B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis.
The occurrence of delayed neutropenia following rituximab is poorly defined and of unknown cause. We hypothesized it may be related to perturbations of stromal derived factor-1 (SDF-1) and granulocyte homeostasis. Late-onset neutropenia (LON) was investigated in 130 patients with untreated aggressive B-cell lymphoma receiving DA-EPOCH (dose-adjusted etoposide, prednisone, Oncovin [vincristine], cyclophosphamide, and hydroxydaunorubicin) chemotherapy with or without rituximab. All patients were in remission and had no known causes for neutropenia. LON occurred in 6 (8%) of 76 patients receiving rituximab and 0 of 54 patients not receiving rituximab (P = .04). The median onset was 175 days (range, 77-204 days) after treatment with a median duration of 14 days (range, 11-16 days). In a subset of 24 patients, a significant correlation was found between rapid B-cell recovery and granulocyte decline over the 6-month recovery period (R = -0.53; P = .04). Rapid B-cell recovery directly correlated with prerecovery SDF-1 levels (R = 0.65; P = .015) and SDF-1 decline (R = -0.67; P = .013) after recovery. Our results suggest that early B-cell lymphopoiesis is important for B-cell recovery following rituximab, and that perturbation of SDF-1 during B-cell recovery retards neutrophil egress from the bone marrow. These findings illustrate the dual role of SDF-1 in human B-cell and granulocyte homeostasis.
Dunleavy
Kieron
K
Experimental Transplantation and Immunology Branch, CCR, NCI, Bldg 10, Rm 12-N-226, Bethesda, MD, 20892-1868, USA.
Hakim
Frances
F
Kim
Hyun Kyung
HK
Janik
John E
JE
Grant
Nicole
N
Nakayama
Takayuki
T
White
Therese
T
Wright
George
G
Kwak
Larry
L
Gress
Ronald
R
Tosato
Giovanna
G
Wilson
Wyndham H
WH
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood / Q000502:physiology*; D004341:Drug Evaluation; D005260:Female; D006098:Granulocytes / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D016393:Lymphoma, B-Cell / Q000150:complications / Q000188:drug therapy; D038041:Lymphopoiesis; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000209:etiology; D012038:Regeneration; D012189:Retrospective Studies; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D000069283:Rituximab
Cancer Res. 2001 Jul 1;61(13):5028-37
11431337
Exp Hematol. 2002 Sep;30(9):973-81
12225788
J Exp Med. 1981 Sep 1;154(3):737-49
7024458
Immunity. 1999 Apr;10(4):463-71
10229189
Blood. 2004 Jul 15;104(2):565-71
15054039
Nature. 1998 Jun 11;393(6685):595-9
9634238
Immunity. 2003 Oct;19(4):583-93
14563322
J Leukoc Biol. 2003 Nov;74(5):880-8
12960279
Immunol Today. 1994 Sep;15(9):450-4
7524522
Nat Immunol. 2002 Jul;3(7):687-94
12068293
Eur J Immunol. 1986 Aug;16(8):881-7
3091375
Immunity. 2001 Aug;15(2):323-34
11520466
Nat Med. 2004 Aug;10(8):858-64
15235597
Immunity. 2004 Jun;20(6):707-18
15189736
Bone Marrow Transplant. 2004 May;33(9):921-3
15034544
J Immunol. 1980 Oct;125(4):1678-85
6157744
Blood. 2003 Jun 15;101(12):4653-9
12609827
J Clin Oncol. 1997 Oct;15(10):3266-74
9336364
J Clin Oncol. 2000 Sep;18(17):3135-43
10963642
J Clin Invest. 2003 Jan;111(2):187-96
12531874
N Engl J Med. 2003 Jun 26;348(26):2691-4; discussion 2691-4
12826650
Blood. 1997 Nov 1;90(9):3789-98
9345067
Blood. 1994 Jan 15;83(2):435-45
7506951
Br J Haematol. 2003 Jun;121(6):913-8
12786803
N Engl J Med. 2002 Jan 24;346(4):235-42
11807147
Blood. 2002 Apr 15;99(8):2703-11
11929756
Blood. 2002 Apr 15;99(8):2685-93
11929754
J Clin Oncol. 1999 Jun;17(6):1851-7
10561225
J Immunol. 1998 Feb 1;160(3):1522-31
9570576
Blood. 2005 Sep 1;106(5):1538-43
15914552