Treatment with tyrosine kinase inhibitors (TKIs) like imatinib, nilotinib, and dasatinib, has increased the rates of survival and response over previously available therapies for chronic myeloid leukemia (CML). If patients are able to achieve deep molecular responses (DMRs) with TKIs and maintain this level of response for at least one year, they may be able to discontinue therapy and maintain molecular relapse-free survival (RFS).
This could help patients reduce the risk for treatment-related adverse events (AEs) and high health-care costs, according to results from the European Stop TKI (EURO-SKI) study that were published in The Lancet Oncology by corresponding author François-Xavier Mahon, MD, PhD, of the Institut Bergonié in Bordeaux, France, and co-researchers.
“If we want to increase the success of therapy for CML patients, we need to be ‘patient for the patient’ and treat them for a longer period of time,” Dr. Mahon told ASH Clinical News. “In our study, each additional year of DMR prior to imatinib cessation increased the RFS rate by 2 to 3 percent.”
This report updates earlier results from the multicenter, non-randomized trial, when data were available for the first 200 patients evaluable for molecular RFS at six months, with the goal of defining precise conditions for safe treatment discontinuation. The study enrolled 758 patients (median age at diagnosis = 52.0 years; range = 11.2-85.5 years) with chronic-phase CML who had taken TKIs for at least three years without treatment failure and had a documented major molecular response (MMR; defined as >0.1% BCR-ABL1 transcripts on the International Scale) for at least one year.
Study researchers used reverse transcription polymerase chain reaction to assess molecular response. Assessments were performed once a month during the initial six-month period after discontinuation of TKI therapy. Additional assessments of molecular response were performed every six months until month 12, and every three months thereafter for up to three years.
After a median follow-up of 27 months (range = 21-34 months) from study enrollment and TKI discontinuation, rates of six-month and 24-month RFS were 61 percent and 50 percent among the 755 patients evaluable for molecular response, respectively.
Almost half of patients (n=373; 49%) lost MMR following discontinuation of TKI; 13 (2%) of these patients were reinitiated on TKI treatment while in MMR. Eighty-six percent of these patients (n=321/373) restarted treatment and regained an MMR (including 302 who were in DMR) within a median of 2.8 months (range = 2.7-2.9 months). However, the researchers noted, “because half of the patients had a follow-up of less than one year after restarting treatment (median = 11 months; range = 8-15 months), these results are preliminary.”
In a “learning sample” of 405 imatinib-treated participants, the following factors were associated with a greater likelihood of maintaining MMR at six months:
- longer TKI duration (odds ratio [OR] per year = 1.14; 95% CI 1.05-1.23; p=0.001)
- longer DMR duration (OR per year =1.13; 95% CI 1.04-1.23; p=0.0032)
These findings were also observed in a validation sample comprising patients treated with any firstline TKI therapy (n=171), though the associations were not statistically significant:
- longer TKI duration (OR per year = 1.09; 95% CI 0.98-1.21; p=0.13)
- longer DMR duration (OR per year = 1.13; 95% CI 0.98-1.29; p=0.08)
While results from the learning sample suggest that the optimal cutoff for DMR duration is 3.1 years and the optimal imatinib duration is 5.8 years when considering TKI cessation, these cutoff values could not be confirmed in the validation sample. “The likelihood of treatment discontinuation succeeding might decrease or increase with otherwise shorter or longer treatment durations,” the authors wrote.
“In spite of persisting leukemic cells at a significant level (MR4), patients do not relapse,” he added. “Most of the molecular recurrences occurred during the first six months after TKI cessation, but knowledge of factors that could influence late relapse or recurrence is necessary.”
No serious AEs were reported in the trial. While 31 percent (n=233) of patients experienced TKI withdrawal syndrome, these mostly consisted of transient symptoms (e.g., musculoskeletal or joint pain). Ten patients died during follow-up, and all patient deaths were considered unrelated to CML: four died while in MMR (due to myocardial infarction, lung cancer, renal cancer, and heart failure) and six (2%) died in chronic-phase CML after loss of MMR and reinitiation of TKI therapy (due to myocardial infarction, cerebral infarction, pancreatic cancer, septicemia, pneumonia, and heart failure).
The authors also calculated costsavings associated with TKI discontinuation, finding that – because branded imatinib costs an average of €2,262 per month – participants would have saved an estimated €22 million by stopping TKI therapy.
When asked how these findings might affect clinical practice, Dr. Mahon proposed that “TKIs could be stopped outside the clinical-trial environment provided that strict molecular monitoring is performed.”
As a potential limitation of the study, the researchers noted that, because “the date of the first observation of DMR was retrieved retrospectively, … [they] might not always be exact.” The study also was not designed to detect differences in response and survival according to the type of TKI used, and did not report long-term success of re-initiating TKIs in patients who relapsed following cessation.
The corresponding authors report financial relationships with the ELN Foundation, Novartis, Bristol-Myers Squibb, Pfizer, Incyte, Janssen, Celgene, Alexion, Servier, Institute for Hematology and Oncology, Amgen, Ariad, and the French National Cancer Institute. The formal sponsor of the study was Heidelberg University, on behalf of the ELN Foundation.
Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018 May 4. [Epub ahead of print]