The Evaluation of Melatonin Effects on Mobilization and Engraftment in Autologous Hematopoietic Stem Cell Transplant Recipients; A Randomized, Double-blind and Placebo-controlled Trial

Document Type : Research article


1 Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Food Safety Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

4 Taleghani Bone Marrow Transplantation Center, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

5 Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.



Mobilization and engraftment of Hematopoietic Stem Cells (HSCs) are challenging issues in Autologous HSC transplantation (AHSCT) so several attempts such as colony-stimulating factors (CSF) and plerixafor have been used for enhancement of HSCs mobilization and engraftment. In this randomized, double-blind and placebo-controlled study, we evaluated the melatonin’s efficacy and safety, as endogenous CSF inducer, co-administered with Filgrastim in mobilizing and engraftment of HSC. AHSCT patients were randomized to receive either Melatonin or placebo plus filgrastim. Of Fifty-one patients, 26 patients received the melatonin (In mobilization phase 3 mg sublingual twice daily, then 9 mg single dose 30 min before apheresis session and then 3 mg twice daily from +1 until engraftment) and 25 patients received the placebo. The mean number of CD34 cells/kg × 106 in the melatonin group was 6.54 versus 4.22 in the placebo group (p = 0.025). The mean day to neutrophil engraftment in the melatonin group was 11.69 ± 2.093, whereas 12.68 ± 2.42 days in the placebo group (p = 0.021). In this study, the second apheresis session requirement, the use of plerixafor and hospital stay duration, were comparable between the two groups. Considering the result of the study, it could be suggested that melatonin plus Filgrastim can be effectively used in AHSCT patients to enhance the number of peripheral CD34 cells/kg × 106 and decrease the day number of neutrophil engraftment.

Graphical Abstract

The Evaluation of Melatonin Effects on Mobilization and Engraftment in Autologous Hematopoietic Stem Cell Transplant Recipients; A Randomized, Double-blind and Placebo-controlled Trial


(1) DiPersio JF, Stadtmauer EA, Nademanee A,
Micallef IN, Stiff PJ, Kaufman JL, Maziarz RT,
Hosing C, Früehauf S and Horwitz M. Plerixafor
and G-CSF versus placebo and G-CSF to mobilize
hematopoietic stem cells for autologous stem cell
transplantation in patients with multiple myeloma.
Blood (2009) 113: 5720-6.
(2) Devine H, Tierney DK, Schmit-Pokorny K and
McDermott K. Mobilization of hematopoietic stem
cells for use in autologous transplantation. Clin. J.
Oncol. Nurs. (2010) 14: 212-22.
(3) Ghavamzadeh A, Kasaeian A, Rostami T and
Kiumarsi A. Comparable outcomes of allogeneic
peripheral blood versus bone marrow hematopoietic
stem cell transplantation in major thalassemia: a
multivariate long-term cohort analysis. Biol. Blood 
Kazeminia N et al. / IJPR (2021), 20 (4): 117-124
Marrow Transplant. (2019) 25: 307-12.
(4) Panch SR, Szymanski J, Savani BN and Stroncek
DF. Sources of Hematopoietic Stem and Progenitor
Cells and Methods to Optimize Yields for Clinical
Cell Therapy. Biol. Blood Marrow Transplant.
(2017) 23: 1241-9.
(5) Bruserud Ø, Tjønnfjord G, Gjertsen BT, Foss B
and Ernst P. NewStrategies in the Treatment of
Acute Myelogenous Leukemia: Mobilization and
Transplantation of Autologous Peripheral Blood
Stem Cells in Adult Patients. Stem Cells. (2001)
19: 94-9.
(6) Perea G, Sureda A, Martino R, Altés A, Martinez C,
Cabezudo E, Amill B, Martín-Henao G, González
Y and Muñoz L. Predictive factors for a successful
mobilization of peripheral blood CD34+ cells in
multiple myeloma. Ann. Hematol. (2001) 80: 592-
(7) Wuchter P, Ran D, Bruckner T, Schmitt T, WitzensHarig M, Neben K, Goldschmidt H and Ho AD.
Poor mobilization of hematopoietic stem cells—
definitions, incidence, risk factors, and impact on
outcome of autologous transplantation. Biol. Blood
Marrow Transplant. (2010)16: 490-9.
(8) Chen J, Lazarus HM, Dahi PB, Avecilla S and Giralt
SA. Getting blood out of a stone: Identification and
management of patients with poor hematopoietic
cell mobilization. Blood Rev. (2020) 47: 100771.
(9) Boeve S, Strupeck J, Creech S and Stiff P. Analysis
of remobilization success in patients undergoing
autologous stem cell transplants who fail an initial
mobilization: risk factors, cytokine use and cost.
Bone Marrow Transplant. (2004) 33: 997-1003.
(10) Domingues MJ, Nilsson SK and Cao B. New agents
in HSC mobilization. Int. J. Hematol. (2017) 105:
(11) Namdaroglu S, Korkmaz S and Altuntas F.
Management of mobilization failure in 2017.
Transfus. Apher. Sci. (2017) 56: 836-44.
(12) Gawroński K, Rzepecki P, Sawicki W and Wajs
J. Mobilization of Hematopoietic Stem Cells for
Hematopoietic Cells Autologous Transplantation
with Use of Plerixafor. Ann. Transplant. (2017) 22:
(13) Zisapel N. New perspectives on the role of
melatonin in human sleep, circadian rhythms and
their regulation. Br. J. Pharmacol. (2018) 175:
(14) Gitto E, Romeo C, Reiter R, Impellizzeri P, Pesce
S, Basile M, Antonuccio P, Trimarchi G, Gentile C
and Barberi I. Melatonin reduces oxidative stress
in surgical neonates. J. Pediatr. Surg. (2004) 39:
(15) Kücükakin B, Lykkesfeldt J, Nielsen HJ, Reiter RJ,
Rosenberg J and Gögenur I. Utility of melatonin to
treat surgical stress after major vascular surgery–a
safety study. J. Pineal Res.(2008) 44: 426-31.
(16) Guo Y, Shi D, Li W, Liang C, Wang H, Ye Z,
Hu L and Li Y. Effects of cerebral microvascular
endothelial cells and vascular endothelial growth
factor on the proliferation and differentiation of
NSCs: a comparative study. Br. J. Neurosurg.
(2010) 24: 62-8.
(17) Greish K, Sanada I, Saad AED, Hasanin E,
Kawasuji M, Kawano F and Maeda H. Protective
effect of melatonin on human peripheral blood
hematopoeitic stem cells against doxorubicin
cytotoxicity. Anticancer Res. (2005) 25: 4245-8.
(18) Gholami M, Saki G, Hemadi M, Khodadadi
A and Mohammadi-asl J. Melatonin improves
spermatogonial stem cells transplantation
efficiency in azoospermic mice. Iran. J. Basic Med.
Sci. (2014) 17: 93-9.
(19) Kumar A, Kumar K, Singh R, Puri G, Ranjan R,
Yasotha T, Singh R, Sarkar M and Bag S. Effect
of mitotic inducers and retinoic acid blocker on
expression of pluripotent genes in ES cells derived
from early stage in vitro-produced embryos in
buffalo. In Vitro Cell. Dev. Biol. - Anim. (2012) 48:
(20) Gao S, Wang ZL, Di KQ, Chang G, Tao L, An L,
Wu FJ, Xu JQ, Liu YW and Wu ZH. Melatonin
improves the reprogramming efficiency of murine‐
induced pluripotent stem cells using a secondary
inducible system. J. Pineal Res. (2013) 55: 31-9.
(21) Bondy SC, Campbell A. Melatonin and regulation
of immune function: impact on numerous diseases.
Curr. Aging Sci. (2020) 13: 92-101.
(22) Maestroni GJ, Covacci V and Conti A.
Hematopoietic rescue via T-cell-dependent,
endogenous granulocyte-macrophage colonystimulating factor induced by the pineal
neurohormone melatonin in tumor-bearing mice.
Cancer Res. (1994) 54: 2429-32.
(23) Yu X, Li Z, Zheng H, Ho J, Chan MT and Wu
WKK. Protective roles of melatonin in central
nervous system diseases by regulation of neural
stem cells. Cell Prolif. (2017) 50: 12323