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Expert Breaks Down Data With TKI Discontinuation in CML

Angelica Welch
Published: Friday, Nov 09, 2018

Meagan A. Jacoby, MD, PhD

Meagan A. Jacoby, MD, PhD

Most chronic-phase chronic myeloid leukemia (CP-CML) is effectively controlled by TKIs, and data have shown that many patients can safely stop therapy after a few years. However, the challenge is determining who can discontinue treatment.

"Treatment-free remissions (TFRs) are kind of the new treatment goal now. In CP-CML, there have been multiple trials of TKIs that have shown that TFRs are feasible in select patients," said Meagan A. Jacoby, MD, PhD. "But which patients—and how do you pick them?"

In a presentation during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Jacoby, assistant professor, Department of Medicine Oncology, Division of Bone Marrow Transplantation & Leukemia, Washington University School of Medicine St. Louis, discussed TFRs in patients with CP-CML.

"There are treatment response milestones that you should think about when treating your CP-CML patient. By 3 months, and certainly by 6 months, you should have less than 10% BCR-ABL1 transcripts by International Scale (IS),” said Jacoby. “Failure to achieve this by 6 months constitutes a TKI failure."

Molecular responses in patients with CML are reported relative to a standardized baseline, she explained. The gold standard is the IS, as most clinical trials and guidelines are based on measurements by this scale.

At 12 and 15 months, transcript levels should be less than 1%, as this usually correlates with a complete cytogenetic response. If that is achieved by 15 months, Jacoby said that patients can be monitored every 3 months.

The 144-week results from the ENESTop trial of long-term TFR in patients with CP-CML stopping second-line nilotinib (Tasigna) were presented at the 2018 ASCO Annual Meeting.1

The rationale for this study was based on the ENESTcmr study, which looked at patients who received second-line imatinib (Gleevec) who achieve complete cytogenetic remission, but failed to achieve a deep molecular remission (DMR).2 Patients who failed to achieve a DMR on imatinib were either switched to nilotinib or continued on imatinib. At 2 years, twice as many patients achieved a molecular response of 4.5 with switching to nilotinib than remaining on imatinib. Findings from this study showed that switching to nilotinib may provide a path to DMR and an attempt at a TFR, said Jacoby.

ENESTop evaluated patients with CP-CML who had not achieved a DMR on imatinib and then switched to nilotinib with a TKI treatment duration of ≥3 years, with at least 2 of those years being on nilotinib. These were patients who achieved a molecular response of 4.5 on nilotinib. The primary endpoint was the proportion of patients who were able to maintain a TFR at 48 weeks after discontinuing therapy.

Of 126 patients, 61 remained in TFR at data cutoff, 58 patients restarted nilotinib, and 7 discontinued the study. At 144 weeks, the TFR rate was 48.4% (95% CI, 39.4%-57.5%). Of the 58 patients who restarted nilotinib, 34 had loss of major molecular response. Of those patients, 33 (97.1%) regained major molecular response and 31 (91.2%) regained a molecular response.

Of the 24 remaining patients who restarted nilotinib due to loss of molecular response, 23 (95.8%) regained molecular response. Additionally, stable molecular response was achieved by 42 of 54 patients (77.8%) who regained molecular response.

At week 96, there were an additional 6 patients in TFR, but they experienced a confirmed loss of molecular response (n = 3), death (n = 2), or study discontinuation (n = 1) by week 144. No disease progression or deaths due to CML were reported from the ENESTop trial, with a 144-week treatment-free survival rate of 52.0% (95% CI, 42.9%-60.4%).

Most adverse events (AEs) were reported after TKI discontinuation, also known as "TKI withdrawal," explained Jacoby. Clinically notable AE groupings seen in both arms included cardiovascular events and fluid retention. Additionally, most musculoskeletal pain events were of grade 1/2.

"The conclusion from this study was that a TFR can be durable after second-line nilotinib. Most patients who lose remission do so within the first 24 weeks, but late relapses can occur, so you do need to be diligent about monitoring patients. Most patients can re-attain stable DMR after loss of major molecular response," concluded Jacoby.

The current NCCN guidelines state that treatment discontinuation can be attempted if there is no history of accelerated-phase or blast-crisis CML, if the patient has been on a TKI for at least 3 years, and if the patients experienced a molecular response (BCR-ABL1 ≤0.01% IS) for at least 2 years. These patients should be monitored every month for 1 year, every 6 weeks for the next year, and then every 3 months after that. If there is a loss of major molecular response, TKI should be resumed ≤1 month after. Additionally, TKI withdrawal syndrome should be monitored.


  1. Mahon F, Boquimpani C, Takahashi N, et al. Long-term treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib: ENESTop 144-wk results. J Clin Oncol. 2018;36(suppl; abstr 7003).
  2. Hughes TP, Lipton JH, Spector N, et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014;124(5):729-736. doi: 10.1182/blood-2013-12-544015.

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