CMV viral load kinetics predict CMV end-organ disease and mortality after hematopoietic cell transplant (HCT)

2021 ◽  
Author(s):  
Anat Stern ◽  
Yiqi Su ◽  
Henry Dumke ◽  
Jiaqi Fang ◽  
Roni Tamari ◽  
...  
Keyword(s):  
Viral Load ◽  
Hematopoietic Cell Transplantation ◽  
Area Under The Curve ◽  
Hematopoietic Cell ◽  
Cancer Center ◽  
Cell Transplant ◽  
Elite Controllers ◽  
Hematopoietic Cell Transplant ◽  
Cox Models ◽  
One Year

Abstract Background We investigated the association between time-averaged area under the curve (AAUC) of CMV viral load (VL) by D100 and overall survival (OS) at one-year post-hematopoietic cell transplantation (HCT). Methods A retrospective cohort study, including patients receiving HCT between 2010.6 and 2017.12 from Memorial Sloan Kettering Cancer Center. AAUC was calculated for patients with detected VL. Patients were categorized into “non-controllers” (Q4) and “controllers” (Q1-3) using the highest AAUC quartile as cutoff. Kaplan-Meier analyses and Cox models were used to estimate the association between AAUC and OS. Patients with non-detected CMV VL were categorized into “elite-controllers” (R+ or R-/D+) and “R-/D-”. Results The study (N=952) included 282 controllers, 93 non-controllers, 275 elite-controllers, and 302 R-/D-. OS was 80.1% and 58.1% for controllers and non-controllers, respectively. In multivariable models, non-controllers had worse OS versus controllers (adjusted hazard ratio [HR] 2.65, 95% CI 1.71-4.12). In landmark analyses, CMV controllers had similar OS as elite-controllers (HR 1.26, 95% CI 0.83-1.91) or R-/D- (HR 0.98, 95% CI 0.64-1.5). Conclusion CMV non-controllers had worse OS at one-year post-HCT. CMV controllers had similar OS as elite-controllers or R-/D-. Future studies are needed to validate our AAUC cutoff across different cohorts and CMV management strategies.

scholarly journals Adenovirus Viral Kinetics and Mortality in Ex Vivo T Cell-Depleted Hematopoietic Cell Transplant Recipients With Adenovirus Infection From a Single Center

2020 ◽  
Vol 222 (7) ◽  
pp. 1180-1187
Author(s):  
Yeon Joo Lee ◽  
Jiaqi Fang ◽  
Phaedon D Zavras ◽  
Susan E Prockop ◽  
Farid Boulad ◽  
...  
Keyword(s):  
T Cell ◽  
Ex Vivo ◽  
Area Under The Curve ◽  
Absolute Lymphocyte Count ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Viral Kinetics ◽  
Cox Models ◽  
Viral Loads

Abstract Background We report on predictors of adenovirus (ADV) viremia and correlation of ADV viral kinetics with mortality in ex vivo T-cell depleted (TCD) hematopoietic cell transplant (HCT). Methods T cell-depleted HCT recipients from January 1, 2012 through September 30, 2018 were prospectively monitored for ADV in the plasma through Day (D) +100 posttransplant or for 16 weeks after the onset of ADV viremia. Adenovirus viremia was defined as ≥2 consecutive viral loads (VLs) ≥1000 copies/mL through D +100. Time-averaged area under the curve (AAUC) or peak ADV VL through 16 weeks after onset of ADV viremia were explored as predictors of mortality in Cox models. Results Of 586 patients (adult 81.7%), 51 (8.7%) developed ADV viremia by D +100. Age <18 years, recipient cytomegalovirus seropositivity, absolute lymphocyte count <300 cells/µL at D +30, and acute graft-versus-host disease were predictors of ADV viremia in multivariate models. Fifteen (29%) patients with ADV viremia died by D +180; 8 of 15 (53%) died from ADV. Peak ADV VL (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.52–3.33) and increasing AAUC (HR, 2.95; 95% CI, 1.83–4.75) correlated with mortality at D +180. Conclusions In TCD HCT, peak ADV VL and ADV AAUC correlated with mortality at D +180. Our data support the potential utility of ADV viral kinetics as endpoints in clinical trials of ADV therapies.

Higher Mycophenolate Dose Requirements in Children Undergoing Hematopoietic Cell Transplant (HCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3011-3011
Author(s):  
Pamala A. Jacobson ◽  
Jiayin Huang ◽  
Nancy Rydholm ◽  
MyHang Tran ◽  
Todd DeFor ◽  
...  
Keyword(s):  
Mycophenolic Acid ◽  
Hematopoietic Cell Transplantation ◽  
Organ Transplant ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Hematopoietic Cell Transplant ◽  
Mycophenolic Acid Glucuronide

Abstract Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), is commonly used as part of the immunosuppressive regimen after hematopoietic cell transplantation (HCT). Although MMF is widely used in HCT transplant recipients, systemic exposure has not been thoroughly studied in pediatric HCT recipients. Hence, the dosing strategies used in children undergoing kidney transplantation have been adopted or the adult dose has been extended to HCT children. Therefore, we studied mycophenolate pharmacokinetics in 19 children with median age of 17 (3–140) months with nonmalignant diseases undergoing myeloablative HCT who received mycophenolate in combination with cyclosporine for graft-versus-host disease prophylaxis. All subjects, except two, received 15 mg/kg mycophenolate intravenously every 8 hours. Pharmacokinetics were studied once between days 3–7 and again between days 10–14 post-transplant. The median [range] MPA total area under the curve (AUC)0-8 was 12.6 mcg hr/ml [4.9–49.2] and unbound AUC0-8 was 0.274 mcg hr/ml [0.037–1.4]. Unbound MPA fraction was 1.7% [0.76–5.1]. The median total mycophenolic acid glucuronide (MPAG) AUC0-8 was 269.1 mcg hr/mL [127.6–957.0]. Total and unbound MPA trough concentrations were 0.24 [0.03–2.9] and 0.005 [0–0.034] mcg/mL, respectively, with 8 hour dosing. MPA troughs were not good surrogates for overall exposure (AUC)0-8,[r2≤0.55]. MPA exposures did not change significantly between weeks 1 and 2 (p≤0.51), although several patients had an increase or decrease in AUC by 50% or more. SCr, CrCl, bilirubin, age, weight and albumin were poorly correlated with MPA AUC0-8 (all r2<0.40). Twenty % of the AUC’s achieved a total MPA target previously associated with better donor chimerism and 54% met the unbound MPA targets associated with reduced acute GVHD risk in adults undergoing nonmyeloablative transplant. These data suggest that 15 mg/kg every 8 hours may be too low. However, whether these targets are relevant in the pediatric myeloablative setting is not known. MMF given 15 mg/kg every 8 hours intravenously in our patients achieved an exposure similar to that previously observed in adult nonmyeloablative HCT recipients receiving 1gm every 12 hours intravenously. MPA exposure in pediatric HCT recipients is lower than pediatric organ transplant recipients despite receiving a 33% higher dose. Children undergoing HCT should receive an MMF dose of at least 15 mg/kg intravenously every 8 hours to achieve systemic concentrations near those proposed to be therapeutic in the adult HCT population. The optimal MPA exposure target, particularly the upper limit of safety, in children undergoing myeloablative HCT has yet to be determined.

scholarly journals Management of Herpesvirus Infections in Hematopoietic Cell Transplant Recipients

2021 ◽  
Vol 2 (1) ◽  
pp. 8-21
Author(s):  
Jan Styczynski
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cellular Therapy ◽  
Hematopoietic Cell ◽  
Host Cells ◽  
Preventive Strategy ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Screening Assay ◽  
Specific Level

Following primary infection, herpesviruses establish latency in infected individuals in the host cells and may reactivate upon external stimuli and during periods of immunosuppression. The objective of this paper was to the present current strategies on preventive and therapeutic management of infections with herpesviruses in recipients of hematopoietic cell transplantation. Strategies of antiviral management include prophylaxis, pre-emptive treatment and targeted treatment. Empirical therapy is not used in antiviral strategies. Prophylaxis can be done at universal (preventive strategy) and specific level. Universal prophylaxis includes non-pharmacologic methods of prevention of infection or reactivation. Risk-adapted specific prophylaxis includes use of specific antivirals or cellular therapy or other specific methods in order to prevent specific infection, in high-risk groups. Pre-emptive therapy means use of therapeutic approaches in asymptomatic infection, detected by a screening assay. Targeted therapy is used in established specific viral end-organ infections. The following sections of the paper refer to prophylaxis and treatment strategies, respectively, against CMV, EBV, HSV, VZV, HHV-6, HHV-7, and HHV-8 after allogeneic hematopoietic cell transplantation.

scholarly journals The Hematopoietic Cell Transplant Comorbidity Index predicts survival after allogeneic transplant for nonmalignant diseases

Blood ◽  
2019 ◽  
Vol 133 (7) ◽  
pp. 754-762 ◽  
Author(s):  
Monica S. Thakar ◽  
Larisa Broglie ◽  
Brent Logan ◽  
Andrew Artz ◽  
Nancy Bunin ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Cox Regression ◽  
Bone Marrow Failure ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Research Database ◽  
Hematopoietic Cell Transplant ◽  
Risk Of Death ◽  
Increased Risk ◽  
Comorbidity Index

Abstract Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases.

scholarly journals Invasive mold infections in allogeneic hematopoietic cell transplant recipients in 2020: have we made enough progress?

2021 ◽  
Author(s):  
Romain Samuel Roth ◽  
Stavroula Masouridi-Levrat ◽  
Yves Chalandon ◽  
Anne-Claire Mamez ◽  
Federica Giannotti ◽  
...  
Keyword(s):  
Risk Factors ◽  
Treatment Strategies ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Incidence Risk ◽  
One Year ◽  
Invasive Mold Infections

Abstract Background Despite progress in diagnostic, prevention and treatment strategies, invasive mold infections (IMI) remain leading cause of mortality in allogeneic hematopoietic cell transplant recipients (allo-HCT-recipients). Methods We describe the incidence, risk factors, and mortality of allo-HCT-recipients with proven/probable IMI in a retrospective single-center 10-year (01.01.2010-01.01.2020) cohort study. Results Among 515 allo-HCT-recipients, 48 (9.3%) patients developed 51 proven/probable IMI: invasive aspergillosis (IA; 34/51, 67%), mucormycosis (9/51, 18%) and other molds (8/51, 15%). Overall 35/51 (68.6%) breakthrough-IMI (bIMI) were identified: 22/35 (62.8%) IA and 13/35 (37.1%) non-IA IMI. One-year IMI cumulative incidence was 7%: 4.9% and 2.1% for IA and non-IA IMI, respectively. Fourteen (29.2 %), 10 (20.8%), and 24 (50.0%) patients were diagnosed during the first 30, 31-180, and &gt;180 days post-HCT, respectively. Risk factors for IMI included: prior allo-HCT (SHR:4.06, p=0.004) and ≥grade-2 acute graft-versus-host disease (aGvHD; SHR: 3.52, p&lt;0.001). All-cause 1-year mortality was 33% (170/515): 48% (23/48) and 31.5% (147/467) for patients with and without IMI (p=0.02). Mortality predictors included: disease relapse (HR:7.47, p&lt;0.001), aGvHD (HR:1.51, p=0.001), CMV-serology-positive recipients (HR:1.47, p=0.03), and IMI (HR:3.94, p&lt;0.001). All-cause 12-week mortality for patients with IMI was 35.4% (17/48): 31.3% (10/32) for IA and 43.8% (7/16) for non-IA IMI (logrank 0.47). At 1-year post-IMI diagnosis, 70.8% (34/48) of patients were dead. Conclusions IA mortality has remained relatively unchanged during the last two decades. More than two thirds of allo-HCT-recipients with IMI die by 1-year post-IMI diagnosis. Dedicated intensified research efforts are required to further improve clinical outcomes.

Donor T Cells from B Cell Deficient Mice Inhibit B Cell Development in Normal Recipients after Hematopoietic Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3265-3265
Author(s):  
Antonia M.S. Mueller ◽  
Jessica A. Allen ◽  
David Miklos ◽  
Judith A. Shizuru
Keyword(s):  
T Cells ◽  
B Cell ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Hematopoietic Stem ◽  
Donor Chimerism ◽  
Donor T Cells ◽  
The Impact

Abstract Allogeneic hematopoietic cell transplant (HCT) recipients often exhibit B cell (BC) lymphopenia due, in part, to graft-versus-host-disease (GVHD). Here, we studied the impact of donor T cells (TC) on BC deficiency post minor antigen-mismatched HCT. Following lethal irradiation, BALB.B mice were given FACS purified hematopoietic stem cells (HSC: cKIT+Thy1.1loLin-Sca-1+) alone, with whole splenocytes (SP), CD4 or CD8 TC from minor antigen-mismatched C57BL/6 (B6) mice. Chimerism analyses were performed on day (d) 30, 60, and 90. When pure HSC were transplanted, BCs reconstituted promptly (median 33% of lymphocytes [d30]; 61% [d60]; 74% [d90]), whereas TC engraftment was retarded and did not achieve full donor chimerism. Addition of SP or CD4 TCs, or to a lesser degree CD8 TCs, delayed BC reconstitution, with extremely low percentages of BCs beyond d60. This BC suppression correlated with the degree of acute GVHD, and BC numbers increased with recovery from GVHD. Additionally, this BC suppression was in stark contrast to TC development, with TC transfer resulting in early conversion to full donor chimerism. To test if previous events in the donor sensitize TCs against BC features (e.g. minor antigens), thereby promoting anti-BC cytotoxicity post-HCT, TCs from B6 muMT mice were co-transplanted with HSC. muMT mice are devoid of mature BCs because they lack the mu chain; consequently, their TCs were not exposed to BCs prior to transfer. Remarkably, BC engraftment was completely prevented through d90. TCs regenerated faster, but the vast majority originated from spleen and not HSC. To differentiate this lack of BC engraftment from GVHD-associated, alloreactive BC lymphopenia, syngenic B6 recipients were used. Again, initially complete blockade of BC engraftment was observed, although this suppression was overcome earlier post-HCT as compared to the minor-mismatched pair (median % BC d60: ’HSC only’ recipients 52%; +CD4 17%; +CD8 48%). To clarify if this phenomenon was a purely cytotoxic reaction of muMT TC against BCs, we used WT B6 HSC +/− SP as donors and lethally or sublethally irradiated muMT mice as recipients. All groups, including sublethally irradiated animals, where host muMT TC were still present, engrafted BCs making a direct anti-BC cytotoxicity unlikely as the sole cause of the BC inhibition. FACS analysis of bone marrow was used to assess the developmental stages of BCs (Hardy fractions (Fr.) A-F) and revealed GVHD recipients with peripheral B lymphopenia have a shift of B220+ cells from more mature Fr. D-F to immature Fr. A-C stages and a lower proportion of IgM expressing BC. Recipients of the muMT TCs showed, in addition to a shift to more immature stages, a clear block in BC development with an absent switch to the expression of IgM (stage D to E)(Fig. 1). In conclusion, muMT TCs are capable of blocking BC maturation when transferred into WT mice, suggesting defective TC activity in muMT animals necessary for the co-development of both BCs and TCs. Furthermore, this study provides evidence that mature TCs are capable of interfering with BC regeneration post-HCT. Hence, our HCT combinations using WT and muMT B6 mice provide a powerful tool to study the role of TC function in the process of donor BC development post-HCT.

Spiritual/religious struggle in hematopoietic cell transplant survivors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9573-9573
Author(s):  
Stephen Duane Watkins King ◽  
George Fitchett ◽  
Kenneth I. Pargament ◽  
Do Peterson ◽  
David A. Harrison ◽  
...  
Keyword(s):  
Religious Coping ◽  
Hematopoietic Cell Transplantation ◽  
Religious Affiliation ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Variable Model ◽  
Adult Age ◽  
Disease Information ◽  
Negative Religious Coping

9573 Background: Spiritual/religious (SR) struggle (e.g., feeling abandoned or punished by God) has been associated with poorer coping and quality of life (QOL), greater depression and pain, and health declines in general cancer populations. Few studies have been conducted among survivors of hematopoietic cell transplantation (HCT). This study examined the prevalence and predictors of SR struggle in HCT survivors. Methods: Data were collected as part of an annual questionnaire of adult (age >18 years) survivors of HCT at Fred Hutchinson Cancer Research Center in Seattle, WA. The 2011 survey included a SR module that incorporated the following items: Negative Religious Coping subscale of Brief RCOPE, subscales from the McGill QOL Questionnaire and the SF-36, Patient Health Questionnaire-8, disease information and socio-demographics. SR struggle was defined as any non-zero response on the Negative Religious Coping subscale of the Brief RCOPE. A multi-variable logistic regression model was used to determine factors associated with SR struggle. Results: Of 2113 returned surveys (52% response rate), 83% returned the SR module (n=1745) and of those 1586 were included in this analysis. Subjects were 49% female; 67% Christian and 20% Agnostic/Atheist/No preference; and 91% white. Mean age was 55 years; survivors ranged from 6 months to 40 years post-transplant. Primary indications for transplant were leukemia (49%), lymphoma (20%), and multiple myeloma (15%). Twenty-eight percent indicated SR struggle. In a multi-variable model, SR struggle showed statistically significant associations with age >=65 years (odds ratio [OR] .57, p=.02); patient report of being religious only (OR 3.5, p<.001) or spiritual only (OR 1.8, p<.001) compared to being both religious and spiritual; depression (OR 1.1, p<.001); and better social support (OR 0.77, p<.001). Time since HCT, religious affiliation and race/ethnicity did not show statistically significant associations with SR struggle. Conclusions: SR struggle is common among HCT survivors, even years after HCT.Further study is needed to determine causal relations, longitudinal trajectory, impact of struggle intensity, and effects of SR struggle on health, mood and social roles for HCT survivors.

scholarly journals Steroid-dependent acute GVHD after allogeneic hematopoietic cell transplantation: risk factors and clinical outcomes

2021 ◽  
Vol 5 (5) ◽  
pp. 1352-1359
Author(s):  
Najla El Jurdi ◽  
Ahmad Rayes ◽  
Margaret L. MacMillan ◽  
Shernan G. Holtan ◽  
Todd E. DeFor ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Steroid Dependent ◽  
Steroid Sensitive

Abstract Acute graft-versus-host disease (aGVHD) has various risk factors and outcomes. We defined distinct aGVHD treatment response groups based on response to first-line corticosteroids: steroid sensitive (SS), steroid resistant (SR), and the rarely studied steroid dependent (SD) aGVHD. In 1143 consecutive adult and pediatric allogeneic hematopoietic cell transplant recipients, 385 (34%) developed aGVHD, with 10% having SS aGVHD, 9% SD aGVHD, and 14% SR aGVHD. The only factor significantly associated with SD in comparison with SS was older age (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.4-11.3, when comparing 18- to 60-year-olds with &lt;18-year-olds). Factors significantly associated with SR in comparison with SS were unrelated donor (OR, 3.0; 95% CI, 1.2-7.4) and Minnesota high-risk aGVHD (OR, 2.4; 95% CI, 1.3-4.6). SR aGVHD was independently associated with higher risk for 2-year overall mortality (hazards ratio [HR], 1.8; 95% CI, 1.2-2.8) and nonrelapse mortality (NRM; HR, 2.1; 95% CI, 1.2-3.9). SS and SD GVHD groups had similar overall survival and NRM. The cumulative incidence of chronic GVHD was highest in the SD group, followed by the SR and SS groups (46%, 41%, and 29%, respectively). SD and SS GVHD had similar prognoses, both markedly better than those of the SR groups.

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