Dynamics of antibody titers to SARS-CoV-2 and clinical outcomes after sotrovimab pre-exposure prophylaxis early after allogeneic hematopoietic stem cell transplantation.
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ABSTRACT:
SUBMITTER: Capoferri G
PROVIDER: S-EPMC9933011 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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Dynamics of antibody titers to SARS-CoV-2 and clinical outcomes after sotrovimab pre-exposure prophylaxis early after allogeneic hematopoietic stem cell transplantation.
Capoferri Gioele G Walti Carla Simone CS Urwyler Pascal P Ragozzino Silvio S Passweg Jakob R JR Halter Jörg J Battegay Manuel M Baettig Veronika V Weisser Maja M Arnold Brice B Morin Benedict B Guetlin Yukino Y Torres Diana Albertos DA Barut Güliz Tuba GT Thiel Volker V Egli Adrian A Drexler Beatrice B Khanna Nina N
Bone marrow transplantation 20230216 5
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Project description:Patients treated with allogeneic hematopoietic cell transplantation (HCT) are at risk of cytomegalovirus (CMV) reactivation and disease, which results in increased morbidity and mortality. Although universal antiviral prophylaxis against CMV improves outcomes in solid organ transplant recipients, data have been conflicting regarding such prophylaxis in patients undergoing allogeneic HCT. We conducted a systematic review of randomized trials of prophylactic antivirals against CMV after allogeneic HCT to summarize the evolution of the field over the last 35 years and evaluate the prophylactic potential of antiviral agents against CMV after allogeneic HCT. Electronic databases were queried from database inception through 31 December 2017. For included studies, incidence of CMV infection and all-cause mortality were collected as primary outcomes; CMV disease incidence, use of preemptive therapy, and drug toxicities were collected as secondary outcomes. Nineteen clinical trials conducted between 1981 and 2017 involving a total of 4173 patients were included for review. Prophylactic strategies included use of acyclovir, valacyclovir, ganciclovir, maribavir, brincidofovir, and letermovir compared with placebo or a comparator antiviral. Fourteen trials that compared antiviral prophylaxis with placebo demonstrated overall effectiveness in reducing incidence of CMV infection (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.42-0.58), CMV disease (OR, 0.56; 95% CI, 0.40-0.80), and use of preemptive therapy (OR, 0.51; 95% CI, 0.42-0.62; 6 trials); however, none demonstrated reduction in all-cause mortality (OR, 0.96; 95% CI, 0.78-1.18) except the phase 3 trial of letermovir (week-24 OR, 0.59; 95% CI, 0.38-0.98). Additional research is warranted to determine patient groups most likely to benefit from antiviral prophylaxis and its optimal deployment after allogeneic HCT.
| S-EPMC6113617 | biostudies-literature
Project description:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for many patients with hematological malignancies and nonmalignant hematopoietic disorders. To achieve stable engraftment of donor hematopoietic stem cells (HSCs), recipient HSC deletion is needed to create space for incoming donor HSCs and donor HSCs must escape immune rejection by the recipient. Conventional allo-HSCT requires high dose of irradiation and/or chemotherapy to produce sufficient host stem cell and immune system ablation to permit donor HSC engraftment. However, these procedures also result in nonspecific tissue injury that can cause short- and long-term adverse effects as well as incite and amplify graft-versus-host-disease (GVHD). The delivery of targeted radiotherapy to hematopoietic tissues with the use of a radioimmunoconjugate (ROIC) as a part of transplant preparative regimen has shown clinical benefits. ROIC clinical data provide evidence for decreased relapse without increased transplant-related mortality by delivering higher targeted radiation to sites of malignancy than when given in a nontargeted fashion. An alternative approach to allo-HSCT has been developed and tested in preclinical mouse models in which nonmyeloablative preconditioning with low dose of the alkylating agent (busulfan) or lower systemic dose of irradiation combined with co-stimulatory pathway blockade (CTLA4-Ig, anti-CD40L monoclonal antibody) and/or immunosuppressive drugs have been used. Under these conditions, mixed chimerism and transplantation tolerance to fully MHC mismatched donor marrow was observed. Recently, several novel proof-of-concept antibody-mediated preconditioning methods have been developed that can selectively target hematopoietic stem and immune cells with minimal overall toxicity. Antibody-drug-conjugate (ADC) combined with reduced intensity conditioning or high dose ADC as single dose monotherapy have shown promise for allo-HSCT in preclinical models. The purpose of the current review is to discuss the literature exploring antibody-based conditioning that includes native antibody, radiolabeled antibody conjugates, and ADC for allo-HSCT.
| S-EPMC9632731 | biostudies-literature
Project description:Varicella zoster virus (VZV) disease (usually cutaneous zoster) occurs frequently after hematopoietic cell transplantation (HCT), and postherpetic neuralgia (PHN) results in poor quality of life. The optimal prophylaxis of VZV disease/PHN has not been established. At our center, before 2008, VZV prophylaxis consisted of ∼1 year of post-HCT acyclovir/valacyclovir ("old strategy"), whereas post-2008 prophylaxis consisted of 2 years of acyclovir/valacyclovir followed by immunization using varicella vaccine ("new strategy"). We performed a retrospective study comparing the cumulative incidence of VZV disease and PHN among patients who completed the old strategy (n = 153) vs the new strategy (n = 125). Patients who completed the old strategy had a significantly higher cumulative incidence of VZV disease (33% vs 17% at 5 years, P ≤ .01) and PHN (8% vs 0% at 5 years, P = .02). In conclusion, VZV prophylaxis with 2 years of acyclovir/valacyclovir followed by vaccination appears to result in a low incidence of VZV disease and may eliminate PHN.
| S-EPMC5737163 | biostudies-literature
Project description:BackgroundAcyclovir treatment is an efficient prophylaxis to prevent varicella-zoster virus (VZV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT).AimsThis single center retrospective study tried to determine if the lymphocytes immunophenotyping could help to determine the duration of prophylaxis, and evaluated complications, and associated risk factors for VZV infection.Methods and resultsEighty-four children underwent an allogeneic HSCT, in which 77 received an acyclovir prophylaxis. Twenty-one of the 77 had a VZV infection with an incidence rate of 1.30 per 100 patients-months (exact 95% CI, 0.81 to 2.01). Among these 21 patients with VZV infection, 16 had an infection after withdrawing acyclovir prophylaxis within a median of 49 days (range, 11 days-5.8 months). Thirty-five percent of the VZV infected patients were hospitalized, 9% had a visceral dissemination, and 9% had postherpetic neuralgia. In multivariate analysis, higher VZV infection rate was associated with conditioning regimen with total body irradiation, immunoglobulin substitution, and antithymocyte globulin. The incidence of VZV infection increased significantly when patients had a CD4+ lymphocytes count below 23% (cHR 3.28 [95% CI, 1.09-9.81]; p = 0.03) or a CD4+/CD8+ ratio less than 0.9 (cHR 3.13 [95% CI, 1.04-9.36]; p = 0.04) at the time of stopping acyclovir prophylaxis.ConclusionAfter cessation of acyclovir prophylaxis, VZV reactivation can occur and be responsible for morbidity after allogeneic HSCT. This study suggests that the proportion of CD4+ lymphocytes and the CD4+/CD8+ ratio can inform decisions about the duration of acyclovir prophylaxis after allogeneic HSCT to prevent VZV reactivation.
| S-EPMC11541057 | biostudies-literature
Project description:Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.
| S-EPMC7571859 | biostudies-literature
Project description:BackgroundChemotherapy-induced nausea and vomiting (CINV) is a severe and distressing complication during allogeneic hematopoietic stem cell transplantation (alloHSCT). The antiemetic fosaprepitant has shown favorable results in pediatric and adult patients receiving chemotherapy. Data on fosaprepitant in children and adolescents undergoing alloHSCT are missing.MethodsIn this non-interventional observation study, 120 children and adolescents with a median age of 11.8 years undergoing alloHSCT after a moderately or highly emetogenic conditioning (MEC or HEC) were analyzed. They received an antiemetic prophylaxis with granisetron (2 × 40 µg/kg d-1) with or without fosaprepitant (4 mg/kg; single dose, max. 1 × 150 mg/kg BW), and were analyzed in the control (CG; n = 60) or fosaprepitant group (FG; n = 60). The efficacy and safety of the two antiemetic prophylaxis regimens were analyzed and compared with respect to the acute (0-24 h) and the delayed (> 24-120 h) CINV phase and > 120-240 h after MEC or HEC administration.ResultsDuring MEC, significantly more patients in the CG experienced vomiting during the first 0-24 h (58.6 vs. 25.0%; p = 0.0156) and during > 24-120 h (93.1% vs. 57.1%; p = 0.0020), compared with the FG. Likewise, significantly more vomiting events (269 vs. 136; p < 0.0001) were registered in the CG. During HEC, significantly more patients in the CG experienced vomiting during the first 0-24 h (32.3 vs. 9.4%; p = 0.0319) compared with the FG. Significantly more vomiting events (241 vs. 99; p < 0.0001) were registered in the CG. Laboratory and clinical adverse events were not significantly different between the two groups (p > 0.05).ConclusionsAntiemetic prophylaxis with fosaprepitant and granisetron was well tolerated, safe, and effective in pediatric patients undergoing alloHSCT. However, larger prospective trials are necessary to evaluate these findings.
| S-EPMC7085480 | biostudies-literature
Project description:AbstractPosttransplant cyclophosphamide (PTCy) is a promising graft-versus-host disease (GVHD) prophylaxis in haploidentical and matched unrelated donor hematopoietic stem cell transplantation (HSCT), but its role in matched sibling donor (MSD) transplants remains unclear. We conducted a retrospective study of 413 MSD-HSCT patients receiving peripheral blood stem cell (PBSC) grafts from January 2010 to January 2023. Patients were categorized into 4 groups: group I (calcineurin inhibitor [CNI] + methotrexate [MTX] or mycophenolate mofetil [MMF]), group II (CNI + MTX or MMF + antithymocyte globulin [ATG]), group III (PTCy + ATG + CNI), and group IV (PTCy + CNI + MMF). PTCy was associated with a significant reduction in grade 2- 4 and grade 3-4 acute GVHD and moderate-to-severe chronic GVHD compared with CNI + MTX (or MMF)-containing regimens. PTCy did not increase relapse risk; PTCy reduced nonrelapse mortality, leading to improved GVHD-free/relapse-free survival (GRFS; Hazard Ratio, 0.4; P < .001). PTCy was also associated with improved overall survival. Bloodstream infections were increased with PTCy. The addition of ATG to PTCy did not further improve GRFS and was associated with a higher incidence of clinically significant cytomegalovirus (csCMV) and Epstein-Barr virus (csEBV) reactivation and a numerical increase in NRM. PTCy significantly appeared to improve GRFS in the MSD setting using PBSC grafts. The addition of ATG to PTCy increases csCMV and csEBV reactivation without further improving GRFS. Prospective trials and PTCy dose optimization are warranted.
| S-EPMC11881745 | biostudies-literature
Project description:Traditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to higher mortality. In a retrospective pharmacokinetic/pharmacodynamic (PK/PD) analysis of patients undergoing their first CD34+ T-cell-depleted (TCD) allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area under the curve (arbitrary unit per day/milliliter [AU × day/mL]) using a validated population PK model. We related rATG exposure to nonrelapse mortality (NRM), CD4+ IR (CD4+ ≥50 cells per µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute graft-versus-host disease (aGVHD) to define an optimal rATG exposure. We used Cox proportional hazard models and multistate competing risk models for analysis. In all, 554 patients were included (age range, 0.1-73 years). Median post-HCT rATG exposure was 47 AU × day/mL (range, 0-101 AU × day/mL). Low post-HCT area under the curve (<30 AU × day/mL) was associated with lower risk of NRM (P < .01) and higher probability of achieving CD4+ IR (P < .001). Patients who attained CD4+ IR had a sevenfold lower 5-year NRM (P < .0001). The probability of achieving CD4+ IR was 2.5-fold higher in the <30 AU × day/mL group compared with 30-55 AU × day/mL and threefold higher in the <30 AU × day/mL group compared with the ≥55 AU × day/mL group. In multivariable analyses, post-HCT rATG exposure ≥55 AU × day/mL was associated with an increased risk of NRM (hazard ratio, 3.42; 95% confidence interval, 1.26-9.30). In the malignancy subgroup (n = 515), a tenfold increased NRM was observed in the ≥55 AU × day/mL group, and a sevenfold increased NRM was observed in the 30-55 AU × day/mL group compared with the <30 AU × day/mL group. Post-HCT rATG exposure ≥55 AU × day/mL was associated with higher risk of a GVHD (hazard ratio, 2.28; 95% confidence interval, 1.01-5.16). High post-HCT rATG exposure is associated with higher NRM secondary to poor CD4+ IR after TCD HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.
| S-EPMC8945304 | biostudies-literature
Project description:BackgroundCytomegalovirus (CMV) contributes to morbidity and mortality in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. Pre-emptive antiviral therapy (PET) reduces the incidence of CMV end-organ disease (EOD), though relevant viral thresholds to initiate PET remain undefined. We evaluated the impact of viral loads (VLs) at PET initiation on virologic and clinical outcomes following pediatric allo-HCT.MethodsSingle-center retrospective cohort analysis of children who underwent their first allo-HCT from January 2014 to December 2020. Weekly quantitative plasma CMV polymerase chain reaction was performed until Day +100 and PET was initiated once VL exceeded a pre-defined threshold per institutional guidelines. Patients were followed for 1-year post-HCT to evaluate virologic and clinical outcomes including end-organ disease (EOD), overall survival (OS), and non-relapse mortality (NRM).ResultsAmong 146 allo-HCT recipients, CMV DNAemia occurred in 40 patients (27%) at a median of 15 days post-HCT (interquartile range 6-28.5). Ten percent (n = 4) had spontaneous resolution of DNAemia, while 90% (n = 36) required PET. PET initiated when CMV VL was ≥ 1000 IU/mL (n = 21) vs when VL < 1000 IU/mL (n = 15) resulted in higher peak CMV VL (12,670 vs. 1284 IU/mL, p = 0.0001) and longer time to CMV DNAemia resolution (36 vs. 24 days, p = 0.035). There were no differences in EOD, OS, or NRM at 12 months post-HCT based on VL at PET initiation.ConclusionsInitiating PET when CMV VL was ≥1000 IU/mL resulted in significantly higher peak VL and prolonged DNAemia, with no differences in EOD, OS, or NRM at 12 months post pediatric HCT.
| S-EPMC11666870 | biostudies-literature
Project description:Allogeneic hematopoietic cell transplantation has broad clinical applications extending from the treatment of malignancies to induction of immunologic tolerance. However, adaptive cellular and humoral immunity frequently remain impaired posttransplantation. Here, recovery of T-dependent and T-independent Ab responses was evaluated in mice transplanted with purified hematopoietic stem cells (HSCs) devoid of the mature immune cells believed to hasten immune recovery. Mixed and full donor chimeras were created by conditioning recipients with sublethal or lethal irradiation, respectively, across different donor/host genetic disparities. By 6 wk posttransplantation, all animals demonstrated robust T-independent Ab responses, and all mixed chimeras and recipients of MHC-matched or haploidentical HSCs with a shared MHC haplotype had T-dependent Ab responses equivalent to those of untransplanted controls. Full chimeras that received fully MHC-disparate HSCs showed delayed T-dependent Ab responses that recovered by 12 wk. This delay occurred despite early reconstitution and proper migration to germinal centers of donor-derived T(follicular helper) (T(FH)) cells. Congenic transplants into T(FH)-deficient CD4(-/-) mice revealed restoration of T-dependent Ab responses by 6 wk, leading us to conclude that MHC disparity caused delay in humoral recovery. These findings, together with our previous studies, show that, contrary to the view that depletion of graft lymphocytes results in poor posttransplant immunity, elimination of immune-suppressing graft-versus-host reactions permits superior immune reconstitution. This study also provides insight into the regeneration of T(FH) cells and humoral immunity after allogeneic HSC transplantation.
| S-EPMC5516799 | biostudies-literature