CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation.

BACKGROUND: The use of available antiviral agents for the prevention of cytomegalovirus (CMV) disease is limited by frequent toxic effects and the emergence of resistance. CMX001 has potent in vitro activity against CMV and other double-stranded DNA viruses. We evaluated the safety and anti-CMV activity of CMX001 in patients who had undergone allogeneic hematopoietic-cell transplantation. METHODS: From December 2009 through June 2011, a total of 230 patients with data that could be evaluated were enrolled in the study. We randomly assigned these adult CMV-seropositive transplant recipients from 27 centers to oral administration of CMX001 or placebo. Patients were assigned in a 3:1 ratio to five sequential study cohorts according to a dose-escalating, double-blind design. Randomization was stratified according to the presence or absence of acute graft-versus-host disease and CMV DNA in plasma. Patients received the study drug after engraftment for 9 to 11 weeks, until week 13 after transplantation. Polymerase-chain-reaction analysis of CMV DNA in plasma was performed weekly. Patients in whom CMV DNA was detected at a level that required treatment discontinued the study drug and received preemptive treatment against CMV infection. The primary end point was a CMV event, defined as CMV disease or a plasma CMV DNA level greater than 200 copies per milliliter when the study drug was discontinued. The analysis was conducted in the intention-to-treat population. RESULTS: The incidence of CMV events was significantly lower among patients who received CMX001 at a dose of 100 mg twice weekly than among patients who received placebo (10% vs. 37%; risk difference, -27 percentage points; 95% confidence interval, -42 to -12; P=0.002). Diarrhea was the most common adverse event in patients receiving CMX001 at doses of 200 mg weekly or higher and was dose-limiting at 200 mg twice weekly. Myelosuppression and nephrotoxicity were not observed. CONCLUSIONS: Treatment with oral CMX001 at a dose of 100 mg twice weekly significantly reduced the incidence of CMV events in recipients of hematopoietic-cell transplants. Diarrhea was dose-limiting in this population at a dose of 200 mg twice weekly. (Funded by Chimerix; CMX001-201 ClinicalTrials.gov number, NCT00942305.).

Report of a phase II study of clofarabine and cytarabine in de novo and relapsed and refractory AML patients and in selected elderly patients at high risk for anthracycline toxicity.

PURPOSE: To determine the efficacy and safety of clofarabine and cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and in elderly patients with untreated AML and heart disease. PATIENTS AND METHODS: Patients with relapsed/refractory AML and older patients for whom there was a concern over toxicity from additional anthracyclines received 5 days of clofarabine, 40 mg/m(2) per day i.v. over 1 hour, followed 4 hours later by Ara-C, 1,000 mg/m(2) per day i.v. over 2 hours. RESULTS: Thirty patients were enrolled. The median age was 67 years (range, 38-82 years) and 18 (60%) had received at least one prior therapy. Eleven (37%) patients had a history of cardiovascular disease and were considered to be at high risk for anthracycline toxicity. High-risk cytogenetic abnormalities were present in 14 (47%) patients. The overall response rate (complete remission [CR] plus partial remission) was 53%, including a CR in 14 patients (47%). Responses were observed in all cytogenetic risk groups and in patients who had received up to five prior therapies. The median disease-free survival interval was 9.5 months. The 30-day mortality rate was 20% (de novo AML, 8%; relapsed/refractory AML, 28%). Of the 14 patients achieving a CR, half were able to proceed to curative hematopoietic stem cell transplantation. CONCLUSIONS: Clofarabine in combination with Ara-C is effective in both untreated and previously treated patients with AML. In addition, it represents a useful remission induction strategy to serve as a bridge to transplantation in older patients with AML.

Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.

The anti-cytomegalovirus (CMV) activity and safety of oral maribavir in CMV-seropositive allogeneic stem-cell transplant recipients were evaluated in a randomized, double-blind, placebo-controlled, dose-ranging study. After engraftment, 111 patients were randomized to receive CMV prophylaxis with maribavir (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) or placebo. Within the first 100 days after transplantation, the incidence of CMV infection based on CMV pp65 antigenemia was lower in each of the respective maribavir groups (15%, P = .046; 19%, P = .116; 15%, P = .053) compared with placebo (39%). Similarly, the incidence of CMV infection based on plasma CMV DNA was lower in each of the respective maribavir groups (7%, P = .001; 11%, P = .007; 19%, P = .038) compared with placebo (46%). Anti-CMV therapy was also used less often in patients receiving each respective dose of maribavir (15%, P = .001; 30%, P = .051; 15%, P = .002) compared with placebo (57%). There were 3 cases of CMV disease in placebo patients but none in the maribavir patients. Adverse events, mostly taste disturbance, nausea, and vomiting, were more frequent with maribavir. Maribavir had no adverse effect on neutrophil or platelet counts. These results show that maribavir can reduce the incidence of CMV infection and, unlike ganciclovir, does not cause myelosuppression.

Multicentric Castleman's disease and HIV.

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder found with a higher frequency in HIV-seropositive patients. Human herpes virus 8 is found in virtually all cases of HIV-associated MCD. The majority of cases of MCD in patients with HIV are also associated with Kaposi's sarcoma. The dysregulated production of human IL-6 is thought to be an important factor in the pathogenesis of MCD. HIV-seropositive individuals with MCD have a significantly greater risk of developing non-Hodgkin lymphomas than their HIV-seronegative counterparts. MCD occurring in HIV patients has been associated with a poor prognosis. With newer therapy regimens, it is hoped that the prospects of HIV-infected patients with MCD will improve.