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NOTCH1 mutations identify a chronic lymphocytic leukemia patient subset with worse prognosis in the setting of a rituximab-based induction and consolidation treatment

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Abstract

Induction therapy with fludarabine followed by rituximab and consolidation plus maintenance with rituximab improved response duration (RD) and overall survival (OS) in our patients with chronic lymphocytic leukemia (CLL). The aim of our study was to investigate the clinical impact of NOTCH1 mutations in this setting of patients. The study included 123 progressive CLL patients homogeneously assigned to first-line induction treatment with fludarabine followed by rituximab. Fifty-nine patients either in complete remission (CR) minimal residual disease positive (MRD+) after induction (n = 39) or in partial remission (PR, n = 20) underwent consolidation/maintenance therapy with rituximab. Sixteen patients in CR MRD + or PR underwent observation only. The presence of NOTCH1 mutations was investigated by amplification refractory mutation system (ARMS) PCR and by Sanger sequencing. NOTCH1 mutations occurred in 20 out of 123 (16.3 %) cases. Consolidated patients showed longer OS than unconsolidated patients (p = 0.030). Both NOTCH1 mutated and CR MRD+ or PR NOTCH1 mutated patients showed significantly shorter OS after treatment (p = 0.00014 and p = 0.0021, respectively). Moreover, NOTCH1 wild-type consolidated cases experienced significantly longer RD and OS than NOTCH1 mutated consolidated or not consolidated cases (p = 0.00001 and p = 0.018, respectively). Finally, the independent prognostic impact of NOTCH1 mutations for OS was confirmed in multivariate analysis (p < 0.001). The presence of NOTCH1 mutations identifies a CLL subset with worse prognosis in the setting of a rituximab-based induction and consolidation treatment.

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Acknowledgments

Supported in part by Ministero della Salute (Ricerca Finalizzata I.R.C.C.S.), “Alleanza Contro il Cancro”; Rete Nazionale Bio-Informatica Oncologica/RN-BIO; Progetto Giovani Ricercatori no. GR-2010-2317594, no GR-2009-1475467, and no GR-2008-1138053, Ministero della salute, Rome, Italy; Fondazione Internazionale di Ricerca in Medicina Sperimentale (FIRMS); Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore Group, Italy; Ricerca Scientifica Applicata, Regione Friuli Venezia Giulia (“Linfonet” Project), Trieste, Italy; the Associazione Italiana Ricerca Cancro (AIRC), Special Program Molecular Clinical Oncology, 5x1000, no 10007; Investigator Grant IG-13227, and MFAG-10327, Milan, Italy; “5x1000 Intramural Program,” Centro di Riferimento Oncologico, Aviano, Italy.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, PN, Italy

    Michele Dal Bo, Federico Pozzo, Pietro Bulian, Francesca Maria Rossi, Riccardo Bomben, Antonella Zucchetto & Valter Gattei

  2. Division of Hematology, S. Eugenio Hospital and University of Tor Vergata, Roma, Italy

    Maria Ilaria Del Principe, Dario Ragusa, Pasquale Niscola, Francesco Buccisano, Luca Maurillo, Paolo de Fabritiis, Sergio Amadori & Giovanni Del Poeta

  3. Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    Davide Rossi & Gianluca Gaidano

  4. Department of Human Sciences, Society and Health, University of Cassino and Southern Lazio, Cassino, FR, Italy

    Giovanni Capelli

Authors
  1. Michele Dal Bo
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  2. Maria Ilaria Del Principe
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  3. Federico Pozzo
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  4. Dario Ragusa
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  5. Pietro Bulian
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  6. Davide Rossi
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  7. Giovanni Capelli
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  8. Francesca Maria Rossi
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  9. Pasquale Niscola
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  10. Francesco Buccisano
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  11. Riccardo Bomben
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  12. Antonella Zucchetto
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  13. Luca Maurillo
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  14. Paolo de Fabritiis
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  15. Sergio Amadori
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  16. Gianluca Gaidano
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  17. Valter Gattei
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  18. Giovanni Del Poeta
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Corresponding author

Correspondence to Giovanni Del Poeta.

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Bo, M.D., Del Principe, M., Pozzo, F. et al. NOTCH1 mutations identify a chronic lymphocytic leukemia patient subset with worse prognosis in the setting of a rituximab-based induction and consolidation treatment. Ann Hematol 93, 1765–1774 (2014). https://doi.org/10.1007/s00277-014-2117-x

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  • DOI: https://doi.org/10.1007/s00277-014-2117-x

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