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Update on CML: Focus on Sequential Therapy, Treatment Discontinuation, and Monitoring


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Chronic myeloid leukemia (CML) is a poster child for the success of molecularly targeted therapy, with some patients appearing to be “cured” of their disease and others living for a long time after treatment with a tyrosine kinase inhibitor targeting the BCR-ABL1 protein. However, there are still some issues surrounding the treatment of CML, most notably how best to monitor response and which patients can safely discontinue therapy.

At the 2018 National Comprehensive Cancer Network® (NCCN®) Annual Congress: Hematologic Malignancies™, Jerald P. Radich, MD, a member of the Clinical Research Division of the Fred Hutchinson Cancer Research Center, Seattle, discussed sequential therapy with tyrosine kinase inhibitors, data from clinical trials on the criteria for successful discontinuation of tyrosine kinase inhibitor therapy, and the role of mutational analysis and molecular monitoring in the management of patients with CML.1 Fittingly, he gave his talk on World CML Day.

“Right now, we have an embarrassment of riches in ways to treat CML. The main issues we face are minimizing toxicity, preventing patients from progressing to advanced phase, and selection of appropriate patients for discontinuation of therapy,” Dr. Radich told listeners.

Dr. Radich listed three major accomplishments regarding CML, all made possible by the identification of BCR-ABL1 as the target for therapy: CML is now a chronic disease; CML has proven the concept of targeted therapy; CML demonstrates the promise of molecular monitoring. Open questions relate to why some people respond to tyrosine kinase inhibitor therapy and others do not, why resistance develops, and criteria for discontinuing therapy.

Treatment Initiation

In Dr. Radich’s Opinion, the starting drug depends on the goal of treatment for the patient and the physician. For an older patient (aged 65 or older), imatinib is a good choice. “Imatinib changes the course of disease and leads to long-lasting remission with minimal toxicity, especially minimizing the cardiovascular toxicity that can occur with some of the newer second-generation tyrosine kinase inhibitors,” he noted.


If there is doubt about adherence, the decision to change therapy or not can be made at the 6-month mark.
— Jerald P. Radich, MD

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“Some patients are more appropriately started on second-generation drugs, which can give a deeper molecular response quicker and have been shown to be more effective in blocking the transition to advanced-phase disease,” Dr. Radich stated. “Younger patients who want to start a family may want to get a deep response and discontinue therapy. In addition, chronic-phase patients who appear to be clinically close to an advanced stage of disease might benefit from a second-generation tyrosine kinase inhibitor.”

The choice of second-generation tyrosine kinase inhibitor is based on a number of considerations, including specific mutations identified on mutational testing, comorbidities, and a physician’s comfort level with a specific drug. For example, ponatinib (Iclusig) is the preferred choice if a T3151 mutation is present, but it is also the drug with the highest rate of adverse cardiovascular effects. “In some patients, it may be wise to start with a lower dose, and when possible, use ponatinib as a bridge,” he advised.

Therapeutic Considerations

The goal of tyrosine kinase inhibitor therapy is to eradicate blast crisis. “The 10-year survival rate of roughly 90% is mostly due to eradication of blast crisis. With treatment, blast crisis is now very unusual,” he said.

Imatinib as well as nilotinib (Tasigna), dasatinib (Sprycel), and bosutinib (Bosulif) are used as first-line therapies for CML. Second- and third-line therapies include bosutinib, dasatinib, nilotinib, and ponatinib. Other therapeutic options include enrolling in a clinical trial.

“We need other therapies for patients with a suboptimal response or intolerance. All randomized trials show that nilotinib, dasatinib, and bosutinib have an advantage over imatinib with a better response and less disease progression. However, survival is the same with imatinib and second-generation drugs, and we don’t know the reasons for this,” Dr. Radich continued.

Monitoring

“There has been a remarkable shift in how we follow patients with CML. We don’t do bone marrow testing except at diagnosis. We follow them with peripheral blood based on the level of BCR-ABL1,” he told attendees. Patients who achieve 0.1% BCR-ABL1 have excellent event-free survival. The lower the BCR-ABL1 level, the better the survival rate. “Major molecular response of 0.1% is a safe harbor. Once you reach that level or lower, resistance and progression are rare,” he stated.

Response is determined at 3 months (early molecular response) and at 6 months. Patients with more than 10% BCR-ABL1 at 3 months have a poorer prognosis than do patients with a better response. “But you have to be careful and thoughtful, because at 3 months, a poor response might be because it is early after diagnosis and the patient is having some toxicity and adjusting the intake of the drug. If there is doubt about adherence, the decision to change therapy or not can be made at the 6-month mark,” he continued.

“The group with the worst prognosis includes those with more than 10% BCR-ABL1 at both 3 and 6 months. Their chance of achieving major molecular response is 3.3%. You should think about changing therapy at this point. Now we can salvage patients who have BCR-ABL1 more than 10%,” he said.

Managing Patients With CML

  • Monitoring the level of BCR-ABL1 while a patient is receiving tyrosine kinase inhibitor therapy is critical to prevent progression to accelerated-phase disease. 
  • In the future, duplex sequencing may replace current mutational testing.
  • Discontinuation of tyrosine kinase inhibitor therapy is a possibility, but it should be done under strict criteria.

Once patients reach accelerated (blast) phase, survival is generally as poor as it was in the pre-imatinib era. “One of the main reasons for monitoring patients on tyrosine kinase inhibitor therapy is to prevent blast crisis by initiating transplant for salvaging them,” he noted.

Of the patients who become resistant to initial therapy, 25% to 50% will have resistance due to mutations of the ABL1 kinase domain region, leading to decreased binding of the tyrosine kinase inhibitor. The results of mutational testing can guide the choice of the tyrosine kinase inhibitor chosen as salvage therapy.

Routine testing before resistance is constrained by current methods of mutational testing, which have limited sensitivity and may be prone to false-positive results. “The promising technology of duplex sequencing may allow accurate testing, enabling the detection of one mutated sequence in a background of a million normal sequences, a thousandfold improvement over current methods,” Dr. Radich explained.

Switching Therapy

NCCN Guidelines state that therapy should be switched if patients have more than 10% BCR-ABL1 at 6 months. “Switching to a second-generation drug will rescue some people but not all,” stated Dr. Radich.

If there is no response at 3 months after changing tyrosine kinase inhibitor therapy, he suggested looking for a donor, so the patient can be transplanted. Otherwise, the patient’s disease may progress to accelerated phase, where the results of transplantation are greatly inferior compared with chronic phase.

Treatment Discontinuation

About 20% of patients can safely undergo treatment discontinuation, he noted. “Discontinuation of tyrosine kinase therapy is under intense study. There is a cottage industry of discontinuation trials currently ongoing,” Dr. Radich said.

Ongoing studies are attempting to determine the optimal circumstances for considering treatment discontinuation, but they are not written in stone. Evidence suggests that the depth of response and the duration of response, as well as the time to treatment failure, are important factors to consider.

“Do not try discontinuation at home,” Dr. Radich cautioned. “Follow the NCCN criteria for tyrosine kinase discontinuation.”

Right now, CML is a relatively rare disease, with only 2 cases per 100,000, but projections are that CML is on the rise. With increasing longevity, it may become a fairly common disease. Dr. Radich estimated there will be 120,000 new cases by the year 2020.

“CML will be a common beast in your practice. Think about the complications and do something before they happen,” he advised. ■

DISCLOSURE: Dr. Radich has served as an advisor or consultant to Novartis Pharmaceuticals Corporation.

REFERENCE

1. Radich JP: Optimizing TKI therapy for chronic phase CML: Sequencing of TKI therapy and treatment-free remission. 2018 NCCN Annual Congress: Hematologic Malignancies. Presented September 22, 2018.


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