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Editorials
the most relevant data come from observations after the atomic bomb events in Japan where the incidence of CML peaked at a median of ten years but continued at an increased rate for years thereafter.10 These findings have implications about the frequency or even the necessity of long-term PCR monitoring of patients in long-term remis- sion. I have adopted a non-data-driven approach and continue testing approximately every six months after three years of undetectable transcripts. However, we urgently need further information about this.
It is also important to appreciate that only a minority of chronic phase patients can achieve long-term TFR. Most treatment trials describe the rates of molecular response using cumulative incidence analyses, meaning that a patient achieved that level of response at least once. It is more difficult, however, to identify the rates of sustained response, a requirement for considering stopping. In the imatinib-based German CML IV and IRIS trials (the two largest studies with long-term follow up), the rate of MR 4.5 was approximately 50% at five years and >60% at ten years, respectively, although these estimates were not based on the “intent to treat” population11,12 and only included patients for whom data were available at these time points.
Using a somewhat generous estimate of 40% sustained MR4.5 in newly diagnosed chronic phase patients, and a relapse rate of 50%, only approximately 20% of patients will successfully achieve TFR. Calculations may differ somewhat using continuous MR4 as the eligibility cutoff or if patients were treated initially with second-genera- tion TKI which produce higher response rates. Nonetheless, the reality is that the large majority of patients will require life-long treatment, and even those who stop successfully would have required many years of treatment prior to a trial of cessation. Therefore, opti- mal CML treatment will continue to depend on the skills of physicians familiar with ameliorating the side effects of therapy and health systems that deal more effectively with the costs of this chronic treatment.
And this raises the question of whether all patients require the “standard” dose to maintain response or if many of the benefits of stopping, such as reduced side effects and costs, can be achieved with lower doses. Again, data are fragmentary, but many clinical trials and observational studies report that a significant proportion of patients are maintained long term on lower than the initial “standard” doses of TKI.13,14 A recent pilot trial in newly diagnosed patients demonstrated what appear to be identical response rates with less toxicity, using 50 mg of dasatinib versus the standard 100 mg dose.15 Indeed, based on these data, I have been decreasing the dasatinib dose to 50 mg in patients with stable high-grade respons- es on 100 mg with no evidence of loss of benefit in approximately a dozen patients.16
Perhaps the most systematic data come from the UK DESTINY trial in which patients eligible for consideration for a TFR trial had their doses reduced by 50% for one year before drug discontinuation.17 Two per cent of patients who entered the trial with levels of MR4 lost MMR during the first year, while only 18% of those who began with sustained MR3 lost MMR within the year. It is not known how patients would have fared long term
on the lower dose since they went on to the TFR portion of the study. Those who “relapsed” within the first year had therapy restarted, but it is possible that that may not have always been necessary. In fact, a recent modeling exercise using data from large clinical trials suggests that the rise in transcript numbers after dose reduction can be transient in many patients, and that MMR response might have recovered without increasing the dose.18 It is, therefore, clear that a substantial number of patients can do well with lower doses of TKI, but prospective trials addressing this question would be welcomed.
To conclude, the report from the GIMEMA group con- firms that TFR can be achieved in routine clinical practice and indicates that discontinuation be considered in appropriately selected patients outside the clinical trial setting.4 The relapse rate has been consistently in the 50% range in all trials, and future research should focus on the mechanisms by which recurrence is suppressed in the hope that new approaches, possibly immunomodula- tory, can improve these results. In addition, patients should continue to be monitored to assess whether very late relapses develop.
References
1. Bower H, Björkholm M, Dickman PW, et al. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34(24):2851-2857.
2. Etienne G, Guilhot J, Rea D, Rigal-Huguet F, 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.
3. 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.
4. Fava C, Rege-Cambrin G, Dogliotti I, et al. Observational Study of CML Chronic Myeloid Leukemia Italian patients who discontinued Tyrosine Kinase Inhibitors in clinical practice. Haematologica. 2019; 104(8):1589-1596.
5. Hughes TP, Ross DM. Moving treatment-free remission into main- stream clinical practice in CML. Blood. 2016;128(1):17-23.
6. Ilander M, Olsson-Strömberg U, Schlums H, et al. Increased propor- tion of mature NK cells is associated with successful imatinib discon- tinuation in chronic myeloid leukemia. Leukemia. 2017;31(5):1108- 1116.
7. Réa D, Henry G, Khaznadar Z, et al. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discon- tinuation in chronic myeloid leukemia: the IMMUNOSTIM study. Haematologica. 2017;102(8):1368-1377.
8. Mustjoki S1, Ekblom M, Arstila TP, et al. Clonal expansion of T/NK- cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia. 2009;23(8):1398-1405.
9. Schiffer CA, Cortes J, Hochhaus A, et al. Lymphocytosis following treatment with dasatinib in chronic myeloid leukemia: effects on response and toxicity. Cancer. 2016;122(9):1398-1407.
10. Hsu WL, Preston DL, Soda M, et al. The Incidence of Leukemia, Lymphoma and Multiple Myeloma among Atomic Bomb Survivors: 1950–2001. Radiat Res. 2013;179(3):361-382.
11. Hehlmann R, Lauseker M, Saußele S, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017;31(11):2398-2406.
12. Hochhaus A, Larson RA, Guilhot F, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017;376(10):917-927.
13. Faber E, Divoká M, Skoumalová I, et al. A lower dosage of imatinib is sufficient to maintain undetectable disease in patients with chron- ic myeloid leukemia with long-term low-grade toxicity of the treat- ment. Leuk Lymphoma. 2016;57(2):370-375.
14. Visani G, Breccia M, Gozzini A, et al. Dasatinib, even at low doses, is an effective second-line therapy for chronic myeloid leukemia
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