Optimal duration of imatinib treatment/deep molecular response for treatment‐free remission after imatinib discontinuation from a Canadian tyrosine kinase inhibitor discontinuation trial

Abstract

Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/ or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0Á05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cutoff with a P value 0Á01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61Á8%) compared to those with less treatment (36Á0%). Also, 4Á5 years MR4 duration as the shortest cut-off with a P value 0Á003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4Á5 years showed a higher mRFS rate (64Á2%) than those with a shorter MR4 duration (41Á9%).

Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

“…The EURO-SKI trial documented that longer DMR durations were associated with an increased probability of TFR (41). The recent TRAD study further reported that one additional year of MR4.0 duration decreased the risk of TFR failure by 14.0% and proposed six years as the shortest imatinib duration (65). Several studies reported the depth of molecular response at the study baseline could predict TFR (22,25,32).…”

Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia

“…Survival is like that of sex- and age-adjusted people without CML in Europe, but not in the US and certainly not in resource-poor countries [ 33 ]. Considerable data suggest people with CML achieving a stable deep molecular response (DMR; ≥MR 4 ; 4-log BCR::ABL1 transcript decrease from the standardized baseline, corresponding to a transcript level ≤0.01% on the International Scale) can discontinue therapy, about one-half of whom achieving TFR [ 34 – 49 ]. The clinical advantage of TFR over lifelong TKI-therapy is obvious, but the road to achieving this goal is not simple, cheap or rewarding for everyone.…”

“…Expert consensus statements and clinical practice guidelines recommend >5 years of imatinib and >3 to 5 years of a 2G-TKI, with a response ≥ MR 4 for ≥2 years [ 2 , 7 – 9 , 38 , 44 , 46 , 48 , 49 ]. Convincing data supporting these recommendations are lacking [ 10 ].…”

“…Such a trial has not and will not be done. Also, the issue is not whether one or the other therapy is better but which therapy is more appropriate for different persons at different times after CML diagnosis and after observing response to TKI therapy [ 22 , 23 , 26 , 27 , 43 , 44 , 49 , 77 ]. Both therapies have worse outcomes in older people, people with a poor performance score and those with co-morbidities, but these gradients are steeper for transplant recipients compared with persons receiving TKIs.…”

Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review

“… 115 , 143 , 144 , 146 , 147 Recent study by Kim et al proposed six years imatinib treatment and 4.5 years of MR 4 response as the optimal duration for starting TFR. 147 …”