Making Treatment-Free Remission (TFR) Easier in Chronic Myeloid Leukemia: Fact-Checking and Practical Management Tools

Abstract

In chronic-phase chronic myeloid leukemia (CML), tyrosine kinase inhibitors (TKIs) are the standard of care, and treatmentfree remission (TFR) following the achievement of a stable deep molecular response (DMR) has become, alongside survival, a primary goal for virtually all patients. The GIMEMA CML working party recently suggested that the possibility of achieving TFR cannot be denied to any patient, and proposed specific treatment policies according to the patient's age and risk. However, other international recommendations (including 2020 ELN recommendations) are more focused on survival and provide less detailed suggestions on how to choose first and subsequent lines of treatment. Consequently, some grey areas remain. After literature review, a panel of Italian experts discussed the following controversial issues: (1) early prediction of DMR and TFR: female sex, non-high disease risk score, e14a2 transcript and early MR achievement have been associated with stable DMR, but the lack of these criteria is not sufficient to exclude any patient from TFR; (2) criteria for first and subsequent line therapy choice: a number of patient and drug characteristics have been proposed to make a personalized decision; (3) monitoring of residual disease after discontinuation: after the first 6 months, the frequency of molecular tests can be reduced based on MR4.5 persistence and short turnaround time; (4) prognosis of TFR: therapy and DMR duration are important to predict TFR; although immunological control of CML plays a role, no immunological predictive phenotype is currently available. This guidance is intended as a practical tool to support physicians in decision making.

A successful treatment-free remission is achievable also by chronic myeloid leukemia patients lacking optimal requirements

“…In agreement with the findings from EuroSKI and many other studies [ 1 , 10 , 12 ] we found that the duration of stable DMR was the most relevant prognostic factor for TFR success. In a large real-life cohort of 284 patients, the duration of MR 4.0 or MR 4.5 ≥5 years was the only variable associated to a superior TFR success, with and estimated 5-year TFR rate of 87% and 92%, respectively [ 12 ].…”

Elevated plasma levels of IL-6 and MCP-1 selectively identify CML patients who better sustain molecular remission after TKI withdrawal

“…At more than 3 years, 65% of patients maintained TFR, and similarly to Euroski trial the duration of DMR was a significant predictive factor of molecular relapse-free survival [ 4 ]. The similarity between the two trials is remarkable considering that a significant proportion of our patients were treated with generic TKIs; the higher rate of molecular remission could be attributed to the better knowledge of discontinuation criteria [ 5 ] that allowed to optimize patients enrollment and harmonized molecular monitoring available from all Argentinean molecular labs [ 6 ]. IL-6 and MCP-1 differed significantly between groups with an overall model accuracy of 87%.…”

Patient‐reported symptom monitoring and adherence to therapy in patients with newly diagnosed chronic myeloid leukemia

“…32 This finding may have major implications because, regardless of the front-line TKI used, patients who achieve optimal responses at 3 months (early molecular response) have significantly better longterm outcomes, including event-free survival and overall survival, compared with nonoptimal responders. 6 Furthermore, early molecular response is a known predictor of a stable deep molecular response, 33 which is a prerequisite to safely stop treatment (i.e., treatment-free remission), 23 hence with key potential benefits on patients' well-being 34,35 and on a reduction of the financial burden for patients and health care systems because of the high costs of TKIs. 36 Our web-based platform was also well accepted by patients and physicians.…”