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A phase I–II study of plerixafor in combination with fludarabine, idarubicin, cytarabine, and G-CSF (PLERIFLAG regimen) for the treatment of patients with the first early-relapsed or refractory acute myeloid leukemia

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Abstract

Clinical outcomes of patients with acute myeloid leukemia (AML) showing the first primary refractory or early-relapsed disease remain very poor. The Programa Español de Tratamientos en Hematología (PETHEMA) group designed a phase I–II trial using FLAG-Ida (fludarabine, idarubicin, cytarabine, and G-CSF) plus high-dose intravenous plerixafor, a molecule inducing mobilization of blasts through the SDF-1α-CXCR4 axis blockade and potentially leading to chemosensitization of the leukemic cells. We aimed to establish a recommended phase 2 dose (RP2D) of plerixafor plus FLAG-Ida, as well as the efficacy and safety of this combination for early-relapsed (first complete remission (CR/CRi) < 12 months) or primary refractory AML. Between 2012 and 2015, 57 patients were enrolled, and 41 received the RP2D (median age 52 years [range, 18–64]). Among these patients, 20 (49%) achieved CR/CRi, and 3 (7%) died during induction. CR/CRi rate was 50% (13/26) among primary refractory and 47% (7/15) among early relapse. Overall, 25 patients (61%) were allografted. Median overall and disease-free survivals were 9.9 and 13 months, respectively. In summary, the combination of plerixafor plus FLAG-Ida resulted in a relatively high CR/CRi rate in adult patients with primary refractory or early relapsed AML, with an acceptable toxicity profile and induction mortality rate, bridging the majority of patients to allogeneic stem cell transplantation. ClinicalTrials.gov Identifier: NCT01435343

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Change history

  • 23 February 2018

    The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernández in the original article.

    The original version of this article was revised: The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernández.

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Acknowledgements

The authors thank Shirley Weiss, David Pellicer, María D. García, and Mar Benlloch for data collection and management and Rafael Andreu for helping in the interpretation of the inmunophenotype analyses.

Funding

This work was partially financed with FEDER funds (CIBERONC (CB16/12/00284)). This work was supported by research funding from Sanofi-Genzyme.

Author information

Authors and Affiliations

  1. Hematology Department, Hospital Universitari i Politècnic, La Fe, Avinguda Fernando Abril Martorell, 106, 46026, València, Spain

    David Martínez-Cuadrón, Blanca Boluda, Rebeca Rodríguez-Veiga, Lourdes Cordón, Amparo Sempere, Federico Moscardó, Miguel A. Sanz & Pau Montesinos

  2. CIBERONC, Instituto Carlos III, Madrid, Spain

    David Martínez-Cuadrón, Lourdes Cordón, Amparo Sempere, Miguel A. Sanz & Pau Montesinos

  3. Hospital 12 de Octubre, Madrid, Spain

    Pilar Martínez & Ana Jiménez-Ubieto

  4. Hospital San Pedro de Alcántara, Cáceres, Spain

    Juan Bergua & Julio Prieto-Delgado

  5. Hospital Clinic, Barcelona, Spain

    Jordi Esteve & Marina Díaz-Beyá

  6. Hospital ICO-Universitari Germans Trias i Pujol, José Carreras Leukemia Research Institute, Badalona, Spain

    Susana Vives

  7. Hospital Reina Sofía, Córdoba, Spain

    Josefina Serrano

  8. Hospital Universitario de Salamanca, Salamanca, Spain

    Belen Vidriales

  9. Hospital Universitari Vall d’Hebron, Barcelona, Spain

    Olga Salamero

  10. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Ana Garrido

  11. Hospital Clínico San Carlos, Madrid, Spain

    Celina Benavente

  12. Hospital Universitario Virgen del Rocío, Sevilla, Spain

    José Antonio Pérez-Simón

  13. Department of Medicine, University of Valencia, Valencia, Spain

    Miguel A. Sanz

Authors
  1. David Martínez-Cuadrón
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  2. Blanca Boluda
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  4. Juan Bergua
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  7. Susana Vives
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  11. Lourdes Cordón
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  13. Ana Jiménez-Ubieto
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  16. Ana Garrido
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  18. José Antonio Pérez-Simón
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  19. Federico Moscardó
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  20. Miguel A. Sanz
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  21. Pau Montesinos
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Consortia

on behalf of the CETLAM and PETHEMA groups

Contributions

F.M, P. Montesinos, and M.A.S conceived the study. D.M and P. Montesinos analyzed and interpreted the data; D.M, P. Montesinos, and M.A.S wrote the paper; D.M and P. Montesinos performed the statistical analyses; A.S and L.C performed and interpreted the inmunophenotype analyses; B.B, P. Martínez, J.B, R.R, J.E, S.V, J.S, B.V, O.S, A.J, J.P, M.D., A.G, C.B, and J.A.P included data of patients treated in their institutions. All authors reviewed the manuscript and contributed to the final draft.

Corresponding author

Correspondence to Pau Montesinos.

Ethics declarations

Informed consent was obtained from all patients. According to the Declaration of Helsinki, the trial was approved by the Research Ethics Board of each participating hospital.

Conflicts of interest

The authors declare that they have no conflict of interest.

Additional information

The original version of this article was revised: The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernández.

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Martínez-Cuadrón, D., Boluda, B., Martínez, P. et al. A phase I–II study of plerixafor in combination with fludarabine, idarubicin, cytarabine, and G-CSF (PLERIFLAG regimen) for the treatment of patients with the first early-relapsed or refractory acute myeloid leukemia. Ann Hematol 97, 763–772 (2018). https://doi.org/10.1007/s00277-018-3229-5

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  • DOI: https://doi.org/10.1007/s00277-018-3229-5

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