Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

Purpose:Chronic lymphocytic leukemia (CLL) cells treatedwith dasatinib in vitro undergo apoptosis via inhibition of Lyn kinase. Thus, in this study we tested the activity of dasatinib in patients with relapsed CLL. Experimental Design: Patients were eligible for this phase II trial if they had documented CLL/SLL and had failed at least 1 prior therapy with a fludarabine-containing regimen and if they required therapy according to NCI-WG criteria. The starting dose of dasatinib was 140 mg daily. Results: Fifteen patients were enrolled, with a median age of 59 and a median of 3 prior regimens. All patients had received fludarabine, and 5 were fludarabine-refractory. Eleven of the 15 (73%) had high risk del(11q) or del(17p) cytogenetics. The primary toxicity was myelosuppression, with grade 3 or 4 neutropenia and thrombocytopenia in 10 and 6 patients, respectively. Partial responses by NCI-WG criteria were achieved in 3 of the 15 patients (20%; 90%CI: 6–44). Among the remaining 12 patients, 5 had nodal responses by physical exam, and 1 patient had a nodal and lymphocyte response but with severe myelosuppression. Pharmacodynamic studies indicated apoptosis in peripheral bloodCLL cells within 3 to 6 hours after dasatinib administration, associated with downregulation of Syk (spleen tyrosine kinase)

[1]  Ronald Levy,et al.  Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. , 2010, Blood.

[2]  J. Leonard,et al.  Activity of SYK and PLCγ2 Predict Apoptotic Response of Chronic Lymphocytic Leukemia Cells to SRC Tyrosine Kinase Inhibitor Dasatinib. , 2009 .

[3]  Martin C. Müller,et al.  Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. , 2008, Blood.

[4]  A. Sanil,et al.  Phase I Study of the Effect of Gastric Acid pH Modulators on the Bioavailability of Oral Dasatinib in Healthy Subjects , 2009, Journal of clinical pharmacology.

[5]  G. Altavilla,et al.  Dasatinib induces a response in chronic lymphocytic leukemia. , 2009, Blood.

[6]  N. K. Williams,et al.  Crystal Structures of the Lyn Protein Tyrosine Kinase Domain in Its Apo- and Inhibitor-bound State* , 2009, Journal of Biological Chemistry.

[7]  M. Hallek,et al.  The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes. , 2008, Blood.

[8]  S. Romano,et al.  The effect of FK506 on transforming growth factor β signaling and apoptosis in chronic lymphocytic leukemia B cells , 2008, Haematologica.

[9]  G. Roos,et al.  The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia. , 2008, Leukemia research.

[10]  Jennifer R. Brown,et al.  Pseudohyperkalemia in chronic lymphocytic leukemia. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  Luca Laurenti,et al.  The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. , 2008, Blood.

[12]  A. Kater,et al.  c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches. , 2008, Blood.

[13]  G. Leone,et al.  Constitutive Activation of the Protein Tyrosine Kinase Syk in Chronic Lymphocytic Leukemia B-Cells. , 2007 .

[14]  R. Küppers,et al.  The GNAS1 T393C Polymorphism Is Associated with Disease Progression and Survival in Chronic Lymphocytic Leukemia , 2006, Clinical Cancer Research.

[15]  P. Sherrington,et al.  B-cell receptor translocation to lipid rafts and associated signaling differ between prognostically important subgroups of chronic lymphocytic leukemia. , 2005, Cancer research.

[16]  K. Do,et al.  Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  J. Ting,et al.  CATERPILLER 16.2 (CLR16.2), a Novel NBD/LRR Family Member That Negatively Regulates T Cell Function* , 2005, Journal of Biological Chemistry.

[18]  A. Brunati,et al.  Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. , 2005, The Journal of clinical investigation.

[19]  M. Hilgarth,et al.  Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2 , 2005, Leukemia.

[20]  F. Lee,et al.  The SRC/ABL Inhibitor BMS-354825 Overcomes Resistance to Imatinib Mesylate in Chronic Myelogenous Leukemia Cells through Multiple Mechanisms. , 2004 .

[21]  Ping Chen,et al.  Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor , 2004, Science.

[22]  J. Byrd,et al.  Frequency and type of serious infections in fludarabine‐refractory B‐cell chronic lymphocytic leukemia and small lymphocytic lymphoma , 2002, Cancer.

[23]  H. Kantarjian,et al.  Results of First Salvage Therapy for Patients Refractory to a Fludarabine Regimen in Chronic Lymphocytic Leukemia , 2002, Leukemia & lymphoma.

[24]  M Chilosi,et al.  Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia. , 2001, Blood.

[25]  C Stratowa,et al.  CDNA microarray gene expression analysis of B‐cell chronic lymphocytic leukemia proposes potential new prognostic markers involved in lymphocyte trafficking , 2001, International journal of cancer.

[26]  B. Cheson,et al.  Clinical trials referral resource. Clinical trials with perillyl alcohol. , 1997, Oncology.

[27]  M. Grever,et al.  National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. , 1996, Blood.

[28]  R. Geha,et al.  Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2 , 1994, The Journal of experimental medicine.

[29]  N. Chiorazzi,et al.  mechanisms of disease Chronic Lymphocytic Leukemia , 2010 .

[30]  S. Gibson,et al.  Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro. , 2008, British journal of haematology.

[31]  M. Merville,et al.  NF- kappa B2/p100 induces Bcl-2 expression. , 2003, Leukemia.