De-Escalation or Discontinuation of TKI in Patients with Chronic Myeloid Leukemia:a Multicentral,Open-Lable, Prospective Trial in China

Aim:To observe and assess whether TKI can be de-escalated or discontinued without occurrence of molecular relapse in CML patients,who with continuous effective TKI over 5 years and maintain MR4.5(BCR-ABL^IS≤0.0032%) at least 18 months.

Methods: In this study,we conducted half standard TKI dose or discontinued treatment in patients with CML who were aged 18 years and older and duration effective TKI treatment at least 5 years,duration MR4.5 monitored by quantitative polymerase chain reaction(Q-PCR) in recent 18 months.Blood concentration and immune function were also monitored.Molecular relapse was defined as loss of MMR(BCR-ABL^IS>0.1%), these patients restore the original dose at once.

Results: 44 patients were enrolled between Jan 2016,and Jun 2019,35 in de-escalation group and 9 in discontinue group.In the de-escalation group,45.7% males,median age was 48(23-75) years,valid TKI therapy duration 84(60-204) months,and median sustained MR4.5 was 25(19-160) months.Follow-up 1 year,5(14.3%) of these 35 patients occurrence of molecular relapsed(3 before 6 months,one at month 8, one at month 9),all of them showed decreases in their BCR-ABL levels after reintroduction of original TKI dose.In the discontinue arm,55.6% males,the age ranged from 28 to 56,the median effective TKI treatment was 72(60-108) months and remained of MR4.5 was 36(18-72) months.Molecular recurrence-free events were 66.7% at 12 months,3 patients relapsed events occurred in discontinuous month 1,month 6 and month 12,respectively.All of them showed great reaction when treatment was restarted.Supervised patients blood concentration between standard treatment group and half-dose group,founded half-dose group was lower than standard group(1083.61±371.80ng/ml vs. 1622.28±771.36ng/ml ,P=0.000).The immune function of the relapse and non-relapse arm was observed,in relapsed group the proportion of CD3-/CD56+ cells was declined significantly(P=0.013).

Conclusions: Treatment-free remission(TFR) has become the main therapeutic target for CML patients. With 85.7% TFR in 12 months follow-up after de-escalation TKI treatment ,our study demonstrates that de-escalated TKI would suitable for Chinese CML patients who with a sustained deep molecular response.The vivo insufficient of drug concentration and the damaged of NK cells may cause the recurrence events.