Dasatinib Plus CAR T-Cell Therapy Shows Efficacy in Ph+ Acute Lymphoblastic Leukemia

Dasatinib Plus CAR T-Cell Therapy

in Ph+ ALL | Image credit: © Nittaya

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Frontline treatment with dasatinib (Sprycel) followed by sequential CAR T-cell therapy and maintenance dasatinib monotherapy elicited responses with acceptable safety in patients with newly diagnosed Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL), according to data from a nonrandomized phase 2 study (NCT04788472) published in JAMA Oncology.1

All 28 patients completed 2-week induction treatment with vindesine, dexamethasone, and continuous dasatinib at 100 mg daily and achieved a complete hematological remission (CHR) rate of 100% (95% CI, 88%-100%) and a complete molecular remission (CMR) rate of 25% (95% CI, 11%-45%).

After 1 patient who had achieved a CHR withdrew because of effects associated with dasatinib, the remaining 27 patients went on to receive CD19-targeted CAR T-cell therapy; these patients were included in the efficacy analysis. Post–CAR T, the CMR rate was 85% (95% CI, 66%-96%), which significantly exceeded the prespecified critical value of P < .001 and resulted in a rejection of the null hypothesis. A total of 25 patients completed sequential treatment with a CD22-targeted CAR T-cell therapy and subsequently achieved a CMR rate of 76% (95% CI, 55%-91%).

“The results of this trial suggest that the combination of CAR T-cell therapy and dasatinib was associated with encouraging efficacy and acceptable toxic effects as frontline therapy in adults with newly diagnosed Ph-positive ALL,” Mingming Zhang, MD, PhD, of Bone Marrow Transplantation Center of The First Affiliated Hospital and Liangzhu Laboratory, Zhejiang University School of Medicine, in Hangzhou, China, and coauthors, wrote in the paper.

The single-arm study, which was conducted at the First Affiliated Hospital of Zhejiang University School of Medicine, enrolled patients with B-cell ALL with positivity for the Ph chromosome, BCR/ABL1 fusion gene, and leukemia cells that were positive for CD19 and CD22.2 Patients were at least 18 years of age, had a left ventricular ejection fraction of at least 50%, a prognosis of longer than 3 months, and an ECOG performance status ranging from 0 to 2.

First patients underwent 2-week induction, and those who achieved a CHR received sequential CD19- and CD22-targeted CAR T-cell therapies, which were linked with reduced relapse in relapsed/refractory B-cell ALL, according to the study authors.1 CAR T cells were given at a target dose of 2 x 106 cells/kg following lymphodepletion comprised of fludarabine and cyclophosphamide. All patients were given single-agent dasatinib was maintenance at a daily dose of 100 mg.

The trial’s primary end point was CMR following CD19-targeted CAR T-cell therapy, and secondary end points comprised CMR following CD22-targeted CAR T-cell therapy, leukemia-free survival (LFS), overall survival (OS), and safety. Investigators also examined characteristics associated with leukemia relapse.

Between March 5, 2021, and April 13, 2024, a total of 28 patients were enrolled in the study. The median patient age was 48.5 years (range, 18.0-69.0), and most were female (64%). The median white blood cell count was 19,400 μL (range, 1700-553700) at diagnosis, and slightly more than half (57%) had the p190 fusion protein. Additional genetic abnormalities included IKZF1 alterations (21%), PAX5 rearrangements (7%), KMT2D variants (7%), RUNX1 alterations (7%), ZNF384rearrangements (4%), hypodiploidy (4%), and CDKN2A/B deletion (4%).

The median time between pretreatment to dasatinib treatment, between initiation of induction to apheresis, between apheresis and infusion of CD19-targeted CAR T-cell therapy, and between 2 infusions was 4.5 days (range, 1-8), 41 days (range, 29-56), 15 days (range, 8-97), and 88 days (range, 59-186).

Additional efficacy data showed that at a median follow-up of 23.9 months (range, 7.3-47.7), two hematological relapses were reported; both patients had baseline IKZF1 deletions and died of disease progression. At the data cutoff date of February 10, 2025, 78% (95% CI, 58%-91%) continued to be in CMR. Moreover, 4 patients remained in BCR/ABL1-positive CHR, which investigators noted to be durable (range, 11.9-42.8).

Additionally, the OS and LFS rates at 2 years were 92% (95% CI, 82%-100%), although inferior OS (100% vs 66.7%; P = .01) and LFS (100% vs 66.7%; P = .01) were noted in the subset of patients with baseline IKZF1 alterations vs those who did not.

In terms of safety, the most common grade 3 or higher toxicities reported were hematologic, and they were considered to be linked with induction and lymphodepletion. Of the 52 CAR T-cell therapies used, 21 cases of cytokine release syndrome were reported—all grade 1. No cases of immune effector cell–associated neurotoxicity syndrome occurred.

“The main limitations included a short follow-up and relatively small sample size,” the study authors concluded. “Continued monitoring and larger future studies are warranted.”

Reference

Zhang M, Fu S, Feng J, et al. Dasatinib and CAR T-cell therapy in newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia: A nonrandomized clinical trial. Published online April 17, 2025. doi:10.1001/janaoncol.2025.0674