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
- 502 Downloads
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
KeywordsAcute myeloid leukemia Plerixafor FLAG-Ida Resistance Relapse
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.
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.
This work was partially financed with FEDER funds (CIBERONC (CB16/12/00284)). This work was supported by research funding from Sanofi-Genzyme.
Compliance with ethical standards
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.
- 1.Bergua JM, Montesinos P, Martinez-Cuadrón D, Fernández-Abellán P, Serrano J, Sayas MJ et al (2016) A prognostic model for survival after salvage treatment with FLAG-Ida +/− gemtuzumab-ozogamicine in adult patients with refractory/relapsed acute myeloid leukaemia. Br J Haematol 174:700–710CrossRefPubMedGoogle Scholar
- 8.Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al (2010) Refinement of cytogenetic classification in acute myeloid leukaemia: determination of prognostic significance of rarer recurring chromosomal abnormalities amongst 5,876 younger adult patients treated in the UK Medical Research Council trials. Blood 116:354–365CrossRefPubMedGoogle Scholar
- 9.Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al (2003) Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 21:4642–4649CrossRefPubMedGoogle Scholar
- 12.Karanes C, Kopecky KJ, Head DR, Grever MR, Hynes HE, Kraut EH et al (2009) A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia Southwest Oncology Group Study. Leuk Res 23:787–794CrossRefGoogle Scholar
- 18.Jackson G, Taylor P, Smith GM, Marcus R, Smith A, Chu P et al (2001) A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts. Br J Haematol 112:127–137CrossRefPubMedGoogle Scholar
- 19.Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N et al (2015) Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol 16:1025–1036CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Heil G, Hoelzer D, Sanz MA, Lechner K, Liu Yin JA, Papa G et al (1997) A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood 90:4710–4718PubMedGoogle Scholar