Human Herpesvirus-6 Reactivation and Disease Are Infrequent in Chimeric Antigen Receptor T-cell Therapy Recipients.

Human herpesvirus-6B (HHV-6B) reactivation and disease are increasingly reported after CAR-T-cell therapy (CARTx). HHV-6 reactivation in the CAR-T-cell product was recently reported, raising questions about product and patient management. Due to overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide two lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks post-infusion, HHV-6B reactivation occurred in eight of 89 participants; three had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval (CI), 2.2-12.5%). HHV-6B detection was low level (median peak, 435 copies/mL; IQR, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in blood and/or cerebrospinal fluid (CSF) within 12 weeks post-infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing with detection in one. Among 34 patients with CSF HHV-6 testing, one patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94%), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.

Human herpesvirus-6 reactivation and disease after allogeneic haematopoietic cell transplantation in the era of letermovir for cytomegalovirus prophylaxis.

OBJECTIVES: Letermovir for cytomegalovirus (CMV) prophylaxis in allogeneic haematopoietic cell transplant (HCT) recipients has decreased anti-CMV therapy use. Contrary to letermovir, anti-CMV antivirals are also active against human herpesvirus-6 (HHV-6). We assessed changes in HHV-6 epidemiology in the post-letermovir era. METHODS: We conducted a retrospective cohort study of CMV-seropositive allogeneic HCT recipients comparing time periods before and after routine use of prophylactic letermovir. HHV-6 testing was at the discretion of clinicians. We computed the cumulative incidence of broad-spectrum antiviral initiation (foscarnet, (val)ganciclovir, and/or cidofovir), HHV-6 testing, and HHV-6 detection in blood and cerebrospinal fluid within 100 days after HCT. We used Cox proportional-hazards models with stabilized inverse probability of treatment weights to compare outcomes between cohorts balanced for baseline factors. RESULTS: We analysed 738 patients, 376 in the pre-letermovir and 362 in the post-letermovir cohort. Broad-spectrum antiviral initiation incidence decreased from 65% (95% CI, 60-70%) pre-letermovir to 21% (95% CI, 17-25%) post-letermovir. The cumulative incidence of HHV-6 testing (17% [95% CI, 13-21%] pre-letermovir versus 13% [95% CI, 10-16%] post-letermovir), detection (3% [95% CI, 1-5%] in both cohorts), and HHV-6 encephalitis (0.5% [95% CI, 0.1-1.8%] pre-letermovir and 0.6% [95% CI, 0.1-1.9%] post-letermovir) were similar between cohorts. First HHV-6 detection occurred at a median of 37 days (interquartile range, 18-58) in the pre-letermovir cohort and 27 (interquartile range, 25-34) in the post-letermovir cohort. In a weighted model, there was no association between the pre-versus post-letermovir cohort and HHV-6 detection (adjusted hazard ratio, 1.08; 95% CI, 0.44-2.62). DISCUSSION: Despite a large decrease in broad-spectrum antivirals after the introduction of letermovir prophylaxis in CMV-seropositive allogeneic HCT recipients, there was no evidence for increased clinically detected HHV-6 reactivation and disease.

Anti-HLA antibodies in recipients of CD19 versus BCMA-targeted CAR T-cell therapy.

Antibodies against foreign human leukocyte antigen (HLA) molecules are barriers to successful organ transplantation. B cell-depleting treatments are used to reduce anti-HLA antibodies but have limited efficacy. We hypothesized that the primary source for anti-HLA antibodies is long-lived plasma cells, which are ineffectively targeted by B cell depletion. To study this, we screened for anti-HLA antibodies in a prospectively enrolled cohort of 49 patients who received chimeric antigen receptor T-cell therapy (CARTx), targeting naïve and memory B cells (CD19-targeted, n = 21) or plasma cells (BCMA-targeted, n = 28) for hematologic malignancies. Longitudinal samples were collected before and up to 1 year after CARTx. All individuals were in sustained remission. We identified 4 participants with anti-HLA antibodies before CD19-CARTx. Despite B cell depletion, anti-HLA antibodies and calculated panel reactive antibody scores were stable for 1 year after CD19-CARTx. Only 1 BCMA-CARTx recipient had pre-CARTx low-level anti-HLA antibodies, with no follow-up samples available. These data implicate CD19neg long-lived plasma cells as an important source for anti-HLA antibodies, a model supported by infrequent HLA sensitization in BCMA-CARTx subjects receiving previous plasma cell-targeted therapies. Thus, plasma cell-targeted therapies may be more effective against HLA antibodies, thereby enabling improved access to organ transplantation and rejection management.

Infectious complications after intensive chemotherapy with CLAG-M versus 7+3 for AML and other high-grade myeloid neoplasms.

Contemporary data on infections after intensive chemotherapy for acute myeloid leukemia (AML) are scarce. Cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone ("CLAG-M") may result in higher remission rates than standard-dose cytarabine plus anthracycline ("7 + 3") but may result in more infections. We compared moderate to severe infections occurring up to 90 days after the first induction cycle for AML or other high-grade myeloid neoplasms in patients receiving CLAG-M for newly diagnosed (n = 196) or relapsed/refractory disease (n = 131) or 7 + 3 for newly diagnosed disease (n = 115). For newly diagnosed disease, microbiologically documented infections were more frequent after CLAG-M compared to 7 + 3 (adjusted rate ratio, 1.65 [95% CI, 1.06-2.58]; P = 0.03), with a cumulative incidence of 27.8% and 16.5% by day 90, respectively. Patients receiving CLAG-M for relapsed/refractory disease had the highest cumulative incidence of 50.7%. Bacterial bloodstream infections were the most frequent followed by respiratory tract infections. Among 29 patients (7%) who died, infection was a primary or contributing cause of death in 59%. These data indicate that infections continue to cause substantial morbidity in patients treated for AML, especially those treated for relapsed/refractory disease, and are more common with newer, more myelosuppressive regimens such as CLAG-M. Improved strategies for infection prevention are needed.