John Lister

Lipidoid nanoparticle mediated silencing of Mcl-1 induces apoptosis in mantle cell lymphoma

Conventional chemo-immunotherapy fails to cure the majority of mantle cell lymphoma patients and causes substantial toxicity. Resistant mantle cell lymphoma cells commonly overexpress and are dependent on the anti-apoptotic protein, Mcl-1, for survival. In this study, we use potent lipidoid nanoparticles to deliver siRNA to silence Mcl-1 expression. Studies were conducted using two different mantle cell lymphoma cell lines, a normal (JeKo-1) and an aggressive (MAVER-1) line, to assess the ability of lipidoid nanoparticles to be used broadly in the treatment of mantle cell lymphoma. Mcl-1 mRNA silencing and protein knockdown was observed as early as one day after treatment and the lipidoid nanoparticles achieved sustained silencing of Mcl-1 mRNA for at least four days in both JeKo-1 and MAVER-1 cells. Eighty percent silencing was achieved at three days post-transfection in JeKo-1 cells while 50% silencing was achieved in MAVER-1 cells, which are more resistant to transfection. Interestingly, silencing of Mcl-1 induced apoptosis in nearly 30% of both JeKo-1 and MAVER-1 cells three days post-transfection. Additionally, Mcl-1 silencing and the resultant apoptosis in mantle cell lymphoma cells were dose dependent. These data suggest that lipidoid nanoparticles siRNA therapy targeting Mcl-1 has potential as a new treatment modality for mantle cell lymphoma and many other cancers that overexpress Mcl-1. The combination of anti-Mcl-1 lipidoid nanoparticles with other forms of targeted therapy offers hope for reducing or replacing cytotoxic chemotherapy as standard treatment for mantle cell lymphoma.

Efficacy and tolerability of treatment with azacitidine for 5 days in elderly patients with acute myeloid leukemia

Acute myeloid leukemia (AML) patients aged ≥60 years tolerate standard induction chemotherapy poorly. Therapy with azacitidine at a dose of 75 mg/m2/day for 7 days appears to be better tolerated, and is approved by the Food and Drug Administration (FDA) for the treatment of elderly AML patients with bone marrow (BM) blast counts of 20–30%. Here, we report the results of a prospective, phase 2, open‐label study that evaluated the tolerability and efficacy of a 5‐day regimen of single‐agent subcutaneous azacitidine 100 mg/m2/day administered every 28 days in 15 elderly patients with newly diagnosed AML, 14 of whom had BM blast counts >30%. The overall response rate was 47%. Complete remission, partial remission, and hematologic improvement were achieved by 20, 13, and 13% of patients, respectively. Median overall survival was 355 days for the entire cohort, and 532 days for responders. Median time to best response was 95 days, and median treatment duration was 198 days (range = 13–724 days). Grade 3–4 hematologic toxicities comprised predominantly febrile neutropenia (40%) and thrombocytopenia (20%). Febrile neutropenia was the most common cause of hospitalization. Nonhematologic toxicities, consisting of injection‐site skin reactions and fatigue (Grades 1–2), occurred in 73% (n = 11) of patients. No treatment‐related deaths occurred during the study. The dose and schedule of therapy remained constant in all but four patients. The findings of this study suggest that administration of subcutaneous azacitidine 100 mg/m2/day for 5 days every 28 days is a feasible, well‐tolerated, and effective alternative to standard induction chemotherapy in elderly patients with AML.

A comparison of ED and direct admission care of cancer patients with febrile neutropenia

OBJECTIVEnWe compared the quality of care in admitted febrile neutropenic cancer patients presenting through the emergency department (ED) vs those directly admitted (DA) from the clinic or infusion center. We hypothesized that the quality of care would be comparable between these 2 pathways.nnnMETHODSnWe conducted a retrospective, observational cohort study of all adult cancer patients hospitalized with subjective or objective fever (≥100.4°F) and documented neutropenia (absolute neutrophil count ≤1000/mm(3)) from January 1, 2011 to June 30, 2013, at 2 hospitals. Two investigators retrieved data including patient age, sex, race, tumor type, blood culture growth, temperature (actual or reported), pathway to admission (ED or DA), time to antibiotic administration, length of stay, and the Multinational Association for Supportive Care in Cancer (MASCC) risk score. The primary outcome measures were time to antibiotic administration, appropriateness of antibiotic(s) administered based on published guidelines, length of stay, and MASCC score-based risk assessment. We used the t test for the difference between 2 means with unequal population variances to compare these outcome measures between ED and DA patients.nnnRESULTSnOne hundred twenty-seven visits met inclusion criteria (42 [33%] ED visits, 85 [67%] DA visits). Mean time to antibiotic administration, mean length of stay, appropriateness of antibiotics, and MASCC score-based risk assessment were comparable between ED and DA visits (P>.05 for all comparisons).nnnCONCLUSIONnThe quality of care for febrile neutropenia in patients presenting through the ED was comparable to those directly admitted to the hospital in this 2-center study.

Frontline treatment of diffuse large B-cell lymphoma in elderly: a systematic review of clinical trials in post-rituximab era

Abstract Treatment of diffuse large B cell lymphoma (DLBCL) remains challenging in elderly population and systematic reviews are lacking in this area. Medline and Cochrane Register of Controlled Trials in addition to conference proceedings were searched for therapeutic clinical trials on frontline treatment of DLBCL in adults ≥60 in post-rituximab era. Forty-one out of 713 reviewed papers met our inclusion criteria. Six cycles of rituximab, cyclophosphamide, vincristine, prednisone (R-CHOP) administered every 21 d remain the standard treatment for fit elderly, with no role for maintenance rituximab. For individuals ≥80, the strongest evidence favors rituximab/ofatumumab-miniCHOP. Numerous alternative approaches including the use of liposomal anthracyclines, dose and regimen adjustment to frailty/comorbidity score, brief duration regimens, and consolidative radioimmunotherapy have produced promising outcomes and could be considered for R-CHOP inappropriate elderly. Phase III randomized trials studying the efficacy of liposomal vincristine, extended-exposure rituximab, and lenalidomide plus R-CHOP are ongoing.

Lipid nanoparticle siRNA cocktails for the treatment of mantle cell lymphoma

Abstract Mantle cell lymphoma is an aggressive and incurable subtype of non‐Hodgkin B cell lymphoma. Patients typically present with advanced disease, and most patients succumb within a decade of diagnosis. There is a clear and urgent need for novel therapeutic approaches that will affect mantle cell lymphoma through a unique mechanism compared to current therapies. This study examined the use of RNA interference (RNAi) therapy to attack mantle cell lymphoma at the mRNA level, silencing genes associated with cancer cell proliferation. We identified a lipid nanoparticle formulated with the lipidoid 306O13 that delivered siRNA to JeKo‐1 and MAVER‐1 mantle cell lymphoma cell lines. Three therapeutic gene targets were examined for their effect on lymphoma growth. These included Cyclin D1, which is a cell cycle regulator, as well as Bcl‐2 and Mcl‐1, which prevent apoptosis. Gene knockdown with siRNA doses as low at 10 nM increased lymphoma cell apoptosis without carrier‐mediated toxicity. Silencing of Cyclin D1 induced apoptosis despite a twofold “compensation” upregulation of Cyclin D2. Upon simultaneous silencing of all three genes, nearly 75% of JeKo‐1 cells were apoptosing 3 days post‐transfection. Furthermore, cells proliferated at only 15% of their pretreatment rate. These data suggest that lipid nanoparticles‐formulated, multiplexed siRNA “cocktails” may serve as a beneficial addition to the treatment regimens for mantle cell lymphoma and other aggressive cancers.