We aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic ...hematopoietic stem cell transplantation (Allo-SCT).
We conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted.
The median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS.
CMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.
•Recipient CMV seropositive status was significantly associated with CMV viremia and disease.•Risk of CMV viremia and disease was not abrogated with the use of Letermovir prophylaxis.•CMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation.
Persistent cytopenia in the post-hematopoietic cell transplantation (HCT) setting can occur despite adequate engraftment of donor cells. PLX-R18, a placental-derived mesenchymal-like cell product, is ...expanded ex vivo in a 3-dimensional environment. PLX-R18 cells secrete a large array of hematopoietic factors, which promote regeneration, maturation, and differentiation of hematopoietic cells and stimulate their migration to peripheral blood. This phase 1, first-in-human study (NCT03002519), included 21 patients with incomplete hematopoietic recovery post-HCT. Patients were treated with escalating doses of PLX-R18: 3 patients received 1 million cells/kg, 6 received 2 million cells/kg, and 12 received 4 million cells/kg via multiple intramuscular injections. While patients received only two administrations of cells during the first week, peripheral blood counts continued to increase for months, peaking at 6 months for hemoglobin (Hb, p = 0.002), lymphocytes (p = 0.008), and neutrophils (ANC, p = 0.063), and at 9 months for platelets (p < 0.001) and was maintained until 12 months for all but ANC. The need for platelet transfusions was reduced from 5.09 units/month at baseline to 0.55 at month 12 (p = 0.05). Likewise, red blood cell transfusions decreased from 2.91 units/month at baseline to 0 at month 12 (p = 0.0005). PLX-R18 was safe and well tolerated and shows promise in improving incomplete hematopoietic recovery post-HCT.
We investigated the outcomes after adult haploidentical (haplo) and matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) in a single-center study (
= 452) including 276 MUD and 176 ...haplo transplants. Myeloablative (37%) and reduced-intensity conditioning (63%) were performed. Graft sources included peripheral blood (50%) and bone marrow (50%). GVHD prophylaxis included tacrolimus/methotrexate (53%) and post-transplant cyclophosphamide-based (47%). In MUD versus haplo HCT recipients, a similar incidence of neutrophil engraftment (18 vs 17 days,
= 0.895), grade II-IV acute GVHD (51% vs 50%,
= 0.773), relapse (26% vs 23%,
= 0.578), non-relapse mortality (22% vs 23%,
= 0.817), 1-year disease-free survival (62% vs 63%.
= 0.921), and 1-year overall survival (73% vs 74%,
= 0.744) were observed. Earlier platelet engraftment (22 vs 27 days,
< 0.001) and higher chronic GVHD (45% vs 35%,
= 0.040) were noted in MUD as compared to haplo HCT. Allogeneic transplantation should be done promptly whenever indicated, utilizing either matched unrelated or haploidentical donors.
Background
Hematopoietic stem cell transplant (HSCT) recipients are at increased risk of mortality and morbidity with coronavirus disease 2019 (COVID‐19) due to severe immune dysfunction.
Methods
A ...literature search was performed on PubMed, Cochrane, and Clinical trials.gov from the date of inception to 12/08/2021. We identified 19 original studies reporting data on COVID‐19 in HSCT recipients after screening 292 articles. Data were extracted following preferred reporting items for systematic reviews and meta‐analysis guidelines. Quality evaluation was done using the National Institutes of Health (NIH) quality assessment tool. Inter‐study variance was calculated using Der Simonian–Laird Estimator. Pooled analysis was conducted using MetaXL. A random‐effects model was used to estimate the proportions with 95% confidence intervals (CI).
Results
Of 6711 patients in 19 studies, 2031 HSCT patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection were analyzed. The median age of patients was 56.9 (range 1–81.6) years, and 63% patients were men according to 14 studies. The median time from transplant to SARS‐CoV‐2 infection for autologous (auto) and allogeneic (allo) HSCT patients was 23.2 (0.33–350.5) months and 16.4 (0.2–292.7) months, respectively. The median follow‐up time after COVID‐19 diagnosis was 28 (0–262) days. The COVID‐19 mortality rate was 19% (95% CI 0.15–0.24, I2 = 76%, n = 373/2031). The pooled mortality rate was 17% (95% CI 0.12–0.24, I2 = 78%, n = 147/904) in auto‐HSCT patients and 21% (95% CI 0.16–0.25, I2 = 60%, n = 231/1103) in allo‐HSCT patients.
Conclusions
HSCT recipients have a high risk of mortality and clinical complications due to COVID‐19. There is a need for ongoing vigilance, masks, and social distancing, vaccination, and aggressive management of SARS‐CoV‐2 infection in HSCT recipients.
Epstein-Barr virus (EBV) is directly implicated in several B-cell lymphoid malignancies. EBV-associated lymphomas are characterized by prominent activation of the NF-κB pathway and targeting this ...pathway establishes a rationale for a therapeutic approach. The ubiquitin/proteasome signaling plays an essential role in the regulation of the NF-κB pathway. Ixazomib is an FDA-approved, orally bioavailable proteasome inhibitor. Here we report the first preclinical evaluation of ixazomib-mediated growth-inhibitory effects on EBV-infected B-lymphoblastoid cell lines Raji and Daudi. Ixazomib induced apoptosis in these cell lines in a dose-dependent manner. Cell-cycle analysis demonstrated ixazomib treatment induced cell-cycle arrest at the G
-M phase with a concomitant decrease in G
-G
and S phases. The results further revealed an increase in p53, p21, and p27 levels and a decrease in survivin and c-Myc protein levels. Mechanistically, ixazomib treatment resulted in the accumulation of polyubiquitinated proteins, including phosphorylated IκBα with a significant reduction of p65 subunit nuclear translocation. Altogether, our preclinical data support the rationale for
testing of ixazomib in EBV-associated B-cell neoplasms. IMPLICATIONS: This preclinical study supports the use of oral proteasome inhibitor ixazomib for targeting NF-κB signaling in the treatment of EBV-associated B-cell neoplasms.
http://mcr.aacrjournals.org/content/molcanres/17/4/839/F1.large.jpg.
Chimeric antigen receptor (CAR) T-cell therapy is an investigational immunocellular therapy that reprograms a patient's cytotoxic T cells to engage and eliminate malignant cells. CAR T-cell therapies ...targeting the CD19 antigen have demonstrated high efficacy in clinical trials for patients with B-cell malignancies and may potentially be available on a broader scale in the future. CAR T-cell therapy begins with the collection of a sufficient number of T cells from a patient's peripheral blood through leukapheresis. Several factors must be considered when patients undergo leukapheresis for CAR T-cell therapy, including age and prior therapies. The leukapheresis material is shipped to a manufacturing facility, followed by return of the CAR T cells to the treatment center. Careful coordination of a multidisciplinary team composed of physicians, nurses, pharmacists and other hospital personnel is critical for the proper care of the patient before, during and after CAR T-cell therapy. CAR T-cell therapy has been associated with adverse events (AEs) such as cytokine release syndrome, which requires rapid attention by the emergency department, intensive care unit and hospital pharmacy. In this review, we discuss several aspects of institutional preparation for leukapheresis, CAR T-cell infusion and AE management based on our experience with clinical trials of the CD19 CAR T-cell therapy CTL019.
Hemopoietic progenitor cells (HPC) from myeloproliferative neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of ...JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2-mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 cells, and primary CD34+ myelofibrosis (MF)-MPN cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs.
We investigated the outcomes after Coronavirus disease 2019 (COVID) in hematopoietic cell transplant (HCT) or chimeric antigen receptor-T cell (CART) therapy recipients in a single-centre study ...including all (
= 261)HCT/CART recipients (allogeneic-HCT 49%, autologous-HCT 40%, CART 11%). The median age was 60 (22-80) years. COVID severity was mild (74%), moderate (11%), and severe/critical (16%) with a mortality rate of 7% and a median duration of infection of 5.7 weeks. Significant predictors of COVID severe disease or mortality included concurrent infection (HR 14.9, 95% CI 2.2-5.6) and immunosuppressive therapy (OR 4.8, 95% CI 1.2-3.4).HCT/CART recipients have a higher risk of mortality with COVID and warrant vigilant interventions.
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