Treatment-free remission (TFR) is feasible after 2 or more years of frontline nilotinib treatment in patients with chronic myeloid leukemia in chronic phase (CML-CP), reported researchers in a study published in Leukemia.

Advances in the treatment of CML have improved outcomes for those with the disease; however, long-term treatment with tyrosine kinase inhibitors has potential adverse effects ranging from cardiovascular and musculoskeletal toxicity to fatigue that can negatively affect quality of life. The costs of life-long treatment add to the burden on patients. Together, these factors may result in nonadherence to treatment. Therefore, treatment goals have shifted to improved quality of life, with current guidelines supporting TFR.

The ENESTfreedom study ( Identifier: NCT01784068) sought to assess TFR in patients with CML-CP who achieve deep molecular response (DMR) after more than 3 years of frontline treatment with nilotinib. DMR was defined as MR4.5 in the most recent assessment, at least 2 assessments between MR4 (defined as BCR-ABL1 ≤0.01% on the International Scale) and MR4.5, and no assessment worse than MR4 in the last 4 quarterly real-time quantitative polymerase chain reaction (RQ-PCR) assessments.

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The study population were patients aged 18 years and older with Philadelphia chromosome-positive CML-CP who had received frontline nilotinib therapy for at least 2 years and achieved MR4.5. In the study, nilotinib was continued for a 52-week consolidation phase during which MR was monitored every 12 weeks by RQ-PCR.

As patients achieved sustained DMR, nilotinib was discontinued and the patient entered the TFR phase. During this phase patients were monitored every 4 weeks for the first 48 weeks, every 6 weeks for the next 48 weeks, then every 12 weeks thereafter. Duration of TFR in this ongoing study will be up to 10 years after the last patient enters the TFR phase.

Nilotinib was reinitiated if an assessment indicated loss of major molecular response (MMR), which was defined as BCR-ABL1 >0.1% on the International Scale. These patients were monitored every 4 weeks for the first 24 weeks after reinitiation and every 12 weeks thereafter or more frequently as clinically indicated in those who did not regain MMR.

Of 215 patients originally enrolled, 190 entered the TFR phase. Primary analysis data showed that TFR was maintained in 51.6% of patients at 48 weeks (0.9 years) after discontinuing nilotinib treatment. At 96 weeks (1.8 years), 48.9% of patients remained in MMR, which was defined as BCR-ABL1 ≤0.1% or better). In this report, the researchers presented an updated analysis after 5 years of follow-up.

The TFR rate at this analysis was 41.6% with very few relapses after more than 1 year following discontinuation of nilotinib. Most of the patients who experienced loss of MMR regained it after reinitiating treatment (90 of 91 patients). Frequent monitoring is key to sustaining TFR, although this study was designed with increasing time between assessments as the TFR phase progressed. Infrequent monitoring could be a concern as early molecular relapses may be missed, potentially increasing the time needed to regain response. “However, our results show that treatment re-initiation as soon as the loss of MMR was identified (within 5 weeks) caused BCR-ABL1IS transcript levels to fall quickly, highlighting the safety of TFR even with quarterly monitoring,” said the researchers.

No disease progression or CML-related deaths were reported among participants in this study, and the incidence of adverse effects declined from 96 weeks after the start of TFR. However, an increase in frequency of adverse effects was noted in patients who experienced loss of MMR and reinitiated treatment.

“Our results suggest that shorter treatment duration with nilotinib before attempting TFR does not substantially decrease the proportion of patients achieving MR4.5 and results in decreased frequency of AEs compared with continuous nilotinib treatment,” the researchers reported.

Disclosure: Multiple authors declared affiliations with and/or received funding from the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Radich JP, Hochhaus A, Masszi T, et al. Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial. Leukemia. Published online March 11, 2021. doi:10.1038/s41375-021-01205-5