Historically, hematologists have feared Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) because of its poor prognosis. However, new research suggests that dual BCR::ABL1 kinase inhibition with dasatinib and asciminib is a safe treatment for patients with de novo Ph+ ALL. Marlise Luskin, MD, MSCE, of Dana-Farber Cancer Institute in Boston, and colleagues published their findings in Blood.
“This is a rare disease that occurs more commonly in older patients who need an effective and well-tolerated regimen,” Dr. Luskin said.
She explained that the first use of a tyrosine kinase inhibitor (TKI), imatinib, represented a game-changer for Ph+ ALL, especially when the TKI was combined with chemotherapy or hematopoietic cell transplantation (HCT). Over time, studies revealed that using more potent TKIs such as dasatinib for the initial treatment of Ph+ ALL could induce deep remissions in most patients with no or minimal additional chemotherapy. Such remissions could then be followed by chemotherapy or HCT. Unfortunately, however, even with dasatinib, some patients relapse, so researchers have focused on identifying a better TKI or TKI combination.
For the current study, Dr. Luskin and colleagues hypothesized that treating patients with Ph+ ALL with a combination of an adenine triphosphate-competitive inhibitor (dasatinib) and an allosteric inhibitor (asciminib) of BCR::ABL1 kinase could deepen responses, limit mutational resistance, and have an acceptable side effect profile. They thus designed a trial to test the dual TKI therapy as an induction regimen for Ph+ ALL. The resulting phase I dose escalation study included 24 adults with Ph+ ALL, two of whom had chronic myeloid leukemia in lymphoid blast crisis (CML-LBC) previously treated with imatinib. The investigators treated patients with escalating doses of asciminib in combination with dasatinib 140 mg daily plus prednisone 60 mg/m2 daily to determine the maximum tolerated dose. After this 28-day induction, the investigators continued dasatinib and asciminib indefinitely or until HCT.
Dr. Luskin explained that perhaps because of their age, patients with Ph+ ALL frequently also have cardiac risk factors. Both dasatinib and asciminib are generally well tolerated by older adults without vascular effects, and the study found that the once-a-day combination of the two drugs was also associated with excellent tolerability. Dr. Luskin added that pleural effusion was the most clinically relevant side effect, and it could be managed with standard supportive measures and dasatinib dose reductions. No vaso-occlusive events, cytopenias beyond induction, liver toxicity, or excess infections were reported.
The researchers initiated their study in patients with Ph+ ALL, as other studies evaluated the effects of asciminib in patients with CML. Across studies, including the one by Dr. Luskin and colleagues, asciminib was commonly associated with elevated pancreatic enzymes without clinical symptoms of pancreatitis. Despite the apparent limited clinical implications of the elevated enzymes, and out of an abundance of caution, the team expanded the 80 mg dose of asciminib. Hematologists now agree that elevated pancreatic enzymes are a common lab abnormality without clinical sequelae. Dr. Luskin thus expressed interest in continuing the trial to determine the optimal dosing of asciminib in combination with dasatinib.
All patients with de novo ALL in the study achieved hematologic and cytogenetic remission. Almost all patients (89%) achieved measurable residual disease negativity by multiple flow cytometry, and 74% and 26% achieved BCR::ABL1 RT-PCR of less than 0.1% and less than 0.01%, respectively. The two patients with CML-LBC, however, progressed on dual TKI therapy within one year. Eight eligible patients were able to proceed to HCT; these patients either received no intervening therapy (n=4) or received a brief course of blinatumomab (n=4).
“This regimen deserves more study and attention,” Dr. Luskin said, calling the trial a success.
To that end, the investigators have opened an expansion cohort that adds blinatumomab early in therapy (beginning on day 1 of cycle 2) in hopes of further sparing patients the experience of consolidation therapy with cytotoxic chemotherapy, HCT, or both.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Luskin MR, Murakami MA, Keating JH, et al. Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia [published online ahead of print, 2024 October 7]. Blood. doi: 10.1182/blood.2024025800.
