Javier Pinilla-Ibarz, MD, PhD
ENESTfreedom is an important study that set the current guidelines for TFR. The trial included 190 patients treated with front line nilotinib at 300mg twice daily for two years that had achieved an MR4.5, followed by one year of consolidation maintaining deep molecular response of at least MR4 were allowed to discontinued therapy. A recent 5 year update of the trial showed that 81/190 patients (42.6%) still remained on TFR (MR4) with 76 (40.0%) in MR4.5. From the patients who lost major molecular response (MMR) and were re-treated, 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR4.5. More important, no disease progression or CML-related deaths were observed, and the adverse event profile was consistent with that reported previously, including a declined incidence of AEs at 96 weeks of the TFR follow up (with low incidence CV AEs), while an expected increase on those in the treatment re-initiation phase. As previously has been described in other trials, Low Sokal risk score, BCR-ABL1 IS levels at 48 weeks of TFR and stable MR4.5 response for the first year of TFR were associated with higher TFR rates.
When looking at patients who can be candidates for TFR, it is important to take in consideration the likelihood of successful discontinuation and educate patients on certain factors that may contribute to good outcomes. The Australian CML group had previously reported the importance of the initial decline rate of BCR-ABL1 measured as halving time as an important factor associated to deep molecular response. The same group, in a very interesting publication , reported the impact of halving time as a strong predictor of sustained TFR post-tyrosine kinase inhibitor (TKI) cessation in CML patients treated with front line TKI therapies.
Out of 115 patients who attempted TFR and had ≥12 months of follow-up, 55% sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, similar percentage seen in other studies. However, when the time taken for the BCR-ABL1 value to halve was applied, it became the strongest independent predictor of sustained TFR with 80% in patients with a halving time of <9.35 days (first quartile) compared with only 4% if the halving time was >21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR.