title: Mobilization of human immature hematopoietic progenitors through combinatory use of bortezomib and immunomodulatory drugs.
abstract: Combination use of the proteasome inhibitor bortezomib and the immunomodulatory drugs lenalidomide or thalidomide has provided superior outcomes in multiple myeloma over their single use; however, these combinations can produce significant toxicities. Unexpectedly, we found a small but significant increase in the population of immature granulocytes and erythrocytes/megakaryocytes in peripheral blood in 16 of 22 patients (73%) treated with dexamethasone in combination with bortezomib and immunomodulatory drugs (triplet), but not in any of 25 patients treated with either bortezomib or immunomodulatory drugs with dexamethasone (doublet). These immature cells gradually increased to a peak level (mean 2.6% per white blood cells) with triplet therapy, and disappeared immediately after therapy cessation. The numbers of circulating CD34+cells and colony-forming cells derived from peripheral blood mononuclear cells increased after triplet therapy compared with those in patients treated by either bortezomib or immunomodulatory drugs plus dexamethasone. Furthermore, triplet regimen downregulated the expression of CXCR4, a chemokine receptor essential for bone marrow retention, on CD34+cells, suggesting an unexpected effect on normal hematopoietic stem/progenitor cells through the reduced interaction with the bone marrow microenvironment. Our observations suggest that combination use should be carefully evaluated to exert synergistic anti-myeloma effects while avoiding unexpected adverse events.
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Tochigi
authors.affiliation: Department of Hematology, Harasanshin Hospital, Fukuoka, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan. kikusige@intmed1.med.kyushu-u.ac.jp.
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Kikushige
authors.affiliation: Department of Hematology, Harasanshin Hospital, Fukuoka, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kamimura
authors.affiliation: Department of Hematology, Harasanshin Hospital, Fukuoka, Japan.
authors.forename: Yoshikiyo
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shima
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Goichi
authors.initials: G
authors.lastname: Yoshimoto
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kamezaki
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Takenaka
authors.affiliation: Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.|Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000368:Aged; D018952:Antigens, CD34 / Q000187:drug effects; D001773:Blood Cells / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D000069286:Bortezomib / Q000009:adverse effects* / Q000627:therapeutic use; D003907:Dexamethasone / Q000009:adverse effects / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects* / Q000627:therapeutic use; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy; D019718:Receptors, CXCR4 / Q000187:drug effects; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D018952:Antigens, CD34; C527276:CXCR4 protein, human; D007155:Immunologic Factors; D019718:Receptors, CXCR4; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D000077269:Lenalidomide
keywords: CXCR4; Hematopoietic stem cell mobilization; Immunomodulatory drugs; Multiple myeloma