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Neil P. Shah, MD, PhD

NEW YORK—If any oncology drugs warrant a high price, BCR-ABL tyrosine kinase inhibitors (TKIs) could make a strong case, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.

TKIs have revolutionized the therapeutic landscape in chronic myeloid leukemia (CML), said Neil P. Shah, MD, PhD, of the UCSF
Helen Diller Family Comprehensive Cancer Center in San Francisco.

Five-year overall survival is 93% in CML patients treated with imatinib. And 80,000 people are estimated to be living with CML in 2014, a number that is expected to double by 2035.

Yet the increase in life expectancy places a burden on the healthcare system, Dr Shah said, particularly since the price of BCR-ABL TKIs has risen dramatically.

A year of imatinib therapy circa 2001 cost approximately $30,000, and by 2013, approximately $92,000. Second-generation (2G) TKIs cost even more, at about $115,000 annually, and the third-generation TKI ponatinib costs about $138,000 annually.

Confounding the financial picture will be the advent of generic imatinib, which will be available in the US in early 2016.

Generic imatinib will, presumably, be less expensive than the brand-name drug. However, it is not clear whether it will be as effective or what impact it will have on the 2G and 3G TKIs.

With all that in mind, Dr Shah provided some options for maximizing therapeutic outcomes in a fiscally responsible manner.

He based his potential solutions on evidence-based premises. First, imatinib is a highly active therapy for many chronic-phase CML patients. The 8-year update of the IRIS study shows that 53% of patients sustain complete cytogenetic remission (CCyR) with imatinib.

Second, patients who are likely to do well on TKI therapy can be identified early based on their BCR-ABL PCR levels after 3 months of therapy.

This important 3-month milestone has been incorporated into the NCCN guidelines. Patients who achieve BCR-ABL/ABL levels of 10% or less have a significantly better overall survival than those who have levels greater than 10%.

Third, the ENESTnd and DASISION studies demonstrated that nilotinib and dasatinib elicit achievement of important treatment milestones (PCR<10% at 3 months and CCyR after 12 months) in a significantly higher proportion of patients than imatinib. But to date, neither agent has produced a significant improvement in overall survival.

And fourth, while nilotinib and dasatinib have an undisputable clinical benefit over imatinib in terms of transformation to accelerated phase/blast crisis (AP/BC), these agents cost between $23,000 and $31,000 more than imatinib for an annual course of treatment.

Dr Shah calculated that to achieve approximately 10 fewer AP/BC transformations over 5 years, approximately 300 patients would need to be treated at an additional cost of $37.5 million. This equates to $3.75 million in additional costs for 1 transformation event spared over 5 years.

“We do have to keep in mind transformation events are not cheap,” he said. “So when these happen, patients need to be hospitalized for chemotherapy, typically, or they have to go to allogeneic stem cell transplantation.”

So Dr Shah proffered 3 potential approaches for fiscally sustainable TKI use.

The first approach would be to initiate imatinib in most, if not all, chronic-phase CML patients. If they achieve BCR-ABL levels <10% at 3 months or partial CyR after 12 months, then continue imatinib. If not, switch to a 2G TKI.

Dr Shah noted that 40% to 60% of patients will have a deep, durable response to imatinib.

The second approach would be to initiate 2G TKIs in newly diagnosed patients. And when they achieve CCyR or major molecular response (MMR), enroll them in a clinical trial.

These trials could investigate a switch to imatinib, use of a lower dose of the 2G TKI, a switch to interferon-alfa, the addition of a CYP3A4 inhibitor (such as grapefruit) and a lower dose, or another investigational option.

And the third approach would be to initiate imatinib or an approved 2G TKI in newly diagnosed patients. When they achieve targeted molecular remission, enroll them in a treatment-discontinuation trial.

Dr Shah pointed out that in the STIM study, 61% of patients remained in complete molecular remission 60 months after discontinuing imatinib, and 40% experienced treatment-free survival.

Taking into account the cost of imatinib and the number of months without treatment, STIM investigators estimated the savings to be €4,587,500, or approximately $6 to $7 million.

Patients who relapsed 6 to 9 months after discontinuing imatinib tended to respond well to a rechallenge with imatinib. But Dr Shah cautioned that, at present, discontinuation should only be performed in the context of a clinical trial. ht-logo-end

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