Chronic Myeloid Leukemia
Chronic Myeloid Leukemia at EHA2023: Conference Roundup
The EHA2023 Hybrid Congress featured state-of-the-art presentations on a broad range of topics that are relevant to the treatment of patients with chronic myeloid leukemia (CML). Among the topics presented were updates on tyrosine kinase inhibitor (TKI) therapies alone and in combination for patients with CML, including those with the T315I mutation.
Following the presentations, featured expert Daniel J. DeAngelo, MD, PhD, was interviewed by Christopher Ontiveros, PhD. Dr DeAngelo’s clinical perspectives are presented here.
Chief, Division of Leukemia
“Asciminib is an excellent treatment option for patients with the T315I mutation, but response rates are much higher for patients who have not been previously exposed to ponatinib.”
There were 2 presentations on the EURO-SKI study at EHA2023 (abstracts S155 and S159). I think that both are important studies that highlight the potential for TKI discontinuation, specifically after treatment with imatinib. Abstract S155 by Pfirrmann et al assessed prognostic factors for patients being able to maintain a major molecular response (MMR) after discontinuing TKI treatment for 3 years. In order to be eligible for TKI discontinuation, patients enrolled in EURO-SKI had to achieve a deep molecular response (DMR) of BCR::ABL1 transcript 0.01% or lower on the International Scale. After discontinuation, if patients’ BCR::ABL1 transcript increased to greater than 0.1%, they resumed treatment with imatinib. After 3 years, 41% of patients remained in MMR and off therapy. Prognostic factors for staying in MMR were a longer duration of treatment with imatinib, a longer period of DMR while receiving imatinib, and lower peripheral blast counts in the blood at the time of initial diagnosis. Additionally, a BCR::ABL1 transcript type of e14a2 (+e13a2) was more favorable when compared with the e13a2 transcript.
In abstract S159, Efficace and colleagues looked at quality of life among patients in the EURO-SKI study. Researchers found that the greatest health improvement was in fatigue score, with the 2 younger age groups (ie, 18-39 years and 40-59 years) reporting a statistically significant decrease of burden of fatigue and the 2 older age groups (ie, 60-69 years and ≥70 years) reporting no statistically significant improvements. I found these results to be somewhat surprising (ie, no quality-of-life improvement in older patients after TKI discontinuation).
The goal of therapy for each individual patient with CML is different, and not everyone has the ultimate goal to stop treatment. For example, if a patient has a high risk of disease recurrence, I may want to treat them with a TKI for a longer duration. But the treatment goal may be very different in a young woman who has not started a family. In the latter example, the patient may want to maximize her ability to enter a successful TKI discontinuation trial as quickly as possible. In total, only approximately 25% of newly diagnosed patients can ultimately remain off therapy, and, while that is just a small group of patients, it can be very meaningful for many people.
Asciminib is a first-in-class, Specifically Targeting the ABL Myristoyl Pocket (also referred to as STAMP) inhibitor of BCR::ABL1 and is a non-ATP mimetic agent. It was approved by the US Food and Drug Administration in 2021 as a third-line therapy for adult patients with chronic-phase CML and for those with the T315I mutation. Kuzmina and colleagues reported on 82 patients with chronic-phase CML who received asciminib through a managed access program in Russia after previously being treated with 2 or more TKIs (abstract P673). Of the 82 patients in the analysis, 23 had T315I mutations. Patients were followed for a median of 21 months. These were heavily pretreated patients; 45% had received at least 4 prior lines of therapy. Overall survival at 24 months was 100%. MMR at 24 months was 57%, and MMR was much higher in the ponatinib-naive patients than in the ponatinib-pretreated group at 90% vs 25%, respectively. Overall, 54% of patients reported adverse events of any grade, and 17% reported grade 3 adverse events. None of the patients discontinued asciminib treatment due to toxicity. Asciminib is an excellent treatment option for patients with the T315I mutation, but response rates are much higher for patients who have not been previously exposed to ponatinib.
Also presented at EHA2023, Ernst and colleagues reported findings from the ongoing phase 2 FASCINATION study (NCT03906292) evaluating frontline asciminib in combination with nilotinib, dasatinib, or imatinib in 144 patients with chronic-phase CML (abstract S156). The rate of MR4 after 12 months of combination therapy was 37.7%. Further, grade 3 to 4 adverse events were reported in 37.6% of patients, and 17% discontinued combination therapy within the first 12 months due to toxicities.
I think that the clinical role of combination therapies will depend on the goals of therapy. This may be a reasonable approach if the patient’s goal is to achieve a DMR so that they can enter a TKI discontinuation trial (eg, in a younger patient who is in the midst of family planning or has other issues). However, for the average patient, especially a patient with a low Sokal or Hasford score and a very high chance of responding to single-agent TKI therapy, this combinatorial approach may be more toxic than necessary.
Atallah E, Schiffer CA. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when and for whom? Haematologica. 2020;105(12):2738-2745. doi:10.3324/haematol.2019.242891
ClinicalTrials.gov. Frontline asciminib combination in chronic phase CME (CMLXI). Updated May 10, 2023. Accessed June 28, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03906292
Efficace F, Mahon F-X, Richter J, et al. Health-related quality of life of patients with chronic myeloid leukemia after discontinuation of tyrosine kinase inhibitors: results from the EURO-SKI study [abstract S159]. Abstract presented at: European Hematology Association 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany.
Ernst T, Le Coutre P, Crysandt M, et al. Frontline asciminib combination in chronic phase chronic myeloid leukemia patients. The FASCINATION trial [abstract S156]. Abstract presented at: European Hematology Association 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany.
Kuzmina E, Lomaia E, Morozova E, et al. Asciminib management in chronic myeloid leukemia (CML) patients with T315I mutation [abstract P673]. Abstract presented at: European Hematology Association 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany.
Pfirrmann M, Mahon F-X, Dulucq S, et al. Prognostic factors for 3-year major molecular response maintenance in chronic myeloid leukaemia patients in the European Stop Kinase Inhibitors (EURO-SKI) trial [abstract S155]. Abstract presented at: European Hematology Association 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany.
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