Chronic Myeloid Leukemia: 5 Things to Know

Victoria Stern, MA

Disclosures

September 17, 2019

3. TKI adherence is a problem for younger patients.

Compliance with TKIs is critical for achieving a complete molecular response. Younger patients (≤ 50 years) with CML are less likely than their older peers to adhere to their drug regimen.[10,11,12]

The financial drain of TKI therapy affects compliance but probably has more to do with a patient's insurance coverage and out-of-pocket expenses than with age.[13,14] The main drivers of poor adherence in younger patients appear to center around quality-of-life issues, including concerns about drug-related side effects, ability to work, and fertility, as well as inadequate information about treatment and medication.[10,15]

4. Novel approaches may better predict treatment-free remission.

Patients who exhibit a robust and rapid response to TKIs may be more likely to achieve a deep molecular response and ultimately treatment-free remission. Hitting certain milestones within the first year on TKIs—such as BCR-ABL1 transcript levels ≤ 10% by 3 months and < 0.1% by 12 months—is particularly important for predicting treatment success.[9] Currently, clinicians use real-time quantitative polymerase chain reaction (PCR) to track the path of a patient's response to TKIs. But this conventional PCR method comes with a major limitation: It cannot detect BCR-ABL1 levels below a certain threshold (≤ 0.0032%).

Being able to measure BCR-ABL1 levels with greater granularity may allow clinicians to better predict a patient's chance of sustaining treatment-free remission. A growing body of research reveals that a PCR technique called digital PCR can detect BCR-ABL levels with more sensitivity and accuracy than real-time PCR. A 2019 analysis found that digital PCR improved clinicians' ability to identify patients in durable deep molecular remission, as well as potential candidates for TKI discontinuation.[16] Another method—long‐range nested real-time PCR combined with ultra‐deep sequencing of BCR-ABL—can identify TKI-resistant BCR-ABL mutations.[17] Pinpointing these mutations could help clinicians assess a patient's response to TKI therapy with greater accuracy, as well as whether (and when) a patient should switch drugs.

5. Emerging CML inhibitors could move the needle closer to a cure.

Several new CML inhibitors in preclinical and clinical trials show promise to enhance outcomes, especially for patients who are resistant or intolerant to available TKIs.

One novel inhibitor, asciminib (ABL001), binds to a different pocket on the BCR-ABL oncoprotein than the current collection of TKIs. Combining asciminib with a TKI—thus inhibiting two targets on BCR-ABL—may enhance major molecular response rates and help curb resistance.[18] So far in phase 1 studies, asciminib has demonstrated clinical activity and a solid safety profile in patients resistant or intolerant to two or more TKIs and in patients with the T315I mutation.[19]

Janus kinase (JAK) inhibitors, when combined with a TKI, may also improve the likelihood that patients will reach a complete or major molecular response. Preclinical data show that dual therapy—a JAK2 inhibitor plus imatinib, nilotinib (Tasigna), or dasatinib (Sprycel)—can eradicate CML cells and restore TKI sensitivity in resistant CML cell lines.[20] The JAK inhibitor ruxolitinib (Jakafi) has already received FDA approval to treat myelofibrosis, polycythemia vera, and acute graft-versus-host disease. A clinical trial now underway is exploring whether ruxolitinib plus nilotinib can eliminate the CML stem cell population in patients with chronic-phase disease.

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