Conference Coverage

New data and trial outcomes clarify path to TFR in CML



The rate of reduction in BCR-ABL1 value during the first 3 months of tyrosine kinase inhibitor therapy for chronic myeloid leukemia (CML) independently predicts the likelihood of sustained treatment-free remission (TFR) in eligible patients, a recent study shows.

The findings, along with the 10-year outcomes data from the phase 3 ENESTnd trial reported in 2019, can help with complex TFR decision-making, lead author Timothy P. Hughes, MD, said at the Society of Hematologic Oncology virtual meeting.

In 115 chronic-phase CML patients who were eligible and attempted TFR and had at least 12 months of follow-up, the probability of sustained TFR, defined as major molecular response off tyrosine kinase inhibitor therapy for 12 continuous months, was 55%. The time to halving of the BCR-ABL1 value after the start of therapy was the strongest independent predictor of success. Sustained TFR occurred in 80% of those in the first quartile of response time (halving time of less than 9.4 days), compared with 4% of those in the last quartile (halving time of more than 21.9 days), said Dr. Hughes of the South Australian Health and Medical Research Institute, Adelaide.

The model assumes molecular response of 4.5 status duration for 3 years – not just achievement of MR4.5.

“So that’s the other variable in this equation,’ he said.

The findings, which were published online Sept. 1 in Blood, were validated in an independent dataset.

Dr. Hughes and colleagues concluded that the data “support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.”

As an example of how the findings, along with those from ENESTnd, can help with TFR decision-making, Dr. Hughes presented a case involving a 59-year-old man with chronic-phase CML diagnosed 5 years prior with intermediate EUTOS long-term survival score (ELTS) and Sokal scores and a low Framingham Risk Score at diagnosis.

The patient was treated with frontline nilotinib at a standard dose of 300 mg twice daily and he responded well, achieving an MR4 molecular response after 18 months, and MR4.5 score at 2.5 years, which was maintained at 5 years.

“That’s a BCR-ABL level of less than 0.01% on the International Scale,” he said, noting that the patient’s BCR-ABL level started at 290% and had “a very, very steep fall to 0.26% at 3 months.”

Cardiovascular risk a factor

The patient was interested in attempting TFR when eligible, but had some vascular toxicity risks; he was being treated for hypertension and hypercholesterolemia and also had a family history of coronary artery disease.

Hypercholesterolemia is a recognized effect of nilotinib therapy, but both where being treated and were under control, Dr. Hughes noted.

The patient’s Framingham Risk Score had increased from 9 (low risk) to 16 (intermediate risk).

In determining whether to attempt TFR and closely monitor the patient or delay the attempt and perhaps either change to imatinib therapy or reduce the nilotinib dose, Dr. Hughes said it was important to consider the cardiovascular event risks as elucidated in ENESTnd.

It was hoped that the increased cardiovascular event risk demonstrated in years 0-5 of the study would diminish in the later years, but the 10-year finding actually showed persistent risk with nilotinib treatment: In years 0-5, 7.2%, 11.9% and 1.8% of patients in study arms receiving nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib 400 mg once daily, respectively, experienced a cardiovascular event. In years 5-10, the corresponding rates were 9.3%, 11.9%, and 1.8%.

“I think it’s an important message that the risk is there, at about the same rate, in the second 5 years,” said Dr. Hughes, the first author of the study.

The ENESTnd data also show how the Framingham Risk Score, which is based mainly on age, cholesterol levels, blood pressure, smoking history, and diabetes history, is associated with cardiovascular event rates in the treatment arms.

Patients with a low Framingham score who were receiving nilotinib had no greater risk of a cardiovascular event than did those receiving nilotinib during years 0-5.

“I think that makes it an attractive option in patients where you’re focusing on early achievement of deep molecular response and eligibility for treatment-free remission,” he said, adding that it’s a different story for those with intermediate or high Framingham scores, who have “ a really quite substantial” risk in the first 5 years.

The 5- to 10-year ENESTnd data, however, show that this lack of risk in low Framingham scores did not hold true. Even in those with a low-risk Framingham score, the overall 10-year event rate was 7.3% with nilotinib versus 1.1% with imatinib.

“This is an important message that it’s probably not appropriate to assume that your patient with low Framingham Risk Score at diagnosis is not having a higher risk of cardiovascular events in the period after 5 years out to 10 years,” Dr. Hughes said.

Of note, the case patient was considered eligible for TFR under all of the mandatory requirements of both the 2020 European LeukemiaNET recommendations and the National Comprehensive Cancer Network 2020 guideline for CML, which have slight differences but are “generally in accord.”

Based on those recommendations, the patient would be “eligible and probably recommended,” for TFR, he said.

The 10-year ENESTnd findings and the findings by Dr. Hughes and colleagues with respect to the tempo of early tyrosine kinase inhibitor response provide further confirmation of the patient’s eligibility.

“I would feel very happy to say to this patient: ‘You’ve got an excellent chance of achieving treatment-free remission today; going on with therapy is probably not in your interest given the risk of a cardiovascular event, so I’d recommend stopping,’ ” he said. “If the patient was not keen to stop, then I’d recommend switching to imatinib, because I don’t think we’re getting any great benefit from pushing on with nilotinib if the plan is not to attempt treatment-free remission.”

However, if the patient preferred another year of treatment before attempting TFR, it might be worth considering reducing the dose or switching to low-dose dasatinib, he noted, concluding that “the vascular risk profile and the prospect of treatment-free remission need to be carefully considered in every patient, particularly patients on second-generation drugs, before deciding whether to recommend treatment-free remission or extending therapy longer and whether it’s appropriate to just reduce the dose or switch.”

Dr. Hughes has received grant or research support and honoraria from Novartis and Bristol-Myers Squibb, and has been a paid consultant and advisory committee or review panel member for both companies.

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