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International Journal of Hematology
Published in: International Journal of Hematology 4/2017

01-04-2017 | Original Article

Mobilization of human immature hematopoietic progenitors through combinatory use of bortezomib and immunomodulatory drugs

Authors: Taro Tochigi, Takatoshi Aoki, Yoshikane Kikushige, Tomohiko Kamimura, Yoshikiyo Ito, Takahiro Shima, Takuji Yamauchi, Yasuo Mori, Goichi Yoshimoto, Kenjiro Kamezaki, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Koichi Akashi, Toshihiro Miyamoto

Published in: International Journal of Hematology | Issue 4/2017

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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.
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Literature
1.
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–20.CrossRefPubMedPubMedCentral
2.
Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001;61:3071–6.PubMed
3.
Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107:4907–16.CrossRefPubMedPubMedCentral
4.
Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA. 2003;100:9946–51.CrossRefPubMedPubMedCentral
5.
LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res. 2002;62:4996–5000.PubMed
6.
Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem. 2002;277:16639–47.CrossRefPubMed
7.
Chang X, Zhu Y, Shi C, Stewart AK. Mechanism of immunomodulatory drugs’ action in the treatment of multiple myeloma. Acta Biochim Biophys Sin (Shanghai). 2014;46:240–53.CrossRef
8.
Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327:1345–50.CrossRefPubMed
9.
Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–5.CrossRefPubMed
10.
John LB, Ward AC. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol. 2011;48:1272–8.CrossRefPubMed
11.
Ito T, Handa H. Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs. Int J Hematol. 2016;104:293–9.CrossRefPubMed
12.
Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343:305–9.CrossRefPubMed
13.
Zhu YX, Braggio E, Shi CX, Kortuem KM, Bruins LA, Schmidt JE, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood. 2014;124:536–45.CrossRefPubMedPubMedCentral
14.
Chamberlain PP, Lopez-Girona A, Miller K, Carmel G, Pagarigan B, Chie-Leon B, et al. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014;21:803–9.CrossRefPubMed
15.
Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Nimer SD, et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006;108:618–21.CrossRefPubMedPubMedCentral
16.
Gorgun G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood. 2010;116:3227–37.CrossRefPubMedPubMedCentral
17.
Kumar S, Raje N, Hideshima T, Ishitsuka K, Roccaro A, Shiraishi N, et al. Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs. Leukemia. 2005;19:1253–61.CrossRefPubMed
18.
Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000;96:2943–50.PubMed
19.
Hideshima T, Chauhan D, Schlossman R, Richardson P, Anderson KC. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene. 2001;20:4519–27.CrossRefPubMed
20.
Noborio-Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M, et al. Bortezomib overcomes cell-adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene. 2009;28:231–42.CrossRefPubMed
21.
Chang TP, Poltoratsky V, Vancurova I. Bortezomib inhibits expression of TGF-beta1, IL-10, and CXCR4, resulting in decreased survival and migration of cutaneous T cell lymphoma cells. J Immunol. 2015;194:2942–53.CrossRefPubMedPubMedCentral
22.
Kikushige Y, Shima T, Takayanagi S, Urata S, Miyamoto T, Iwasaki H, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell. 2010;7:708–17.CrossRefPubMed
23.
Kikushige Y, Yoshimoto G, Miyamoto T, Iino T, Mori Y, Iwasaki H, et al. Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival. J Immunol. 2008;180:7358–67.CrossRefPubMed
24.
Imamura R, Miyamoto T, Yoshimoto G, Kamezaki K, Ishikawa F, Henzan H, et al. Mobilization of human lymphoid progenitors after treatment with granulocyte colony-stimulating factor. J Immunol. 2005;175:2647–54.CrossRefPubMed
25.
Girbl T, Lunzer V, Greil R, Namberger K, Hartmann TN. The CXCR4 and adhesion molecule expression of CD34+ hematopoietic cells mobilized by “on-demand” addition of plerixafor to granulocyte-colony-stimulating factor. Transfusion. 2014;54:2325–35.CrossRefPubMedPubMedCentral
26.
Rettig MP, Ansstas G, DiPersio JF. Mobilization of hematopoietic stem and progenitor cells using inhibitors of CXCR4 and VLA-4. Leukemia. 2012;26:34–53.CrossRefPubMed
27.
Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075–85.CrossRefPubMed
28.
Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011;118:5752–8 (quiz 982).CrossRefPubMed
29.
Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679–86.CrossRefPubMedPubMedCentral
30.
Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myelome. J Clin Oncol. 2014;32:2712–7.CrossRefPubMed
31.
Li S, Fu J, Mapara M, Lentzsch S. IMiD® compounds affect the hematopoiesis via CRBN dependent degradation of IKZF1 protein in CD34+ cells. Blood. 2014;124:418.
32.
Koh KR, Janz M, Mapara MY, Lemke B, Stirling D, Dorken B, et al. Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood. 2005;105:3833–40.CrossRefPubMed
33.
Pal R, Monaghan SA, Hassett AC, Mapara MY, Schafer P, Roodman GD, et al. Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia. Blood. 2010;115:605–14.CrossRefPubMed
34.
Dumortier A, Kirstetter P, Kastner P, Chan S. Ikaros regulates neutrophil differentiation. Blood. 2003;101:2219–26.CrossRefPubMed
35.
Ghobadi A, Rettig MP, Cooper ML, Holt MS, Ritchey JK, Eissenberg L, et al. Bortezomib is a rapid mobilizer of hematopoietic stem cells in mice via modulation of the VCAM-1/VLA-4 axis. Blood. 2014;124:2752–4.CrossRefPubMedPubMedCentral
36.
Neish AS, Williams AJ, Palmer HJ, Whitley MZ, Collins T. Functional analysis of the human vascular cell adhesion molecule 1 promoter. J Exp Med. 1992;176:1583–93.CrossRefPubMed
37.
Niesvizky R, Mark TM, Ward M, Jayabalan DS, Pearse RN, Manco M, et al. Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization. Clin Cancer Res. 2013;19:1534–46.CrossRefPubMedPubMedCentral
38.
James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, et al. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium. J Clin Oncol. 2014;32:2067–73.CrossRefPubMedPubMedCentral
39.
Shi CX, Kortum KM, Zhu YX, Jedlowski P, Bruins L, Braggio E, et al. Proteasome inhibitors block Ikaros degradation by Lenalidomide in Multiple Myeloma. Haematologica. 2015;100:e315–17.CrossRefPubMedPubMedCentral
40.
Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, Leleu X, et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood. 2009;113:4341–51.CrossRefPubMedPubMedCentral
41.
Miyamoto T, Yoshimoto G, Kamimura T, Muta T, Takashima S, Ito Y, et al. Combination of high-dose melphalan and bortezomib as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma. Int J Hematol. 2013;98:337–45.CrossRefPubMed
42.
43.
Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest. 2003;111:187–96.CrossRefPubMedPubMedCentral
44.
Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283:845–8.CrossRefPubMed
45.
Li S, Zou D, Li C, Meng H, Sui W, Feng S, et al. Targeting stem cell niche can protect hematopoietic stem cells from chemotherapy and G-CSF treatment. Stem Cell Res Ther. 2015;6:1–10.CrossRef
46.
Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O, et al. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol. 2013;31:247–55.CrossRefPubMed
Metadata
Title
Mobilization of human immature hematopoietic progenitors through combinatory use of bortezomib and immunomodulatory drugs
Authors
Taro Tochigi
Takatoshi Aoki
Yoshikane Kikushige
Tomohiko Kamimura
Yoshikiyo Ito
Takahiro Shima
Takuji Yamauchi
Yasuo Mori
Goichi Yoshimoto
Kenjiro Kamezaki
Koji Kato
Katsuto Takenaka
Hiromi Iwasaki
Koichi Akashi
Toshihiro Miyamoto
Publication date
01-04-2017
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 4/2017
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-016-2148-2

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