Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although some patients can be cured by current therapies, novel agents are needed to further improve outcomes. We hypothesized that Src tyrosine kinase inhibition by dasatinib may have antilymphoma effects. Here, we demonstrate that dasatinib inhibits cell growth through G(1)-S blockage in five of seven DLBCL cell lines at clinically achievable concentrations. Compared to resting B cells, DLBCL has increased tyrosine phosphorylation activities. As expected, dasatinib inhibits phosphorylation of several Src family kinase members. However, this inhibition occurs in all cell lines regardless of their proliferative response to the drug. In contrast, the activity of two downstream signaling molecules, Syk and phospholipase Cgamma2 (PLCgamma2), are well correlated with cell line sensitivity to dasatinib, suggesting that these molecules are crucial in mediating the proliferation of activated lymphoma cells. Furthermore, dasatinib inhibits B-cell receptor signaling in primary lymphoma cells. Together, our findings not only show dasatinib as a potentially useful therapy for DLBCL but also provide insights into the pathogenesis of the lymphoma. The results further suggest the possibility of using Syk and PLCgamma2 as biomarkers to predict dasatinib therapeutic response in prospective clinical trials.

Synergy of vaccine strategies to amplify antigen-specific immune responses and antitumor effects.

Several different vaccine strategies have been evaluated and combined in an attempt to amplify T-cell responses toward induction of antitumor immunity. The model tumor antigen used was carcinoembryonic antigen (CEA). While initial T-cell activation studies were conducted in conventional mice, combined vaccine strategy studies and antitumor studies were conducted in transgenic mice in which CEA is expressed in normal gastrointestinal tissue and CEA protein is found in sera. The studies reported here demonstrate: (a) A recombinant avipox (fowlpox, rF) vector expressing the signal 1 (CEA) and the B7-1 costimulatory molecule transgenes (designated rF-CEA/B7-1) is more potent in inducing CEA-specific T-cell responses than rF-CEA; one administration of recombinant fowlpox vector expressing CEA and three different costimulatory molecule transgenes (B7-1, ICAM-1, LFA-3, designated rF-CEA/TRICOM) was more potent in inducing CEA-specific T-cell responses than four vaccinations with rF-CEA or two vaccinations with rF-CEA/B7-1. Moreover, up to four vaccinations with rF-CEA/TRICOM induced greater CEA-specific T-cell responses with each vaccination. (b) A diversified prime and boost strategy using a prime with a recombinant vaccinia vector expressing CEA and the triad of costimulatory molecules (designated rV-CEA/TRICOM) and a boost with rF-CEA/TRICOM was more potent in inducing CEA-specific T-cell responses than the repeated use of rF-CEA/TRICOM alone. (c) The addition of granulocyte macrophage colony-stimulating factor (GM-CSF) to the rF-CEA or rF-CEA/TRICOM vaccinations via the simultaneous administration of a rF-GM-CSF vector enhanced CEA-specific T-cell responses. These strategies (TRICOM/diversified prime and boost/GM-CSF) were combined to treat CEA-expressing carcinoma liver metastases in CEA-transgenic mice; vaccination was initiated 14 days posttumor transplant. Antitumor effects in terms of survival and CD8(+) and CD4(+) responses specific for CEA were also observed in this CEA-transgenic mouse model. These studies demonstrate that the use of cytokines and diversified prime and boost regimens can be combined with the use of recombinant vectors expressing signal 1 and multiple costimulatory molecules to further amplify T-cell responses toward more effective vaccine strategies.

Desensitization to allopurinol after allopurinol hypersensitivity syndrome with renal involvement in gout.

This is a case report of a 36-year-old male with tophaceous gout for 16 years. He started therapy with 300 mg/day of allopurinol. He had received variable dexamethasone doses by self-prescription for 16 years. When allopurinol was initiated, he had hyperuricemia and normal renal function. Twenty days after starting allopurinol, he presented diffuse maculopapular rash, conjunctivitis, increase in serum creatinine values, leukocytosis and eosinophilia and the diagnosis of allopurinol hypersensitivity (AH) syndrome was made. He completely recovered from the AH and renal function normalized. However, the gout worsened over the following years in spite of treatment with benzobromarone, low doses of prednisone, and colchicine. Allopurinol desensitization was successful beginning with an oral low dose scheme (6.5 mug/day) until we reached 300mg/day. Today the patient receives allopurinol with no side effects. We believe that this is the first reported example of successful desensitization in full-blown AH with renal involvement. Our cautious regimen might be tried in other such patients.