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

doi:10.1183/23120541.00773-2020

Figures

Tables
Related Data

Download figure
Open in new tab
Download powerpoint
FIGURE 1
Study flow diagram for treatment. Patients identified by 01-XX. BM: bone marrow.
Download figure
Open in new tab
Download powerpoint
FIGURE 2
Individual changes in a) forced vital capacity (FVC) and b) diffusing capacity of the lung for carbon monoxide (D_LCO) during follow-up.

TABLE 1

Baseline characteristics of patients

	Low dose (10×10⁶ MSCs)	Intermediate dose (50×10⁶ MSCs)	High dose (100×10⁶ MSCs)	Total
Subjects	3	3	7	13
Age years	60.5 (54.4–68.0)	65.6 (64.3–78.0)	70.2 (66.1–78.0)	68.0 (64.3–77.2)
Male/female	3/0	3/0	6/1	12/1
Time since IPF symptoms years	4.1±1.7	3.5±3.7	3.0±1.6	3.3±2.1
Time since IPF diagnosis years	1.9±2.1	3.5±4.0	1.6±1.7	2.1±2.4
Current or former smoker	3 (100)	2 (66.67)	5 (71.43)	10 (76.9)
Smoking pack-years	19.7±4.5	20.0±0	22.5±22.1	21.0±13.8
BMI kg·m⁻²	27.7±1.9	29.4±1.0	26.3±2.7	27.4±2.5
Baseline S_pO₂	96.0±2.6	94.7±0.6	95.3±1.6	95.3±1.7
MRC dyspnoea scale 0/1/2/3	1/1/0/1	1/2/0/0	0/6/1/0	2/9/1/1
Cough intensity 0/1/2/3	0/0/2/1	0/1/2/0	1/3/1/2	1/4/5/3
Cough frequency	5 (5–7)	3 (2–4)	3 (2–4)	3 (2–5)
SGRQ symptoms	39.4 (23.8–50.7)	21.2 (0–39.0)	30.5 (23.8–36.9)	30.5 (23.8–39.0)
SGRQ activity	67.2 (0–73.0)	67.1 (35.5–73.8)	48.3 (41.5–67.1)	48.5 (41.5–67.2)
SGRQ impact	49.7 (0–50.1)	24.1 (11.6–36.0)	15.3 (10.3–30.6)	16.0 (11.6–36.0)
SGRQ total	53.3 (4.0–57.1)	37.8 (20.5–49.0)	24.2 (23.2–44.1)	28.9 (23.2–49.0)
Baseline P_aO₂ mmHg	76.7±14.2	72.7±4.7	68.0±4.1	71.3±7.9
FVC % pred	83.7±36.5	69.4±15.6	74.9±15.8	75.6±20.3
FEV₁ % pred	82.3±33.3	75.2±12.0	77.1±16.7	77.9±18.9
FEV₁/FVC %	78.7±2.1	84.0±7.5	80.1±7.3	80.7±6.4
TLC % pred	66.0±25.2	58.5±9.0	60.9±9.8	61.5±13.2
D_LCO adj % pred	45.7±18.5	57.0±18.7	43.1±5.7	46.9±12.9
6MWD m	476.0±114.5	491.0±56.7	491.9±63.6	488±69.2
6MWT S_pO₂ nadir	87.0±8.9	88.0±1.7	77.9±6.8	82.3±7.9
HRCT findings
Traction bronchiectasis	3	3	6	12
Reticular pattern	3	3	7	13
Honeycombing	1	2	7	10
Pulmonary biopsy	2 (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; S_pO₂: peripheral oxygen saturation; MRC: Medical Research Council; SGRQ: St George's Respiratory Questionnaire; P_aO₂: arterial oxygen tension; FVC: forced vital capacity; FEV₁: forced expiratory volume in 1 s; TLC: total lung capacity; D_LCO: 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 code	Patients	Severity (mild/moderate/severe/life-threatening)	Seriousness (nonserious/serious)	First 3 months after infusion	Outcome at 12 months
Bronchitis	10006451	8 (61.5)	8/0/0/0	8/0	5	Resolved
IPF clinical progression or worsening without hospitalisation	10067761	5 (38.5)	0/3/2/0	5/0	1	4 IPF progression 1 lung transplant
IPF worsening with hospitalisation (2 patients)	10067761 10054112	3 (23.1)^#	0/2/1/0	0/3	1	1 death
Fever and/or dyspnoea after infusion	10013968 10037660	3 (23.1)	1/2/0/0	3/0	3	Resolved
Upper respiratory tract infection/sinusitis	10046309	2 (15.4)	2/0/0/0	2/0	2	Resolved
Flu-like syndrome	10022004	2 (15.4)	2/0/0/0	2/0	6	Resolved
Acute gastroenteritis	10066762	1 (7.7)	1/0/0/0	1/0	1	Resolved
Skin lesion	10040882	1 (7.7)	1/0/0/0	1/0	1	Resolved
Legionella pneumonia with hospitalisation	10035718	1 (7.7)	0/0/0/1	0/1	0	1 death
Abdominal pain, weight decreased, and general deterioration	10000081 10000159 10049438	1 (7.7)	0/1/0/0	1/0	1	1 death
Prostate adenocarcinoma	10060862	1 (7.7)	0/1/0/0	0/1	0	On treatment
Small cell lung cancer	10041067	1 (7.7)	1/0/0/0	0/1	0	On treatment
Radiotherapy side-effects with hospitalisation (prostate cancer treatment)	10037759	1 (7.7)	0/1/0/0	1/0	0	Resolved

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 month	2 months	3 months	6 months	9 months	12 months
Subjects	13	11	13	10	7	6
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 mL	27±267	−79±187	−151±315	−169±370	−260±338	−345±374
ΔTLC % change	0.5±4.1	−1.3±2.9	−2.3±4.9	−2.7±5.9	−4.3±5.0	−5.5±5.5
ΔD_LCO 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
ΔD_LCO %	−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 m	5.3±32.4	9.0±34.6	1.8±71.4	−9.8±37.3	−40.0±83.1	−16.7±41.3
Patients with FVC decline <10%	11	7	7	6	4	4
Patients with D_LCO decline <15%	12	10	8	7	2	4
ΔSGRQ symptoms	6.0±14.3	4.9±16.6	5.6±19.9	3.1±16.4	10.8±30.8	3.6±27.6
ΔSGRQ activity	3.7±16.7	−1.4±20.2	−0.8±23.2	−3.8±27.1	7.0±27.9	3.8±28.6
ΔSGRQ impact	−0.5±11.3	−0.7±10.8	0±16.0	1.6±13.0	6.0±20.8	−2.9±15.3
ΔSGRQ total	0.7±11.2	−0.8±12.6	−0.5±16.2	−0.5±15.7	5.2±19.8	−2.0±17.6

Data are presented as n or mean±sd. FVC: forced vital capacity; TLC: total lung capacity; D_LCO: 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 identifier	Dose n cells	Baseline FVC %	Baseline D_LCO %	Functional outcome at 3 months	Last visit	Overall outcome at last visit/ or follow-up contact	Observations: death/lung transplant^¶
01_01	10×10⁶	53	35	Progression	6 months	Progression
01_03	10×10⁶	74	35	Stable	3 months	Other	Lung transplant at 6 months
01_05	10×10⁶	124	67	Stable	12 months	Stable
01_06	50×10⁶	57	42	Stable	9 months	Progression
01_07	50×10⁶	87	78	Progression	12 months	Stable
02_01	50×10⁶	64	51	Progression	12 months	Progression
01_09	100×10⁶	73	42	Progression	3 months	Other	Death at 5 months
01_10	100×10⁶	61	35	Stable	9 months	Progression
01_11	100×10⁶	96	53	Stable	12 months	Stable
01_13	100×10⁶	90	47	Progression	12 months	Progression
01_14	100×10⁶	52	39	Stable	6 months	Other	Death at 8 months
01_15	100×10⁶	69	43	Progression	3 months	Other	Death at 9 months
01_17	100×10⁶	83	43	Progression	12 months	Progression

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