This publication includes a summary of data on therapeutic agents for the current and future treatment landscape of chronic myeloid leukemia. Hematologic oncology experts provide key insights on approaching disease management, including a discussion on treatment options through later-line settings.

Articles

Current and Future Trends in Chronic Myeloid Leukemia

Gabriela Hobbs, MD, clinical director of Leukemia Service and assistant in medicine at Massachusetts General Hospital, discusses the role of molecular testing to determine resistance in chronic myeloid leukemia (CML).

In CML, BCR-ABL1 kinase domain mutational testing is an important tool to guide treatment decisions, says Hobbs. However, because patients with CML rarely present with 

 mutations, ABL1 testing is not typically indicated up front. Instead, patients who do not meet their treatment milestones per National Comprehensive Cancer Network or European Leukemia Net guidelines should undergo testing to determine if they have acquired resistance, Hobbs explains. 

Although acquired resistance mutations are rare, their presence can inform treatment selection, Hobbs says. For example, patients with 

 mutations are not going to benefit from second-generation TKIs. Instead, these patients should receive ponatinib (Iclusig) and be considered for transplant, concludes Hobbs. 

Videos

Gabriela Hobbs, MD, discusses the role of molecular testing to determine resistance in chronic myeloid leukemia.  



Dr. Hobbs on the Role of Molecular Testing to Determine Resistance in CML 

Elias Jabbour, MD, a professor of the Department of Leukemia, of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses selecting ponatinib (Iclusig) after failure of a second-generation TKI in chronic myeloid leukemia (CML). 

In the second-line setting, treatment selection for patients with CML may be based on mutational status, explains Jabbour. For example, patients with 

 mutations are eligible to receive ponatinib. Alternatively, dasatinib (Sprycel) should be avoided in patients with 

 mutations, where nilotinib (Tasigna) is preferred, Jabbour says. 

Notably, all patients who progress on second-generation TKIs should be considered for ponatinib, irrespective of their 

 mutation status, says Jabbour. The response rates tend to be low when patients are switched to another second-generation TKI versus response rates of greater than 50% with ponatinib, concludes Jabbour. 

Elias Jabbour, MD, discusses selecting ponatinib after failure of a second-generation TKI therapy in chronic myeloid leukemia.  



Dr. Jabbour on Selecting Ponatinib After Second-Generation TKI Failure in CML 

Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University, discusses the future of ponatinib (Iclusig) in the treatment of patients with chronic myeloid leukemia (CML).

Data from recent studies on ponatinib could help inform better management of the drug, and potentially even explore its use in early-line setting, Cortes says. In the OPTIC trial, ponatinib was evaluated at 3 starting doses (45 mg, 30 mg, and 15 mg daily) in participants with CML who are resistant to prior TKI therapy or have 

 mutation. Once patients achieved a response, they were able to reduce the daily dose to 15 mg. However, results from the study suggest that the 45 mg dose offers the best benefit to these patients, according to Cortes.

Additionally, the risk of arterial occlusive events (AOEs) seems to be much less than what had been seen before, which suggests better management of the drug; this could be due to patient selection, dose reduction, or the improved management of comorbidities, concludes Cortes.

Jorge E. Cortes, MD, discusses the future of ponatinib in the treatment of patients with chronic myeloid leukemia. 

Dr. Cortes on the Future of Ponatinib in CML Treatment

Gabriela Hobbs, MD, clinical director of Leukemia Service and assistant in medicine at Massachusetts General Hospital, shares advice on how to choose the appropriate second-line treatment option for patients with chronic lymphocytic leukemia (CLL) who are resistant to TKIs.

If a patient with CLL proves to be resistant to a second-generation TKI, subsequent administration of imatinib (Gleevec) would not be recommended, according to Hobbs. Instead, a choice should be made among other second-generation agents. At this point in the treatment journey, is important to ensure that the patient is taking their medications as prescribed and that a BCR-ABL1 kinase mutational analysis is conducted, adds Hobbs; this will help to inform which TKI a patient should receive.

 indicated that some patients who prove to be resistant to a TKI are not often switched to the correct subsequent TKI based on their mutations, says Hobbs. For example, a patient with a 

 mutation should not be put on a second-generation drug; rather, that patient should be switched to ponatinib (Iclusig). Patients who are not switched to the correct TKI can have negative outcomes, Hobbs concludes.

Gabriela Hobbs, MD, shares advice on how to choose the appropriate second-line treatment option for patients with chronic lymphocytic leukemia who are resistant to TKIs.



Dr. Hobbs on Choosing Optimal Second-Line Treatment Option for TKI-Resistant CLL

Kendra Sweet, MD, an assistant member of the Department of Malignant Hematology at Moffitt Cancer Center, as well as an assistant professor in the Department of Oncologic Sciences at University of South Florida Morsani College of Medicine, discusses key findings from the OPTIC trial with ponatinib (Iclusig) in chronic myeloid leukemia (CML).

the interim analysis of the randomized phase 2 OPTIC trial

, which were presented during the 2020 ASH Annual Meeting & Exposition, showed high response rates with good survival outcomes in patients with CML who progressed on prior second-generation TKIs. Moreover, the study evaluated various doses of ponatinib. Patients were started at 45 mg of daily ponatinib, which was decreased to 15 mg daily in the presence of a response. The data suggest that patients require a 45-mg starting dose of ponatinib, Sweet explains. Additionally, the safety results confirmed that toxicity was significantly improved with the 15-mg dose compared with the 45-mg dose. 

Another key takeaway was that patients with 

 mutations, who are known to respond well to ponatinib, may benefit from earlier integration of the agent. The survival advantage may be because these patients receive fewer prior lines of therapy compared with patients who do not harbor 

 mutations and receive additional second-generation TKIs.

Kendra Sweet, MD, discusses key findings from the OPTIC trial with ponatinib in chronic myeloid leukemia.  



Dr. Sweet on Key Findings From the OPTIC Trial With Ponatinib in CML 

Kendra Sweet, MD, an assistant member of the Department of Malignant Hematology at Moffitt Cancer Center, as well as an assistant professor in the Department of Oncologic Sciences at University of South Florida Morsani College of Medicine, discusses efforts made to mitigate toxicities associated with ponatinib (Iclusig) in patients with chronic myeloid leukemia (CML).

Ponatinib was the subject of controversy when it was temporarily pulled from the market due to significant arterial occlusive events observed in patients who were receiving treatment in the PACE trial, according to Sweet. Although this warranted further investigation of the agent, Sweet notes that much has been learned in the years following the trial. If what is currently known about the drug and its adverse effects (AEs) were known during the course of the PACE trial, Sweet says the results may have been different.

After utilizing ponatinib in practice over the past 7 years, Sweet shares that she has not observed the level of toxicities that had been reported in the trial; this is likely due to more widespread knowledge of these AEs and efforts are being made to mitigate these toxicities up front. Some techniques to reduce the risk of these AEs include the utilization of cardioprotective measures and referring patients to a cardiologist up front, Sweet concludes.

Kendra Sweet, MD, discusses efforts made to mitigate toxicities associated with ponatinib in patients with chronic myeloid leukemia.



Dr. Sweet on the Awareness and Mitigation of AEs Associated With Ponatinib in CML

Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University, shares advice for navigating among first- and second-generation TKIs in the frontline treatment of patients with chronic myeloid leukemia (CML).

Currently, 4 drugs are approved by the FDA for the frontline treatment of patients with CML: the first-generation TKI imatinib (Gleevec), as well as 3 second-generation TKIs, which include dasatinib (Sprycel), erlotinib (Tarceva), and bosutinib (Bosulif), according to Cortes. When deciding on a treatment strategy, the first consideration should be whether a second-generation TKI should be used or imatinib is a more appropriate choice, Cortes says. 

Imatinib can have some advantages over second-generation TKIs in certain clinical scenarios, such as cost and less arterial occlusive events and pleural effusions. However, fewer patients achieve deep molecular responses with imatinib compared with the newer-generation TKIs, and responses do not tend to be as rapid. If patients do not have the goal of treatment-free remission or for those who have concerns regarding certain adverse effects, imatinib may be the stronger option to begin with, Cortes concludes.

Jorge E. Cortes, MD, shares advice for navigating among first- and second-generation TKIs in the frontline treatment of patients with chronic myeloid leukemia.

Dr. Cortes on Navigating Among Frontline TKIs in the CML Paradigm

Elias Jabbour, MD, a professor of the Department of Leukemia, of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses data with asciminib in patients with chronic-phase chronic myeloid leukemia (CML).

One of the agents that has emerged in recent years is asciminib, which is not an adenosine triphosphate binding pocket inhibitor but a myristate pocket binding inhibitor. A phase 1 study has demonstrated efficacy with the agent at different dosing schedules. In the ASCEMBL trial, which was presented during the 2020 ASH Annual Meeting & Exposition, patients who had received at least 2 prior TKIs experienced a statistically significant and clinically meaningful improvement in major molecular response with the agent at 24 weeks. 

Arterial-occlusive events were reported in 3.2% of patients who received asciminib vs 1.3% of those who were given bosutinib. On the investigative arm, this was comprised of myocardial ischemia and coronary artery disease.

Elias Jabbour, MD, discusses data with asciminib in patients with chronic-phase chronic myeloid leukemia.

Dr. Jabbour on the ASCEMBL Data With Asciminib in Chronic-Phase CML

Gaby Hobbs, MD, clinical director, Leukemia Service, assistant in medicine, Massachusetts General Hospital, discusses managing ponatinib (Iclusig)-associated toxicities in chronic myeloid leukemia (CML).

During the 2020 ASH Annual Meeting & Exposition, findings from the phase 2 PACE and OPTIC trials showed that ponatinib resulted in high response rates with good outcomes in patients with chronic-phase CML who have progressed on second-generation TKIs. 

Regarding safety, ponatinib has been associated with an increased risk of cardiovascular events. As such, trials are evaluating whether patients who achieve a remission with the 45 mg starting dose of ponatinib can be dose reduced to 15 mg or 30 mg and remain in remission, explains Hobbs. Dose reductions could lower the risk of cardiovascular events, Hobbs adds.

Ultimately, data have demonstrated that ponatinib has utility as a treatment for patients with CML, Hobbs says. However, like all TKIs, it is important to manage the risk of serious adverse effects, particularly cardiovascular events. For example, patients receiving ponatinib should receive concurrent aspirin, says Hobbs. Additionally, consulting the patient’s cardiologist, primary care physician, or a cardio-oncologist may lend additional insight into managing the risk of cardiovascular events, concludes Hobbs.

Gaby Hobbs, MD, discusses managing ponatinib-associated toxicities in chronic myeloid leukemia.  



Dr. Hobbs on Managing Ponatinib-Associated Toxicities in CML 

Kendra Sweet, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, assistant professor, Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, discusses treatment selection with TKIs in chronic myeloid leukemia (CML).

Currently, the TKIs imatinib (Gleevec), nilotinib (Tasigna), dasatinib (Sprycel), and bosutinib (Bosulif) are approved for the frontline treatment of patients with CML, says Sweet. Additionally, the third-generation TKI ponatinib (Iclusig) is approved for later-line use, Sweet explains.

In the frontline setting, treatment selection is largely dependent on physician preference, patient comorbidities, the safety profile of the drug, and insurance, says Sweet. In most instances, Sweet will select imatinib for patients with newly diagnosed CML who have low Sokal scores. Conversely, one of the second-generation TKIs may be preferable for patients with intermediate- or high-risk Sokal scores, Sweet says. 

Second- and later-line treatment selection is based on patient comorbidities, the reason for stopping first-line therapy, and mutational profile, concludes Sweet.

Kendra Sweet, MD, discusses treatment selection with TKIs in chronic myeloid leukemia.  



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