(A) Cumulative incidence of LFI in adults based on history of GVHD.

(A) Cumulative incidence of LFI in adults based on history of GVHD.

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Background: We analyzed late fatal infections (LFI) in allogeneic stem cell transplant (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. Methods: We analyzed the incidence, infection types and risk factors contributing to LFI in 10336 adult and 5088 pediatric subjects surviving ≥2 years after first H...

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Context 1
... a higher cumulative incidence of LFI (P < .0001) compared with patients without any reported GVHD (Table 3 and Figure 2A). In contrast, there was no statistically significant increased risk of LFI in patients with aGVHD (HR, 1.09; P = .7310) ...
Context 2
... significantly associated with a significantly increased risk of LFI (Table 4) and a higher cumulative incidence of LFI (P < .001) ( Figure 2B). Karnofsky/Lansky Performance Score, race and ethnicity, sex, previous autologous HCT, preexisting fungal infections, HIV seropositivity, CIBMTR Disease Risk Index, time from diagnosis to HCT, conditioning regimen intensity, graft source, use of TBI, use of ATG or alemtuzumab before HCT, donor/recipient CMV serostatus, geographic region, and year of HCT were factors that did not increase the risk of LFI. ...

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Citations

... Transplant strategies and supportive care advances have significantly improved survival rates for transplant and cellular therapy (TCT) patients in recent decades [1][2][3] . However, survivors continue to experience acute and chronic health conditions that impact their physical health, quality of life, and mental well-being [4][5][6][7] . Despite the growing use of TCT, substantial variations in practice remain across centers. ...
... Hammouda et al., results in immunosuppression; 2) post-transplant, patients receive immunosuppressive drugs to prevent graft-versus-host disease (GVHD) [5,6] , which further weakens their immune system; 3) the preparative regimen for HSCT can damage mucosal barriers in the gastrointestinal tract, facilitating easier invasion by intestinal parasites [7] . These factors collectively heighten susceptibility to infections among HSCT recipients, necessitating cautious monitoring and preventive measures. ...
... Prior studies have shown that HCT recipients remain at a higher risk of infections compared to cancer survivors treated with non-HCT therapy and general population even beyond 2 years post-HCT [21], albeit, it is unclear how these risks have changed with improvements in supportive care and use of antimicrobial prophylaxis. Additionally, chronic GVHD and ongoing immune suppression are known risk factors for fatal infections [22]. On the contrary, from the studies focusing on childhood cancer survivors, it is also evident that extended school absences could significantly impact survivors' their academic attainment, their future employment opportunities, and become productive members of the society [23,24]. ...
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To understand transplant center recommendations on return-to-school timing and related support for hematopoietic cell transplant (HCT) survivors, we conducted a two-phase, cross-sectional, web-based survey: In Phase I, medical directors of pediatric HCT centers from the National Marrow Donor Program/ Be The Match Registry were asked regarding the availability of a return to school standardized operating procedure (SOP). In Phase II, HCT physician members of the Pediatric Transplantation and Cellular Therapy Consortium were approached to study inter-physician practice variability regarding return to school post-HCT, factors affecting their decision-making, and support provided by HCT centers for return to school. Out of 46 respondents in Phase I (55% response rate), 28 (61%) reported having a SOP. Wide variations in recommendations were noted in 12 received SOPs. In Phase II, 122 physicians (60 centers) responded (30.6% response rate). The majority (60%) recommended autologous HCT recipients return to school within 6 months post-HCT but 65% recommended allogeneic HCT recipients return to school after 6 months or once off immunosuppression. Our findings indicate a lack of consensus within and across HCT centers regarding recommended return to school timing and underscore need for a guideline to standardize this process to ensure patient safety and re-integration into school.
... Since continuation of immunosuppressive drugs might be associated with a higher risk of fatal infectious diseases after allo-HCT, the impact of PTCY on the discontinuation of these drugs might significantly affect long-term survival after allo-HCT. 22 As there was rather limited follow-up of surviving patients in this study, further research with longer follow-up is needed to clarify the impact of the PTCY dose on immune tolerance. ...
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Haploidentical haematopoietic cell transplantation (haplo‐HCT) using post‐transplant cyclophosphamide (PTCY) as graft‐versus‐host disease (GVHD) prophylaxis is the standard of care for various haematological malignancies. The original PTCY dose after haplo‐HCT was 100 mg/kg, but no dose‐finding studies have been performed to identify the optimal dose. We performed a retrospective analysis to compare standard‐dose PTCY (100 mg/kg) with reduced‐dose PTCY (80 mg/kg): 969 in the standard‐dose group and 538 in the reduced‐dose group. As there was a significant difference between the two groups regarding patient and transplant characteristics, we performed propensity score (PS) matching. After PS matching, 425 patients in each group were included. The probabilities of 2‐year OS were 55.9% in the standard‐dose group and 47.0% in the reduced‐dose group (p = 0.36). The cumulative incidences of 2‐year non‐relapse mortality were 21.3% in the standard‐dose group and 20.5% in the reduced‐dose group (p = 0.55). There was no significant difference in the incidence of acute (grade II–IV 29.2% [95% CI, 24.9–33.6] vs. 25.3% [95% CI, 21.3–29.6]; grade III–IV 7.3% [95% CI, 5.1–10.0] vs. 6.6% [95% CI, 4.5–9.3]) or chronic GVHD. In conclusion, reduced‐ and standard‐dose PTCY were comparable in terms of major clinical outcomes.
... 21 Additionally, chronic GVHD and ongoing immune suppression are known risk factors for fatal infections. 22 However, it is unclear how these risks have changed with improvements in supportive care and use of antimicrobial prophylaxis. It is also unclear whether the risks of these infections outweigh the bene t of attending in-person school. ...
Preprint
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... Recently published studies analyzing aspects of late posttransplant mortality showed a decrease over the last three decades in late mortality in patients after allogeneic HCT during childhood [2], and also a significant role of fatal infections in late phase, contributing to one-third of all deaths in this phase [3]. ...
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We previously analyzed trends in incidence and factors associated with lethal complications in ALL/AML/CML patients (causes of deaths; COD-1 study). The objective of this study was the analysis of incidence and specific causes of death after HCT, with focus on infectious deaths in two time periods, 1980–2001 (cohort-1) and 2002–2015 (cohort-2). All patients with HCT for lymphoma, plasma cell disorders, chronic leukemia (except CML), myelodysplastic/myeloproliferative disorders, registered in the EBMT-ProMISe-database were included (n = 232,618) (COD-2 study). Results were compared to those in the ALL/AML/CML COD-1 study. Mortality from bacterial, viral, fungal, and parasitic infections decreased in very early, early and intermediate phases. In the late phase, mortality from bacterial infections increased, while mortality from fungal, viral, or unknown infectious etiology did not change. This pattern was similar for allo- and auto-HCT in COD-1 and COD-2 studies, with a distinct and constant lower incidence of all types of infections at all phases, after auto-HCT. In conclusion, infections were the main cause of death before day +100, followed by relapse. Mortality from infectious deaths significantly decreased, except late phase. Post-transplant mortality has significantly decreased in all phases, from all causes after auto-HCT; it has decreased in all phases after allo-HCT except late phase.
... 6 Traditionally, therapeutic agents for GVHD have consisted of additional broad systemic immunosuppression, which have been associated with less than satisfactory response rates and resulted in an increased risk for opportunistic infection. 7 Following preclinical investigations which further elucidated the pathophysiological mechanisms of both acute and chronic GVHD, the therapeutic landscape has shifted toward to the use of targeted agents with the hope of achieving improved clinical responses with less off-target effects. [8][9][10] Since 2017, there have been 4 approvals by the US Food and Drug Administration (FDA) for GVHD: ruxolitinib (acute and chronic GVHD), ibrutinib (chronic GVHD), and belumosudil (chronic GVHD) ( Table 1). ...
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... The prolonged use of immunosuppressants in cGvHD is common (with only 18% of patients being off immunosuppressive therapy after 2 years in a combined paediatric/adult study) and is associated with an increased incidence of infection and mortality (238). cGvHD is a risk factor for bacterial, fungal and viral infections (239)(240)(241) and increased TRM (240,242). 7 | Summary of recommended approaches for the taper of immunosuppressive agents used in the treatment of cGvHD (review of recent literature). ...
... The prolonged use of immunosuppressants in cGvHD is common (with only 18% of patients being off immunosuppressive therapy after 2 years in a combined paediatric/adult study) and is associated with an increased incidence of infection and mortality (238). cGvHD is a risk factor for bacterial, fungal and viral infections (239)(240)(241) and increased TRM (240,242). 7 | Summary of recommended approaches for the taper of immunosuppressive agents used in the treatment of cGvHD (review of recent literature). ...
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... The interplay between infection and cGvHD may be mutual: antigenaemia and an inflammatory environment stimulate the development or exacerbation of cGvHD, while immunodeficiency related to cGVHD itself and its treatment favour reactivation and infection (31,32). We assume that the immunomodulatory effect of ECP as treatment pre and post SARS-CoV-2 infection (together with prednisone) may have allowed the development of immune tolerance with sustained control of severe cGvHD without further risk of infection or ALL relapse (33). Foss et al. reported a case of attenuated SARS-CoV-2 infection in a patient with severe cGvHD treated with ruxolitinib and ECP (34). ...
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Graft-vs. -host disease (GvHD) is a serious and complex immunological complication of haematopoietic stem cell transplantation (HSCT) and is associated with prolonged immunodeficiency and non-relapse mortality. Standard treatment of chronic GvHD comprises steroids in combination with other immunosuppressive agents. Extracorporeal photopheresis (ECP), with its immunomodulatory mechanism, is applied as part of steroid-sparing regimens for chronic GvHD. Immunocompromised, chronically ill patients are at particular risk of severe disease courses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. T-cell immunity in SARS-CoV-2 infection is well-described but the role of the humoral immune responses is not fully understood. This case report describes a moderate course of SARS-CoV-2 infection in a patient <9 months after HSCT who was suffering from active, severe, chronic GvHD treated with prednisone and ECP. Following HSCT from a matched unrelated donor to cure acute lymphoblastic leukaemia, the 25-year-old male patient experienced multiple infectious complications associated with cytopenia, B-cell dyshomeostasis and autoantibody production followed by development of severe chronic GvHD thereafter at day +212. The steroid-sparing treatment plan consisted of supportive care, topical treatment, prednisone and ECP. He was diagnosed with SARS-CoV-2 infection at day +252, experiencing loss of smell and taste as well as a cough. The patient's oxygen saturation was between 94 and 97% on room air, and computed tomography images showed evolution of typical of SARS-CoV-2 infiltrates. In addition to cytopenia and immune dyshomeostasis, laboratory tests confirmed macrophage activating syndrome, transaminitis and Epstein-Barr virus viraemia. At that time, anti-SARS-CoV-2 monoclonal antibodies were not available in Austria and remdesivir seemed contraindicated. Surprisingly, despite severe lymphopenia the patient developed SARS-CoV-2-specific antibodies within 15 days, which was followed by clearance of SARS-CoV-2 and EBV with resolution of symptoms. Thereafter, parameters of immune dysregulation such as lymphopenia and B-cell dyshomeostasis, the latter characterised by elevated CD21 low B cells and autoantibody expression, normalised. Moreover, we observed complete response of active chronic GvHD to treatment.
... 7 Furthermore, the most common identified causes of death were related to cGVHD and infection, suggesting that cGVHD and its ongoing treatment are largely responsible for the sustained risk for death in this population. 23 Although the association between cGVHD and NRM has long been appreciated, this study provides further evaluation of cGVHDrelated factors and their association with NRM. Previous studies have identified patient-and transplantation-related factors associated with the development of cGVHD, such as patient age, donor type, graft source, and previous acute GVHD. ...
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Full-text available
Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for non-relapse mortality (NRM), we analyzed patient, transplant, and chronic GVHD-related variables, risk factors, and causes of non-relapse deaths in an updated cohort of 937 subjects enrolled on two prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (0.1 months - 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years and increased over time with a projected 40% (95%CI, 30-50) at 12 years. Centers reported that chronic GVHD (37.8%) was the commonest cause of NRM and was associated with organ failure, infection, or additional cause not otherwise specified. The next most frequent causes without mention of chronic GVHD were infection (17%) and respiratory failure (10%). In multivariate analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, NIH skin score 2-3, NIH lung score 1-3, worse modified HAP adjusted activity score, and decreased distance on walk test. In conclusion, chronic GVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung chronic GVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options are needed that do not predispose patients to infections.