The discontinuation of a tyrosine kinase inhibitor (TKI) is considered safe and appropriate in consenting patients with chronic-phase chronic myeloid leukemia (CML) under specific circumstances and with careful molecular monitoring, according to the updated National Comprehensive Cancer Network (NCCN) management guideline for CML.
“We estimate that no more than 50% of patients who were started on a TKI ultimately have the opportunity to stop treatment,” said Neil P. Shah, MD, PhD, Program Leader, Hematopoietic Malignancies Program, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, who presented the updated CML management guideline at the NCCN 2019 Conference. “The others will not get to the sufficiently deep molecular response to enable them to even try this.”
Based on several TKI discontinuation clinical trials, the NCCN panel concluded that achieving and maintaining at least 4-log drop (MR4) in BCL-ABL transcripts for at least 2 years is required before considering TKI discontinuation outside of a clinical trial.
If major molecular response (MMR) is lost, TKI therapy should be resumed immediately, with monthly monitoring until MMR is regained.
TKI discontinuation in CML is most beneficial in women of childbearing potential who are interested in having children and in younger adults, who may want to minimize possible late toxicities as well as financial burden.
The Stop Imatinib (STIM) clinical trial transformed the thinking about stopping TKI therapy in consenting patients who achieved an MMR. Long-term follow-up from STIM showed that 38% of patients remained in remission at 60 months after stopping imatinib (Gleevec) therapy without recurrence. Patients who were eligible for TKI discontinuation had to achieve a 5-log reduction (MR5) in BCR-ABL1 transcripts.
In several TKI discontinuation clinical trials, the treatment-free remission rates after maintaining deep molecular response for at least 1 year were 40% to 60%. In these studies, no significant difference in relapse was observed, according to the depth of molecular response at discontinuation (MR4 vs MR4.5 vs MR5), noted Dr Shah.
As a result, the updated NCCN guideline liberalized the depth of disease remission and the duration of remission necessary before stopping TKI therapy when it instituted its stopping criteria. The threshold for resuming TKI therapy should be liberalized as well, Dr Shah noted, to loss of a 3-log reduction, as the current guideline states.
In patients whose disease relapsed after stopping TKI treatment for the first time, a second TKI therapy discontinuation may be successful when deep molecular response is regained after TKI therapy rechallenge.
The potential biologic mechanisms behind successful treatment-free remission are leukemic stem-cell erosion or exhaustion until a deep molecular response is achieved and immune surveillance, as evidenced by a higher number of immune effector cells in patients with CML who successfully discontinued imatinib treatment.
Although all 3 of the second-generation TKIs improve the rate of deep molecular response over time compared with imatinib, none is associated with significantly improved overall survival or transformation-free survival compared with imatinib, said Dr Shah. Approximately 20% of patients who stop TKI treatment will have a TKI withdrawal syndrome, which is characterized mostly by musculoskeletal symptoms.
“In some instances, these patients elected to go back on their TKI, not to treat their CML, but to treat the musculoskeletal discomfort that arose,” said Dr Shah. “It’s something the patients need to be aware of, so they’re not blindsided if they stop treatment and all of a sudden they have pain in their shoulders, spine, or hips.”
According to the updated guideline, in addition to stable molecular response, other criteria for discontinuing TKI therapy include:
- No history of accelerated- or blast-phase CML
- Treatment with an approved TKI therapy for at least 3 years
- Access to a reliable quantitative polymerase chain reaction test with a sensitivity of detection of at least MR4.5.
Patients who maintained deep molecular responses and discontinued TKI therapy in the context of a clinical trial have had more frequent molecular monitoring than is typically recommended for patients receiving TKI therapy, the guideline notes.
“Because the rate of loss of response is greatest within the first 12 months, we do monthly monitoring for the first 12 months, and then every 6 weeks during the second 12 months if they have not lost MMR, and then we go back to every 12 weeks,” said Dr Shah. “In case they lose that MMR and go back on therapy, they should be followed monthly initially to make sure they go back into an MMR,” he added.