patients with newly diagnosed cpCML will have sustained MR4.5; therefore, a majority of patients will not meet the eligibility requirements for TKI discontinuation. Even for those patients who qualify, approximately 50% relapse and resume TKI therapy. According to Dr Schiffer’s estimate, only approximately 20% of patients will successfully achieve treatment-free remission.1

However, TKI discontinuation is not the only option for patients with cpCML. Dose reduction is also being studied in clinical trials.1 For example, in the DESTINY trial (ClinicalTrials.gov Identifier: NCT01804985), only 2% of patients with MR4 who received half-dose therapy had molecular recurrence after 12 months. The study also reported reduced adverse effects such as lethargy, diarrhea, rash, and nausea.7 Dr Schiffer has also reported no loss of benefit after decreasing dasatinib dose from 100 mg to 50 mg in patients with stable high-grade responses.1 Thus, dose reduction may provide a route for more patients to experience fewer or less severe chronic long-term side effects of TKIs and reduced costs.

References

  1. Schiffer CA. Discontinuation of tyrosine kinase inhibitors in patients with chronic myelogeneous leukemia – You can do this at home if you read the instructions. Haematologica. 2019;104(8):1508-1511. doi:10.3324/haematol.2019.222216
  2. Bower H, Björkholm M, Dickman PW, Höglund M, Lambert PC, Andersson TM-L. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34(24):2851-2857. doi:10.1200/JCO.2015.66.2866
  3. Schorr A, Mann M. CML Patient story: A 20-year survivor shares his clinical trial experience | chronic myeloid leukemia (CML) | patient power. https://www.patientpower.info/video/cml-patient-story-a-year-survivor-shares-his-clinical-trial-experience. Published 2019. Accessed September 6, 2019.
  4. Fava C, Rege-Cambrin G, Dogliotti I, et al. Observational study of chronic myeloid leukemia Italian patients who discontinued tyrosine kinase inhibitors in clinical practice. Haematologica. 2019;104(8):1589-1596. doi:10.3324/haematol.2018.205054
  5. Etienne G, Guilhot J, Rea D, et al. Long-term follow-up of the French stop imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol. 2017;35(3):298-305. doi:10.1200/JCO.2016.68.2914
  6. Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747-757. doi:10.1016/S1470-2045(18)30192-X
  7. Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Lancet Haematol. 2017;4(7):e310-e316. doi:10.1016/S2352-3026(17)30066-2