Lymphoplasmacytic Cells and Mast Cells Are Targets for Imatinib Mesylate (Gleevec, Glivec) in Waldenstrom’s Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4929-4929 ◽  
Author(s):  
Olivier Tournilhac ◽  
Daniel Ditzel Santos ◽  
Lian Xu ◽  
Evdoxia Hatjiharissi ◽  
Yu Tsu ◽  
...  
Keyword(s):  
Mast Cells ◽  
Imatinib Mesylate ◽  
Cell Lines ◽  
Ex Vivo ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Recently, we demonstrated that in Waldenstrom’s macroglobulinemia (WM), clonal lymphoplasmacytic cells (LPC) appear to derive growth and survival signals from excess mast cells (MC) present in the bone marrow (BM). (Tournilhac et al, JCO 2004 22:571S). We therefore have sought agents which could target both LPC and MC. One such candidate is imatinib mesylate which has shown activity in certain mast cell disorders likely on the basis of its ability to target the tyrosine kinases, CD117 (Stem Cell Factor Receptor, c-kit), and Platelet Derived Growth Factor Receptor (PDGFa-R). By flow cytometric analysis, we demonstrated CD117 expression on sorted LPC from 17/22 (76.2%) WM patients, above 20% in 13 cases, whose expressionwe confirmed by RT-PCR analysis. Moreover, we also demonstrated expression of PDGFa-R along with its ligand PDGFa in BM LPC from 16/18 (88.9%) and 7/10 (70%) WM patients.. In addition to CD117, we found by RT-PCR analysis a PDGFa expression in LAD and HMC-1 MC lines and in KU the basophilic cell lines KU as well as in sorted BM MC (FcER1+ CD117+) from 3/10 (30%) WM patients. Importantly, co-culture of sorted LPC from WM patients along with 0.5% paraformaldehyde fixed LAD cells or ex vivo expanded (EVE) BM MC induced proliferation of sorted LPC from WM patients, which was inhibited at pharmacologically achievable levels of imatinib mesylate with an IC50 of 0.5–10 μmoles/L. Moreover, imatinib mesylate inhibited the LAD, HMC-1 and KU cell lines as well as EVE cord blood MC or EVE BM MC at an IC50 of 0.01–1 μmoles/L. Lastly, imatinib mesylate also inhibited proliferation of both MC and LPC when unfixed LAD or ex vivo MC were incubated with WM LPC with an IC50 of 1–10 μmoles/L. These studies therefore demonstrate that both LPC and MC are therapeutic targets for imatinib mesylate, and provide the framework for clinical studies evaluating its use in WM.

Sequence Analysis in the BLYS and APRIL Receptor TACI Reveals Novel Variants with a Potential Pathogenetic Role in Waldenstrom’s Macroglobulinemia (WM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 991-991
Author(s):  
Zachary R. Hunter ◽  
Xavier Leleu ◽  
Daniel D. Santos ◽  
Susannah Hamilton ◽  
Sigitas Verselis ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
B Lymphocyte ◽  
Suppressor Gene ◽  
Pcr Analysis ◽  
Waldenström’S Macroglobulinemia ◽  
Exon 1 ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
B Cell Homeostasis ◽  
Waldenström's Macroglobulinemia

Abstract B-lymphocyte stimulator protein (BLYS) and a proliferation inducing ligand (APRIL) are members of the tumor necrosis family of ligands which play an important role in normal and malignant human B-cell homeostasis through their receptors BCMA, TACI (for BLYS and APRIL) and BAFF-R (for BLYS only). We previously demonstrated via multicolor flow cytometric and RT-PCR analysis the expression of BLYS and APRIL, along with BCMA, TACI and BAFF-R on lymphoplasmacytic cells (LPC) as well as mast cells, which provide LPC growth support in patients with Waldenstrom’s Macroglobulinemia (WM) (Blood 104:917a). Based on these studies, we performed sequence analysis for BLYS, APRIL, BCMA, TACI and BAFF-R from DNA obtained from CD19+ selected bone marrow LPC from 15 patients with the consensus panel diagnosis of WM, who also demonstrated active disease. These studies demonstrated multiple variants in exons 3 and 5 of TACI in 5/15 patients, and exon 1 of BAFF-R in 2/15 patients. The finding of genetic variants in the TACI gene in WM patients is of particular interest given its recently described role as a potential tumor suppressor gene, and potential involvement in the generation of autoimmunity (Immunity2003; 8:279–88), which is a common complication in patients with WM. Moreover, variants in TACI have been reported in patients with common variable immunodeficiency (CVID) (Nat Genet2005;37:820–8), a finding significant to patients with WM who chronically demonstrate IgA and IgG hypogammaglobulinemia, even following successful therapeutic intervention as we recently reported (Blood 104:306b). The results of these studies suggest that variants in TACI, and possibly BAFF-R may play a significant role in the pathogenesis of WM.

Vascular Endothelial Growth Factor (VEGF) Is a Growth and Survival Factor in Waldenstrom’s Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4892-4892 ◽  
Author(s):  
Oliver Tournilhac ◽  
Steven Le Gouill ◽  
Daniel Ditzel Santos ◽  
Klaus Podar ◽  
Lian Xu ◽  
...  
Keyword(s):  
Pcr Analysis ◽  
Serum Starvation ◽  
Waldenström’S Macroglobulinemia ◽  
Growth And Survival ◽  
Survival Factor ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Induced Apoptosis ◽  
Waldenström's Macroglobulinemia

Abstract Waldenstrom’s macroglobulinemia (WM) is a B-cell disorder characterized by excess of bone marrow (BM) IgM secreting lymphoplasmacytic cells (LPC). In previous studies, we and others have demonstrated that VEGF within the BM micro-environment plays a role in the growth, survival and migration of myeloma plasma cells. Conversely, we demonstrated that BM mast cells (MC), which produce and secrete VEGF (Boesiger, J Exp Med, 1998) support growth and survival of WM LPC (Tournilhac et al, JCO2004; 22:517S). In the present studies we therefore explored the role of VEGF in WM pathogenesis. Using RT-PCR analysis, we detected VEGF receptors R1 (Flt-1) and R2 (flk1/KDR) transcripts in sorted LPC from 4/4 (100%) and 15/16 (94%) WM patients respectively. Moreover, we showed functionality for VEGF as a growth and survival factor in WM. Specifically, recombinant human VEGF (rh-VEGF) at 25 ng/ml induced dose dependent proliferation of sorted LPC from WM patients and prevented serum starvation- induced apoptosis. Inhibition of VEGF signaling pathways both induced apoptosis and blocked mast cell- induced proliferation of sorted WM LPCs in 4 of 6 and 4 of 4 patients, respectively. Besides the known MC-derived WM LPC growth and survival factors CD40 ligand (CD40L) (JCO2004; 22;517S) and B-lymphocyte stimulator protein (BLYS) (Ditzel Santos et al, ASH 2004 submitted), the present study demonstrates also a role of VEGF in WM pathogenesis. We therefore suggest VEGF as an additional therapeutic target in WM treatment regimens.

CD52 Is Expressed on Human Mast Cells and Is a Therapeutic Target for the Anti-CD52 Monoclonal Antibody Campath-1H in Waldenstrom’s Macroglobulinemia and Mast Cell Disorders.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4885-4885 ◽  
Author(s):  
Daniel Ditzel Santos ◽  
Evdoxia Hatjiarissi ◽  
Olivier Tournilhac ◽  
Lian Xu ◽  
Andrew Branagan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Mast Cell ◽  
Mast Cells ◽  
B Cell ◽  
Therapeutic Target ◽  
Waldenström’S Macroglobulinemia ◽  
Healthy Donors ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Campath-1H is a monoclonal antibody used in the treatment of CD52 expressing B-cell malignancies. Recently, we and others have observed that Campath-1H shows unusually high activity in patients with relapsed/refractory Waldenstrom’s macroglobulinemia (WM), a B-cell malignancy with excess bone marrow mast cells (BMMC). Importantly, as we have recently shown, BMMC appear to provide direct support for WM tumor cell growth (Tournilhac et al, JCO 2004 22:571S), and are therefore a potential therapeutic target in WM. We therefore examined BMMC from patients with WM and other mast cell disorders for cell surface expression of CD52, and targeting by Campath-1H in preclinical studies. Multicolor flow cytometric analysis demonstrated CD52 expression on BMMC (FceRI+, CD117+) from 13/15 WM; 2/2 systemic mastocytosis (SM) patients; 2/4 healthy donors; as well as on the LAD and HMC MC lines. Moreover, RT-PCR analysis confirmed CD52 expression in sorted BMMC from 6/7 WM, along with 6/6 healthy donors. Importantly, Campath-1H induced high levels of antibody dependent cell mediated cytotoxicity (ADCC) actvity against LAD mast cells using activated NK effector cells. No direct cytotoxicity or antiproliferative activity by Campath-1H on LAD cells was observed. These studies demonstrate that CD52 is widely expressed on human MC and provide support for the use of Campath-1H in the treatment of WM and other systemic mast cell disorders.

A Novel Functional Role for Soluble CD27 in the Pathogenesis of Waldenstrom’s Macroglobulinemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4701-4701 ◽  
Author(s):  
Allen W. Ho ◽  
Xavier Leleu ◽  
Evdoxia Hatjiharissi ◽  
Olivier Tournilhac ◽  
Lian Xu ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Tumor Cells ◽  
Functional Role ◽  
Flow Cytometric Analysis ◽  
Waldenström’S Macroglobulinemia ◽  
Flow Cytometric ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract The tumor necrosis factor (TNF) receptor family member, CD27, is a transmembrane co-stimulatory molecule present on primed T and B lymphocytes that also secrete a soluble form (sCD27). Recent evidence has suggested that interactions between CD27 and its TNF-like ligand, CD70, play a critical role in regulating B-cell activation and survival, though the detailed mechanism(s) by which this occurs remain unclear. Waldenstrom’s Macroglobulinemia (WM) represents a lymphoplasmacytic lymphoma characterized by a monoclonal IgM gammopathy and possesses a mast cell component that may contribute to its pathogenesis (Blood 104; 646a). Using ELISA assays, we observed that WM patients displayed significantly higher levels of sCD27 in their sera (median 7.45, range 0–19.42 U/ml) versus healthy donors (median 0, range 0–2.78 U/ml; p=2.5 x 10−7). CD27 was expressed in 7/7 patients using RT-PCR analysis, but was expressed on the cell surface of tumor cells in 5/12 patients using flow cytometric analysis. Conversely, CD70 expression was widely expressed on both tumor cells (6/6 patients) and mast cells (10/11 patients) using flow cytometric analysis. In order to define the functional role of sCD27 in WM, we cultured BCWM.1 (CD27−CD70+) WM cells, and LAD1 (CD27−CD70+) mast cells with sCD27 (0.1–50 ug/mL), and observed no effect on proliferation or induction of apoptosis. Culture of LAD1 cells with sCD27 did, however, result in marked upregulation of the TNF family ligands CD40L (CD154) and a proliferation induction ligand (APRIL), which previous work in our laboratory had implicated as mast cell proliferation and survival factors in WM. Taken together, these studies suggest a novel functional role for sCD27, and imply a pivotal role in the pathogenesis of WM.

Imatinib Mesylate (Gleevec®) Is Active in Relapsed/Refractory Waldenstrom’s Macroglobulinemia: Planned Interim Results of WMCTG Clinical Trial 05-140.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2484-2484
Author(s):  
Steven P. Treon ◽  
Jacob D. Soumerai ◽  
Christopher J. Patterson ◽  
Zachary R. Hunter ◽  
Rose Villarreal ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Waldenström’S Macroglobulinemia ◽  
Growth And Survival ◽  
Best Response ◽  
Median Serum ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Intent To Treat ◽  
Waldenström's Macroglobulinemia ◽  
Cell Disorder

Abstract Waldenstrom’s macroglobulinemia is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells (LPC) in the bone marrow (BM), along with an IgM monoclonal gammopathy. Characteristic of WM is an increased number of mast cells (MC) which are found in association with LPC, and stimulate LPC growth through several TNF-family members including CD40L, APRIL and BLYS (Ann Oncol17:1275; Blood104:917A). As such, we have targeted MC in WM. One important growth and survival factor for MC is stem cell factor (SCF), which signals through CD117. Imatinib mesylate blocks SCF signaling through CD117, and induces apoptosis of WM BM MC and LPC, both of which highly express CD117 (Blood2004; 104:314b). As such, we performed this Phase II study of imatinib mesylate in patients with relapsed and refractory WM. Intended therapy consisted of imatinib mesylate which was initiated at 400 mg po qD over the first month, and subsequently dose escalated to 600 mg po qD for up to 2 years. Dose de-escalation to 300 mg po qD was permitted for toxicity. Thirteen patients were enrolled and are eligible for evaluation at interim analysis. Median age was 64 (range 53–80 years), and median prior therapies was 2 (range 1–5). Nine and four patients had relapsed and refractory disease, respectively. Following a median of 3 months of therapy, median serum IgM levels for all evaluable patients declined from 3190 (range 763–8130 mg/dL) to 2095 (range 695–7340 mg/dL) at best response (p=0.009). On an intent to treat analysis, 6/13 (46.2%) of patients attained a ≥25% decrease in serum IgM. Responses were prompt, and occurred at a median of 2.5 months. Overall, therapy was well tolerated with ≥grade 2 toxicities as follows: anemia (n=4); edema (n=3); hyperglycemia (n=2); leukopenia (n=2); thrombocytopenia (n=1); neutropenia (n=1); and resulted for 4 patients in dose modification (n=4) or treatment cessation (n=3). The interim results of this study demonstrate that imatinib mesylate is an active and well-tolerated salvage therapy for WM.

Sign in / Sign up

Export Citation Format

Share Document