PD-1/PD-L1 Blockade Strengthens Salvage Therapy in R/R ALL

The addition of PD-1/PD-L1 checkpoint inhibitors to either chemotherapy or chimeric antigen receptor T-cell (CAR T) therapy significantly improved clinical outcomes without increasing toxicity in patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL), a phase 2 trial published in Leukemia Research found.¹

In this randomized, multicenter, open-label study, 168 patients aged 12 to 65 years with R/R ALL were assigned to receive either salvage chemotherapy with FLAG (fludarabine, cytarabine, granulocyte-colony stimulating factor support) combined with nivolumab (Opdivo), anti-CD19 CAR-T cell therapy combined with atezolizumab (Tecentriq), or FLAG chemotherapy alone.

Both checkpoint inhibitor-based combination strategies outperformed chemotherapy alone across multiple efficacy end points, with the CAR T combination arm deriving the most benefit from PD-1/PD-L1 blockade addition. The chemotherapy/nivolumab and CAR T/atezolizumab arms had significantly higher rates of minimal residual disease (MRD) negativity compared with those receiving chemotherapy alone (19.5% vs 27.8% vs 3%; P <.001).

Improvements in progression-free survival (PFS) mirrored these findings. Median PFS reached 7.7 months in the chemotherapy/nivolumab arm and 11.7 months in the CAR T/atezolizumab arm, compared with 4.1 months in the chemotherapy-alone group (P <.001). Overall survival (OS) was also significantly prolonged in both combination arms relative to chemotherapy alone, with median OS reaching 10.75, 13.5, and 5.65 months, respectively (P <.001). Investigators noted a clear separation of Kaplan-Meier survival curves between groups for both PFS and OS.

Importantly, these efficacy gains were achieved without increasing toxicity. The addition of PD-1/PD-L1 inhibitors was well tolerated and yielded comparable rates of hematologic toxicities with chemotherapy alone. Of note, bacterial infection was less frequent in both combination arms (chemotherapy, 19.4%; CAR T, 14.9%) compared with chemo alone (28.4%).

Exploratory Biomarker Analysis

Investigators also collected peripheral blood and bone marrow samples at baseline, during treatment, and at progression or remission to evaluate changes in immune-related biomarkers. Analyses focused on T-cell subsets, exhaustion marker expression, PD-L1 expression, cytokine levels, and other inflammatory markers.

Their biomarker analysis identified several potential prognostic indicators. For instance, higher baseline PD-L1 expression was independently associated with improved survival (HR, 0.90; P =.002). This association suggests that PD-L1 may serve not only as a prognostic marker but also as a potential predictor of benefit from checkpoint blockade.

Conversely, investigators also noted that patients with higher disease burden at baseline, reflected by increased bone marrow blasts, continued to experience inferior survival outcomes (HR, 1.05; P =.001), underscoring the importance of early intervention.

Clinical Implications

Outcomes for patients with R/R ALL remain poor despite advances in immunotherapy, with many patients failing to achieve durable remissions after salvage chemotherapy or relapsing following CAR-T therapy. Resistance mechanisms, including T-cell exhaustion and immune escape mediated by PD-1/PD-L1 signaling, have been increasingly recognized as contributors to treatment failure. As a result, strategies aimed at reinvigorating antitumor immunity have become an area of active investigation in this setting, prompting this investigation.

“[Our findings] support the integration of immune checkpoint blockade into salvage strategies for R/R ALL, offering a new therapeutic avenue beyond traditional chemotherapy and standalone CAR-T therapy,” Zou et al, study authors, wrote in the manuscript.¹

Investigators acknowledged several limitations, including the phase 2 design, relatively short follow-up, and lack of stratification by molecular subtype, highlighting the need for confirmation in larger, randomized phase 3 trials.

“Future randomized phase [3] trials are needed to confirm these results and determine the optimal sequencing and timing of checkpoint inhibitors in relation to chemotherapy and CAR-T infusion,” the authors added.

REFERENCES

1. Zou M, Wan B, Hu J. Efficacy and safety of PD-1/PD-L1 inhibitors in combination with chemotherapy or CAR-T cells for relapsed/refractory acute lymphoblastic leukemia: A multicenter phase ii trial. Leukemia Res. 2025;160:108148-108148. doi:10.1016/j.leukres.2025.108148