Pb1967: evaluation of a trial of imatib* dose tapering in the treatment of chronic myeloid leukemia in chronic phase: results at 4.5 years

Topic: 8. Chronic myeloid leukemia - Clinical Background: The introduction of targeted therapies: tyrosine kinase inhibitors (TKIs) in the lead, Imatinib, in the treatment of chronic myeloid leukemia (CML) has made major molecular responses (MMR: ratio < 0.1%) but also deep MRs (PMR) (MR4 and more: ratio < 0.01%) and durable, so the life expectancy of patients (pts) with chronic-phase CML and treated with TKIs is approaching that of the general population and treatment discontinuation have thus been proposed. The British Destiny trial showed the possibility of de-escalating the dose of Imatinib to 200 mg per day for 12 months before stopping it in pts with persistent MMR. Aims: Results of de-escalation dose of generic Imatinib (Imatib*) for one year and then stopping in Algerian patients with persistent MMR Methods: Over a period of 2 years, from October 2017 to October 2019, a therapeutic de-escalation trial according to the criteria of the Destiny trial was conducted. It involved 87 pts with chronic-phase CML, aged >18 years and treated with Imatib* 400 mg for more than 3 years and having a sustained and confirmed MMR or PMR on 3 molecular points during the year preceding de-escalation. It concerns 51 men and 36 women (sex ratio = 1.4), median age 44 years (22 - 76). Of these 87 pts, 25 (29%) were in MR3 and 62 (71%) were in MR4 or above. Molecular monitoring was done every two months during the 12 months of de-escalation and during the year following cessation of treatment and then every three months from the 3rd year by Gene Expert. The evaluation is done on August 30, 2022 with a median follow-up of 57 months (35-58) Results: During de-escalation 11 pts out of 87 (12.6%) had a molecular relapse after a median of 4 months (2 - 12) for MR3 (4/25 pts or 16%) and 4 months (4-10) for MR4 (7/ 62 pts or 11.3%) (p = 0.55). Resumption of Imatib* 400mg in the 11 pts resulted in MMR in all (400mg: 10 pts, 600mg: 1 pt). Of the 87 pts, 76 (87.3%) stopped treatment after reaching 12 months of de-escalation, 21 pts/76 (27.6%) in MR3 and 55 pts/76 (72.3%) in MR4. Among the 76 pts, 40 (52.6%) lost MMR after a median of 3 months (3- 9) for MMR3 (12/ 21 or 57%° and 4 months (2-39) for MMR4 (28/ 55 or 51%). All relapses occurred within the first year for MR3 versus 75% for MR4. Resumption of Imatib* 400 mg in all 40 pts resulted in MMR in all. No progression to accelerated or acutization phase in this trial. Two MMR patients died of non-CML related causes. At 36 months, relapse-free survival (RFS) was 42.8% for MMR3 versus 51.6% for MMR4 with a statistically significant difference (0.05 < p < 0.02). Summary/Conclusion: The comparison of our results with those of the Destiny trial shows an identical distribution of pts according to the depth of molecular response. No difference in terms of percentage of relapse during de-escalation for MR3 (19% versus 16%) but this difference is significant for MR4 (11.3% versus 2.4%) (p < 0.01).The RFS for MR3 is close to that of the Destiny trial (36% versus 42.8%), but for MR4 the DFS is different (51.6% versus 72%). The gradual discontinuation of Imatib* seems interesting in our pts whether they are in RM3 or RM4 but a longer follow-up with a larger sample will allow to draw definitive conclusion. Keywords: Imatinib, Chronic myeloid leukemia