May 2014, Vol 3, No 3

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Molecular Monitoring Can Provide Treatment Guidance in CML

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Monitoring molecular response to tyrosine kinase inhibitor (TKI) therapy for chronic myelogenous leukemia (CML) may help guide the decision to switch therapy and the timing of progression to second- and third-line therapy, said Jerald P. Radich, MD, at the 2014 meeting of the National Comprehensive Cancer Network (NCCN).

Response rates to TKI therapy in CML are high, and many times these responses can be measured only at the molecular level. The reliance on molecular monitoring as a sensitive measure to monitor response is increasing. Molecular monitoring detects the presence of BCR-ABL1 mRNA using real-time quantitative polymerase chain reaction. A major molecular response (MMR) is defined as a reduction in BCR-ABL transcript levels of at least 3 logs compared with a standardized baseline obtained from patients with untreated newly diagnosed CML.

“The concept of MMR…ended up having profound clinical utility,” said Radich, a member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center and professor of medicine at the University of Washington, Seattle, WA. “It indicates patients who are very stable. Once you reach MMR, unless you discontinue medications, your chance of progressing to accelerated phase or becoming resistant is almost nil.”

A BCR-ABL transcript level <10% at 3 months predicts clinical outcome. The 8-year probability of survival after first-line imatinib therapy improved to 93% with a BCR-ABL transcript level ?10%, compared with a 57% probability at a level >10%. Similar findings have been obtained with dasatinib and nilotinib.

The BCR-ABL transcript level at 3 months can also predict MMR, he said, with poor achievement of MMR with a BCR-ABL transcript level >10% as opposed to “an outstanding chance of achieving MMR in those who have their disease fall off the cliff in a few months.”

When to Switch Therapy
The NCCN considers the lack of a complete molecular response at 3 months a treatment failure, at which time it recommends applying a different therapy. “If somebody has had an incomplete exposure to any of the TKIs at a few months, and they’re not at 10%, you can be patient,” he said. “But if somebody has been taking their drug religiously for 3 months, and they’re not below 10%, then you have to think [about switching].”

The European LeukemiaNet (ELN) recommends waiting until 6 months to determine the need for a change. “The reason is because there are no data that show that early switching has anything to do with changing the natural history of the disease,” Radich continued. “A fair amount of people who don’t reach 10% by 3 months will progress to accelerated phase or blast crisis by 6 months. So you’ll lose some of those people if you’re too patient.”

Up to 200 resistance mutations have been found in CML. Mutational analysis may provide additional information for patients with inadequate response. The NCCN and ELN also recommend mutational analysis when patients lose response, progress to accelerated phase or blast crisis, or experience a 1-log increase in BCR-ABL transcript levels with loss of MMR.

Salvage therapy with second-generation TKIs produce a complete cytogenetic response (CCyR) 25% to 50% of the time. Eventual relapse is common in patients who achieve CCyR with salvage therapy. “You have to think about what’s down the line for them, such as transplantation,” he said.

When starting salvage therapy, “3 months of therapy is enough to tell you how people are going to do. If they have a CCyR at 3 months, they do great,” he said, noting that CCyR is the only factor independently associated with event-free and overall survival in patients on second-line TKIs.

“If they don’t achieve CCyR, you have to go to plan C. That turns out to be a really convenient time because most unrelated donor searches take around 3 to 4 months,” he said.

Median survival is about 10 months for patients who progress to accelerated phase or blast crisis. Undergoing transplantation is the only option for cure in these patients, with survival rates decreasing from 85% in patients in chronic phase to 40% in accelerated phase to 10% to 20% in blast crisis. “You have to make sure to move these people to more aggressive therapy, and you need to move them there in a timely fashion, not when they’ve blown up to advanced phase disease,” said Radich.

About 40% of patients can remain in complete molecular remission for up to 2 years after TKI discontinuation. Stopping TKI therapy after achievement of complete molecular remission should not be attempted outside of a clinical trial, he said.

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