Mice with a targeted deletion of either the interferon (IFN)-gamma gene or the IFN-gamma receptor gene (IFN-gamma R(0/0) mice) fail to survive infection with the Bacillus Calmette-Guerin (BCG) strain ...of Mycobacterium bovis. Here we show that resident peritoneal macrophages isolated 2 weeks after BCG infection from IFN-gamma R(0/0) mice produced significantly less nitric oxide (NO) than wild-type macrophages. However, the response to lipopolysaccharide (LPS) was not completely abrogated in the IFN-gamma R(0/0) macrophages. BCG infection of wild-type mice led to a marked increase in their urinary nitrite/nitrate levels, as previously described. This increase in urinary nitrite/nitrate was not detected in BCG- infected IFN-gamma R(0/0) mice, indicating that no other cytokine can replace IFN-gamma as a mediator of increased NO synthesis after BCG infection in the intact organism. A comparison of circulating levels of IFN-gamma in BCG-infected animals revealed that sera from IFN-gamma R(0/0) mice contained up to 66-fold more IFN-gamma than sera from identically treated wild-type mice. To determine if the higher levels of circulating IFN-gamma were due to increased IFN-gamma synthesis, we compared the amounts of IFN-gamma mRNA present in the spleens of BCG-infected wild-type and IFN-gamma R(0/0) mice. No increase in IFN-gamma mRNA levels was detected in the spleens from IFN-gamma R(0/0) mice. Since the generation of IFN-gamma protein in cultured spleen cells was also not increased in IFN-gamma R(0/0) mice, we conclude that clearance of IFN-gamma from the circulation is impaired in IFN-gamma R(0/0) mice, thus revealing a heretofore unrecognized important role for the IFN-gamma receptor in the regulation of IFN-gamma levels in the intact organism.
Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, ...pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenstrom macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing. (C) 2017 by American Society of Clinical Oncology
Veno-occlusive disease (VOD) of the liver remains a major complication after hematopoietic stem cell transplantation (SCT). VOD is thought to develop after hepatic endothelial cells are damaged by ...high-dose chemotherapy or radiation, causing microthrombosis in hepatic venules. However, the precise mechanisms leading to VOD are not well defined, and a diagnosis is often difficult to establish. It is also difficult to predict which patients are most likely to develop VOD. Elevated levels of homocysteine (HC) have been associated with thrombosis, and prothrombin fragment 1 + 2 (F1 + 2) is a measurable marker for coagulation. Therefore, we performed a prospective cohort study to determine if HC or F1 + 2 levels could be used to predict the development of VOD prior to SCT, or to help establish a diagnosis of VOD in association with other clinical parameters. Plasma levels of these factors were measured before conditioning and serially for 21 days after SCT in 42 consecutive patients undergoing SCT. Eleven of 26 allogeneic SCT recipients developed VOD, whereas no autologous SCT recipient (n = 16) developed VOD (p = 0.008). In patients who developed VOD, HC levels were consistently higher than those seen in non-VOD patients after day 7 of SCT. Patients with VOD also had higher levels of F1 + 2 after SCT, although this marker was less consistently elevated over time. A logistic regression model that evaluated all serial measures of HC and F1 + 2 showed a moderate sensitivity and specificity in diagnosing VOD in allogeneic SCT patients, but neither marker was useful to predict development of VOD when tested prior to SCT.
ABT-263 is a novel, orally bioavailable BH3 mimetic that binds with high affinity (Ki ≤1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263 displays potent mechanism-based activity ...(EC50 ≤ 1μM) against human lymphoid and small cell lung cancer cell-lines. Mechanistic toxicities observed preclinically include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased survival of circulating platelets, presumably mediated by inhibition of Bcl-w, Bcl-2 and Bcl-XL, respectively. Study M06-814, a phase 1 dose-escalation study is employing a modified Fibonaci 3 + 3 design to assess ABT-263 safety, pharmacokinetics and anti-tumor activity of two dosing schedules in patients with relapsed or refractory lymphoid malignancies. Enrollment continues with 42 patients (39 on a 14/21 day and 3 on a 21/21 day dosing schedule) enrolled. ABT-263 given on a 14/21 day dosing schedule began at 10 mg and continued escalation to 440 mg, with 315 mg defined as tolerable. The pharmacokinetic profile of ABT-263 on the 14/21 day schedule was linear from 10 – 440 mg with a t1/2 of 14 – 20 h. Consistent with preclinical models, a dose-dependent reduction in circulating platelets was observed. Typically, platelet nadirs were transient, occurring on days 3–5 with subsequent recovery during continued dosing, consistent with accelerated platelet apoptosis and compensatory increased bone marrow release and production. Thrombocytopenia was predictable and manageable. A one week lead-in dosing period at 150mg ABT-263 and a 21/21 day dosing schedule beginning at 200 mg, are being evaluated as measures to ameliorate the platelet nadir. Dose limiting toxicities on cycle 1 in the 14/21 day dosing schedule occurred at 160 mg (bronchitis), 315 mg (elevated ALT and gr 4 thrombocytopenia), and 440 mg (dyspnea). Responses were observed in 3 patients including a 75% and 99% reduction of bulky masses in 2 CLL/SLL and a 75% reduction in a NK/T cell lymphoma. Minor nodal responses occurred in 4 patients with follicular lymphoma and 3 patients with CLL/SLL. Additionally, 2 patients with CLL/SLL had ≥50% decreases in leukemic cells for at least 2 months. ABT-263 is a well tolerated oral small molecular inhibitor of Bcl-2 family proteins with a linear PK, toxicity profile indicative of on-target activity and anti-tumor activity in patients with relapsed or refractory lymphoid malignancies. Accrual continues.
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