New Understanding of Chronic Myeloid Leukemia Allows for Better Targeted Treatments

While tyrosine kinase inhibitors the current standard of care for most patients with CML, investigators may need to look at new options and combinations for those with TKI resistance.

Tyrosine kinase inhibitors (TKIs) have proven to be a landscape-changing therapy for the treatment of patients with chronic myeloid leukemia (CML), but they come with their own set of challenges that create unmet needs for certain patients with CML at all phases of the disease.

“TKIs are going to remain the standard of care for most patients with CML. However, for patients with TKI resistance, we may need to move away from TKIs, or for patients with advanced disease, we may need to combine TKIs with other agents,” explained Mhairi Copland, MD, PHD, in an interview before the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022) with The SOHO Daily News.

Copland, professor of translational hematology at the University of Glasgow’s Paul O’Gorman Leukaemia Research Centre, in her presentation “Beyond TKI Therapy in CML”during the chronic myeloid leukemia session at 8:00 AM on September 29, 2022, will look at how to address these unmet needs. She will also address the challenges with TKI therapy that clinicians should be aware of when creating a treatment plan. In particular, Copland will focus on how clinicians have learned more about the biology of CML stem cells that will likely lead to better treatment outcomes for patients with all phases of CML.

“The biggest issues we still need to address within CML are looking to improve outcomes for patients with blast phase CML by improving overall survival and treatment tolerability. We also need to improve treatment [adherence] and side effects through dose optimization and patient education,” said Copland. “We then need to increase the number of patients who are achieving a deep molecular response who can successfully maintain treatment-free remission when stopping TKIs.”

Remaining Challenges With Current TKIs

Currently there are 6 TKIs approved for patients with CML, including imatinib mesylate (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), ponatinib (Iclusig), and asciminib (Scemblix).1,2 Ponatinib is also approved to treat patients with a T315I mutation in their disease and is 1 of the most potent TKIs.

These TKIs are generally used as frontline therapy in patients with CML, but newer TKIs need to be studied more to identify the optimal dose as TKIs traditionally have a serious toxicity profile, according to Copland. Moreover, serious adverse events on TKIs force patients off the drug due to, in some cases, interstitial lung disease.

“In addition, patients can develop a resistance to the TKIs. [This can be] specific to the drug itself where they develop mutations within the part of the BCR-ABL1 protein that binds to the TKI, meaning the TKI can’t bind anymore,” she said. “Or they might have BCR-ABL1 independent mechanisms of resistance that affect CML stem cells and are driven by other cellular strategies.”

Patients with CML who then develop resistance to TKIs are often referred for allogeneic hematopoietic cell transplantation (HCT), but new data show that for patients with mutations in their BCR-ABL1 protein, outcomes are worse.3

In an analysis of transplant outcomes for 315 patients with CML who underwent HCT between 2006 and 2016, researchers found point mutations in 152 patients, of which 66% (n = 101) harbored T315I mutations. The rest (51 patients) harbored mutations other than T315I. The overall survival rate at 3 years was worse for patients with mutations at 53% compared with 71% in patients without mutations (HR 1.50; 95% CI, 1.0-2.2, P = .038). Moreover, when comparing patients with non-T315I mutations to those without a mutation, their outcomes were significantly worse still (HR = 1.69; 95% CI, 1.0-2.8, P = .035).

“For each individual patient, you need to consider their stage of disease and whether or not they have the presence of BCR-ABL1 mutations, which will affect the TKI that you can give,” Copland explained. “But what’s becoming increasingly important is evaluating their existing comorbidities and reflecting on the possible side effects of the individual TKI so they can pick the TKI that’s most appropriate for the individual patient.”

Looking At New Targets in CML

When TKIs are successful they can result in remission of the patient’s disease, but they do not eliminate the leukemia stem cells responsible for disease development.4 According to clinicians, this explains why when patients discontinue TKIs there is a rapid leukemia relapse, meaning that patients need continuous treatment to address their disease.

CML stem cells utilize multiple cell-intrinsic pathways that, combined with microenvironmental and immune cell interactions, help create resistance to current therapies. However, at the University of Glasgow CML laboratories where Copland is a leading researcher, the new hypothesis is that identification of targets on the CML stem cell, such as BCL-2, p53, c-MYC, or EZH2, can lead to improved therapies for patients with all stages of CML and overcome resistance (FIGURE). Previous studies have shown the benefit of targeting leukemic stem cells like p53 and c-MYC, which leads to cell death instead of inhibiting the BCR-ABL1 pathway itself.5

According to Copland, these biomarkers can help predict the success, or lack thereof, in patients with CML because CML stem cells persist in every dimension of the disease. They are also looking at proteins within patients’ plasma to see if differences in these proteins can predict whether these patients are likely to maintain a treatment-free remission. Copland also noted that they are looking at immune cells within patients to understand the role the immune system plays in the treatment of this disease, and if immunotherapy can play a larger role in CML.

References
1. Pophali PA, Patnaik MM. The role of new tyrosine kinase inhibitors in chronic myeloid leukemia. Cancer J. 2016;22(1):40-50. doi:10.1097/PPO.0000000000000165
2. FDA approves asciminib for Philadelphia chromosome-positive chronic myeloid leukemia. FDA. October 29, 2021. Accessed August 23, 2022. https://bit.ly/3Ctly1L
3. Tachibana T, Kondo T, Uchida N, et al; Adult-CMLMPN-working-group-of-the-Japanese-Society-for-Transplantation-and-Cellular-Therapy. The clinical significance of bcr-abl1 mutations in patients with Philadelphia chromosome-positive chronic myeloid leukemia who underwent allogeneic hematopoietic cell transplantation. Transplant Cell Ther. 2022;28(6):321.e1-321.e8. doi:10.1016/j.jtct.2022.03.009
4. Bhatia R. Novel approaches to therapy in CML. Hematology Am Soc Hematol Educ Program. 2017;2017(1):115-120. doi: 10.1182/asheducation-2017.1.115
5. Abraham SA, Hopcroft LE, Carrick E, et al. Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature. 2016;534(7607):341-346. doi:10.1038/nature18288