Efficacy of high-dose corticosteroid-based treatment for chronic lymphocytic leukemia patients with p53 abnormalities in the era of B-cell receptor inhibitors.

PURPOSE: High-dose methylprednisolone (HDMP) with or without anti-CD20 antibody treatment in the pre B-cell receptor inhibitor (BCRi) era was used as potential salvage therapy for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) patients bearing the 17p deletion. PATIENTS AND METHODS: Outcomes were compared in retrospect between r/r patients treated with HDMP (n = 20), ibrutinib (n = 39) and idelalisib with rituximab (n = 14). RESULTS: Higher overall response rates were found in those patients undergoing BCRi therapy compared to HDMP (79.2% vs. 0%; p < 0.0001), along with longer median progression-free survival (not reached vs. 24.1 months; p < 0.01). Nevertheless, there were no differences in the overall survival (HDMP 35.87 months vs. not reached; p = 0.58). CONCLUSION: HDMP treatment was significantly inferior in terms of response rate and progression-free survival in r/r CLL/SLL patients with the 17p deletion, and may only be used whenever novel compounds are unavailable.

Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma.

BACKGROUND: Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton's kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. METHODS: We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma. RESULTS: IQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest. CONCLUSIONS: These results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies.

Preclinical pharmacology of the novel antitumor agent adaphostin, a tyrphostin analog that inhibits bcr/abl.

PURPOSE: To define several pharmacological properties for the potential anticancer agent, adaphostin, in order to determine whether the compound is appropriate for clinical evaluation as an anticancer agent. METHODS: The analytical procedure involved high-performance liquid chromatography and utilized an analytical J'Sphere ODS H-80 column. RESULTS: The stability of adaphostin at two different concentrations was determined at temperatures of 37 degrees C, 4 degrees C, and -80 degrees C, in the plasma of mice, rats, dogs, and humans. The compound was most stable at the lower temperatures. At all temperatures, adaphostin was generally most stable in human plasma and least stable in dog plasma. Adaphostin bound strongly (>93%) to proteins in plasma from all four species. Following intravenous (i.v.) administration to mice (50 mg/kg; 150 mg/m(2)), plasma concentrations declined rapidly from 50 microM at 2 min to 1 microM at 2 h. Elimination was triexponential, with t (1/2) values of 1.1, 9.1, and 41.2 min. The Cl(tb) was 0.411 L/(min.m(2)), the V (dss) was 24.6 L/m(2), and the AUC was 927 microM.min. In a comparison of vehicles for intraperitoneal (i.p.) dosing, PEG 300 allowed the highest plasma concentrations of adaphostin. Bioavailability following an i.p. dose was greater than that following a subcutaneous dose, or that for a dose administered by oral gavage. For rats dosed i.v. with adaphostin (50 mg/kg; 300 mg/m(2)), plasma concentrations also decreased triexponentially, with t (1/2) values of 1.8, 10.6, and 136 min. Other pharmacokinetic values were Cl(tb) = 0.466 L/(min.m(2)), AUC = 1,161 microM.min, and V (dss)=8.0 L/m(2). Analysis of samples collected from two dogs dosed i.v. with adaphostin (7.5 mg/kg; 150 mg/m(2)) showed that plasma concentrations decreased in a biphasic manner, with individual values for t (1/2alpha) of 6.0 and 9.8 min for the distribution phase and t (1/2beta) of 40.6 and 66.2 min for the elimination phase. Other pharmacokinetic values were Cl(tb) = 0.565 and 0.852 L/(min.m(2)), AUC = 673 and 446 microM min, and V (dss) = 29.6 and 56.8 L/m(2). CONCLUSIONS: The stability of adaphostin in plasma varies with species. In mice and dogs dosed with adaphostin, plasma concentrations of the compound decreased rapidly. The clearance of adaphostin from plasma, on an m(2) basis, was equivalent for mice and rats but more rapid in dogs. These results are relevant for assessing the pharmacologic and toxicologic profiles and the antitumor activity of adaphostin in humans.