Updated: January 10, 2025
Philadelphia chromosome (Ph)-positive (BCR::ABL1+) acute lymphoblastic leukemia (ALL) is the most common genetic subtype of ALL in adults and increases in frequency with age. Ph+ ALL has historically been associated with an extremely poor prognosis because the disease does not respond well to chemotherapy and many patients are unable to receive effective treatment due to age and other health conditions. Approximately 25 years ago, the introduction of imatinib, the first BCR::ABL1 tyrosine kinase inhibitor (TKI), into Ph+ ALL chemotherapy treatment was a major advance as it allowed more patients to achieve durable remissions, and in some cases be cured. However, relapses remained quite common, particularly in patients who are ineligible to receive intensive treatment with an allogeneic hematopoietic stem cell transplant (HSCT).
One approach to improving outcomes is to treat patients with a better TKI. Multiple studies have investigated dasatinib, a second-generation TKI, and ponatinib, a third-generation TKI with good results. However, patients remain vulnerable to relapse and, particularly with ponatinib, may experience serious side effects. Most relapses in Ph+ ALL are associated with resistance mutations in ABL1 that inhibit drug binding, suggesting that leukemia blast cells in patients who relapse after TKI treatment remain addicted to ABL1 kinase activity.
Together with Mark Murakami, MD, and other colleagues, we have been investigating asciminib (Novartis), an allosteric inhibitor of ABL1 that binds to a site spatially distinct from the catalytic domain targeted by traditional TKIs. Asciminib, now approved for Ph+ chronic myeloid leukemia (CML), is an attractive drug because it is extremely potent, has efficacy against mutations that confer resistance to standard TKIs, and is very well tolerated. Importantly, in contrast to ponatinib, this drug is not associated with serious cardiovascular events.
Our phase I trial was designed to treat patients with both a traditional ABL1 kinase catalytic domain inhibitor (dasatinib) and the allosteric inhibitor asciminib, with a goal of safely achieving deeper and more durable remissions. The results of this Dana-Farber investigator-initiated phase 1 study (NCT03595917) were presented as an oral abstract at the American Society of Hematology Annual Meeting in 2023 and were recently published in the prestigious journal Blood (https://pubmed.ncbi.nlm.nih.gov/39374521/). In it, we report that dual targeting of the BCR::ABL1 in Ph+ acute leukemia is safe, and that the treatment has promising efficacy.
We continue our efforts in developing this promising approach. The initial trial focused on the early part of treatment (induction), and most patients transitioned to allogeneic HSCT, an intensive approach not available to all patients. Now, we are testing dual ABL1 inhibition with dasatinib and asciminib in combination with blinatumomab, a bi-specific T-cell engager, with the goal of achieving excellent outcomes for more patients without the rigors of transplantation. The investigators are also studying optimized doses of asciminib and dasatinib, to improve efficacy and tolerability.
We believe that this regimen offers an effective therapy for patients with Ph+ ALL of all ages, including older patients and those with cardiac disease and cardiac risk factors. Designing and conducting this trial collaboratively with colleagues at several other leading institutions has been incredibly meaningful, as it has been gratifying to see patients responding so well with minimal side effects. This approach to treating Ph+ ALL was presented at the 2024 American Society of Hematology Annual Meeting.
In addition to the clinical efforts, Dr. Murakami is conducting cutting-edge correlative science in his laboratory to identify biomarkers of response to combined BCR::ABL1 blockade and targetable molecular features of minimal residual disease (MRD), based on targeted tumor sequencing and serial single-cell RNA sequencing of leukemia and immune populations from patient blood and bone marrow. This exciting research provides an opportunity to learn more about biology of Ph+ ALL and generate knowledge for the benefit of future patients.
The unique, collaborative environment at Dana-Farber between clinicians and scientists, nurtured by the Institute, has proven essential in this project’s success.
