Recurrence-Free Survival May Be Sustainable After De-Escalation or Stoppage of TKI Therapy in CML

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Following 2 years on study, disease recurrence remained low in patients who reduced or discontinued TKI therapy after achieving major response.
Following 2 years on study, disease recurrence remained low in patients who reduced or discontinued TKI therapy after achieving major response.

Tyrosine kinase inhibitor (TKI) de-escalation, or stopping therapy completely, may be an effective management strategy among patients with chronic myeloid leukemia (CML) who have responded to therapy, according to an oral presentation at the 23rd Annual Congress of the European Hematology Association in Sweden.1

Interim analyses of the De-Escalation and Stopping Treatment with Imatinib, Nilotinib or sprYcel (DESTINY) study previously revealed that after 2 years on study, disease recurrence remained low among patients who reduced or discontinued TKI therapy after achieving major response. 

In this final analysis of the DESTINY study (ClinicalTrials.gov Identifier: NCT01804985), investigators presented findings after 12 additional months of complete treatment cessation. Researchers originally enrolled 174 patients in the first chronic phase who had received treatment with the same TKI for at least 3 years and were in either stable deep molecular response (MR4; BCR-ABL qPCR transcript levels < 0.1%) or stable major molecular response (MMR; BCR-ABL qPCR transcript levels between 0.1% and 0.01%).

Previous findings of the trial showed that 23.2% (29 of 125) of patients with stable MR4 had molecular recurrence, and patients in MMR had a recurrence rate of 59.2% (29 of 49) (P< .001). 

Updated data showed that in the following 12 months only 5 additional instances of recurrence had occurred, all among patients with stable MR4, resulting in a recurrence-free survival of 72% (90% CI, 65-79) after 36 months. The overall recurrence rate was still higher in the MMR group compared with the MR4 group (39% RFS overall (90% CI: 29-52%); 20 of 36 patients during cessation; P≤ .001)

Multivariable analysis showed that the duration of TKI treatment was a predictive factor (P= .047) for RFS, but baseline PCR levels were not. The RFS probability remained unrelated to age, gender, prior type of TKI treatment, and performance status. 

No patients experienced progression to the advanced phase, and 1 patient lost hematological response. All cases of relapses regained MMR within 4 months of re-initiating TKI therapy. No differences in RFS were observed between patients who had MR4.5 (PCR level < 0.0032%) at entry compared with those who did not. 

The authors concluded that the findings suggest that “initial de-escalation is not simply delaying recurrence, though the mechanism of its benefit is not yet clear. Possibilities include gradual mobilisation of leukaemic stem cells into cycle and/or gradual improvement in the anti-leukaemic immune response at a time when TKI is still present. These require further study.”

References

  1. Clark R, Polydoros F, Apperley J, et al. Final results of the DESTINY study of de-escalation and stopping treatment in chronic myeloid leukaemia. Oral presentation at: 2018 European Hematology Association 23rd Annual Congress; June 2018; Stockholm, Sweden.

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