New Perspectives in CML Management: Personalized Approaches and Adaptive Strategies

Experts gathered at the Society of Hematologic Oncology 2024 meeting to discuss treatment of patients with chronic myeloid leukemia (CML) including overcoming treatment obstacles, optimizing dosing, managing mutations, monitoring long-term adverse effects (AEs), and expanding treatment considerations to allograft stem cell therapy (Allo-SCT).

Mutations can significantly affect a patient’s response or resistance to treatment, potentially circumventing the effects of specific agents at particular dosages. Image Credit: © stockdevil - stock.adobe.com.

Patients and clinicians can face many obstacles when managing treatment for CML, potentially preventing optimal treatment responses and health outcomes. Tyrosine kinase inhibitors (TKI) are therapies that target the abnormal BCR::ABL1 proteins that cause the uncontrolled growth of malignant cells. Over the years, their demonstrated success in clinical trials led to their use as first- and second-line treatments for CML. Treatments approved include imatinib (Gleevec; Novartis), dasatinib (Sprycel; Bristol-Myers Squibb), nilotinib (Tasigna; Novartis), and bosutinib (Bosulif; Pfizer) in the first-line, as well as ascminib (Scemblix; Novartis) and ponatinib (Iclusig; Takeda Pharmaceuticals USA Inc) in the second line for patients who already received 2 or more lines of prior TKI therapy or have a T315I mutations.

As is the case with many other disease states, the leading goal of CML treatment is overall survival (OS), which, today, is close to the normal population. Considering the positive trend in OS, clinicians now aim to determine the best treatment pathways to induce sustained treatment-free remission (TFR). During his presentation “Choosing the Best First Line Drug - Does Efficacy Make You Think About,” Elias Jabbour, MD, fellow from the Anderson Cancer Center in Houston, discussed the potential of optimal biotic dosing to provide patients with efficacious treatments at lower doses capable of providing deep, sustained remission and safety.

“We need to deliver the lowest dose that can maintain efficacy without long term measurable adverse events,” said Jabbour.

Jabbour points specifically to imatinib, a first-line TKI for CML. According to multiple clinical trials, the data showed that imatinib treatment resulted in a 92% 10-year survival rate, which is comparable to the general population. Cost-effectiveness was indicated as another significant benefit for patients, especially for the generic version. The lifetime cost of imatinib therapy was estimated to be around $12,500, which is significantly lower than the cost of newer TKIs and increases the accessibility and affordability for patients. Jabbour also highlights that when using lower, adjusted doses of imatinib, for example 50 mg daily, the safety profile was considered to be equivalent or better than some of the newer TKIs.

Various randomized trials indicate that use of second or third generation TKIs improve depth of response, speed of response, and had less transformation; however, there was no significant survival benefit. Considering these data, Jabbour suggested starting with imatinib as a generic and more affordable option and is still capable of achieving comparable OS to second generation TKIs. The use of imatinib was seemingly controversial amongst the chairs leading the session, as well as the attendees. Following discussions of preferred agents and dosing, there was a shared emphasis on patient-centric approaches that consider the best treatments depending on disease state, presence of mutations, and affordability.

Dosing needs can vary from patient to patient; however, the approved doses and schedules for TKIs are often fixed and applied in clinical practice regardless of patient-specific factors. Fixed dosing can be rigid as it doesn't allow for adjustments based on changes in a patient's health condition, underscoring the need for more flexible dosing strategies across agents.

“Number one is that we use fixed doses for all of them,” Jorge E Cortés, MD, director of the Georgia Cancer Center, said during his presentation. “The other thing is that there are some drugs for which we use different doses in different stages of the disease, whereas in others, we use the same dose. And the result of how we come to these doses depends on what we started, what the study was, the aim to how it was designed, and what the dose selected for that study was.”

Mutations can significantly affect a patient’s response or resistance to treatment, potentially circumventing the effects of specific agents at particular dosages. TKI resistant mutations in BCR::ABL1 have been the only clinically relevant and actionable mutations to in CML; however, evolving knowledge of CML indicates that chronic phase disease may not as genetically homogeneous as previously understood.

Simona Soverini, PhD, associate professor in the Department of Medical and Surgical Sciences at the University of Bologna, Italy, indicated mutation testing in cases of failure or warning, according to existing European LeukemiaNet guidelines, relapse, or after allogeneic stem cell transplantation. However, it is not recommended at diagnosis prior to beginning TKI therapy. In the applicable cases, utilizing next generation sequencing can provide clinicians with accurate, validated assays that detect low-level mutations, allowing for more informed clinical decision-making.

“We use 200 milligrams twice daily. Patients that don't have the T359 mutation, we use 40 milligrams twice daily, or 80 milligrams once daily—a 5-fold difference in the doses that we use,” said Cortés. “And that is, in a way, justified, because in the preclinical data or in the non-clinical data, you see that the concentrations required for the IC50 for cells that have the T359 mutation are much higher than for the cells that have only BCR::ABL1 type.”

With more flexible dosing strategies and knowledge of mutations opens avenues to reconsidering starting dosages, transitioning to alternate agents, or potentially tapering down doses for patients that may benefit from lower doses treatments. Additionally, understanding mutation status can help clinicians to best tailor the use of expensive, potentially toxic agents for patients.

However, patients can be hesitant to adjust their treatment doses. In cases of achieved remission, some may be uncomfortable with TFR, preferring to remain on a maintenance regimen. The effectiveness to treatment regimens and potential for TFR is largely dependent on comprehensive monitoring of long-term AEs associated with TKI therapy including medical history, drug history, as well as quality of life (QOL) assessments. There are various psychological and emotional impacts associated with treatment, and some data suggests that despite depth of response, patients with poorer QOL tend to have worse outcomes.

Comorbidities is another significant factor impacting decisions around use of specific agents and dosing strategies. As patients age, they can develop conditions unrelated to CML that require treatment with new medications, which result in adverse interactions between medications or issues with compliance. In these cases, effective communication between care teams and pharmacies is crucial to ensuring safe use of various agents to treat patients with multiple comorbidities.

In cases where TKI inhibitors are ineffective, Jerald P Radich, MD, medical oncologist at the Fred Hutchinson Cancer Research Center in Seattle, suggests Allo-SCT. With the advent of TKIs, Allo-SCT has dropped in popularity despite being the “bread and butter” of CML. This treatment requires a high volume of physical pills, which Radich indicates may deter patients compared with the availability of TKIs that are only a single pill. Patients who would best benefit from Allo-SCT are intolerant to TKIs in the chronic, accelerate, and blast phases of disease.

As treatment approaches become more personalized, there is a call for greater flexibility in dosing, deeper exploration of genetic mutations, and a patient-centered focus on quality of life. Advancing care in CML will depend on a commitment to individualized treatment strategies that balance efficacy, safety, and patient preferences to improve health outcomes.

REFERENCE

Kantarjian H, Lipton J, Jabbour E, et al. Chronic myeloid leukemia. Society of Hematologic Oncology 2024 Annual Meeting. September 5, 2024; Houston, TX