Three nonradioisotopic polymerase chain reaction (PCR)-based detection techniques were evaluated for sensitivity and specificity in detecting human immunodeficiency virus type 1 (HIV-1) proviral DNA in peripheral blood mononuclear cells. The Roche prototype HIV-1 PCR assay, the Du Pont enzyme-linked oligonucleotide sandwich assay (ELOSA), and the Gen-Probe hybridization protection assay (HPA) were compared with a standard radioisotopic oligonucleotide solution hybridization (OSH) technique. A panel of 111 well-characterized clinical samples that included peripheral blood mononuclear cells from 48 healthy, low-risk, HIV-1 antibody-negative subjects, 24 antibody-positive subjects with stable CD4 counts of less than 200/mm3, and 39 antibody-positive subjects with stable CD4 counts of greater than 800/mm3 were studied. Each method demonstrated good specificity, ranging between 96 and 100%; those of the OSH and ELOSA (Du Pont) were 1O00%, those of the HPA (Gen-Probe) were 1O00 with one probe and 96% with the other probe, and that of the HIV-1 PCR assay (Roche) was 96%. Sensitivities ranged from 96 to 100% for the low-CD4-count group, with the OSH, the HIV-1 PCR assay (Roche), and the HPA (Gen-Probe) all attaining a sensitivity of 100%o. For the high-CD4-count group, sensitivities ranged from 69 to 97%, with the OSH attaining a sensitivity of 97% and the HPA attaining sensitivities of 97% with one probe and 95% with the other probe. These data indicate that the nonradioisotopic techniques are sensitive and specific for the detection of HIV-1 proviral DNA in clinical samples.
This study reports the rates of phenotypic switching in strains of Candida albicans isolated from superficial and invasive infections. Of 19 invasive strains, 68% showed switching activity, often at very high rates, compared with only 28% of 40 strains isolated from superficial sites (P = 0.004).
Background: For patients with diffuse large B-cell lymphoma (DLBCL), resistance to standard R-CHOP immunochemotherapy remains an urgent and unmet clinical challenge. Aberrant DNA methylation likely contributes to chemoresistance and may represent a therapeutic target.In a phase I study of R-CHOP plus subcutaneous azacitidine, a DNA methyltransferase inhibitor, complete responses (CRs) were achieved in 10/11 high-risk DLBCL patients (Clozel et al. Cancer Discovery 2013), providing the rationale for this study of oral azacytidine (CC-486) plus R-CHOP. Previously reported data from the dose escalation phase of this study demonstrated promising response rates in patients with high-risk DLBCL (Martin et al. Blood 2017). Here, we present results from both the dose escalation and expansion phases after substantially longer follow-up. Methods: CC-486-DLBCL-001 (NCT02343536) is a phase I, open-label, multicenter study of CC-486 plus standard R-CHOP in patients with previously untreated DLBCL, grade 3B follicular lymphoma (FL), or transformed FL. Eligible patients were aged ≥18-80 years with no active viral hepatitis, had an International Prognostic Index (IPI) score ≥2 or DLBCL double-positive for BCL2 and c-MYC, an Eastern Cooperative Oncology Group performance status ≤2, and Ann Arbor stage II-IV disease. Patients in the dose escalation phase were enrolled sequentially into 4 dose cohorts of CC-486 (100, 150, 200, and 300 mg) using the time-to-event continual reassessment method. Additional patients were enrolled in the expansion phase to evaluate preliminary efficacy. Patients received up to six 21-day cycles. CC-486 was administered for 7 days before initiation of R-CHOP and on days 8-21 of cycles 1-5. Granulocyte-colony stimulating factor was mandated by protocol and anti-emetics were standard treatment. The primary objectives were to determine safety (per NCI CTCAE v4.03) and the recommended phase 2 dose (RP2D) of CC-486 in combination with standard R-CHOP. Secondary endpoints included pharmacokinetics and preliminary efficacy per the International Working Group criteria (Cheson et al.J Clin Oncol 2014). Results: Fifty-nine patients were enrolled as of May 31, 2018, including 40 treated at the RP2D of CC-486 300 mg. The median age in the overall population was 66 years (range, 25-80), 76% were aged >60 years, 59% were male, and 59% had an IPI score ≥3. Fifty-four patients (92%) completed all 6 planned cycles of study treatment. Thirteen patients (22%) had CC-486 dose reductions because of adverse events (AEs). Two patients discontinued CC-486 due to AEs: febrile neutropenia (n=1; 150 mg) and sepsis (n=1; 300 mg). The most common AEs were gastrointestinal, which were mainly grade 1/2; hematologic AEs were the most common grade 3/4 toxicity (Table 1). Grade 3/4 AEs related to CC-486 occurred in 36 (61%) patients, most commonly neutropenia (41%) and febrile neutropenia (20%). Febrile neutropenia was more common among older patients (9/15 patients with this AE were aged >70 years) and those with IPI scores ≥3 versus ≤2 (31% vs 17%) but was not correlated with CC-486 dose. One patient died during the study (acute respiratory failure possibly related to study treatment). All patients were evaluable for response. The overall response rate was 95%, with 52 patients (88%) achieving a CR; response rates were generally similar in patients with IPI scores ≥3 and ≤2 and in patients treated at the RP2D (Table 2). Median progression-free survival (PFS) was not reached (median follow-up of 12 months); estimated 1-year PFS rates were similar in the overall population (86%) and in patients with IPI scores ≥3 (84%) and ≤2 (89%). Conclusions: Epigenetic priming with CC-486 before R-CHOP demonstrated promising clinical activity in patients with high-risk, previously untreated DLBCL, transformed FL, or grade 3B FL. AEs were generally consistent with the known safety profile of azacitidine and toxicities associated with R-CHOP. These results support further investigation of oral azacitidine (CC-486) in combination with R-CHOP, including patients with high-risk disease. Disclosures Martin: Gilead: Consultancy; Janssen: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy. Bartlett:Astra Zeneca: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Research Funding; Immune Design: Research Funding. Chavez:Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Humanigen: Consultancy. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding. Smith:Portola: Honoraria; BMS: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau. Jones:Celgene: Employment, Equity Ownership. Drew:Celgene Corp.: Employment. Wu:Celgene: Employment, Equity Ownership. Cerchietti:Celgene: Research Funding; Weill Cornell Medicine: Employment. Leonard:ADC Therapeutics: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; BMS: Consultancy; Juno: Consultancy; Celgene: Consultancy; Biotest: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Sutro: Consultancy; United Therapeutics: Consultancy.
Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated -year and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.