Cognitive Functioning After Hematopoietic Cell Transplantation for Hematologic Malignancy: Results From a Prospective Longitudinal Study

2018 ◽  
Vol 36 (5) ◽  
pp. 463-475 ◽  
Author(s):  
Noha Sharafeldin ◽  
Alysia Bosworth ◽  
Sunita K. Patel ◽  
Yanjun Chen ◽  
Emily Morse ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Executive Function ◽  
Cognitive Functioning ◽  
Hematopoietic Cell Transplantation ◽  
Fine Motor ◽  
Healthy Controls ◽  
Allogeneic Hct ◽  
Motor Dexterity ◽  
Autologous Hct ◽  
Reduced Intensity

Purpose Cognitive impairment is well-recognized after myeloablative allogeneic hematopoietic cell transplantation (HCT). However, cognitive functioning after reduced-intensity allogeneic or autologous HCT remains unclear. Methods A total of 477 HCT recipients (236 autologous, 128 reduced-intensity allogeneic, 113 myeloablative allogeneic) underwent standardized neuropsychologic testing before HCT and at 6 months and 1, 2, and 3 years after HCT. Ninety-nine frequency-matched healthy controls underwent testing at commensurate time points. Primary outcomes of the study were practice effect–adjusted domain-specific T scores and global deficit scores. Piecewise generalized estimating equation models were used to compare groups and to identify associated variables and post-HCT trends of cognitive impairment. Results Median age was 52 years (range, 18 to 74 years) for HCT recipients and 55 years (range, 19 to 73 years) for controls. Post-HCT scores were comparable between controls and autologous and reduced-intensity HCT recipients. Myeloablative HCT recipients had significantly lower ( P < .001) post-HCT scores than controls for executive function, verbal speed, processing speed, auditory memory, and fine motor dexterity. Pre-HCT to 6 months post-HCT scores did not change after reduced-intensity HCT but declined significantly for fine motor dexterity ( P < .001) after myeloablative HCT. However, pre-HCT to 3 years post-HCT scores declined significantly ( P < .003) in reduced-intensity HCT recipients for executive function, verbal fluency, and working memory. Older age, male sex, and lower education, income, and cognitive reserve were associated with post-HCT cognitive impairment. At 3 years post-HCT, global cognitive impairment was present in 18.7% of autologous and 35.7% of allogeneic HCT recipients. Conclusion Myeloablative allogeneic HCT recipients showed significant cognitive decline compared with healthy controls. Reduced-intensity allogeneic HCT recipients showed evidence of delayed decline. Cognitive functioning in autologous HCT recipients generally was spared. The study identified vulnerable subpopulations that could benefit from targeted interventions.

Feasibility and Prognostic Value of VO2peak in Patients Undergoing Hematopoietic Cell Transplantation (HCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4152-4152
Author(s):  
William A Wood ◽  
Allison M Deal ◽  
Claudio L Battaglini ◽  
Bryce B Reeve ◽  
Amy P Abernethy ◽  
...  
Keyword(s):  
Gas Exchange ◽  
Physical Function ◽  
Cell Transplantation ◽  
Exercise Testing ◽  
Prognostic Value ◽  
Hematopoietic Cell Transplantation ◽  
Prognostic Models ◽  
Allogeneic Hct ◽  
Autologous Hct ◽  
Reduced Intensity

Abstract Abstract 4152 Background: Peak oxygen consumption (VO2peak, in mL/kg*min) is assessed by cardiopulmonary exercise testing (CPET) and reflects overall physical fitness. VO2peak has prognostic value in healthy and chronically ill patients, including patients with solid tumor malignancies. To our knowledge, direct measurement of peak oxygen uptake has not previously been examined in patients undergoing HCT, an area in which prognostic models are needed to understand and limit treatment-related toxicity. Current HCT prognostic models measure disease-related risk or indirectly measure patient fitness by assessing comorbidity burden. The purpose of this study was to evaluate the feasibility of assessing functional status in HCT patients by exercise testing and physiological measurements, and to investigate the potential prognostic usefulness of these variables in this population. Patients and methods: We evaluated the feasibility of assessing cardiopulmonary fitness (CPET with gas exchange on cycle ergometer), body composition (Dual Energy X-ray Absorptiometry-DEXA), and physical function (6 minute walk test-6MW) in 32 patients undergoing planned HCT (10 autologous HCT patients, 11 myeloablative allogeneic HCT patients, 11 reduced intensity allogeneic HCT patients). Tests were conducted prior to receipt of conditioning chemotherapy and again at 100 days following stem cell infusion (D+100). Feasibility was determined by the ability of patients to successfully and safely complete a full set of tests. Exploratory analyses to investigate the relationships of variables with one another and with survival utilized Kruskal-Wallis and Wilcoxon Signed Rank tests, Pearson Correlation coefficients, and Cox regression analyses. Median age of the sample was 55 years (range 18–70). Sixteen patients (50%) were female. Most autologous HCT patients had myeloma (N=8, 80%) and most allogeneic HCT patients had acute leukemia (16, 72%); other diagnoses included NHL (4), CML, MDS and AA. Twenty-six patients (84%) had intermediate or late stage disease, and 16 patients (50%) had a Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score of > 3. Results: VO2peak testing was successfully completed prior to HCT in 29 (91%) patients with no adverse events during testing. Two patients had lower limb limitations preventing participation in cycle ergometry, and one patient had baseline EKG abnormalities with exclusion per clinician discretion. No significant differences in median VO2peak were observed at baseline among patients undergoing autologous, myeloablative allogeneic, and reduced intensity allogeneic HCT (20.1 (15.20–28.0), 20.8 (9.2–35.4), and 23.8 (10.8–28.7) mL/kg*min respectively, p=0.9). Across cohorts, eight (28%) patients had a VO2peak <16ml/kg*min, which has been shown in other studies to be associated with lack of functional independence. Physical function assessed via 6MW at baseline was not significantly different between groups (448 (305–590), 480 (320–690), and 493 (313–600) meters respectively, p=0.44). Baseline VO2peak was correlated with 6MW (r=0.65, p<0.001) but not with age, HCT-CI, or other baseline variables. D+100 testing was completed in 14 (44%) patients, with significant post-HCT changes observed in median total mass (−2056g, p=0.01) and median lean mass (−1601g, p=0.01) among these 14 patients. With a median follow-up of 9 months, 24 (75%) patients were alive. When including all patients, a baseline VO2peak of > 16 mg/kg*min was associated with a lower risk for mortality after transplant (HR 0.11 (0.02–0.59), p<0.01). No associations between age (p=0.30), HCT-CI (p=0.17), or EBMT risk score (p=0.17) with post-HCT mortality were observed. The association of 6MW with post-HCT mortality approached significance (p=0.09). Conclusions: Baseline comprehensive functional and exercise testing that includes CPET with gas exchange is feasible in patients undergoing HCT, including older patients with comorbid illness and advanced disease. The feasibility and potential prognostic usefulness of D+100 testing were limited by post-HCT morbidity and logistical concerns, though data from patients undergoing testing showed significant attrition in muscle mass. Baseline VO2peak reflects underlying physiological fitness and may be a novel prognostic marker in patients undergoing HCT. Larger studies are warranted to confirm this finding. Disclosures: No relevant conflicts of interest to declare.

Single Nucleotide Polymorphisms (SNPs) Associated with Cognitive Impairment in Patients Treated with Hematopoietic Cell Transplantation (HCT): A Longitudinal Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 824-824 ◽  
Author(s):  
Noha Sharafeldin ◽  
Alysia Bosworth ◽  
Yanjun Chen ◽  
Sunita K Patel ◽  
Purnima Singh ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cognitive Impairment ◽  
Cognitive Functioning ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
P Value ◽  
Allogeneic Hct ◽  
Blood Brain ◽  
Telomere Homeostasis ◽  
Autologous Hct

Abstract Purpose: Pre-HCT, HCT-related, and post-HCT therapeutic exposures place HCT recipients at risk for cognitive impairment, albeit with significant inter-individual variability in the risk, suggesting a role for genetic susceptibility. We hypothesized that the following mechanisms could impact cognitive functioning: impaired capacity to effectively pump genotoxic agents out of the cell, maintain telomere homeostasis, repair damaged DNA, in addition to reduced neural repair capacity and neurotransmitter activity. Methods: We established a prospective longitudinal cohort of patients with hematologic malignancies receiving HCT at a single institution. Comprehensive assessment of 8 domains of cognitive functioning (executive function; processing speed; working memory; auditory memory; visual memory; verbal speed; verbal fluency; and fine motor dexterity) using a battery of 14 standardized tests was performed at predefined time-points: pre-HCT, 6m, 1y, 2y, and 3y post-HCT. Intelligence quotient (IQ) was assessed pre-HCT as a measure of cognitive reserve. Demographic variables (age, sex, race, education, and income) were self-reported and clinical variables (primary diagnosis, conditioning regimen, type of HCT, risk of relapse at HCT, and remission status post-HCT) were abstracted from patient medical records. Blood or saliva for DNA were obtained pre-HCT. We used the Global Deficit Score (GDS), a widely accepted summary score of cognitive impairment, to represent the overall neuropsychological performance. (Carey et al. 2004; Blackstone et al. 2012) GDS ≥0.50 was used to indicate cognitive impairment - a cutoff previously shown to yield an optimal balance between sensitivity and specificity in classifying impairment. Generalized estimating equation models were fitted to test the association of each individual SNP with GDS, adjusting for time of neurocognitive testing, age at HCT, sex, race, pre-HCT IQ, and HCT type. Genetic association analysis involved 985 carefully-curated SNPs in 68 candidate genes. The number of independent tests was 326 (excluding SNPs in Linkage Disequilibrium) yielding an overall p-value threshold of 1.5 x 10-4using Bonferroni correction for multiple testing. Results: The study cohort included 277 patients (58.5% males; 68.6% non-Hispanic whites; median age at HCT: 51.6y, range: 19-73); 148 (53.4%) received an autologous HCT and 129 (46.6%) allogeneic HCT (41.9% matched related and 58.1% matched unrelated). Most common primary diagnoses were non-Hodgkin lymphoma (42.6%) and multiple myeloma (36.5%) in autologous HCT recipients, and acute myeloid leukemia (54.3%) in allogeneic HCT recipients. Factors significantly associated with higher risk of cognitive impairment included: age at HCT ≥50 years (odds ratio (OR)=2.85, 95% CI, 1.3-6.1, p=0.007), male gender (OR=2.62, 95%CI, 1.3-5.1, p=0.005), race other than non-Hispanic white (OR=2.83, 95%CI, 1.4-5.9, p=0.005), and pre-HCT IQ ≤ median (OR=6.58, 95%CI, 3.2-13.3, p<0.0001). Four SNPs were significantly associated with cognitive impairment: rs11837182(OR=4.2, 95%CI, 2.1-8.5, p=4.2 x 10-5) on SLCO1A2 (blood brain barrier);rs330792 (OR=9.2, 95%CI, 4.0-21.1, p=1.2 x 10-7) on MSH6 (DNA repair), rs4725015 (OR=10.7, 95%CI, 4.9-23.5, p=3.6 x 10-9) on RPA3 (DNA repair), and rs16900343 (OR=4.2, 95%CI, 2.0-8.9, p=1.3 x 10-4) on XRCC4 (DNA repair). We also conducted mechanism-specific analyses using the Bonferroni-corrected p-value threshold for each mechanism of cognitive impairment, based on the number of independent SNPs associated with each mechanism. Four additional associations were found to be statistically significant: rs4148734 (OR=6.1, 95%CI, 2.3-16.5, p=3.1 x 10-4) and rs10259849 (OR=6.1, 95%CI, 2.3-16.4, p=3.1 x 10-4) on ABCB1 (blood brain barrier, p-value threshold=1.04 x 10-3), and rs718742 (OR=3.7, 95%CI,1.8-7.7, p=4.3 x 10-4) and rs17152302 (OR=4.0, 95%CI, 1.8-8.6, p=4.1 x 10-4) on PINX1 (telomere homeostasis, p-value threshold=8.7 x 10-4). Conclusion: Our findings provide preliminary evidence for the role of blood brain barrier transporters, telomere homeostasis and DNA repair in the pathogenesis of cognitive impairment after HCT. These findings may help identify HCT recipients at highest risk for cognitive impairment, thus facilitating targeted interventions. Disclosures No relevant conflicts of interest to declare.

Full-Intensity Transplantation and Short Telomeres Increase The Risk Of Cognitive Impairment After Allogeneic Hematopoietic Cell Transplantation (HCT) – Results Of a Prospective Longitudinal Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 913-913
Author(s):  
Alysia Bosworth ◽  
Yanjun Chen ◽  
Sunita K. Patel ◽  
Emily Blum ◽  
Can-Lan Sun ◽  
...  
Keyword(s):  
Working Memory ◽  
Cognitive Impairment ◽  
Executive Function ◽  
Cognitive Function ◽  
Processing Speed ◽  
Visual Memory ◽  
Reduced Intensity Conditioning ◽  
Motor Dexterity ◽  
Full Intensity ◽  
Reduced Intensity

Abstract Background Impaired cognition – an increasingly recognized concern after HCT – has significant potential to impact societal reintegration. Previous studies have focused on recipients of full-intensity allogeneic HCT; the trajectory of cognitive function after reduced-intensity HCT is unclear. Furthermore, the pathogenesis of cognitive impairment after HCT is unknown. Telomeres are repetitive DNA-protein structures localized to chromosome ends that protect chromosome integrity. Telomeric shortening occurs with each cell division; chemo/radiation hastens telomeric attrition. Glial cells are mitotic and susceptible to telomeric shortening. Constitutional telomere length using blood DNA is representative of the whole organism. Telomeric shortening (measured in blood) is associated with Alzheimer's disease severity. Shorter telomeres could play a role in cognitive impairment after HCT. Methods The longitudinal trajectory of cognitive function was assessed from pre-HCT (n=194), to 6m (n=165), 1y (n=155), 2y (n=125) post-HCT using standardized neuropsychological tests (14 tests assessing 8 domains: executive function, processing speed, verbal speed, verbal fluency, working memory, auditory memory, visual memory, fine motor dexterity). IQ was assessed to estimate cognitive reserve. Cognitive function was also assessed in age-, gender-matched healthy controls (HC: n=98) at corresponding time points. Generalized estimating equations (GEE) were fitted to transformed HC scores using time, IQ and sex as covariates; these were then used to compute fitted scores and residuals (fitted – observed scores) in HCT recipients, thus ensuring that HCT residuals were devoid of practice effects. Standardized HCT residuals were transformed to T-scores (mean=50 and SD=10) for GEE analysis. Blood germline DNA was procured pre-HCT (n=142) to assess relative telomere length (RTL: ratio of telomeres to single genes) using qPCR-based telomere assay. RTL was dichotomized as short vs. long (< vs. ≥ median). p≤0.01 was used as critical value to account for multiple comparisons. Results Median age at study was 49y for HCT recipients (range: 19-71) and 51y for HCs; primary diagnoses included acute leukemia (69%), lymphoma (14%) and others (17%). Reduced-intensity conditioning was used in 53% of HCT recipients. Myeloablative total body irradiation was used in 72% of full-intensity HCT recipients. Fifty-one percent of all HCT recipients developed chronic graft-versus-host disease. Compared with HCs, HCT recipients as a whole demonstrated lower cognitive function post-HCT in executive function, p=0.0008; processing speed, p=0.003; verbal fluency, p=0.003; motor dexterity, p=0.001. Multivariable longitudinal analysis of HCT recipients identified older age, male gender, Hispanic ethnicity, low education, income and cognitive reserve, high risk of relapse and high fatigue as significant contributors to cognitive impairment after HCT. After adjusting for these variables, cognitive function was worse in patients who received full-intensity HCT (compared with reduced-intensity) conditioning in executive functioning, p=0.01; processing speed, p=0.0005; verbal speed, p<0.0001; visual memory, p=0.002 (Fig 1). Importantly, there were no significant differences in cognitive functioning between reduced-intensity HCT recipients and HCs (p>0.1; Fig 1). Longitudinal multivariable analysis showed a significant association between short telomeres measured prior to HCT and post-HCT cognitive reduction in female HCT recipients for executive function, p=0.004; processing speed, p=0.009; verbal speed, p=0.009; and working memory, p=0.003 (Fig 2). Conclusions We demonstrate several new findings in this study: patients receiving full-intensity HCT are at risk for cognitive impairment in executive functioning, processing speed, verbal speed and visual memory; those receiving reduced-intensity HCT are generally spared. In addition, telomeric shortening prior to HCT is associated with poorer executive function, processing speed, verbal speed and working memory in females after HCT, and not males. Identifying vulnerable subpopulations will facilitate implementation of prevention strategies. Disclosures: No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation for Benign Hematological Disorders and Solid Tumors

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 372-397 ◽  
Author(s):  
Rainer F. Storb ◽  
Guido Lucarelli ◽  
Peter A. McSweeney ◽  
Richard W. Childs
Keyword(s):  
Autoimmune Diseases ◽  
Aplastic Anemia ◽  
Solid Tumors ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Family Members ◽  
Hematopoietic Cell ◽  
Allogeneic Hct ◽  
The Status ◽  
Autologous Hct

Abstract Allogeneic hematopoietic cell transplantation (HCT) has been successfully used as replacement therapy for patients with aplastic anemia and hemoglobinopathies. Both autologous and allogeneic HCT following high-dose chemotherapy can correct manifestations of autoimmune diseases. The impressive allogeneic graft-versus-tumor effects seen in patients given HCT for hematological malignancies have stimulated trials of allogeneic immunotherapy in patients with otherwise refractory metastatic solid tumors. This session will update the status of HCT in the treatment of benign hematological diseases and solid tumors. In Section I, Dr. Rainer Storb reviews the development of nonmyeloablative conditioning for patients with severe aplastic anemia who have HLA-matched family members. He also describes the results in patients with aplastic anemia given HCT from unrelated donors after failure of responding to immunosuppressive therapy. The importance of leuko-poor and in vitro irradiated blood product transfusions for avoiding graft rejection will be discussed. In Section II, Dr. Guido Lucarelli reviews the status of marrow transplantation for thalassemia major and updates results obtained in children with class I and class II severity of thalassemia. He also describes results of new protocols for class III patients and efforts to extend HCT to thalassemic patients without HLA-matched family members. In Section III, Dr. Peter McSweeney reviews the current status of HCT for severe autoimmune diseases. He summarizes the results of autologous HCT for systemic sclerosis, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, and reviews the status of planned Phase III studies for autologous HCT for these diseases in North America and Europe. He also discusses a possible role of allogeneic HCT in the treatment of these diseases. In Section IV, Dr. Richard Childs discusses the development and application of nonmyeloablative HCT as allogeneic immunotherapy for treatment-refractory solid tumors. He reviews the results of pilot clinical trials demonstrating graft-versus-solid tumor effects in a variety of metastatic cancers and describes efforts to characterize the immune cell populations mediating these effects, as well as newer methods to target the donor immune system to the tumor.

Results of Alemtuzumab-Based Reduced-Intensity Allogeneic Transplantation for Advanced Chronic Lymphocytic Leukemia: A BSBMT Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2899-2899
Author(s):  
Julio Delgado ◽  
Kirsty Thomson ◽  
Nigel Russell ◽  
Joanne Ewing ◽  
Wendy Stewart ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Fungal Infections ◽  
Progression Free Survival ◽  
Allogeneic Transplantation ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Autologous Hct ◽  
Reduced Intensity ◽  
Related Mortality

Abstract We report 41 consecutive patients with advanced chronic lymphocytic leukemia (CLL) who underwent allogeneic hematopoietic cell transplantation (HCT) following fludarabine, melphalan and alemtuzumab reduced intensity conditioning. Donors were 24 HLA-matched siblings and 17 unrelated volunteers (4 of them mismatched). Median age at transplant was 54 (range 37–67) years, interval from diagnosis to HCT was 54 (10–164) months, and number of previous chemotherapy regimens was 3 (1–6). Eleven patients were refractory to fludarabine at the time of transplant and 3 others (8%) had it stopped due to immune cytopenias. Eleven patients had failed autologous HCT. At the time of transplant, 7 patients (17%) had chemo-refractory and 34 (83%) chemo-sensitive disease, but only 5 (12%) were in complete remission. All but 3 patients had initial hematological recovery, but 5 more patients had delayed graft failure that responded to subsequent stem-cell infusions. Median intervals to neutrophil (&gt; 0.5 × 109/l) and platelet (&gt; 20 × 109/l) recovery were 14 (range 9–30) and 11 (range 8–45) days, respectively. Eleven patients (27%) relapsed and received escalated donor lymphocyte infusions, but only 3 of them had a sustained response. Acute and chronic graft-versus-host disease (GVHD) was observed in 17 (41%) and 13 (33%) patients, respectively. With a median follow-up of 15 (range 0.2–62) months, 17 patients have died, 5 of progressive disease and 12 of transplant-related complications. The 2-year overall survival, progression-free survival and transplant-related mortality are 51% (CI 33%–69%), 45% (27%–62%) and 26% (14%–46%), respectively (Figure 1). In multivariate analysis, fludarabine refractoriness prior to transplant was the only factor to predict a worse progression-free survival in this setting. In conclusion, the alemtuzumab-based regimen was feasible and effective in patients with CLL with a relatively low rate of GVHD. However, transplant-related mortality remains relatively high as a result of a variety of viral and fungal infections. Ongoing studies are aiming to address the efficacy of reduced doses of alemtuzumab in this group of very immunosupressed patients. Figure Figure

The Effect of In Vivo T-Cell Depletion with Alemtuzumab on Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3014-3014
Author(s):  
Julio Delgado ◽  
Srinivas Pillai ◽  
Reuben Benjamin ◽  
Dolores Caballero ◽  
Rodrigo Martino ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Lymphocytic Leukemia ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Mixed Chimerism ◽  
Allogeneic Hct ◽  
Reduced Intensity

Abstract Reduced-intensity allogeneic hematopoietic cell transplantation (HCT) is increasingly considered as a therapeutic option for young patients with advanced chronic lymphocytic leukemia (CLL). We report 59 consecutive CLL patients who underwent allogeneic HCT following fludarabine and melphalan conditioning at four different institutions. For graft-versus-host disease (GVHD) prophylaxis, 38 patients (Cohort 1) received alemtuzumab (20–100 mg) and cyclosporine; and 21 patients (Cohort 2) received cyclosporine plus methotrexate or mycophenolate. Donors were 47 HLA-matched siblings and 12 unrelated volunteers, 6 of whom were mismatched. Median age at transplant was 53 (range, 34–64) years and median number of previous chemotherapy regimens was 3 (1–6), with 39% of patients being refractory to fludarabine. Nine patients had previously failed an autologous HCT. Fluorescent in-situ hybridization and IgVH mutation status data were available in 33 (56%) and 31 (53%) patients, respectively, being unfavorable (17p- or 11q-) in 22 (67%) and unmutated in 24 (77%) of them. All but 1 patient engrafted, and the median interval to neutrophil recovery (> 0.5 × 109/l) was 14 (range, 10–36) days. Twenty patients (34%), mostly from Cohort 1, received escalated donor lymphocyte infusions due to mixed chimerism or disease relapse. The overall complete response rate among 53 patients with measurable disease at the time of transplantation was 70%, whereas 21% had stable disease. Grade II-IV acute GVHD was observed in 14 (37%) and 12 (57%) patients from Cohorts 1 and 2, respectively (P = 0.17). Extensive chronic GVHD was observed in 3 (8%) and 10 (48%) patients from Cohorts 1 and 2, respectively (P < 0.01). The incidence of cytomegalovirus reactivation was not significantly different between cohorts (67% vs 47%, P = 0.23). With a median follow-up of 36 (range, 3–99) months for survivors, 18 (30%) patients have died, 3 of progressive disease and 15 of transplant-related complications. The 3-year overall survival (OS), progression-free survival (PFS) and non-relapse mortality were 66% (95% CI 48–84%), 38% (20–56%) and 21% (8–34%), respectively, for Cohort 1 and 65% (44–86%), 54% (32–76%) and 29% (10–48%) for Cohort 2 (P = 0.66; P = 0.33; and P = 0.53). Despite low patient numbers, alemtuzumab seemed particularly effective for unrelated donor recipients, with a 3-year OS and PFS of 54% and 40% for Cohort 1; and 33% and 0% for Cohort 2 (P = 0.02 and P = 0.07). In conclusion, results with reduced-intensity allogeneic HCT are promising for these poor-prognosis patients. Furthermore, the alemtuzumab-based regimen was effective in reducing the chronic GVHD rate with no negative effect on NRM, PFS or OS.

scholarly journals Cognitive impairment from early to middle adulthood in patients with affective and nonaffective psychotic disorders

2019 ◽  
Vol 50 (1) ◽  
pp. 48-57 ◽  
Author(s):  
Josephine Mollon ◽  
Samuel R. Mathias ◽  
Emma E. M. Knowles ◽  
Amanda Rodrigue ◽  
Marinka M. G. Koenis ◽  
...  
Keyword(s):  
Working Memory ◽  
African American ◽  
Cognitive Impairment ◽  
Executive Function ◽  
Cognitive Functioning ◽  
Cognitive Ability ◽  
Processing Speed ◽  
Psychotic Disorders ◽  
General Cognitive Ability ◽  
Middle Adulthood

AbstractBackgroundCognitive impairment is a core feature of psychotic disorders, but the profile of impairment across adulthood, particularly in African-American populations, remains unclear.MethodsUsing cross-sectional data from a case–control study of African-American adults with affective (n = 59) and nonaffective (n = 68) psychotic disorders, we examined cognitive functioning between early and middle adulthood (ages 20–60) on measures of general cognitive ability, language, abstract reasoning, processing speed, executive function, verbal memory, and working memory.ResultsBoth affective and nonaffective psychosis patients showed substantial and widespread cognitive impairments. However, comparison of cognitive functioning between controls and psychosis groups throughout early (ages 20–40) and middle (ages 40–60) adulthood also revealed age-associated group differences. During early adulthood, the nonaffective psychosis group showed increasing impairments with age on measures of general cognitive ability and executive function, while the affective psychosis group showed increasing impairment on a measure of language ability. Impairments on other cognitive measures remained mostly stable, although decreasing impairments on measures of processing speed, memory and working memory were also observed.ConclusionsThese findings suggest similarities, but also differences in the profile of cognitive dysfunction in adults with affective and nonaffective psychotic disorders. Both affective and nonaffective patients showed substantial and relatively stable impairments across adulthood. The nonaffective group also showed increasing impairments with age in general and executive functions, and the affective group showed an increasing impairment in verbal functions, possibly suggesting different underlying etiopathogenic mechanisms.

Frequent genomic alterations in epithelium measured by microsatellite instability following allogeneic hematopoietic cell transplantation in humans

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3389-3396 ◽  
Author(s):  
Philipp Faber ◽  
Paul Fisch ◽  
Miguel Waterhouse ◽  
Annette Schmitt-Gräff ◽  
Hartmut Bertz ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Genomic Alterations ◽  
Graft Versus Host ◽  
Allogeneic Hct ◽  
Colonic Crypts ◽  
Autologous Hct

Abstract Although typically found in cancers, frameshift mutations in microsatellites have also been detected in chronically inflamed tissues. Allogeneic hematopoietic cell transplantation (HCT) may potentially produce chronic tissue stress through graft-versus-host reactions. We examined non-neoplastic epithelial tissues (colon, buccal) obtained 1 to 5061 days after human allogeneic HCT for the presence of genomic alterations at 3 tetranucleotide and 3 mononucleotide microsatellite loci. Novel bands indicative of microsatellite instability (MSI) at tetranucleotide repeats were detected in laser-microdissected colonic crypts and in buccal smears of 75% and 42% of patients who received an allograft, respectively. In contrast, no MSI was found in similar tissues from control subjects and from patients after intensive chemotherapy or in buccal cells from patients after autologous HCT. The MSI found in colon, which was often affected by graft-versus-host disease, was not due to loss of expression or nitrosylation of DNA repair proteins. MSI in clinically intact oral mucosa was more frequently found at later time points after HCT. MSI was also found in 3 posttransplant squamous cell cancers examined. Our data show that genomic alterations in epithelium regularly occur after allogeneic HCT and may be implicated in the evolution of posttransplantation diseases, including secondary cancer.

scholarly journals Measles Reactivity in Windsor Patients Post Autologous Versus Allogeneic Hematopoietic Cell Transplantation: A Retrospective Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-30
Author(s):  
Kayla Negus ◽  
Mohammad Jarrar ◽  
Indryas L. Woldie ◽  
Sindu M. Kanjeekal ◽  
Kit McCann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hematopoietic Cell Transplantation ◽  
Cellular Therapy ◽  
Immune Status ◽  
The United States ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Post Transplant ◽  
Allogeneic Hct ◽  
Autologous Hct

Background As the antivaccine movement has increased, vaccine preventable illnesses have also increased. The resurgence of measles globally has been noted, specifically the United States received 1200 new cases of measles in 2019, which is the highest number of cases since 1994. Measles is a highly contagious pathogen; the virus has an attack rate of up to 90% in susceptible individuals. Standard of care for patients post hematopoietic cell transplant (HCT) includes repeating all childhood vaccinations. However, compliance with recommendations is unknown. No previous reports have been created measuring the difference in measles, mumps, and rubella (MMR) reactivity between autologous and allogeneic HCT patients post treatment. Methods A retrospective chart review investigated HCT patients between 2000-2019 from the Windsor Regional Hospital (WRH) cancer centre. Patients were excluded from data collection if they were deceased before an MMR reactivity test could be done or if they were lost to follow up. A total of 83% of autologous HCT (N=57) and 66% of allogeneic HCT (N=47) patients had serology tested to measure MMR reactivity post-transplant prior to live vaccinations. MMR titres were drawn from autologous patients a median of 395 days after HCT and a median of 907 days after HCT for allogeneic patients. Results Overall, allogeneic HCT patients had more reactivity than autologous HCT patients as seen in Table 1. Conclusion All patients not reactive to measles need to be re-vaccinated 24 months after treatment according to 2019 American Society for Transplantation and Cellular Therapy guidelines. Our patients are treated in a variety of transplant centers in Ontario, Canada as well as Detroit, Michigan; which is of concern because measles cases have been reported in Detroit. The majority (66%) of allogeneic HCT patients had a myeloid malignancy, while 70% of autologous patients has a diagnosis of multiple myeloma. As evidenced by the poor MMR response, less robust immune systems may be accounted for by multiple myeloma patients. This does emphasize the need for MMR vaccinations post HCT for multiple myeloma patients and raises the question regarding immunization for at risk non-transplant eligible patients. We suggest that it may be reasonable to assess MMR immune status in all myeloma patients to determine if this is a transplant effect or an effect of the underlying immune status of the myeloma patient. This study does emphasize the need to assess MMR status post transplant in all myeloma patients, as the vast majority in our study did not demonstrate immunity post stem cell transplant. Figure Disclosures Hamm: Amgen: Consultancy.

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