Ella J. Ariza-Heredia

Background: Cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) prevents CMV reactivation after hematopoietic cell transplant (HCT). Trends in CMV-CMI using the QuantiFERON-CMV assay and its clinical utility in a Phase 3 study were evaluated. Methods: Cytomegalovirus-seropositive allogeneic HCT recipients who received letermovir prophylaxis through ∼100 days post-HCT were randomized to receive letermovir or placebo through ∼200 days post-HCT. QuantiFERON-CMV was performed at 100 days, 200 days, and Week 48 post-HCT. QuantiFERON-CMV results after prophylaxis completion (∼100 and ∼200 days post-HCT in placebo and letermovir groups, respectively) were evaluated for predicting postprophylaxis clinically significant CMV infection (CS-CMVi) through Week 48 post-HCT. Results: QuantiFERON-CMV assay positivity was similar at study entry between letermovir (n = 82) and placebo (n = 47) groups (30.5% vs 31.9%), higher for placebo group at 200 days post-HCT (48.8% vs 74.5%), and comparable between groups at Week 48 post-HCT (65.9% vs 74.5%). Postprophylaxis CS-CMVi occurred by Week 48 in 10.5% (6/57) of participants with a positive result versus 19.0% (8/42) with a negative result at 200 days post-HCT in the letermovir group and 10.3% (3/29) of participants with a positive result versus 20.7% (6/29) with a negative result at 100 days post-HCT in the placebo group. Assay sensitivity, specificity, positive predictive value, and negative predictive value were 60.0%, 57.1%, 89.5%, and 19.0% for tests at 200 days post-HCT (letermovir) and 53.1%, 66.7%, 89.7%, and 20.7% for tests at 100 days post-HCT (placebo). Conclusions: Positive QuantiFERON-CMV results increased after letermovir prophylaxis completion. Predictive utility of the QuantiFERON-CMV assay may be limited in the HCT setting.

Background: Refractory and/or resistant (R/R) cytomegalovirus (CMV) infection is a serious complication after allogeneic hematopoietic cell transplantation (HCT). Maribavir, an oral antiviral agent, was approved in November 2021 for the treatment of R/R CMV in transplant recipients. However, real‐world data on the use of maribavir in HCT recipients and hematologic malignancy (HM) patients are limited. We described our early experience with the use of maribavir in the year after its Food and Drug Administration approval in HCT recipients and HM patients. Methods: We performed a retrospective study of all patients who received maribavir for treatment of CMV infection at our center from November 2021 to December 2022. Clinical characteristics and outcomes of CMV infection were collected for each case. Descriptive statistics were calculated. Results: Our study included 13 patients (11 of whom were HCT recipients and two with HM) who received a median of 58 days of maribavir therapy. While on maribavir, nine (69%) patients had a resolution of CMV infection. Treatment‐emergent maribavir resistance was documented in one patient with a CMV UL97 C480F mutation. Patients with higher baseline viral loads were less likely to achieve CMV resolution compared to those with lower levels. Additionally, six patients received combination therapy with maribavir. Six patients developed dysgeusia, none requiring maribavir discontinuation. Conclusion: Maribavir is an effective and safe option for the treatment of R/R CMV infections in HCT recipients and HM patients. Our study highlights the complexities of managing CMV infections in this patient population and some challenges associated with maribavir therapy. image

Background: Patients with cancer are at elevated risk for tuberculosis (TB) reactivation. Diagnosis of latent TB infection and TB disease remains challenging in this patient population despite the advent of interferon‐γ release assays (IGRA). Methods: We retrospectively reviewed medical records of all patients with cancer who had IGRA testing (QuantiFERON–TB [QFT‐TB] or T‐SPOT. TB ) at a major cancer center in the United States from June 2010 to July 2017. The results were analyzed with respect to the likelihood of latent TB infection and TB disease. Results: A total of 1299 patients were included with 1599 tests performed: 586 QFT‐TB and 1013 T‐SPOT. TB . Forty‐nine (4%) patients were diagnosed with latent TB, and four (1%) with TB disease. T‐SPOT. TB was more likely to yield an actionable result (positive or negative) than QFT‐TB (89% vs. 65%, p < 0.001). The rate of indeterminate results for QFT‐TB was higher than the rate of invalid results for T‐SPOT. TB (35% and 10%, respectively, p < 0.001). On multivariate analysis, independent predictors of an invalid T‐SPOT. TB included prior receipt of alemtuzumab, lower hemoglobin, absolute lymphocyte count, or serum albumin ( p < 0.05 each), whereas the independent predictors of an indeterminate QFT‐TB were female gender, prior receipt of systemic corticosteroids, and lower hemoglobin, or serum albumin or higher absolute neutrophil count ( p < 0.05 each). Conclusions: T‐SPOT. TB yielded more actionable results than QFT‐TB in patients with cancer. T‐SPOT. TB might be a better IGRA for screening for latent TB infection in patients with cancer, although a direct comparison would be needed to definitively determine this. image

Patients undergoing immune effector cell therapy (IECT) are at high risk for infections. We assessed seropositivity against pneumococcus, tetanus, and diphtheria in patients before and after IECT and the patients’ response to vaccination. We enrolled patients who underwent IECT from January 2020 to March 2022. Antibody levels for diphtheria, tetanus, and pneumococcus were measured before IECT, at 1 month, and 3–6 months after. Eligible patients were vaccinated after IECT. In non-seroprotected patients, we discontinued testing. Before IECT, most patients had seroprotective antibody levels against tetanus (68/69, 99%) and diphtheria (65/69, 94%), but fewer did against pneumococcus (24/67, 36%). After IECT, all patients had seroprotective antibody levels for tetanus at 1 month (68/68) and 3–6 months (56/56). For diphtheria, 65/65 patients (100%) had seroprotective antibody levels at 1 month, and 48/53 (91%) did at 3–6 months. For pneumococcus, seroprotective antibody levels were identified in 91% (21/23) of patients at 1 month and 79% (15/19) at 3–6 months following IECT. Fifteen patients received a pneumococcal vaccine after IECT, but none achieved seroprotective response. One patient received the tetanus-diphtheria vaccine and had a seroprotective antibody response. Because some patients experience loss of immunity after IECT, studies evaluating vaccination strategies post-IECT are needed.

Background: Patients with B-cell lymphoma and acute lymphoblastic leukemia (ALL) who receive chimeric antigen receptor T-cell (CAR-T) therapy may experience clinically significant cytomegalovirus infection (CS-CMVi). However, risk factors for CS-CMVi are not well defined. The aims of our study were to identify risk factors for CS-CMVi and the association between CS-CMVi and nonrelapse mortality (NRM) in lymphoma and ALL patients after CAR-T therapy. Methods: We performed a retrospective single-center cohort analysis of CAR-T recipients between January 2018 and February 2021 for treatment of lymphoma and ALL. We collected data on demographics, oncologic history, CAR-T therapy–related complications, and infectious complications within 1 year of therapy. Results: Of 230 patients identified, 22 (10%) had CS-CMVi. At 1 year following CAR-T therapy, 75 patients (33%) developed relapsed disease and 95 (41%) died; NRM at 1 year was 37%. On Cox regression analysis, Asian or Middle Eastern race (adjusted hazard ratio [aHR], 13.71 [95% confidence interval {CI}, 5.41–34.74]), treatment of cytokine release syndrome/immune effector cell–associated neurotoxicity syndrome with steroids (aHR, 6.25 [95% CI, 1.82–21.47]), lactate dehydrogenase at time of CAR-T therapy (aHR, 1.09 [95% CI, 1.02–1.16]), and CMV surveillance (aHR, 6.91 [95% CI, 2.77–17.25]) were independently associated with CS-CMVi. CS-CMVi was independently associated with NRM at 1 year after CAR-T therapy (odds ratio, 2.49 [95% CI, 1.29–4.82]). Conclusions: Further studies of immunologic correlatives and clinical trials to determine the efficacy of prophylactic strategies are needed to understand the role of CS-CMVi and post–CAR-T mortality.

Ruxolitinib, a selective inhibitor of Janus kinases, is a standard treatment for intermediate/high-risk myelofibrosis (MF) but is associated with a predisposition to opportunistic infections, especially herpes zoster. However, the incidence and characteristics of invasive fungal infections (IFIs) in these patients remain uncertain. In this report, we present the case of a 59-year-old woman with MF who developed disseminated histoplasmosis after seven months of ruxolitinib use. The patient clinically improved after ten weeks of combined amphotericin B and azole therapy, and ruxolitinib was discontinued. Later, the patient received fedratinib, a relatively JAK2-selective inhibitor, without relapse of histoplasmosis. We also reviewed the literature on published cases of proven IFIs in patients with MF who received ruxolitinib. Including ours, we identified 28 such cases, most commonly due to Cryptococcus species (46%). IFIs were most commonly disseminated (39%), followed by localized lung (21%) infections. Although uncommon, a high index of suspicion for opportunistic IFIs is needed in patients receiving JAK inhibitors. Furthermore, the paucity of data regarding the optimal management of IFIs in patients treated with JAK inhibitors underscore the need for well-designed studies to evaluate the epidemiology, pathobiology, early diagnosis, and multimodal therapy of IFIs in patients with hematological malignancies receiving targeted therapies.

Cytomegalovirus (CMV) infection is a common opportunistic infection after allogeneic hematopoietic cell transplant (alloHCT). We explored whether a change in CMV cell-mediated immunity during the first month after transplant predicts the risk of development of CMV infection and all-cause mortality. This follow-up analysis is based on data from the REACT study, a multicenter prospective observational study of recipients of alloHCT who were CMV-seropositive. Production of interferon γ following ex vivo stimulation with CMV antigens IE1 (immediate early 1) and pp65 (phosphoprotein 65) was assessed by CMV ELISPOT assay at baseline and 2 and 4 weeks after transplant. Clinically significant CMV infection (CS-CMVi) was defined as CMV viremia and/or disease necessitating antiviral therapy. We evaluated the impact of CMV CMI changes on the risk of CS-CMVi and post transplant mortality. The analysis included 226 recipients of alloHCT with CMV cell-mediated immunity data at baseline and 2 and/or 4 weeks after transplant. CS-CMVi occurred in 64 patients (28%). On Cox regression analyses, independent predictors of CS-CMVi included a negative Δ change from baseline to week 2 of pp65 spot counts (hazard ratio, 3.65 [95% CI, 1.65–8.04]; P = .001) to week 4 of IE1 spot counts (hazard ratio, 2.79 [95% CI, 1.46–5.35]; P = .002), anti-thymocyte globulin conditioning regimen, type of transplant, female sex, and corticosteroid use. Kaplan-Meir analysis showed a significant association of a negative IE1 change from baseline to week 4 and increased all-cause mortality after transplant (log rank test = 0.041). A decrease in CMV-specific T-cell responses during the first month after transplant may predict CS-CMVi and is associated with all-cause mortality in recipients of alloHCT.

Infectious complications in cancer patients (pts) who have received T-cell therapies are similar to those in autologous hematopoietic stem cell transplant (HCT) recipients, who - because they lose prior acquired immunity after undergoing conditioning regimens and transplantation- may be at an increased risk for vaccine-preventable infections. We sought to determine seroprotection rates against pneumococcus and tetanus-diphtheria before and after cellular therapies. In this ongoing prospective observational cohort study, we enrolled pts with any type of cancer who received cellular therapy with chimeric antigen receptor modified T cell (CAR-T), natural killer CAR-T, or T-cell receptor- directed immunotherapies at MD Anderson Cancer Center from January 2020 through May 2021. We performed antibody assays for diphtheria, tetanus, and pneumococcus before, at 1 month, and between 3-6 months after T-cell therapy for each pt regardless of vaccination history. Of 38 pts enrolled, 27 (71%) were men and 25 (66%) had non-Hodgkin lymphoma (Table 1); 38 (100%) and 17 (45%) had a history of previous diphtheria-tetanus-acellular pertussis (Tdap) and pneumococcal vaccination, respectively (Table 2). Tetanus serologies were positive for all pts tested before, at 1 month and 3-6 months after T cell therapy (37/37 [100%], 22/22 [100%], and 13/13 [100%], respectively). Diphtheria serologies were positive for most pts tested before, at 1 month and 3-6 months after therapy (35/37 [95%], 20/22 [91%], and 11/13 [85%], respectively]. Pneumococcal serologies were positive for 8 out of 37 [22%] pts before therapy, among these 8 pts, 4 had positive serologies 1 month after therapy, and 2 of 3 tested 3-6 months after therapy had positive serologies. One pt received a pneumococcal vaccine 10 months after therapy but had negative serologies post-vaccination. Most pts who received T-cell therapy retained their immunity for diphtheria and tetanus, but most also lost their immunity for pneumococcus. This suggests that the standard of care for pts receiving T-cell therapy should include more robust strategy for pneumococcal vaccination, but its timing, need for booster dosing, and antibody response needs to be determined in future trials. Roy F. Chemaly, MD, MPH, FACP, FIDSA, AiCuris (Grant/Research Support)Ansun Biopharma (Consultant, Grant/Research Support)Chimerix (Consultant, Grant/Research Support)Clinigen (Consultant)Genentech (Consultant, Grant/Research Support)Janssen (Consultant, Grant/Research Support)Karius (Grant/Research Support)Merck (Consultant, Grant/Research Support)Molecular Partners (Consultant, Advisor or Review Panel member)Novartis (Grant/Research Support)Oxford Immunotec (Consultant, Grant/Research Support)Partner Therapeutics (Consultant)Pulmotec (Consultant, Grant/Research Support)Shire/Takeda (Consultant, Grant/Research Support)Viracor (Grant/Research Support)Xenex (Grant/Research Support) Fareed Khawaja, MBBS, Eurofins Viracor (Research Grant or Support) Ella Ariza Heredia, MD, Merck (Grant/Research Support)

Background: Cases of novel coronavirus disease 2019 (COVID-19) were first reported in Wuhan, China, in December 2019. In this report, we describe 3 clusters of COVID-19 infections among healthcare workers (HCWs), not associated with patient exposure, and the interventions undertaken to halt ongoing exposure and transmission at our cancer center.Methods: A cluster of cases was defined as 2 or more cases of severe acute respiratory coronavirus virus 2 (SARS-CoV-2)–positive COVID-19 among HCWs who work in the same unit area at the same time. Cases were identified by real-time reverse transcription polymerase chain reaction testing. Contact tracing, facility observations, and infection prevention assessments were performed to investigate the 3 clusters between March 1 and April 30, 2020, with subsequent implementation of containment strategies.Results: The initial cluster involved HCWs from an ancillary services unit, with contacts traced back to a gathering in a break room in which 1 employee was symptomatic, although not yet diagnosed with COVID-19, with subsequent transmission to 7 employees. The second cluster involved 4 employees and was community related. The third cluster involved only 2 employees with possible transmission while working in the same office at the same time. A step-up approach was implemented to control the spread of infection among employees, including universal masking, enhanced cleaning, increase awareness, and surveillance testing. No nosocomial transmission to patients transpired.Conclusions: To our knowledge, this is the first report of a hospital-based cluster of COVID-19 infections among HCWs in a cancer hospital describing our steps to mitigate further transmission.