0000000000164163
AUTHOR
Thomas J. Kipps
Associations of ofatumumab exposure and treatment outcomes in patients with untreated CLL receiving chemoimmunotherapy
Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median C(max) and C(trough) values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher C(max) and C(trough) values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas …
Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia
We conducted an international phase 2 trial to evaluate 2 dose levels of ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had β2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete respo…
Ofatumumab Combined With Fludarabine and Cyclophosphamide (O-FC) Shows High Activity in Patients With Previously Untreated Chronic Lymphocytic Leukemia: Results From a Randomized, Multicenter, International, Two-Dose, Parallel-Group Phase II Trial
Abstract 207 Introduction: Chemoimmunotherapy regimens have become the treatment standard for patients with CLL. Ofatumumab is a human monoclonal antibody that targets a unique small-loop epitope on CD20 and elicits rapid and efficient in vitro complement-dependent cytotoxicity, as well as antibody-dependent cellular cytotoxicity. Recent studies demonstrated single-agent ofatumumab activity, with high overall response rates (ORR) in patients with refractory CLL. We conducted an international, randomized, parallel group, Phase II trial with two doses of ofatumumab combined with fludarabine and cyclophosphamide (FC) in previously untreated patients with CLL to evaluate the efficacy and tolera…
Correlations Between Ofatumumab Exposure and Treatment Outcomes for patients with Chronic Lymphocytic Leukemia (CLL) Treated with Frontline Ofatumumab, Fludarabine, and Cyclophosphamide Chemoimmunotherapy
Abstract Abstract 1793 Introduction: Results: Seven pts (4 male) with a medianLittle is known about the pharmacokinetics (PK) and pharmacodynamics of CD20 monoclonal antibody (mAb) with chemotherapy in patients (pts) with CLL. Ofatumumab (O) is a human mAb targeting a membrane-proximal small-loop epitope on CD20 and mediates efficient complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Safety and efficacy of O at 2 dose levels in combination with fludarabine and cyclophosphamide (FC) were evaluated in previously untreated pts with CLL. Relationship between O PK, baseline characteristics, and clinical outcomes were studied. Pts and Methods: Pts with active CL…
The down-regulation of miR-125b in chronic lymphocytic leukemias leads to metabolic adaptation of cells to a transformed state
AbstractMiR-125b-1 maps at 11q24, a chromosomal region close to the epicenter of 11q23 deletions in chronic lymphocytic leukemias (CLLs). Our results establish that both aggressive and indolent CLL patients show reduced expression of miR-125b. Overexpression of miR-125b in CLL-derived cell lines resulted in the repression of many transcripts encoding enzymes implicated in cell metabolism. Metabolomics analyses showed that miR-125b overexpression modulated glucose, glutathione, lipid, and glycerolipid metabolism. Changes on the same metabolic pathways also were observed in CLLs. We furthermore analyzed the expression of some of miR-125b–target transcripts that are potentially involved in the…
Quaking and miR-155 interactions in inflammation and leukemogenesis.
Quaking (QKI) is a tumor-suppressor gene encoding a conserved RNA-binding protein, whose expression is downregulated in several solid tumors. Here we report that QKI plays an important role in the immune response and suppression of leukemogenesis. We show that the expression of Qki is reduced in lipopolysaccharide (LPS)-challenged macrophages, suggesting that Qki is a key regulator of LPS signaling pathway. Furthermore, LPS-induced downregulation of Qki expression is miR-155-dependent. Qki overexpression impairs LPS-induced phosphorylation of JNK and particularly p38 MAPKs, in addition to increasing the production of anti-inflammatory cytokine IL-10. In contrast, Qki ablation decreases Fas …