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Immunomodulatory effect of dasatinib plus blinatumomab versus ponatinib plus blinatumomab in newly diagnosed Ph+ acute lymphoblastic leukemia

Leukemia (2026)Cite this article

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Abstract

In Ph+ acute lymphoblastic leukemia, frontline dasatinib plus blinatumomab (dasa+blina) is associated with long-term survival rates of 75–80%. The phase III GIMEMA ALL2820 trial has explored ponatinib with blinatumomab (pona+blina). In the present study, the immune modulation induced by dasa+blina and pona+blina was investigated. Immune cells were analyzed at the end of induction (T0) and after 2, 4 and 5 blinatumomab cycles (T2, T4, T5). Among 153 patients (43 dasa+blina, 110 pona+blina), the dasa+blina combination induced a significantly greater lymphocyte increase at T4 and T5 compared to pona+blina. The Treg counts decreased only in the dasa+blina treated patients. NK and NK-T cells increased significantly in the dasa+blina group, at all timepoints. Complete molecular responders (CMR) after dasatinib induction had significantly higher lymphocytes, T and NK cells compared to non-CMR patients. Bone marrow analyses showed higher activation (CD25, CD69) and lower exhaustion (PD1, TIM3) markers on NK and NK-T cells in dasa+blina treated patients. Dasa+blina patients exhibited a significantly enhanced NK cell capacity compared to ponatinib treated patients. Patients remaining on dasatinib maintained elevated NK cells with a more mature phenotype, suggesting a durable effect. These results highlight the greater dasa+blina immune activation, supporting a potential synergistic effect of the drug combination.

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Fig. 1: Immune-cell subset kinetics over time in the dasa+blina and pona+blina cohorts.
Fig. 2: Evaluation of immune cell subsets according to the CMR status at T0.
Fig. 3: Immune-cell subset dynamics in CMR vs no-CMR patients across the dasa+blina and pona+blina cohorts.
Fig. 4: T/NK-cell activation and exhaustion markers in the bone marrow.
Fig. 5: Dynamics of bone marrow NK cell subsets and inhibitory/exhaustion markers from T0 to T2 in the dasa+blina and pona+blina cohorts.
Fig. 6: Peripheral blood NK-cell maturation markers and subset distribution in long-term follow-up patients and HDs.
Fig. 7: Granzyme B production by NK cells in long-term follow-up patients and HDs.

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Data availability

Original data are available in response to e-mail requests to the corresponding author. Data on the peripheral blood immune cell monitoring of the dasa-blina cohort have been in part reported in Foà R et al. [8] and Puzzolo MC et al. [11].

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Acknowledgements

The authors wish to thank Associazione Italiana per la Ricerca sul Cancro (AIRC) 5×1000, Special Program Metastases (21198), Milan (Italy) to R.F.

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Author notes

  1. These authors contributed equally: Michela Ansuinelli, Nadia Peragine.

Authors and Affiliations

  1. Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy

    Michela Ansuinelli, Nadia Peragine, Maria Stefania De Propris, Maria Cristina Puzzolo, Mariangela Di Trani, Loredana Elia, Sabina Chiaretti, Anna Guarini & Robin Foà

  2. Hematology and Bone Marrow Transplantation Unit, Ospedale Dell’Angelo, Venezia Mestre, Italy

    Cristina Skert

  3. Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Niguarda Cancer Center, Milan, Italy

    Roberto Cairoli

  4. Department of Hematology, Università Cattolica del Sacro Cuore, Rome, Italy

    Simona Sica

  5. Department of Oncology-Hematology, University of Milan, Milan and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy

    Alessandro Rambaldi

  6. Hematology Division, Spedali Civili di Brescia, Brescia, Italy

    Alessandra Tucci

  7. Division of Hematology, Department of Oncology, Presidio Molinette, AOU Città della Salute e Della Scienza, Torino, Italy

    Marco Cerrano

  8. Hematology Unit, Department of Oncology and Hematology, Guglielmo da Saliceto Hospital, Piacenza, Italy

    Daniele Vallisa

  9. Dipartimento di Medicina e Chirurgia, Università di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy

    Valeria Cardinali

  10. Oncohematology Unit, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy

    Antonino Mulè

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Contributions

M.A. and N.P. performed experiments, analyzed data and wrote the manuscript. M.S.D.P. and M.C.P. performed experiments and analyzed data. M.D.T. and L.E. performed experiments. C.S., R.C., S.S., A.R., A.T., M.C., D.V., V.C., A.M. provided clinical data and took care of the patients. S.C. designed clinical trials, provided clinical data, took care of patients and critically reviewed the manuscript. A.G. designed the research, analyzed the data, wrote and critically revised the manuscript; R.F. designed clinical trials and the research, analyzed the data, wrote and critically revised the manuscript.

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Correspondence to Robin Foà.

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The authors have no conflicts of interest to disclose. The results of this study have been presented in part at the last ASH Congress: Ansuinelli M et al., Blood 2024;144 (Supplement 1):838.

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41375_2025_2855_MOESM1_ESM.docx

Supplementary data for: IMMUNOMODULATORY EFFECT OF DASATINIB PLUS BLINATUMOMAB VERSUS PONATINIB PLUS BLINATUMOMAB IN NEWLY DIAGNOSED Ph+ ACUTE LYMPHOBLASTIC LEUKEMIA

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Ansuinelli, M., Peragine, N., De Propris, M.S. et al. Immunomodulatory effect of dasatinib plus blinatumomab versus ponatinib plus blinatumomab in newly diagnosed Ph+ acute lymphoblastic leukemia. Leukemia (2026). https://doi.org/10.1038/s41375-025-02855-5

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