CD20-directed serotherapy in patients with multiple myeloma: Biologic considerations and therapeutic applications

被引:109
作者
Treon, SP
Pilarski, TM
Belch, TR
Kelliher, A
Preffer, FI
Shima, Y
Mitsiades, CS
Mitsiades, NS
Szczepek, AJ
Ellman, L
Harmon, D
Grossbard, ML
Anderson, KC
机构
[1] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Boston, MA USA
[3] Univ Alberta, Cross Canc Inst, Dept Med Oncol, Edmonton, AB, Canada
[4] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA
[5] Harvard Univ, Sch Med, Boston, MA USA
[6] Max Planck Inst, Berlin, Germany
[7] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA
[8] Harvard Univ, Sch Med, Boston, MA 02115 USA
关键词
CD20; multiple myeloma; B cells; rituximab; interferongamma;
D O I
10.1097/00002371-200201000-00008
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Clonotypic B cells circulating in patients with multiple myeloma (MM) express CD20, and it has been suggested that these cells may be clonogenic. Furthermore, 20% of patients with MM express CD20 on their bone marrow plasma cells (BMPCs). Therefore, the authors began a phase 11 clinical study to determine the activity of the anti-CD20 monoclonal antibody rituximab in MM patients. Nineteen previously treated MM patients received 375 mg/m(2) rituximab per week for 4 weeks. Three months after initiation of treatment, patients were assessed for response and received a second course of therapy if their disease was stable (SD) or they achieved a partial response (PR). Six of 19 (32%) patients had either a PR (n = 1) or SD (n = 5), with a median time to treatment failure of 5.5 months (mean, 10.3 months range, 3-27+ months). All six patients who had a PR or SD had CD20(+) BMPC. Overall, rituximab therapy was well tolerated. Because most patients with MM poorly express CD20 on their BMPCs, the authors evaluated agents for their ability to induce CD20 expression and thereby facilitate rituximab binding on MM cells. These studies show that interferon-gamma (IFN-gamma) induced CD20 expression on MM BMPCs, MM B cells, and healthy donor BMPCs. In contrast, CD20 expression on chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma, healthy donor B cells, and progenitor cells was unaffected by IFN-gamma. Rituximab binding to the BMPCs of MM patients was also increased after culture with pharmacologically attainable levels of IFN-gamma ( 1-100 U/mL). In conclusion, these studies suggest that MM patients with CD20(+) BMPCs may benefit from rituximab therapy. Furthermore, IFN-gamma induces CD20 expression on MM BMPCs and B cells and facilitates rituximab binding to MM BMPCs, providing the rationale for clinical trials to examine its use with CD20-directed serotherapies in MM.
引用
收藏
页码:72 / 81
页数:10
相关论文
共 68 条
[1]  
Akbar SMF, 1996, IMMUNOLOGY, V87, P519
[2]   EXPRESSION OF HUMAN B CELL-ASSOCIATED ANTIGENS ON LEUKEMIAS AND LYMPHOMAS - A MODEL OF HUMAN B-CELL DIFFERENTIATION [J].
ANDERSON, KC ;
BATES, MP ;
SLAUGHENHOUPT, BL ;
PINKUS, GS ;
SCHLOSSMAN, SF ;
NADLER, LM .
BLOOD, 1984, 63 (06) :1424-1433
[3]  
BERGSAGEL PL, 1994, BLOOD, V84, pA524
[4]   IN MULTIPLE-MYELOMA, CLONOTYPIC B-LYMPHOCYTES ARE DETECTABLE AMONG CD19(+) PERIPHERAL-BLOOD CELLS EXPRESSING CD38, CD56, AND MONOTYPIC IG LIGHT-CHAIN [J].
BERGSAGEL, PL ;
SMITH, AM ;
SZCZEPEK, A ;
MANT, MJ ;
BELCH, AR ;
PILARSKI, LM .
BLOOD, 1995, 85 (02) :436-447
[5]   THE BONE-MARROW OF MULTIPLE-MYELOMA PATIENTS CONTAINS B-CELL POPULATIONS AT DIFFERENT STAGES OF DIFFERENTIATION THAT ARE CLONALLY RELATED TO THE MALIGNANT PLASMA-CELL [J].
BILLADEAU, D ;
AHMANN, G ;
GREIPP, P ;
VANNESS, B .
JOURNAL OF EXPERIMENTAL MEDICINE, 1993, 178 (03) :1023-1031
[6]  
Coiffier B, 1998, BLOOD, V92, P1927
[7]   AN INTERFERON GAMMA-REGULATED PROTEIN THAT BINDS THE INTERFERON-INDUCIBLE ENHANCER ELEMENT OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I GENES [J].
DRIGGERS, PH ;
ENNIST, DL ;
GLEASON, SL ;
MAK, WH ;
MARKS, MS ;
LEVI, BZ ;
FLANAGAN, JR ;
APPELLA, E ;
OZATO, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (10) :3743-3747
[8]   INTERFERON EXERTS A CYTO-TOXIC EFFECT ON PRIMARY HUMAN MYELOMA CELLS [J].
EINHORN, S ;
FERNBERG, JO ;
GRANDER, D ;
LEWENSOHN, R .
EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY, 1988, 24 (09) :1505-1510
[9]  
FOON KA, 1985, CANCER IMMUNOL IMMUN, V20, P193
[10]   Primary plasma cell leukemia:: Clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics [J].
García-Sanz, R ;
Orfao, A ;
González, M ;
Tabernero, MD ;
Bladé, J ;
Moro, MJ ;
Fernández-Calvo, J ;
Sanz, MA ;
Pérez-Simón, JA ;
Rasillo, A ;
San Miguel, JF .
BLOOD, 1999, 93 (03) :1032-1037