expert roundtables

Effectiveness of Treatments for Chronic Myeloid Leukemia: Raising the Bar

by Gabriela S. Hobbs, MD; Mark J. Levis, MD, PhD; and Neil P. Shah, MD, PhD

Overview

Patients with chronic myeloid leukemia (CML) today may be interested in achieving a treatment response that would allow them to discontinue therapy. Ongoing investigations aim to improve the understanding of the disease and its treatment so that such goals may be realized by more patients.

Q:

What is needed to improve the effectiveness of CML treatments?

Neil P. Shah, MD, PhD

Edward S. Ageno Distinguished Professorship in Hematology/Oncology
Professor, Department of Medicine
Program Leader, Hematopoietic Malignancies Program
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, CA 

“One intriguing area is that of TKI potency. We think of the second-generation TKIs as being potent, but little is known about whether it may be possible to increase that potency.”

Neil P. Shah, MD, PhD

While having a normal life expectancy remains a key goal for patients with CML, there has been a shift in recent years toward another goal, with more patients asking about what can be done to achieve a cure or to enable them to discontinue therapy. With the available tyrosine kinase inhibitor (TKI) therapy, an estimated 40% or 50% of people over the course of several years will achieve the quality of remission that is necessary to attempt treatment discontinuation. Of those who are able to discontinue, approximately half are successful the first time. Some patients successfully discontinue therapy later, after a failed first attempt. It is not a high proportion, but it does raise the question of whether this reflects leukemic stem cell exhaustion or elimination.

With respect to kinase inhibition in CML, there are a number of unknowns that relate to potency. One intriguing area is that of TKI potency. As Dr Levis knows from his work on FLT3-mutant acute myeloid leukemia, the potency of inhibition can have significance. We think of the second-generation TKIs as being potent, but little is known about whether it may be possible to increase that potency. Asciminib targets the ABL myristoyl pocket (STAMP), and this mechanism is intriguing in that regard, as it raises the possibility of targeting BCR-ABL more aggressively without causing toxicities at other targets.

When considering effectiveness, there are also interesting questions related to the thresholds for BCR-ABL1 that we use to determine such things as whether discontinuation of therapy should be considered, as well as whether we should alter therapy or reinitiate treatment. These are working definitions and are a bit arbitrary, and I think that it remains an open question as to whether a patient who does not have a 4-log reduction can successfully discontinue therapy and never lose their 3-log reduction. So, these are all factors that could be investigated that might raise the bar for others in the future.

Mark J. Levis, MD, PhD

Director, Adult Leukemia Service
Co-Division Director, Hematologic Malignancies
Professor of Oncology
The Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University
Baltimore, MD

“A high quality of life and cure represent important outcomes for my patients with CML. We are just at the very beginning in terms of moving the bar with treatment-free remissions."

Mark J. Levis, MD, PhD

A high quality of life and cure represent important outcomes for my patients with CML. We are just at the very beginning in terms of moving the bar with treatment-free remissions. Dr Shah outlined the estimated percentages, and, while I do not have many patients with treatment-free remission who have successfully stayed off therapy for long periods of time, that is certainly a goal. It will be important to develop strategies to help patients achieve deeper remissions. These strategies could include combination therapies, such as asciminib plus a novel agent, and the development of these novel approaches will likely also require sensitive testing.

Additional work is also needed to help improve patients’ quality of life and to reduce symptoms that occur with treatment. Everybody is very different in how they respond to these drugs. All of the TKIs may be associated with edema. Some patients with CML say that they are living and working normally, but they are actually experiencing puffy eyes in the morning and/or aches and pains. And then, for those who have been on these drugs for years and are able to discontinue, sometimes side effects are only truly recognized once they discontinue. These patients will often remark that they had not realized that a certain symptom was from the drug and not from the disease.

In addition, an untapped area that may be further explored is the substantial interpatient variability in the metabolism of CYP3A4 drugs. Investigations could be performed to determine the unique patient-generated metabolites that lead to side effects and the effects that these metabolites have on the potency of BCR-ABL inhibition. Answers regarding drug metabolism could provide insights into more personalized approaches to care.

Gabriela S. Hobbs, MD

Assistant Professor, Medicine
Harvard Medical School
Clinical Director, Leukemia
Massachusetts General Hospital
Boston, MA

“Additional insights are needed to help improve the understanding of the biology of CML at diagnosis, as this may help predict who is going to experience deep remissions and who is going to stay in those deep remissions.”

Gabriela S. Hobbs, MD

Additional insights are needed to help improve the understanding of the biology of CML at diagnosis, as this may help predict who is going to experience deep remissions and who is going to stay in those deep remissions. Currently, there is a fascination among clinicians regarding patients who have been off their TKI for a few years, as there is no way to identify who is destined to relapse vs who will remain in remission.

To raise the bar, it will be important to also learn more about what the immune control mechanisms are that help some patients achieve these remissions. Ultimately, this could be critical in potentially curing patients of their CML, particularly in conjunction with the current TKIs. I think that there is interest in novel upfront approaches (eg, a TKI combination with asciminib or a TKI with an immune-active medication that is limited in toxicity) that may help some patients get into those deep remissions and stay there. Additionally, there are ways to raise the bar by using what we already have, such as learning about dose reductions that can improve tolerability. All of these things are going to be important to help patients with CML.

References

Hehlmann R, Lauseker M, Saußele S, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017;31(11):2398-2406. doi:10.1038/leu.2017.253

Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966-984. doi:10.1038/s41375-020-0776-2

Hochhaus A, Boquimpani C, Rea D, et al. Efficacy and safety results from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class STAMP inhibitor, vs bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs) [abstract LBA-4]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Hochhaus A, Larson RA, Guilhot F, et al; IRIS Investigators. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917-927. doi:10.1056/NEJMoa1609324

Topaly J, Zeller WJ, Fruehauf S. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia. 2001;15(3):342-347. doi:10.1038/sj.leu.2402041

Westerweel PE, Te Boekhorst PAW, Levin M-D, Cornelissen JJ. New approaches and treatment combinations for the management of chronic myeloid leukemia. Front Oncol. 2019;9:665. doi:10.3389/fonc.2019.00665

Yamamoto C, Nakashima H, Ikeda T, et al. Analysis of the cost-effectiveness of treatment strategies for CML with incorporation of treatment discontinuation. Blood Adv. 2019;3(21):3266-3277. doi:10.1182/bloodadvances.2019000745

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