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Endobronchial autologous bone marrow–mesenchymal stromal cells in idiopathic pulmonary fibrosis: a phase I trial

Arantza Campo, José María González-Ruiz, Enrique Andreu, Ana B. Alcaide, María M. Ocón, Juan De-Torres, Jesús Pueyo, Rosa Cordovilla, Eva Villaron, Fermín Sanchez-Guijo, Miguel Barrueco, Jorge Nuñez-Córdoba, Felipe Prósper, Javier J. Zulueta
ERJ Open Research 2021 7: 00773-2020; DOI: 10.1183/23120541.00773-2020
Arantza Campo
1Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain
2Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
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  • For correspondence: acampoe@unav.es
José María González-Ruiz
3Pulmonary Medicine, Hospital Universitario de Salamanca, Salamanca, Spain
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Enrique Andreu
4Hematology – Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain
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Ana B. Alcaide
1Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain
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María M. Ocón
1Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain
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Juan De-Torres
1Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain
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Jesús Pueyo
5Radiology Dept, Clínica Universidad de Navarra, Pamplona, Spain
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Rosa Cordovilla
3Pulmonary Medicine, Hospital Universitario de Salamanca, Salamanca, Spain
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Eva Villaron
6Hematology, Hospital Universitario de Salamanca, Salamanca, Spain
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Fermín Sanchez-Guijo
6Hematology, Hospital Universitario de Salamanca, Salamanca, Spain
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Miguel Barrueco
3Pulmonary Medicine, Hospital Universitario de Salamanca, Salamanca, Spain
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Jorge Nuñez-Córdoba
7Division of Biostatistics, Research Support Service, Central Clinical Trials Unit, Clínica Universidad de Navarra, Pamplona, Spain
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Felipe Prósper
4Hematology – Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain
8These authors contributed equally
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Javier J. Zulueta
1Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain
8These authors contributed equally
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  • Article
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Figures

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  • FIGURE 1
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    FIGURE 1

    Study flow diagram for treatment. Patients identified by 01-XX. BM: bone marrow.

  • FIGURE 2
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    FIGURE 2

    Individual changes in a) forced vital capacity (FVC) and b) diffusing capacity of the lung for carbon monoxide (DLCO) during follow-up.

Tables

  • Figures
  • TABLE 1

    Baseline characteristics of patients

    Low dose (10×106 MSCs)Intermediate dose (50×106 MSCs)High dose (100×106 MSCs)Total
    Subjects33713
    Age years60.5 (54.4–68.0)65.6 (64.3–78.0)70.2 (66.1–78.0)68.0 (64.3–77.2)
    Male/female3/03/06/112/1
    Time since IPF symptoms years4.1±1.73.5±3.73.0±1.63.3±2.1
    Time since IPF diagnosis years1.9±2.13.5±4.01.6±1.72.1±2.4
    Current or former smoker3 (100)2 (66.67)5 (71.43)10 (76.9)
    Smoking pack-years19.7±4.520.0±022.5±22.121.0±13.8
    BMI kg·m−227.7±1.929.4±1.026.3±2.727.4±2.5
    Baseline SpO296.0±2.694.7±0.695.3±1.695.3±1.7
    MRC dyspnoea scale 0/1/2/31/1/0/11/2/0/00/6/1/02/9/1/1
    Cough intensity 0/1/2/30/0/2/10/1/2/01/3/1/21/4/5/3
    Cough frequency5 (5–7)3 (2–4)3 (2–4)3 (2–5)
    SGRQ symptoms39.4 (23.8–50.7)21.2 (0–39.0)30.5 (23.8–36.9)30.5 (23.8–39.0)
    SGRQ activity67.2 (0–73.0)67.1 (35.5–73.8)48.3 (41.5–67.1)48.5 (41.5–67.2)
    SGRQ impact49.7 (0–50.1)24.1 (11.6–36.0)15.3 (10.3–30.6)16.0 (11.6–36.0)
    SGRQ total53.3 (4.0–57.1)37.8 (20.5–49.0)24.2 (23.2–44.1)28.9 (23.2–49.0)
    Baseline PaO2 mmHg76.7±14.272.7±4.768.0±4.171.3±7.9
    FVC % pred83.7±36.569.4±15.674.9±15.875.6±20.3
    FEV1 % pred82.3±33.375.2±12.077.1±16.777.9±18.9
    FEV1/FVC %78.7±2.184.0±7.580.1±7.380.7±6.4
    TLC % pred66.0±25.258.5±9.060.9±9.861.5±13.2
    DLCO adj % pred45.7±18.557.0±18.743.1±5.746.9±12.9
    6MWD m476.0±114.5491.0±56.7491.9±63.6488±69.2
    6MWT SpO2 nadir87.0±8.988.0±1.777.9±6.882.3±7.9
    HRCT findings
     Traction bronchiectasis33612
     Reticular pattern33713
     Honeycombing12710
    Pulmonary biopsy2 (66.67)2 (100)1 (14.29)5 (38.5)

    Data are presented as n, median (interquartile range), mean±sd or n (%). MSCs: mesenchymal stromal cells; IPF: idiopathic pulmonary fibrosis; BMI: body mass index; SpO2: peripheral oxygen saturation; MRC: Medical Research Council; SGRQ: St George's Respiratory Questionnaire; PaO2: arterial oxygen tension; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; TLC: total lung capacity; DLCO: diffusing capacity of the lung for carbon monoxide; 6MWD: 6-min walk distance; 6MWT: 6-min walk test; HRCT: high-resolution computed tomography.

    • TABLE 2

      Adverse events and outcomes

      MedDRA codePatientsSeverity (mild/moderate/severe/life-threatening)Seriousness (nonserious/serious)First 3 months after infusionOutcome at 12 months
      Bronchitis100064518 (61.5)8/0/0/08/05Resolved
      IPF clinical progression or worsening without hospitalisation100677615 (38.5)0/3/2/05/014 IPF progression
      1 lung transplant
      IPF worsening with hospitalisation (2 patients)10067761
      10054112
      3 (23.1)#0/2/1/00/311 death
      Fever and/or dyspnoea after infusion10013968
      10037660
      3 (23.1)1/2/0/03/03Resolved
      Upper respiratory tract infection/sinusitis100463092 (15.4)2/0/0/02/02Resolved
      Flu-like syndrome100220042 (15.4)2/0/0/02/06Resolved
      Acute gastroenteritis100667621 (7.7)1/0/0/01/01Resolved
      Skin lesion100408821 (7.7)1/0/0/01/01Resolved
      Legionella pneumonia with hospitalisation100357181 (7.7)0/0/0/10/101 death
      Abdominal pain, weight decreased, and general deterioration10000081
      10000159
      10049438
      1 (7.7)0/1/0/01/011 death
      Prostate adenocarcinoma100608621 (7.7)0/1/0/00/10On treatment
      Small cell lung cancer100410671 (7.7)1/0/0/00/10On treatment
      Radiotherapy side-effects with hospitalisation (prostate cancer treatment)100377591 (7.7)0/1/0/01/00Resolved

      Data are presented as n (%) or n. MedDRA: Medical Dictionary for Regulatory Activities; IPF: idiopathic pulmonary fibrosis. #: one patient was hospitalised twice during a 2-month period.

      • TABLE 3

        Changes in pulmonary function, 6-min walk test and quality of life

        Time after infusion
        1 month2 months3 months6 months9 months12 months
        Subjects1311131076
        ΔFVC mL−93±240−184±272#−212±275#−200±240#−214±292−212±189#
        ΔFVC % change−3.7±10.8−6.8±12.7−8.1±11.7−7.7±10.5−7.0±10.5−7.6±6.4
        ΔTLC mL27±267−79±187−151±315−169±370−260±338−345±374
        ΔTLC % change0.5±4.1−1.3±2.9−2.3±4.9−2.7±5.9−4.3±5.0−5.5±5.5
        ΔDLCO mL·mmHg−1·min−1−0.2±1.3−0.2±1.7−1.1±1.7#−0.9±1.9−1.2±2.3 n=6−1.5±2.6
        ΔDLCO %−1.7±11.1−2.6±11.6−9.5±14.2−8.3±14.3−12.1±16.8 n=6−11.5±19.5
        Δ6MWD m5.3±32.49.0±34.61.8±71.4−9.8±37.3−40.0±83.1−16.7±41.3
        Patients with FVC decline <10%1177644
        Patients with DLCO decline <15%12108724
        ΔSGRQ symptoms6.0±14.34.9±16.65.6±19.93.1±16.410.8±30.83.6±27.6
        ΔSGRQ activity3.7±16.7−1.4±20.2−0.8±23.2−3.8±27.17.0±27.93.8±28.6
        ΔSGRQ impact−0.5±11.3−0.7±10.80±16.01.6±13.06.0±20.8−2.9±15.3
        ΔSGRQ total0.7±11.2−0.8±12.6−0.5±16.2−0.5±15.75.2±19.8−2.0±17.6

        Data are presented as n or mean±sd. FVC: forced vital capacity; TLC: total lung capacity; DLCO: diffusing capacity of the lung for carbon monoxide; 6MWD: 6-min walk distance; SGRQ: St George's Respiratory Questionnaire. #: significant change compared to baseline values, p<0.05.

        • TABLE 4

          Individual baseline and functional outcomes# at the end of follow-up

          Patient identifierDose n cellsBaseline FVC %Baseline DLCO %Functional outcome at 3 monthsLast visitOverall outcome at last visit/ or follow-up contactObservations: death/lung transplant¶
          01_0110×1065335Progression6 monthsProgression
          01_0310×1067435Stable3 monthsOtherLung transplant at 6 months
          01_0510×10612467Stable12 monthsStable
          01_0650×1065742Stable9 monthsProgression
          01_0750×1068778Progression12 monthsStable
          02_0150×1066451Progression12 monthsProgression
          01_09100×1067342Progression3 monthsOtherDeath at 5 months
          01_10100×1066135Stable9 monthsProgression
          01_11100×1069653Stable12 monthsStable
          01_13100×1069047Progression12 monthsProgression
          01_14100×1065239Stable6 monthsOtherDeath at 8 months
          01_15100×1066943Progression3 monthsOtherDeath at 9 months
          01_17100×1068343Progression12 monthsProgression

          FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide. #: progression defined by fall in FVC ≥10% and/or fall in DLCO ≥15%, otherwise considered stable; ¶: causes of death: 01_09 Legionella pneumonia, 01_14 IPF progression, 01_15 not determined.

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          Endobronchial autologous bone marrow–mesenchymal stromal cells in idiopathic pulmonary fibrosis: a phase I trial
          Arantza Campo, José María González-Ruiz, Enrique Andreu, Ana B. Alcaide, María M. Ocón, Juan De-Torres, Jesús Pueyo, Rosa Cordovilla, Eva Villaron, Fermín Sanchez-Guijo, Miguel Barrueco, Jorge Nuñez-Córdoba, Felipe Prósper, Javier J. Zulueta
          ERJ Open Research Apr 2021, 7 (2) 00773-2020; DOI: 10.1183/23120541.00773-2020

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          Endobronchial autologous bone marrow–mesenchymal stromal cells in idiopathic pulmonary fibrosis: a phase I trial
          Arantza Campo, José María González-Ruiz, Enrique Andreu, Ana B. Alcaide, María M. Ocón, Juan De-Torres, Jesús Pueyo, Rosa Cordovilla, Eva Villaron, Fermín Sanchez-Guijo, Miguel Barrueco, Jorge Nuñez-Córdoba, Felipe Prósper, Javier J. Zulueta
          ERJ Open Research Apr 2021, 7 (2) 00773-2020; DOI: 10.1183/23120541.00773-2020
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