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Preventing viral infections at an early stage is a key strategy for successfully improving transplant outcomes. Preemptive therapy and prophylaxis with antiviral agents have been ...successfully used to prevent clinically significant viral infections in hematopoietic cell transplant recipients. Major progress has been made over the past decades in preventing viral infections through a better understanding of the biology and risk factors, as well as the introduction of novel antiviral agents and advances in immunotherapy. High-quality evidence exists for the effective prevention of herpes simplex virus, varicella-zoster virus, and cytomegalovirus infection and disease. Few data are available on the effective prevention of human herpesvirus 6, Epstein-Barr virus, adenovirus, and BK virus infections. To highlight the spectrum of clinical practice, here we review high-risk situations that we handle with a high degree of uniformity and cases that feature differences in approaches, reflecting distinct hematopoietic cell transplant practices, such as ex vivo T-cell depletion.
Viral infection remains a serious cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Using a series of 5 illustrative cases, Dadwal and colleagues discuss preventative and preemptive therapy for the management of viral infections in patients undergoing HSCT.
Therapies for refractory cytomegalovirus infections (with or without resistance R/R) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through ...the inhibition of UL97 protein kinase.
In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16.
352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference 95% confidence interval (CI): 32.8% 22.80-42.74; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference 95% CI: 9.5% 2.02-16.88; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs.
Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE).
As of 10 April 2020, New York State had 180,458 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 9,385 reported deaths. Patients with cancer comprised 8.4% of deceased ...individuals
. Population-based studies from China and Italy suggested a higher coronavirus disease 2019 (COVID-19) death rate in patients with cancer
, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-19
. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. From 10 March to 7 April 2020, 423 cases of symptomatic COVID-19 were diagnosed at Memorial Sloan Kettering Cancer Center (from a total of 2,035 patients with cancer tested). Of these, 40% were hospitalized for COVID-19, 20% developed severe respiratory illness (including 9% who required mechanical ventilation) and 12% died within 30 d. Age older than 65 years and treatment with immune checkpoint inhibitors (ICIs) were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not. Overall, COVID-19 in patients with cancer is marked by substantial rates of hospitalization and severe outcomes. The association observed between ICI and COVID-19 outcomes in our study will need further interrogation in tumor-specific cohorts.
In this multicenter, dose-ranging study of maribavir for the treatment of cytomegalovirus (CMV) infections deemed refractory or resistant to current antivirals, 67% of patients achieved clearance of ...CMV viremia within 6 weeks, with responses maintained for up to 24 weeks.
Abstract
Background
Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals (valganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains.
Methods
Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs).
Results
From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57–75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses.
Conclusions
Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified.
Clinical Trials Registration
NCT01611974.
Recombinant herpes zoster (HZ) vaccines may be an alternative to the live-attenuated HZ vaccine for immunocompromised individuals. This was a phase 1/2, randomized, observer-blind, placebo-controlled ...study in adults with multiple myeloma, non-Hodgkin lymphoma (B- or T-cell), Hodgkin lymphoma, or acute myeloid leukemia who had undergone autologous hematopoietic stem-cell transplant 50 to 70 days earlier. Subjects (N = 121) were randomized 1:1:1:1 to receive (at months 0, 1, 3) three doses of 50 μg varicella-zoster virus glycoprotein E (gE) adjuvanted with AS01B, 3 doses of gE adjuvanted with AS01E, 1 dose of saline followed by 2 doses of gE/AS01B, or 3 doses of saline. One month after the last dose (6 months after transplant), frequencies of CD4+ T cells expressing ≥2 activation markers after induction with gE and anti-gE antibody concentrations were higher with all gE/AS01 regimens than with saline. Both responses persisted up to 1 year in subjects vaccinated with gE/AS01. Immune responses were higher in the gE/AS01B 3-dose group than in the gE/AS01B 2-dose group but not higher than in the gE/AS01E 3-dose group. One serious adverse event (pneumonia) was considered vaccine related. Both formulations and both schedules were immunogenic and well tolerated in this population. This study was registered at www.clinicaltrials.gov as #NCT00920218.
•HCT recipients have increased susceptibility to herpes zoster, but live-attenuated vaccines are not appropriate for highly immunocompromised people.•An adjuvanted subunit vaccine against herpes zoster elicits strong immune responses with an acceptable safety profile in adult autologous HCT recipients.
Purpose of Review
Transplant recipients are at risk for cytomegalovirus (CMV) infection and associated morbidity and mortality. We summarize recently introduced or currently investigated modalities ...for prevention and treatment of CMV infection in hematopoietic cell (HCT) and solid organ transplant (SOT) recipients.
Recent Findings
Letermovir was recently approved for CMV prevention in HCT recipients. Data from real world studies support its role to improve outcomes in this population. Letermovir is currently under investigation for broader patient populations and indications. Maribavir is in late stages of development for CMV treatment and may provide a safer alternative to currently available anti-CMV drugs. Promising CMV vaccine candidates and adoptive cell therapy approaches are under evaluation. CMV immune monitoring assays are predicted to play a more central role in our clinical decision making.
Summary
In recent years, major advances have been made in CMV prevention and treatment in transplant recipients. Rigorous research is ongoing and is anticipated to further impact our ability to improve outcomes in this population.
A dose-finding study showed that CMX001 at an oral dose of 100 mg twice weekly, as compared with placebo, reduced the risk of cytomegalovirus events from 37% to 10% among patients who had undergone ...hematopoietic-cell transplantation.
Cytomegalovirus (CMV) infection is a common cause of illness after allogeneic hematopoietic-cell transplantation.
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CMV seropositivity in transplant recipients is also associated with an increased risk of death after transplantation, despite preemptive and prophylactic strategies with available antiviral agents.
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Although valganciclovir is approved for prophylaxis against CMV infection after solid-organ transplantation, its use is limited by myelosuppression, particularly after hematopoietic-cell transplantation.
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Thus, there is an unmet need for effective drugs against CMV infection that have a better safety profile.
CMX001 is an orally bioavailable lipid acyclic nucleoside phosphonate that is absorbed in the small intestine and transported . . .
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