Variable Outcomes of Hepatitis E Infections in Patients with Hemato-Oncologic Diseases.

INTRODUCTION: The hepatitis E virus (HEV) represents an important cause of viral hepatitis and could cause chronic infections in immunocompromised patients. However, data about immunocompromised patients other than solid organ transplant recipients are limited. METHODS: We identified patients from a laboratory database and retrospectively compiled and analyzed clinical as well as laboratory data in detail. RESULTS: Overall, 22 severely immunosuppressed patients, excluding solid organ transplant recipients, were identified. Four patients did not experience viral clearance (one without and three despite ribavirin therapy). Three patients acquired the infection after allogeneic hematopoietic stem cell transplantation (alloHSCT) and recovered spontaneously, whereas another patient, infected prior to alloHSCT, developed a chronic infection. Four patients failed to clear HEV, resulting in fatal liver failure in 2 patients. The CD4+ cell counts increased in all but 1 patient attaining a sustained virological response (SVR), as compared to patients with clinical failure. Severe immunoglobulin deficiency did not appear to obviate the control of HEV. Six of ten (60%) patients with and nine of 12 (75%) patients without ribavirin therapy achieved an SVR. CONCLUSIONS: Upfront ribavirin therapy does not appear mandatory in patients without CD4+ lymphopenia, but a prolonged HEV replication carries the risk of liver failure. Our data suggest that chronic HEV infections could cause T-cell exhaustion, which might be overruled with ribavirin therapy.

Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas.

The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.

Expression of chemokines in GVHD target organs is influenced by conditioning and genetic factors and amplified by GVHR.

Graft-versus-host disease (GVHD) is the most significant clinical problem that arises after allogeneic hematopoietic cell transplantation. Because chemokines induced by proinflammatory conditioning treatment may promote T-cell migration into GVHD target tissues, we addressed the influence of conditioning on chemokine expression in GVHD target organs. Our results showed that (1) conditioning leads to rapid and transient chemokine upregulation in GVHD target tissues before the time of GVHD-associated T-cell infiltration; (2) conditioning intensity and mouse strain influence chemokine expression in GVHD target organs; and (3) compared with syngeneic bone marrow transplantation, allogeneic bone marrow transplantation led to marked amplification of chemokine expression in GVHD target organs after myeloablative conditioning. This is also reflected by chemokine protein expression that is measured in the serum and colon. Intestines showed the greatest sensitivity to conditioning intensity, and chemokines affecting T-helper type 1 cells (eg, interferon gamma-inducible protein 10 [CXCL10]) were most strongly expressed there after conditioning and during GVHD. However, severity of GVHD was not significantly different between recipients of CXCR3+/+ or CXCR3-/- splenocytes, indicating that this chemokine pathway does not play a critical role. In summary, our data show that conditioning and recipient strain influence chemokine expression in GVHD target organs and that GVH alloreactivity markedly amplifies this expression, thus contributing to the inflammatory cascade associated with tissue GVHD.

Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1.

Histone deacetylase (HDAC) inhibitors reduce development of graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). Administration of the HDAC inhibitor suberonylanilide hydroxamic acid (SAHA) resulted in a significantly reduced GVHD-dependent mortality following fully major histocompatibility complex-mismatched allogeneic BMT. However, SAHA treatment did not affect T-cell activation or T-cell expansion in vitro and in vivo. Therefore, we focused on the effects of SAHA treatment on cytokine production and intracellular signaling events in vitro and in vivo following GVHD induction. Cultivation in the presence of SAHA broadly inhibited lipopolysaccharide (LPS) and alloantigen-induced cytokine/chemokine production in vitro and led also to a significant decrease in interferon-gamma and tumor necrosis factor-alpha levels in vivo following induction of GVHD. Concomitantly, SAHA treatment inhibited phosphorylation of STAT1 and STAT3 in response to LPS and alloactivation in vitro. Induction of GVHD led to a rapid phosphorylation of STAT 1 in the liver and spleen, which was markedly reduced by SAHA treatment. In conclusion, GVHD is associated with a marked induction of phosphorylation of STAT1 in the liver and spleen, and SAHA-dependent reduction of GVHD is associated with systemic and local inhibition of phosphorylated STAT1 and blunting proinflammatory cytokine production during the initiation phase of GVHD.