Balancing Clinical Data and Real-World Insights in CML Treatment

Michael Mauro, MD

With treatments for chronic myeloid leukemia (CML) evolving, precision and personalization are more needed than ever. According to Michael Mauro, MD, the growing arsenal of tyrosine kinase inhibitors (TKIs) and better understanding of patient-specific factors have helped oncologists tailor therapies to what each individual patient needs.

“Managing CML is a marathon, requiring a minimum of 3 to 5 years of therapy, even with our current best thoughts on the curative pathway, and that is only for a select group of patients. This group of patients can achieve an early and optimum response,” explained Mauro, director of the CML program in the leukemia service at Memorial Sloan Kettering Cancer Center, in an interview with Targeted Oncology^TM.

Mauro highlighted the need for a balanced approach, integrating both real-world data and clinical trial evidence to optimize outcomes. He also discussed asciminib (Scemblix) as a new STAMP inhibitor showing superior efficacy in frontline treatment over imatinib (Gleevec) and even some second-generation TKIs. In October 2024, the FDA granted accelerated approval to asciminib for newly diagnosed Philadelphia chromosome-positive CML in chronic phase.

Long-term data will confirm its potential for achieving higher rates of treatment-free remission and possibly cure. Managing CML remains challenging due to the need for long-term or lifelong therapy, emphasizing the importance of adherence, adverse effect management, and communication between patients and healthcare providers.

In the interview, Mauro delved into the rapidly advancing field of CML treatment.

Microscopic, photorealistic image of chronic myeloid leukemia (CML) cells - Generated with Adobe Firefly

Targeted Oncology: With the increasing number of targeted therapies in CML, how do you approach decision-making and select the most appropriate treatment options for patients?

Mauro: Decision-making for a [patient with] CML can be complicated, depending on the state on the stage you are at when a patient [with CML] is first diagnosed. That is probably the most important point: to do it right [by] looking at all the factors, [including] the disease itself and the patient in great detail–their health, comorbidities, and what is best for them. The [goal should be] to have the highest yield and the lowest risk, to achieve the best response, to be practical with milestones and goals of therapy without shortchanging the patient's meaning. Let us not exclude the possibility of a curative approach for all patients with CML or an optimum approach simply based on fear of adverse events or uncertainty.

The good thing is, we have multiple therapies available, so switching and optimization based on the patient’s response can really make headway, [even] if we do not see exactly the perfect trajectory. Hopefully a cure can still be at least a considered goal for all patients.

What are some of the challenges being faced in managing patients with CML?

Managing CML is a marathon, requiring a minimum of 3 to 5 years of therapy, even with our current best thoughts on the curative pathway, and that is only for a select group of patients. This group of patients is able to achieve an early and optimum response. [However], for the majority of patients, it is chronic or even lifelong therapy—more like an ultramarathon. Managing adherence, compliance, [and] tolerability and keeping the lines of communication open with patients is essential, as adverse events are often lower grade, though serious ones must be managed quickly.

The challenge lies in considering all factors with the patient and making appropriate decisions [based on their situation]. For patients with issues in response, resistance, or tolerance, which are often intertwined, the focus shifts more towards disease biology, therapy choice, mutational analysis, and [exploring] factors like non-BCR-ABL myeloid mutations to improve outcomes.

There are challenges at each turn, [including] treatment cessation, ensuring patients stay engaged, monitor frequently, respond to molecular changes, and consider additional attempts if needed.

How do you balance the use of real-world data and clinical trial evidence when making treatment decisions?

I have the benefit of extensive experience in clinical trials and caring for many patients. It is rewarding to bring this long experience with trials, especially once a drug progresses to approval, to convey confidence and depth of knowledge to patients. This is not something everyone has the ability to do. I see it as a privilege to apply broad research experience in the clinic for patients now receiving an approved drug or one not given in a trial. It is something I cherish.

Can you discuss some of the new drugs emerging in this space?

In 2024, our most significant data comes from trials with asciminib, a novel TKI known as a STAMP inhibitor. This was a known target to BCR-ABL, complementing the ATP-binding pocket, and finally provides an oral, easily delivered therapy that inhibits BCR-ABL through this mechanism. It was approved based on phase 1 and 3 data in later therapy lines, but this year, we saw compelling frontline data presented at [the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting], showing asciminib may be our best first choice. It was statistically [superior to] imatinib and numerically better than the second-generation inhibitors, with comparable or even improved safety.

Now, long-term data is still needed, but I think with ongoing results from phase 1 and 3 trials, we can take a confident step forward. We are not done there, though. Other ATP-competitive inhibitors are in development, [including] second-generation STAMP inhibitors and other drugs in development [globally] and in trials in the US. The focus remains on the high-quality data with asciminib and this new therapeutic class, marking important progress for patients with CML.

What are you specifically most excited to see come regarding new therapies?

With newer drugs showing better efficacy in the frontline, I think the holy grail in CML will be, do they bring more patients to a cure? That would be the most exciting thing for me, because I am focused on, again, high-yield, low-risk therapy. I think some really offer that option, and if we then can see that with better responses and tolerability in the frontline, that converts to more patients reaching a potential treatment-free remission opportunity, or a more successful treatment for remission endeavor, that would be fantastic. That would be the icing and the sprinkles and the cherry on top of the cake.