Barcelona, Spain – Alterations in the TP53 gene represent an intrinsic biomarker of very poor outcomes in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) treated with the anti-CD19 CAR-T therapy tisagenlecleucel (tisa-cel). This was discovered by a group of Spanish researchers, who recently published their findings in the journal Bone Marrow Transplantation.
According to Anna Alonso-Saladrigues of Sant Joan de Déu Hospital in Barcelona and colleagues, these findings support the routine use of molecular screening to guide CAR-T–related treatment decisions, including consolidation with stem cell transplantation or alternative therapies.
“TP53 alterations proved to be a strong and independent risk biomarker for response and survival in our cohort of pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia treated with tisagenlecleucel within currently approved indications,” Alonso-Saladrigues and colleagues wrote. “Systematic screening for TP53 alterations in patients undergoing CAR-T cell therapy could help stratify them into a high-risk group for CAR-T failure and identify candidates for consolidative hematopoietic stem cell transplantation or experimental approaches.”
More Than One in Three Patients Had TP53 Alterations
In this single-center retrospective analysis of 69 patients treated with tisa-cel, TP53 alterations—including mutations and/or deletions—could be assessed in 49 cases and were detected in 17 patients (34.7%).
The median age at infusion was 8.4 years, and patients had previously received a median of two lines of therapy; 39.1% had relapsed after a prior hematopoietic stem cell transplant. Baseline characteristics of patients with available molecular alteration data were comparable to those without such information.
At the molecular level, 13 patients (24.5%) carried TP53 mutations and 12 (24.5%) had TP53 deletions, while eight patients had both abnormalities. The mutations were predominantly missense variants located in the DNA-binding domain (exons 4–8), and no germline alterations were identified.
TP53 Alterations Associated With Adverse Disease Biology and Worse Clinical Outcomes
First, the Spanish team found that TP53 alterations were associated with unfavorable disease biology at baseline, including a higher leukemic burden and a greater likelihood of first refractory relapse.
In addition, clinical outcomes following CAR-T therapy differed markedly according to TP53 status.
Among evaluable patients, complete remission rates were significantly lower in the TP53-altered group compared with the TP53 wild-type group (68.8% vs. 93.8%, P = 0.033). In the overall cohort, 84.9% of patients achieved remission and most obtained measurable residual disease (MRD) negativity; however, relapses were frequent, particularly among carriers of TP53 alterations.
Lower Survival in Patients With TP53 Alterations
Survival analyses also revealed profound and statistically significant differences between patients with TP53 alterations and those with TP53 wild-type disease, with markedly worse outcomes in the altered group.
Median event-free survival (EFS) was 3.8 months (95% CI, 1.2–not estimable) in patients with altered TP53, compared with 50.9 months (95% CI, 23.9–not estimable) in wild-type patients. The 3-year EFS rate was 33.1% versus 56.2% (P = 0.0069), respectively, while 3-year overall survival (OS) was 37.2% versus 81.2% (P = 0.0010).
Outcomes were even worse among patients with TP53 mutations alone, whose 3-year EFS was only 18.5% (P = 0.00016) and 3-year OS was 23.1% (P < 0.0001).
TP53 Status Was an Independent Predictor of Survival
Importantly, TP53 mutational status emerged as the only independent predictor of both EFS and OS in multivariate analysis, with hazard ratios (HRs) of 3.7 (P = 0.012) and 4.7 (P = 0.0056), respectively.
Other clinical factors, including genetic risk group, did not significantly impact survival after CAR-T treatment, underscoring the dominant prognostic role of TP53 alterations.
Large Collaborative Studies Needed to Clarify the Role of Consolidative Transplantation
“In light of these findings, we recommend routine screening for TP53 gene alterations in all patients eligible for CAR-T cell therapy. Patients harboring TP53 alterations face a high risk of early relapse, predominantly CD19-negative, which is not prevented by CAR-T persistence and represents a major challenge for salvage therapy. Therefore, when a TP53 alteration is detected, we recommend early consolidation with hematopoietic stem cell transplantation whenever feasible,” Alonso-Saladrigues and colleagues wrote in their discussion.
However, the researchers noted that data regarding the protective effect of consolidative stem cell transplantation after CAR-T therapy in patients with TP53 alterations remain conflicting. While some studies suggest a potential improvement in outcomes, others have not demonstrated a clear benefit.
Therefore, they emphasized the need for international collaborative studies involving larger patient cohorts to accurately assess the effectiveness of consolidative stem cell transplantation in this specific patient population.
Reference
A. Alonso-Saladrigues et al. Impact of TP53 alterations on outcomes in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia after CD19 CAR T-cell therapy. Bone Marrow Transplantation, 2026.
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