T-Cell Expansion Tracks With Response to Venetoclax-HMA Therapy in AML

Patients with acute myeloid leukemia (AML) who responded to a hypomethylating agent (HMA) combined with venetoclax (Venclexta; AbbVie, Genentech) showed expansion of cytotoxic CD8-positive (CD8+) and CD4-positive (CD4+) T cells and greater T-cell receptor diversity after 1 cycle of treatment, according to a study published in HemaSphere.¹ Nonresponders, by contrast, entered treatment with inflammatory signaling already active in the bone marrow, and their CD8+ T cells persistently expressed the checkpoint receptor LAG-3.

The investigators, based in Milan, Italy, paired outcomes data from 132 patients with single-cell RNA sequencing of marrow samples from 10 patients whose AML was newly diagnosed. They described LAG-3 as a possible biomarker and treatment target.

Durability Gaps With Venetoclax in AML

In October 2020, the FDA granted regular approval to venetoclax with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed AML in adults 75 years or older or in those unable to receive intensive induction chemotherapy. In the phase 3 VIALE-A trial (NCT02993523), venetoclax plus azacitidine extended median overall survival (OS) to 14.7 months compared with 9.6 months for placebo plus azacitidine.² Still, roughly one-third of patients do not respond to the combination, and most who achieve remission eventually relapse.³

Resistance has been tied to MCL1 upregulation and to mutations in BAX, TP53, NRAS, and FLT3, but the contribution of immune dysregulation is poorly defined, the authors noted.¹ In the retrospective cohort, 65 patients (49.2%) were treated in the first line and 67 (50.8%) in later lines. For the single-cell analysis, the team sampled marrow at diagnosis and after cycle 1 (median, day 27) and profiled 127,135 cells. Six patients responded, and 4 were classified as nonresponders, a group combining refractory disease with early relapse within 4 cycles.

Clinical and Genomic Predictors of Response

The composite rate of complete remission with or without full count recovery was 82.3% with first-line use vs 57.6% in later lines (P < .01), although OS did not differ significantly by line of therapy. Patients with IDH2 mutations had not reached median OS, whereas those with TP53 mutations had a median OS of 4.35 months.

At diagnosis, nonresponders had significant enrichment of interferon and TNF-alpha/NF-kB signaling, along with expression of the tolerogenic genes IDO1, METTL7B, and VCAM1. Responders activated these pathways only after treatment, driven by MHC class I molecules and the chemokine CCL5. Among responders, CD8+ T cells rose from 9.6% to 18.2% of marrow cells (P < .001), while the share in nonresponders fell from 13.6% to 11.3%. CD4+ T cells also expanded in responders after cycle 1 (29.5% vs 22.0%; P < .01).

PD-1, CTLA-4, and TIM-3 were expressed at low levels across the cohort, but LAG-3 appeared on roughly 25% of nonresponders’ CD8+ T cells and stayed elevated after treatment. All 4 nonresponders also showed higher MCL1 expression after cycle 1, restricted to immature and monocytic myeloid cells.

“Resistance is characterized by a convergence of immature myeloid phenotypes, chronic inflammation, and rigid, dysfunctional T cell responses marked by immunoregulatory skewing,” the authors wrote. They added that “further exploration of the role of LAG3 in AML is warranted, given also the availability of targeted inhibitors.”

Study Limitations and Immunotherapy Implications

The authors acknowledged that the small single-cell cohort, particularly the few nonresponders, limits generalizability and that several signals were driven by individual patients with specific mutations and should be considered hypothesis-generating. They also noted that persistent LAG-3 expression suggests, but does not establish, T-cell exhaustion and that functional studies are needed.

“However, our initial observations underscore the potential of combining HMA-venetoclax with interventions aimed at restoring T cell fitness or alleviating immune suppression within the leukemic niche to sustain and consolidate clinical remission in AML,” the authors concluded.

References

1. Marchetti A, Lazzaroni F, Da Via’ MC, et al. Immune and cellular determinants of response to HMA-venetoclax regimens in acute myeloid leukemia. HemaSphere. 2026;10(10):e70498. doi:10.1002/hem3.70498

2. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. News release. FDA. October 16, 2020. Accessed November 5, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-regular-approval-venetoclax-combination-untreated-acute-myeloid-leukemia

3. Garciaz S, Hospital MA, Collette Y, Vey N. Venetoclax resistance in acute myeloid leukemia. Cancers (Basel). 2024;16(6):1091. doi:10.3390/cancers16061091