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WO2022101359A1 - Libération réversible de cellules souches à partir de niches de moelle osseuse - Google Patents

Libération réversible de cellules souches à partir de niches de moelle osseuse Download PDF

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Publication number
WO2022101359A1
WO2022101359A1 PCT/EP2021/081419 EP2021081419W WO2022101359A1 WO 2022101359 A1 WO2022101359 A1 WO 2022101359A1 EP 2021081419 W EP2021081419 W EP 2021081419W WO 2022101359 A1 WO2022101359 A1 WO 2022101359A1
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Prior art keywords
stem cells
subject
blood
blood sample
patient
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English (en)
Inventor
Ramona Roemer
Johannes Heinrich ESS
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Roemer and Heigl GmbH
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Roemer and Heigl GmbH
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Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/067—Radiation therapy using light using laser light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N2005/0602—Apparatus for use inside the body for treatment of blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662—Visible light

Definitions

  • the subject-matter of the present invention is the mobilization of stem cells and reversible release from bone marrow niches into peripheral blood via a combination of dexamethasone and intravenous laser light. Further, the present invention relates to stem cells obtained in this manner and their use in the medical treatment.
  • Hematopoietic stem cells are the stem cells that give rise to all other blood cells through the process of hematopoiesis. They are found in the bone marrow, especially in the pelvis, femur and sternum and in small amounts also in peripheral blood. In order to extract hematopoietic stem cells for medical purposes they can be harvested from bone marrow. As an alternative technique, hematopoietic stem cells are commonly obtained from peripheral blood through a process known as apheresis. Since the number of stem cells in the blood is normally too little to obtain larger amounts of them, it is necessary to mobilise stem cells from their site of origin into circulation and increase their number in peripheral blood, thus allowing a more efficient collection of an increased amount of stem cells from the blood circulation.
  • cytokines such as granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) that induce cells to leave the bone marrow and circulate in the blood vessels.
  • G-CSF granulocyte-colony stimulating factor
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • Other examples of factors and agents that are capable of mobilizing stem cells into circulating blood of a subject are CXCR4-receptor inhibitors such as MozobilTM.
  • WO 2008/019371 A1 describes a combination of G- CSF with at least one CXCR4 inhibitor and at least one CXCR2 agonist for mobilizing stem cells into the bloodstream of a subject.
  • U.S. Patent 6,875,753 describes the administration of hyaluronic acid having a molecular weight of less than about 750,000 Da to a stem cell donor for increasing the concentration of blood stem cells in the blood of the donor.
  • WO 2011/138512 describes the combined use of at least one sulphated hyaluronan oligomer or polymer and at least one factor capable of releasing stem cells such as G-CSF.
  • undine diphosphate-glucose is used for mobilizing hematopoietic stem cells from the bone marrow into the peripheral circulation of a subject.
  • stem cells including progenitor and precursor cells, are mobilized and collect in the bone marrow niche. Together with the signaling factors found there, the stem cells enter the bloodstream in increased quantities through the activity of dexamethasone which activates the enzyme Src kinase Lek. In this manner, the number of stem cells in the bloodstream can be substantially increased.
  • a first subject-matter of the present invention is therefore a method of reversibly releasing stem cells from bone marrow niches into the bloodstream of a subject in need of such treatment comprising the steps of
  • steps (a) and (b) The order of the above steps (a) and (b) is not fixed and can basically be chosen as desired.
  • dexamethasone or a derivative or prodrug thereof can be administered first and the subject then treated intravenously with laser light.
  • Hematopoietic stem cells are pluripotent (or multipotent) cells having the ability to form all blood cell types including myeloid and lymphoid lineages.
  • stem celt refers to any type of stem cells including progenitor and precursor cells.
  • the invention deals with those stem cells that can be released from bone marrow niches into the peripheral blood stream such as hematopoietic, mesenchymal and/or endothelial stem cells.
  • the stem cell is a hematopoietic stem cell.
  • Hematopoietic stem cells are currently used for treating certain hematological and non-hematological diseases.
  • Mesenchymal stem cells have the potential to differentiate into various cellular lineages. Therefore, they represent a valuable source for applications in cell therapy and tissue engineering.
  • Mesenchymal stem cells can be derived, e.g., from bone marrow.
  • Endothelial stem cells are multipotent stem cells and can be found in bone marrow.
  • Intravenous irradiation of blood with laser light involves the in vivo illumination of the blood by feeding low-level laser light into a vascular channel.
  • the part of the body into which the laser light is radiated may be chosen arbitrarily.
  • the laser light is radiated intravenously, e.g. into a vein of the forearm.
  • Monochromatic laser light is inserted into the vein by means of a catheter.
  • intravenously applied laser light negatively charges the erythrocytes circulating in peripheral blood at the already negatively polarized glycocalix of the erythrocytes’ surface by intensifying electronegativity of NANA (N-acetyl neuraminic acid)-containing membrane structures if applied intravenously.
  • NANA N-acetyl neuraminic acid
  • erythrocytes are triggered into rotation by radiation with laser light at specific, defined nanometer wavelengths, which causes an electronegative field on the outer surface of the erythrocytes that has a significantly deeper and stronger electronegative effect on its immediate surrounding (also on electric fields of bio-molecules) than was already known from Van der Waals forces or the London force (more intense).
  • zeta potential has a major effect on the interaction of erythrocytes that have been irradiated with laser light, are electro-negatively polarized and thus rotating with the disulphide bridges of the CXCL12-CXCR4 axis that are present as isomers in different conditions.
  • Dexamethasone (9a-fluoro-16a- methylprednisolon) is a synthetic member of the glucocorticoid (GC) class of hormones that possesses anti-inflammatory and immunosuppressant activity and is commonly used to treat chronic inflammatory disorders, severe allergies, and other disease states.
  • GC glucocorticoid
  • Lek is a tyrosine kinase that phosphorylates tyrosine residues of certain proteins involved in the intracellular signalling pathways of lymphocytes.
  • Dexamethasone induces the phosphorylation of Lek and the activation of other downstream mediators in resting human stem cells.
  • dexamethasone upregulates expression of CXCR4 but not CXCR1 and CXCR2.
  • CXCR4-mediated signaling and function is significantly enhanced. This mechanism assists the reversible release of stem cells from bone marrow niches into the bloodstream.
  • Immune system cells anchored in the bone marrow with CXCL12-CXCR4 e.g. neutrophil granulocytes, monocytes, B-cells, and other three to four "white line” cell types like human T-cells
  • CXCL12-CXCR4 e.g. neutrophil granulocytes, monocytes, B-cells, and other three to four "white line” cell types like human T-cells
  • SFKs recruited Src-family kinases phosphorylate TCR ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and chains, which then serve as docking sites for Syk-family kinases. SFKs then phosphorylate and activate the recruited Syk-family kinase. Lek and Fyn are spatially segregated in cell membranes due to differential lipid raft localization, and may undergo sequential activation. In addition to the CD4 and CD8 coreceptors, a recently described adaptor, Unc119, may link SFKs to the T-cell antigen receptor (TCR).
  • TCR T-cell antigen receptor
  • CD45 and Csk provide positive and negative regulatory control of SFK functions, respectively, and Csk is constitutively bound to the transmembrane adapter protein, PAG/Cbp.
  • TCR-based signaling is required at several stages of T- cell development, including at least pre-TCR signaling, positive selection, peripheral maintenance of naive T cells, and lymphopenia-induced proliferation.
  • SFKs are required for each of these TCR-based signals, and Lek seems to be the major contributor.
  • dexamethasone derivatives or salts and prodrugs thereof may also be used.
  • the dosage is preferably in a range of 1 mg to 25 mg dexamethasone per day, more preferably 2.5 to 15 mg per day. If larger amounts of dexamethasone are administered, it is advisable to additionally administer a stomach-protecting medication such as pantoprazole.
  • the treatment can extend over one or more days.
  • a treatment period of 1-5 days is preferred, for example 2-4 days. It is preferable to administer dexamethasone on each day of treatment, preferably in the same dosage. Alternatively, it is also possible to administer larger amounts of dexamethasone on one or more days and smaller amounts or no dexamethasone at all on other days.
  • laser light for use in the present invention comprises green light, preferably with wavelengths in a range of 495-570 nm, in particular about 534 nm, and/or blue light, preferably with wavelengths in a range of 450-495 nm, in particular about 488 nm.
  • laser light in a range of 400-700 nm, 350-600 nm, 500-650 nm, 500-800 nm and/or 450-600 nm can be used.
  • the power of the laser light can be, e.g., in a range of 1-3 nW, for example about 2 nW.
  • stem cells are mobilized from bone marrow niches and released into the bloodstream of a patient via dexamethasone-induced activation of the enzyme Src kinase Lek.
  • the patient may be a human or non-human subject.
  • the subject may also be in need of such treatment in view of a desire to collect stem cells from the peripheral circulation of the subject for the purpose of transplantation, where the transplantation may be autologous or allogenic.
  • the subject is being prepared to donate stem cells, in particular hematopoietic stem cells.
  • the intravenous laser irradiation of the bloodstream is preferably carried out over a period of time that is sufficient to influence large parts of the blood of a subject with laser light.
  • the period of time is at least 30 min, preferably at least 40 min (for both wave lengths of low level laser light in case of e.g. 488 and 543 nm). This period of time is sufficient to release a substantial amount of stem cells from the bone marrow niches into the bloodstream.
  • the subject is not applied any cytokines or other factors or agents that are capable of mobilizing stem cells into circulating blood at the same time.
  • the subject does not receive G-CSF, GM-CSF or CXCR4-receptor inhibitors or any derivatives, analogues, conjugates or mixtures thereof.
  • methionine will be helpful to prepare the disulphide bridges’ region, as referred to in the international literature.
  • any hyaluronic acid or fragments or derivatives thereof are preferably not to be applied to the subject. If stem cells are released from bone marrow they have to pass the layer between bone marrow and bone- marrow sinusoids that contains hyaluronic acid. It was found that the additional administration of hyaluronic acid or derivatives thereof has the negative effect that this barrier effect is even increased.
  • the release of stem cells into the bloodstream of a subject may be used to alter or modulate the relative amounts of blood cells and/or types of blood cells of the subject.
  • Another embodiment of the present invention further includes harvesting the mobilized stem cells from the blood stream.
  • the present invention provides a method for providing a blood sample enriched in stem cells comprising the steps of
  • steps (a) and (b) The order of the above steps (a) and (b) is not fixed and can basically be chosen as desired.
  • dexamethasone or a derivative or prodrug thereof can be administered first and the subject then treated intravenously with laser light.
  • the blood sample obtained by this method contains a significantly larger amount of stem cells than a blood sample from a patient who has neither been administered dexamethasone nor undergone intravenous laser light treatment, or who has received only one of these two treatments.
  • the blood sample is essentially free of these substances.
  • cytokines or substances that naturally occur in a human body are concerned the definition is to be understood in that their amount is not increased as would be the case if a patient had been administered these substances externally.
  • Another embodiment of the present invention is a blood sample from a subject that contains an increased number of stem cells.
  • the number of stem cells in the blood sample is increased by at least 20-60% when compared to the number of stem cells naturally circulating in the bloodstream of a human subject.
  • the amount of CD34+ stem cells in the peripheral blood is significantly increased.
  • the inventive blood sample is preferably free of factors mobilizing stem cells such as G-CSF, in particular exogenous factors mobilizing stem cells and/or factors mobilizing stem cells that have been added to the patient from which the blood sample is derived.
  • factors mobilizing stem cells such as G-CSF, in particular exogenous factors mobilizing stem cells and/or factors mobilizing stem cells that have been added to the patient from which the blood sample is derived.
  • the blood sample can be used for therapeutic purposes.
  • Another object of the present invention relates to a method of providing stem cells from a subject comprising the steps of
  • step (d) isolating stem cells from said blood sample.
  • the order of the above steps (a) and (b) is not fixed and can basically be chosen as desired.
  • dexamethasone or a derivative or prodrug thereof can be administered first and the subject then treated intravenously with laser light.
  • any suitable method can be used.
  • a method, which can be used is apheresis.
  • the cells obtained as such can then be cultivated and/or administered to a recipient subject.
  • stem cells are collected by apheresis or another suitable method and stored as an enriched “mononucleus cell” fraction until use.
  • the stem cells obtained may be used for transplantations.
  • the stem cells can be administered into the same subject from whom they were obtained (autologous transplantation) or into a different subject (allogenic transplantation).
  • the administration is carried out by injection.
  • the stem cells can also be administered by infusion, thereby being transported in the blood through the body.
  • a blood sample containing an increased number of stem cells can also be used.
  • the blood sample preferably contains at least 20-60% more stem cells than naturally circulating in the bloodstream of a human subject.
  • Allogenic transplantations involve a (healthy) donor and a recipient.
  • a disadvantage compared with autologous transplantation is that the donor must have a tissue (HLA) type that matches the recipient.
  • HLA tissue
  • immune-suppressive medicaments is mandatory to mitigate graft vs. host disease.
  • Typical indications for transplantation are rejuvenation and tissue repair.
  • a particularly preferred application is the local treatment of various poorly healing wounds, e.g. ulcus cruris (venous and arterial) as well as burn wounds, large abrasions, bite wounds, etc. Additional indications include lymphomas, myeloma and chronic lymphonic leukemia.
  • autologous transplantation is eligible for a patient treated with chemotherapy or radiotherapy.
  • stem cells are reversible released in the subject using the method of the present invention and harvested from the blood stream.
  • the subject can then be treated with, e.g., high-dose chemotherapy and/or radiotherapy with the intention of eradicating the patient’s malignant cell population at the cost of partial or complete bone marrow ablation.
  • the patient’s own stored stem cells are then transfused into his/her bloodstream where they replace destroyed tissue and resume the patient’s normal blood cell production.
  • stem cells are not limited to the above- mentioned case where a patient is treated with chemotherapy or radiotherapy. It is also possible to obtain stem cells from a subject and then apply them locally to a certain part of the body where these stem cells may be helpful. For example, transplantation of stem cells or of a blood sample enriched in stem cells can be used to provide tissue repair. A particularly preferred application is the local treatment of various poorly healing wounds, e.g. ulcus cruris (venous and arterial) as well as burn wounds, large abrasions, bite wounds, etc. Moreover, the stem cells can be used for the purpose of rejuvenation.
  • various poorly healing wounds e.g. ulcus cruris (venous and arterial) as well as burn wounds, large abrasions, bite wounds, etc.
  • the stem cells can be used for the purpose of rejuvenation.
  • transplantation is accompanied by administration of dexamethasone or a derivative thereof.
  • a further subject of the present invention is a stem cell that has been obtained by the method according to the present invention as well as a pharmaceutical composition comprising said stem cell.
  • the pharmaceutical composition is free of exogenous factors capable of releasing or mobilising stem cells as defined herein above.
  • a further advantage of the present invention is that adverse effects related to the use of factors capable of mobilizing stem cells such as anemia or reduced immunodefense/immunosuppression or autoimmune reactions that are typical, especially in the context of growth factor treatments, are avoided.
  • compositions may additionally comprise pharmaceutically acceptable carriers, adjuvants, excipients, stabilizing, thickening or coloring agents, binding agents, filling agents, lubricating agents, suspending agents, anti-oxidants, preservatives, etc. or components normally found in corresponding products.
  • the pharmaceutical preparations are in a liquid form, such as a solution for injection.
  • the invention is also directed to preparations comprising isolated stem cell populations derived from harvested stem cells produced by a mammalian subject by using the above methods. These preparations and/or cell populations have a clear benefit because they contain stem cells which were released reversibly from their place of origin in bone marrow niches. Therefore, these stem cells are still able to anchor in the bone marrow unless they are needed.
  • Still a further embodiment of the invention is dexamethasone or a derivative or prodrug thereof, for use in the prevention or treatment of a disease or disorder, the prevention or treatment comprising
  • step (e) administering the stem cells obtained in step (d) to a desired target site of the patient.
  • lymphomas myeloma and chronic lymphonic leukemia. Additional indications include damage caused by chemotherapy or radiation treatment and medical conditions where tissue repair or rejuvenation is desirable.
  • a particularly preferred application is the local treatment of various poorly healing wounds, e.g. ulcus cruris (venous and arterial) as well as bum wounds, large abrasions, bite wounds, etc.
  • injection points to which the obtained stem cells are injected in accordance with the invention depend on the indication. In case of pain and inflammation, injection is preferably directly at the maximum point of pain, which can be found by finger pressure, from which the depth of the injection is then also determined. Often the injection points are located close to crossing points of the larger lymphatic system. In order to be able to achieve a therapy of various illnesses that is generally effective via the lymph channels in the body, but also to improve cosmetic criteria (skin/hair, etc.), it is advisable to inject at the main intersection of the lymph vessels at the level of the solar plexus. Experience shows that this point lies approx.
  • stem cells of the CD34-positive stem cell type unfold their repair work on aging, diseased, and sometimes even apoptotic cells via the intercellular alignment of the DNA and RNA base sequences, but also in the area of the protein-forming ribosomes in the rough endoplasmic reticulum, whereby here so-called signaling factors (including cytokines), receptors and energy suppliers such as ATP. NADH and others play a role here.

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Abstract

La présente invention a pour objet un procédé de libération réversible de cellules souches à partir de niches de moelle osseuse dans le sang périphérique et d'isolement de ces cellules souches. Le procédé consiste à administrer de la dexaméthasone à un sujet et à irradier par voie intraveineuse le sang du sujet avec une lumière laser. En outre, la présente invention concerne des cellules souches ainsi obtenues et leur utilisation dans le traitement médical.
PCT/EP2021/081419 2020-11-12 2021-11-11 Libération réversible de cellules souches à partir de niches de moelle osseuse Ceased WO2022101359A1 (fr)

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EP20207122 2020-11-12
EP20207122.1 2020-11-12

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WO2022101359A1 true WO2022101359A1 (fr) 2022-05-19

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6875753B1 (en) 1996-03-14 2005-04-05 The Governors Of The University Of Alberta Methods for cell mobilization using in vivo treatment with hyaluronan (HA)
WO2008019371A1 (fr) 2006-08-07 2008-02-14 Genzyme Corporation Thérapie combinée
WO2011138512A1 (fr) 2010-05-06 2011-11-10 Suomen Punainen Risti Veripalvelu Acide hyaluronique sulfaté combiné au facteur g-csf pour mobiliser des cellules souches sanguines
US20150374736A1 (en) 2012-03-30 2015-12-31 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Uridine diphosphate compounds as mobilizers of hematopoietic progenitor cells
WO2019086597A1 (fr) 2017-11-03 2019-05-09 Roemer & Heigl Gmbh Extraction de cellules souches à partir de niches de moelle osseuse
CN109731002B (zh) * 2019-03-21 2020-02-11 广州沙艾生物科技有限公司 白酒草皂苷r用于制备造血干细胞动员剂的应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6875753B1 (en) 1996-03-14 2005-04-05 The Governors Of The University Of Alberta Methods for cell mobilization using in vivo treatment with hyaluronan (HA)
WO2008019371A1 (fr) 2006-08-07 2008-02-14 Genzyme Corporation Thérapie combinée
WO2011138512A1 (fr) 2010-05-06 2011-11-10 Suomen Punainen Risti Veripalvelu Acide hyaluronique sulfaté combiné au facteur g-csf pour mobiliser des cellules souches sanguines
US20150374736A1 (en) 2012-03-30 2015-12-31 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Uridine diphosphate compounds as mobilizers of hematopoietic progenitor cells
WO2019086597A1 (fr) 2017-11-03 2019-05-09 Roemer & Heigl Gmbh Extraction de cellules souches à partir de niches de moelle osseuse
US20200338359A1 (en) * 2017-11-03 2020-10-29 Roemer & Heigl Gmbh Extraction of stem cells from bone marrow niches
CN109731002B (zh) * 2019-03-21 2020-02-11 广州沙艾生物科技有限公司 白酒草皂苷r用于制备造血干细胞动员剂的应用

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Title
EKA PUTRA WIRA ET AL: "Effect of Dexamethasone Administration toward Hematopoietic Stem Cells and Blood Progenitor Cells Expression on BALB/c Mice", THE JOURNAL OF PURE AND APPLIED CHEMISTRY RESEARCH, vol. 4, no. 3, 1 September 2015 (2015-09-01), pages 100 - 108, XP055877528, ISSN: 2302-4690, DOI: 10.21776/ub.jpacr.2015.004.03.221 *
KUMAR S ET AL: "Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma", BONE MARROW TRANSPLANTATION, vol. 34, no. 6, 2 August 2004 (2004-08-02), GB, pages 485 - 490, XP055877361, ISSN: 0268-3369, Retrieved from the Internet <URL:https://www.nature.com/articles/1704633.pdf> DOI: 10.1038/sj.bmt.1704633 *
STATKUTE L ET AL: "Mobilization, harvesting and selection of peripheral blood stem cells in patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation", BONE MARROW TRANSPLANTATION, vol. 39, no. 6, 5 February 2007 (2007-02-05), GB, pages 317 - 329, XP055877902, ISSN: 0268-3369, Retrieved from the Internet <URL:https://www.nature.com/articles/1705579.pdf> DOI: 10.1038/sj.bmt.1705579 *
VINCENT RAJKUMAR S ET AL: "Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group", vol. 24, no. 3, 20 January 2006 (2006-01-20), pages 431 - 436, XP002670937, ISSN: 0732-183X, Retrieved from the Internet <URL:http://jco.ascopubs.org/content/24/3/431> [retrieved on 20051219], DOI: 10.1200/JCO.2005.03.0221 *

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