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  • 1
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 9057-9060
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
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  • 2
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 14-15
    Abstract: Background: Long-term survivors of childhood Hodgkin lymphoma (HL) are at significant risk for cardiovascular, pulmonary, and endocrine morbidity in addition to subsequent cancers. Emerging evidence suggests that HL survivors may also experience persistent neurocognitive impairment, however the prevalence of neurocognitive impairment has not been well characterized. Further, little work has been done to examine how specific treatments or comorbidities are associated with these impairments. Methods: The current study included 1,760 survivors (52.0% female, mean[sd] 37.5 [6.0] years old, 23.6 [4.7] years from diagnosis) of childhood Hodgkin lymphoma and 3,180 sibling controls (54.5% female, 33.2 [8.5] years old) from the Childhood Cancer Survivor Study. Participants completed questionnaires assessing four domains of neurocognitive impairment (task efficiency, emotional regulation, organization, and memory). Impairment for each domain was defined as a score worse than the 90th percentile of community controls. Treatment exposures were abstracted from the medical record. Second malignancies (SMN) were self-reported and subsequently confirmed by pathology findings or medical record review. Chronic health conditions were self-reported and systematically graded according to the NCI CTCAE v4.3 (Grade 1 mild, Grade 2 moderate, Grade 3 severe/disabling, Grade 4 life-threatening). Generalized estimating equations were used to calculate risk of impairment in survivors compared with siblings adjusted for age, sex, and race. Among HL survivors, multivariable log-binomial regression was used to calculate risk of impairment associated with demographic, clinical, and treatment factors. Separate models examined risk associated with Grade 2+ chronic health conditions adjusted for age, sex, and race. Results: 10.8% of HL survivors reported impaired task efficiency (vs. 7.7% in siblings), 16.6% emotional regulation (vs. 11.5% in siblings), 12.1% organization (vs. 10.3% in siblings), and 8.1% memory (vs. 5.7% in siblings). Compared with siblings, survivors reported significantly higher risk of impairment in each of the four neurocognitive domains after adjusting for age, sex, and race (Table). Female survivors had elevated risk of impairment on emotional regulation (RR [95%CI] 1.4 [1.1,1.9)) and memory (2.0 [1.3,3.0] ). Compared with white survivors (91.8% of the population), non-white survivors had higher risk of impairment in task efficiency (2.1 [1.2, 3.5]) and emotional regulation (1.7 [1.0,2.7] ). Current smokers (12.3%) had higher risk of impairment in task efficiency (1.9 [1.2, 3.1]), emotional regulation (2.5 [1.7,3.7] ), and memory (1.7 [1.0,3.0]). Having a late-relapse ( & gt;5 years from diagnosis) or a second malignancy (20.0%) was associated with elevated risk of impairment in task efficiency (1.6 [1.06,2.3]). While not statistically si gnificant, anthracycline exposure (39.8%) was associated with higher risk of impairment in task efficiency (1.3 [0.7,2.2]) and memory (1.6 [0.9,3.0] ). No statistically significant associations were noted for bleomycin, corticosteroids, or chest radiation. HL survivors with pulmonary morbidity (8.5%) had a higher risk of impairment on task efficiency (1.9 [1.2,3.0]) compared to those without. Cardiovascular conditions (32.9%) were associated with elevated risk of impairment in all domains (RR range from 1.5 to 2.1, all p & lt;0.05, Table). Endocrine (54.3%) and neurologic conditions (6.6%) were associated with an increased risk of task efficiency, emotional regulation, and memory impairments (RR range from 1.4 to 5.5, all p & lt;0.05, Table). Conclusions: Survivors experienced significantly more neurocognitive impairment compared to sibling controls. Among survivors, potentially modifiable risk factors such as smoking and chronic health conditions were associated with neurocognitive impairment while treatment exposures showed little association. Mitigation or prevention of smoking and chronic health conditions may improve neurocognitive functioning in HL survivors Table Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 3
    In: Blood Journal, American Society of Hematology, ( 2023-07-21)
    Abstract: Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplant for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase I/II clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral (SIN-LV) vector expressing the human WAS cDNA under the control of a 1.6kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All subjects were alive and well with sustained multi-lineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections and bleeding diathesis was universal. Immune function was consistently improved despite sub-physiological levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity post-GT, despite similar percentages of WASp-expressing cells and gene marking as those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), IL-10 producing regulatory B cells (Bregs), and transitional B cells. Recovery of the Breg compartment, along with Tregs, thus appears to be protective against development of autoimmunity post-GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered with ClinicalTrials.gov (NCT01410825).
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 537-537
    Abstract: Damage to the gastrointestinal (GI) tract is a major complication of graft versus host disease (GVHD). IL-23 has been shown to be a proximate mediator of GVHD-induced pathology within the GI tract; but the donor immune cell populations that mediate the downstream effects of this cytokine and how IL-23-induced inflammation is regulated are not well understood. To define the functional significance of IL-23R expression on donor cells, we first employed antibody-based and genetic approaches to examine the effect of interruption of IL-23R signaling on GVHD severity. Lethally irradiated Balb/c (H-2d) mice transplanted with C57BL/6 (H-2b) BM and spleen cells, and then treated with an anti-IL-23R antibody had significantly prolonged survival compared to mice administered control antibody (70% versus 0% survival at 60 days, p 〈 0.001). Additionally, recipients reconstituted with IL-23R‾/‾ BM and spleen cells had increased survival and less pathological damage in the colon relative to mice transplanted with grafts from wild type B6 animals. Experiments performed to define the critical IL-23R-expressing population revealed that survival was significantly prolonged in animals transplanted with IL-23R‾/‾ T cells, whereas mortality was unaffected when IL-23R expression was present only on BM-derived cells indicating that IL-23R expression on T cells drove inflammation. Furthermore, transplantation with CD4+ T cells from IL-23R¯/¯ animals resulted in less mortality, demonstrating that the T cell-directed proinflammatory effects of IL-23 were mediated primarily by CD4+ IL-23R+ T cells. We observed that CD4+ IL-23R+ T cells could be identified in the colon of GVHD animals as early as five days post transplantation, and were present in significantly higher numbers when compared to syngeneic recipients. Unexpectedly, we discovered a population of donor-derived CD4+ T cells that expressed the β2 integrins, CD11b and CD11c, and determined that the highest percentage of IL-23R-expressing CD4+ T cells in the colon derived from cells that co-expressed these integrins. Experiments conducted to determine the functional significance of β2 integrin expression on CD4+ T cells revealed that animals transplanted with sorted CD4+ αb+ T cells that lacked expression of both CD11b and CD11c had a significantly reduced number of total donor-derived CD4+ and CD4+ IL-23R+ T cells in the colon, reduced pathological damage, and significantly prolonged survival from lethal GVHD. Furthermore, mice reconstituted with CD4+ IL-23R−/− T cells that expressed at least one β2 integrin had significantly greater survival than animals transplanted with CD4+ IL-23R+/+ T cells that had the same integrin profile, indicating that the pathogenicity of β2 integrin–expressing CD4+ T cells was dependent upon co-expression of the IL-23R. Since IL-10 has been shown to have a critical role in the maintenance of immune homeostasis within the colon and also signals through Stat3, we sought to define whether IL-10 was critical for the regulation of IL-23R-mediated inflammation. Using IL-10 reporter mice (10BiT.Foxp3EGFP) to delineate IL-10 expression in immune cell populations, we observed that thepreponderance of IL-10 in GVHD target tissues derived almost exclusively from donor non-Foxp3-expressing CD8+ T cells. The importance of IL-10 as a critical regulatory cytokine of IL-23R signaling was corroborated by the fact that transplantation with IL-10‾/‾ grafts augmented GVHD mortality, blockade of IL-23R signaling was ineffectual in the absence of donor-derived IL-10 production, and transplantation with CD4+ T cells from IL-23R‾/‾ IL-10‾/‾ animals abrogated the protection that was observed when animals were reconstituted with IL-23R‾/‾ T cells alone. Blockade of IL-23R signaling prolonged survival in the complete absence of functional CD4+ Tregs, indicating that, in contrast to IL-10, there was not an obligate requirement for CD4+ Tregs to observe a protective effect from IL-23R signaling inhibition. A role for IL-23/IL-23R signaling in humans was supported by studies demonstrating increased IL-23 and IL-23-dependent (IL-17A, IL-22, IL-17F, and Reg3γ) gene expression in the GI tract of patients with GVHD. In summary, these studies indicate that the coordinate expression of β2 integrins and the IL-23R in CD4+ T cells defines a novel, pathogenic T cell population that potently induces inflammation in the colon during GVHD. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 5
    In: Blood, American Society of Hematology, Vol. 139, No. 20 ( 2022-05-19), p. 3073-3086
    Abstract: Long-term survivors of childhood Hodgkin lymphoma (HL) experience a high burden of chronic health morbidities. Correlates of neurocognitive and psychosocial morbidity have not been well established. A total of 1760 survivors of HL (mean ± SD age, 37.5 ± 6.0 years; time since diagnosis, 23.6 ± 4.7 years; 52.1% female) and 3180 siblings (mean age, 33.2 ± 8.5 years; 54.5% female) completed cross-sectional surveys assessing neurocognitive function, emotional distress, quality of life, social attainment, smoking, and physical activity. Treatment exposures were abstracted from medical records. Chronic health conditions were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.3 (1 = mild, 2 = moderate, 3 = severe/disabling, and 4 = life-threatening). Multivariable analyses, adjusted for age, sex, and race, estimated relative risk (RR) of impairment in survivors vs siblings and, among survivors, risk of impairment associated with demographic, clinical, treatment, and grade 2 or higher chronic health conditions. Compared with siblings, survivors had significantly higher risk (all, P & lt; .05) of neurocognitive impairment (eg, memory, 8.1% vs 5.7%), anxiety (7.0% vs 5.4%), depression (9.1% vs 7%), unemployment (9.6% vs 4.4%), and impaired physical/mental quality of life (eg, physical function, 11.2% vs 3.0%). Smoking was associated with a higher risk of impairment in task efficiency (RR, 1.56; 95% confidence interval [CI] , 1.02-2.39), emotional regulation (RR, 1.84; 95% CI, 1.35-2.49), anxiety (RR, 2.43; 95% CI, 1.51-3.93), and depression (RR, 2.73; 95% CI, 1.85-4.04). Meeting the exercise guidelines of the Centers for Disease Control and Prevention was associated with a lower risk of impairment in task efficiency (RR, 0.70; 95% CI, 0.52-0.95), organization (RR, 0.60; 95% CI, 0.45-0.80), depression (RR, 0.66; 95% CI, 0.48-0.92), and multiple quality of life domains. Cardiovascular and neurologic conditions were associated with impairment in nearly all domains. Survivors of HL are at elevated risk for neurocognitive and psychosocial impairment, and risk is associated with modifiable factors that provide targets for interventions to improve long-term functional outcomes.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 715-715
    Abstract: Background: BMT is increasingly offered to older patients with HM. The high burden of comorbidity in older BMT survivors places them at a higher risk for chronic severe pain - an issue that has not been comprehensively evaluated. We used BMTSS to investigate the prevalence and predictors of chronic severe pain several years after BMT. We examined the impact of pain on physical performance and frailty and also examined the relation between chronic severe pain and use of prescription pain medications and opioids in this population. Methods: The cohort included 601 HM patients who had received a BMT at age ≥60y at one of 3 transplant centers between 1974 and 2014 and had survived ≥2y after BMT; 183 unaffected siblings also participated. Self-reported domains included sociodemographics, chronic GvHD, physical performance, frailty, and medication use. Clinical information obtained from institutional databases included primary HM diagnosis, donor source, and conditioning regimen. Study participants completed a detailed questionnaire that examined pain in the following 3 domains: moderate-to-severe bodily pain, prolonged pain, and moderate-to-extreme pain interference; these 3 domains were used to create a composite variable, wherein presence of ≥1 domain was indicative of "chronic severe pain". An adjusted multivariable logistic regression model for chronic severe pain was used to compare BMT survivors to siblings. Analyses restricted to BMT survivors were stratified by donor type. Results: Survey participation rates were 62.7% and 60%, for the BMT survivors and siblings, respectively. Median age at study participation was 69.8y (61-89) for BMT survivors and 68.9y (65-80) for siblings. Median time from BMT was 5.0y (2-17) for BMT survivors. Chronic severe pain: Overall, 39.4% of the BMT survivors reported chronic severe pain; multivariable analysis revealed a 2.5-fold greater odds of BMT survivors reporting chronic severe pain (95%CI, 1.7-3.8, p 〈 0.0001) when compared with siblings. Domain-specific prevalence and magnitude of risk of pain are shown in Fig 1. Among allogeneic BMT recipients, survivors with lower education ( 〈 high school: OR=5.2, 95%CI: 1.5-18.3, p=0.01; ref grp: 〉 college) and lower income ( 〈 $50k: OR=6.0, 95%CI, 1.7-20.8, p=0.005; $50k- 〈 $100k: OR=3.8, 95%CI, 1.3-11.4, p=0.02; ref group: ≥$100k) had higher odds of reporting chronic severe pain; presence of active chronic GvHD was associated with 2.3-fold higher odds, but did not reach statistical significance (p=0.1). Among autologous BMT recipients, lower income ( 〈 $50k: OR=2.2, 95%CI, 1.1-4.4, p=0.02) was associated with higher odds of reporting chronic severe pain. Pain and physical performance/frailty: Allogeneic and autologous BMT recipients with chronic severe pain were at a 2.7-fold (95%CI, 1.2-6.0, p=0.02) and 3.0-fold (95%CI, 1.9-4.9, p 〈 0.0001) higher odds of reporting impaired physical performance, respectively, when compared to those without pain. Allogeneic and autologous BMT recipients with chronic severe pain were at 8.2-fold (95%CI, 2.4-27.6, p=0.0007) and 7.5-fold (95%CI, 3.3-16.8, p 〈 0.0001) higher odds, respectively of having frailty when compared to those without pain. Use of prescription pain medications and opioids: Overall, 17.8% of BMT survivors reported using prescription pain medications, and 6.5% reported using opioids; those with chronic severe pain were at a 2.5-fold higher odds of using prescription pain meds (95%CI, 1.6-3.8, p 〈 0.0001) and at a 6.0-fold higher odds of using opioids (95%CI, 2.8-12.9, p 〈 0.0001), when compared with those without pain. Conclusions: Nearly 40% of older BMT survivors followed for a median of 5y after BMT, report chronic severe pain. BMT survivors are at a 2.5-fold higher odds of reporting chronic severe, life-interfering pain as compared with siblings. Chronic severe pain is associated with impaired physical performance and frailty. Finally, nearly 18% of long-term BMT survivors report use of prescription medications and 6.5% are using opioids. This study draws attention to the vulnerability of older BMT survivors and provides evidence for the need to develop effective strategies to address the underlying causes of pain. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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