IMMATURE AND EXHAUSTED NK/T-CELL PROFILE PRECEDES MOLECULAR RELAPSE AND PREDICTS TREATMENT-FREE REMISSION FAILURE: DATA FROM THE DES-CML TRIAL

@article{binelli2026immature,
  title = {{IMMATURE AND EXHAUSTED NK/T-CELL PROFILE PRECEDES MOLECULAR RELAPSE AND PREDICTS TREATMENT-FREE REMISSION FAILURE: DATA FROM THE DES-CML TRIAL}},
  author = {Larissa Sarri BINELLI and Leonardo Carvalho PALMA and Camila Araújo Bernardino GARCIA and Allana Guimarães de CARVALHO and Mariana MEDEIROS and Beatriz Lima ADJAFRE and Leticia Olops MARANI and Rafael Lopes PACCA and Isabela Catarin ARRUDA and Priscila Santos SCHEUCHER and Josiane Lilian Santos SCHIAVINATO and Fabíola Attié de CASTRO and Robert Samuel WELNER and Gislaine Oliveira DUARTE and Fernanda Salles SEGURO and Israel BENDIT and Renato Sampaio TAVARES and Leandro Lustri ALMEIDA and Vaneuza Araújo Moreira FUNKE and Kátia Borgia Barbosa PAGNANO and Carla Maria Boquimpani de MOURA and Lorena Lôbo de Figueiredo PONTES},
  journal = {Hematology, Transfusion and Cell Therapy},
  year = {2026},
  month = oct,
  doi = {10.1016/j.htct.2026.107508},
  url = {https://doi.org/10.1016/j.htct.2026.107508},
  note = {CC BY},
}

TY  - JOUR
TI  - IMMATURE AND EXHAUSTED NK/T-CELL PROFILE PRECEDES MOLECULAR RELAPSE AND PREDICTS TREATMENT-FREE REMISSION FAILURE: DATA FROM THE DES-CML TRIAL
AU  - Larissa Sarri BINELLI
AU  - Leonardo Carvalho PALMA
AU  - Camila Araújo Bernardino GARCIA
AU  - Allana Guimarães de CARVALHO
AU  - Mariana MEDEIROS
AU  - Beatriz Lima ADJAFRE
AU  - Leticia Olops MARANI
AU  - Rafael Lopes PACCA
AU  - Isabela Catarin ARRUDA
AU  - Priscila Santos SCHEUCHER
AU  - Josiane Lilian Santos SCHIAVINATO
AU  - Fabíola Attié de CASTRO
AU  - Robert Samuel WELNER
AU  - Gislaine Oliveira DUARTE
AU  - Fernanda Salles SEGURO
AU  - Israel BENDIT
AU  - Renato Sampaio TAVARES
AU  - Leandro Lustri ALMEIDA
AU  - Vaneuza Araújo Moreira FUNKE
AU  - Kátia Borgia Barbosa PAGNANO
AU  - Carla Maria Boquimpani de MOURA
AU  - Lorena Lôbo de Figueiredo PONTES
PY  - 2026
DA  - 2026/10/23
JO  - Hematology, Transfusion and Cell Therapy
DO  - 10.1016/j.htct.2026.107508
UR  - https://doi.org/10.1016/j.htct.2026.107508
AB  - In Chronic Myeloid Leukemia (CML), only 50% of patients achieving deep molecular response (DMR) maintain long-term treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation. Biomarkers predicting molecular relapse remain undefined. We hypothesized that distinct antitumoral immune signatures mediated by Natural Killer (NK) and T cells drive TFR outcomes. NK and T-cell immunophenotypes were correlated with BCR::ABL1 kinetics in a cohort from the DES-CML study, a multicenter, prospective, phase 2 trial of TKI de-escalation and discontinuation conducted within the Brazilian public healthcare system (SUS) across seven centers. Peripheral blood samples from 20 healthy controls and 118 CML patients were sequentially analyzed by multiparametric flow cytometry at distinct timepoints: diagnosis (DX = 15), Imatinib failure (F = 13), major molecular response (MMR = 10), full-dose DMR (DMR100 = 30), 50% de-escalated dose DMR (DMR50 = 30), sustained TFR (n = 31), and TFR loss (TFRL = 9). Patients who successfully maintained TFR exhibited a highly functional and mature immune phenotype compared to those who relapsed. TFR patients displayed significantly higher frequencies of cytotoxic NK cells (CD56dim, p = 0.001), mature NK (CD57⁺, p = 0.033), and activating receptors (NKG2D, p = 0.043; DNAM-1, p = 0.0002; NKp46, p = 0.033). They also showed increased CD8⁺ effector memory T cells (p = 0.0011), lower CD8⁺ naïve T cells (p < 0.0001), and decreased PD-1 expression on both NK (p = 0.0052) and CD8⁺ T cells (p = 0.046). Conversely, TFRL patients displayed a pre-existing immune deficit even during full-dose therapy (DMR100), characterized by reduced total NK cells, CD56dim NKs, CD56⁺CD57⁺ NK, and CD11b⁺CD27⁻ cytotoxic subsets, alongside lower expression of NKG2D, DNAM-1, and NKp46. Furthermore, CD8⁺ T cells from TFRL patients presented early impairment with lower frequencies of central memory (p = 0.0002), effector memory (p = 0.0011), and terminal effector subsets (p = 0.002). During dose reduction (DMR50), TFRL patients demonstrated an expansion of immature/dysfunctional NK subsets (CD11b⁻CD27⁺) and upregulated inhibitory checkpoints (TIGIT and PD-1) on NK and CD8⁺ T cells (p < 0.05), alongside increased naïve CD8⁺ T cells (p < 0.0001). No significant differences were observed for KIR2DL1, NKG2A, or overall CD3, CD4, and CD8 frequencies. No significant differences were observed for KIR2DL1, NKG2A, or overall CD3, CD4, and CD8 frequencies. Based on these findings, we developed an immunological Predictive TFR Score integrating the expression of activating (NKG2D, DNAM-1) and inhibitory (TIGIT, PD-1) markers. This score demonstrated robust discriminatory capacity to identify patients likely to sustain TFR and was statistically independent of Sokal and ELTS clinical risk scores. Our findings highlight a novel prognostic axis where the immune system acts as an early sensor of residual leukemia dynamics, demonstrating that TFR maintenance depends on the balance between pharmacological suppression and sustained immune surveillance. Specifically, mature, activated, and memory-enriched T and NK cell profiles predict successful TFR, whereas cellular immaturity and exhaustion signal a failure to control residual disease. Because this immune dysregulation precedes BCR::ABL1 elevation, longitudinal monitoring and the DMR100 score during TKI de-escalation emerge as powerful, complementary tools to guide safer, individualized treatment cessation.
SN  - 2531-1379
SN  - 2531-1387
ER  -