Reducing Doses and Stopping Tyrosine Kinase Inhibitors Gain Favor in Chronic Myeloid Leukemia


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Tyrosine kinase inhibitors, such as imatinib, nilotinib (Tasigna), and dasatinib (Sprycel), have revolutionized the treatment of chronic myeloid leukemia (CML). A substantial percentage of patients achieve deep and meaningful remissions on these agents. More recently, partly driven by patients’ and investigators’ concerns about the side effects and costs of these drugs, studies are evaluating the feasibility of using lower doses of tyrosine kinase inhibitors and/or stopping treatment altogether without a negative effect on outcomes.

At the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition, one study showed that lowering the dose of tyrosine kinase inhibitors by half was feasible in some patients and reduced toxicity and cost with low risk of relapse, especially in patients with deep responses.1 A second study found that tyrosine kinase inhibitors could be stopped, but about 50% of patients had a relapse within 2 years of treatment cessation.2

Safety of Reducing Dose or Stopping CML Therapy

  • De-escalating the dose of tyrosine kinase inhibitors by 50% appears feasible in patients with deep molecular remission, with a low rate of relapse.
  • Stopping tyrosine kinase inhibitors in stable patients in chronic-phase CML led to relapses in 50% of patients at 2 years.
  • When patients are restarted on tyrosine kinase inhibitors, they may achieve molecular remission, but the depth and duration of remission are not yet known.
  • For now, it appears safer to reduce the dose of tyrosine kinase inhibitors than to stop therapy, unless patients have been on tyrosine kinase inhibitors for more than 5 years and are in deep remission.

These results should be interpreted with caution, according to expert opinion. At this time, the evidence is stronger for stopping tyrosine kinase inhibitors altogether than for lowering the dose of tyrosine kinase inhibitors in patients with deep remission, depending on the duration of treatment and depth of remission.

Decreasing Doses

Current guidelines for treating CML suggest continuing tyrosine kinase inhibitors indefinitely for patients who achieve remission. It is unclear whether this is necessary for all patients. Side effects of these agents include cramps, fluid retention, excess fluid around the lungs, skin rash, nausea, vomiting, diarrhea, cardiotoxicity, and fatigue, and the drugs are thought to cause congenital abnormalities. Also, the cost of such treatments has increased markedly.

The DESTINY trial enrolled 174 patients with molecular remissions of MR4 (< 0.01% BCR-ABL or undetectable disease) or better as well as those in MR3 (<0.1% BCR-ABL or less deep responses).1 Patients were given half the dose of imatinib, nilotinib, or dasatinib, depending on which drug they were taking.


As patients proceeded through de-escalation of therapy, we saw significant reductions in many side effects within the first 3 months of reduced-dose therapy. After that, there was no further improvement in symptoms over time.
— Mhairi Copland, MB, ChB, MD

Overall, 93% of patients showed no evidence of recurrence within 12 months. Among 174 patients, 12 molecular relapses (ie, loss of MR3 on 2 consecutive samples) occurred between months 2 and 12 of de-escalation. In terms of molecular remission status at study entry, the rate of relapse was 18.4% in those in MR3 (n = 49 patients) and 2.4% in those in MR4 (n = 125 patients). Median time to relapse was longer for those in MR4 at study entry: 8.7 months vs 4.4 months for those in MR3 at study entry.

When relapsing patients were put back on full-dose therapy, all patients recovered to at least MR3 within 4 months.

“As patients proceeded through de-escalation of therapy, we saw significant reductions in many side effects within the first 3 months of reduced-dose therapy. After that, there was no further improvement in symptoms over time,” said Mhairi Copland, MB, ChB, MD, of the University of Glasgow, Scotland, who presented these findings at an ASH press conference and at the ASH Annual Meeting. Lead author Richard Clark, MD, of the University of Liverpool, UK, was unable to attend the meeting.

A financial analysis showed a savings of 46.7% by de-escalating tyrosine kinase inhibitors therapy. Overall, halving treatment saved £1,943,364 from an expected tyrosine kinase inhibitors budget (without de-escalation) of £4,156,969. For the MR4 group, the saving was reduced by 47%, and in the MR3 group, it was reduced by 44.2%. Dr. Copland noted that savings may be even higher in the United States, where drug costs are higher.

Stopping Treatment


Our study used less strict inclusion and relapse criteria than many previous trials. This trial enrolled patients resembling real-life patients, and half are still off treatment without molecular recurrence at 2 years.
— Francois-Xavier Mahon, MD

“Several studies have shown the feasibility of stopping tyrosine kinase inhibitor treatment, with consistent results over time. A sustained deep molecular remission over long-term tyrosine kinase inhibitor therapy seems to be necessary to attempt stopping therapy, but the exact preconditions for stopping CML treatments are not yet defined,” stated lead author Francois-Xavier Mahon, MD, of the University of Bordeaux, France.

Dr. Mahon presented the interim results of the EURO-SKI trial on 755 evaluable patients from 11 European countries who entered the trial between May 2012 and December 2014.2 Patients were on tyrosine kinase inhibitors for at least 3 years and in deep molecular remission (MR4) for at least 1 year prior to study entry.

Of these patients, 373 patients had loss of major molecular response at a median follow-up of 14.9 months (78.3% occurred within the first 6 months of stopping therapy). Median follow-up was 26 months for patients who did not relapse. At 12 months, molecular remission–free survival was 55%; at 24 months, it was 50%; and at 36 months, it was 47%. Molecular recurrence was defined as BCR-ABL > 0.1%.

“Our study used less strict inclusion and relapse criteria than many previous trials. With decentralized but standardized [polymerase chain reaction] monitoring, stopping tyrosine kinase inhibitor therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon stated.

“This trial enrolled patients resembling real-life patients, and half are still off treatment without molecular recurrence at 2 years,” he said. “Longer duration of imatinib therapy, optimally more than 5 years, prior to stopping therapy, correlates with a higher probability of relapse-free survival. Gender, age, and Sokal scores do not predict the probability of successful tyrosine kinase inhibitor stop.” ■

Disclosure: Dr. Copland has received honoraria from Novartis, Amgen, Pfizer, Shire, Bristol-Myers Squibb, and ARIAD; has served as an advisor to Novartis, Pfizer, Bristol-Myers Squibb, and ARIAD; and has received research funding from Novartis and Bristol-Myers Squibb. Dr. Mahon has received honoraria from Novartis, Bristol-Myers Squibb, Pfizer, and ARIAD; has consulted for BMS and Novartis; and has received research funding from Novartis.

References

1. Clark RE, Polydoros F, Apperley JF, et al: Chronic myeloid leukemia patients with stable molecular responses (at least MR3) may safely decrease the dose of their tyrosine kinase inhibitor: Data from the British Destiny Study. 2016 ASH Annual Meeting. Abstract 938. Presented December 5, 2016.

2. Mahon F-X, Richter J, Guilhot J, et al: Cessation of tyrosine kinase inhibitors treatment in chronic myeloid leukemia patients with deep molecular response: Results of the Euro-Ski trial. 2016 ASH Annual Meeting. Abstract 787. Presented December 5, 2016.


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If I see more data reassuring me that the depth of remission is the same when relapsed patients are re-started on therapy, then I will re-think the strategy of stopping tyrosine kinase inhibitors.
— Mikkael Sekeres, MD

In his practice, Mikkael Sekeres, MD, of the...


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