ABSTRACT
Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Glycolipids/administration & dosage , Leukemia, Myeloid, Acute , Adult , Age Factors , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cytarabine/administration & dosage , Cytarabine/adverse effects , Disease-Free Survival , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Glycolipids/adverse effects , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mitoxantrone/administration & dosage , Mitoxantrone/adverse effects , Survival RateABSTRACT
The study of marrow-resident mesodermal progenitors can provide important insight into their role in influencing normal and aberrant hematopoiesis as occurs in acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). In addition, the chemokine competency of these cells provides links to the inflammatory milieu of the marrow microenvironment with additional implications for normal and malignant hematopoiesis. While in vivo studies have elucidated the structure and function of the marrow niche in murine genetic models, corollary human studies have not been feasible, and thus the use of culture-adapted mesodermal cells has provided insights into the role these rare endogenous niche cells play in physiologic, malignant, and inflammatory states. This review focuses on culture-adapted human mesenchymal stem/stromal cells (MSCs) as they have been utilized in understanding their influence in AML and MDS as well as on their chemokine-mediated responses to myeloid malignancies, injury, and inflammation. Such studies have intrinsic limitations but have provided mechanistic insights and clues regarding novel druggable targets.
Subject(s)
Leukemia, Myeloid, Acute , Mesenchymal Stem Cells , Myelodysplastic Syndromes , Humans , Animals , Mice , Bone Marrow/pathology , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Leukemia, Myeloid, Acute/genetics , Hematopoiesis , Tumor MicroenvironmentABSTRACT
Antibody responses to viral infections are sustained for decades by long-lived plasma cells (LLPCs). However, LLPCs have yet to be characterized in humans. Here we used CD19, CD38, and CD138 to identify four PC subsets in human bone marrow (BM). We found that the CD19(-)CD38(hi)CD138(+) subset was morphologically distinct, differentially expressed PC-associated genes, and exclusively contained PCs specific for viral antigens to which the subjects had not been exposed for more than 40 years. Protein sequences of measles- and mumps-specific circulating antibodies were encoded for by CD19(-)CD38(hi)CD138(+) PCs in the BM. Finally, we found that CD19(-)CD38(hi)CD138(+) PCs had a distinct RNA transcriptome signature and human immunoglobulin heavy chain (VH) repertoire that was relatively uncoupled from other BM PC subsets and probably represents the B cell response's "historical record" of antigenic exposure. Thus, our studies define human LLPCs and provide a mechanism for the life-long maintenance of anti-viral antibodies in the serum.
Subject(s)
Antibodies, Viral/immunology , Bone Marrow Cells/immunology , Measles virus/immunology , Mumps virus/immunology , Plasma Cells/immunology , ADP-ribosyl Cyclase 1/metabolism , Adult , Aged , Antibodies, Viral/blood , Antigens, CD19/metabolism , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Membrane Glycoproteins/metabolism , Middle Aged , RNA, Messenger/genetics , Syndecan-1/metabolism , Young AdultABSTRACT
Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.
Subject(s)
Acetamides/therapeutic use , Graft vs Host Disease/drug therapy , Protein Kinase Inhibitors/therapeutic use , Acetamides/administration & dosage , Acetamides/adverse effects , Adult , Aged , Female , Humans , Male , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Treatment Outcome , Young Adult , rho-Associated Kinases/antagonists & inhibitorsABSTRACT
Endothelial cell activation and injury is common after hematopoietic stem cell transplant (HSCT) and is associated with many post-transplant complications. An underexplored mechanism of endothelial cell damage in this population is the infusion of normal saline (NS, 0.9 % sodium chloride) and other crystalloids, as NS use is associated with adverse outcomes in other patient populations. We hypothesized that the infusion of unbalanced crystalloids during HSCT may lead to changes in biomarkers commonly associated with red blood cell (RBC) hemolysis in patients before and after infusion, and that markers of endothelial and end-organ damage during admission may be associated with markers of hemolysis and total crystalloid use. Samples were collected from 97 patients. From pre-fluid infusion to post-fluid infusion, mean haptoglobin decreased (11.7 ug/ml vs 8.4 ug/ml; p < 0.0001), hemopexin decreased (549 vs 512 µg/ml; p = 0.005), and red cell distribution width (RDW) decreased (15.7 vs 15.6; p = 0.0009). During admission (mean 19.4 days, SD 9.9), all markers of tissue and organ damage, including mean creatinine, lactate dehydrogenase (LDH), blood urea nitrogen (BUN), total bilirubin, AST, and ALT, increased from admission to peak levels (p < 0.0001). On linear regression, fluid volume (ml/kg) of crystalloid infusion positively predicted post-fluid infusion cell-free hemoglobin (r(96) = 0.34, p < 0.0001), free heme (r(96) = 0.36, p < 0.0001), and peak LDH during admission (r(75) = 0.23, p = 0.041), and negatively predicted post-fluid infusion hemopexin (r(96) = - 0.34, p < 0.0001). Unbalanced crystalloids may contribute to hemolysis and endothelial damage in HSCT patients. Alternatives such as buffered crystalloid solutions (PlasmaLyte, Lactated Ringer's) may be worth investigating in this population.
Subject(s)
Hematopoietic Stem Cell Transplantation , Hemolysis , Humans , Crystalloid Solutions , Isotonic Solutions/therapeutic use , Hemopexin , Multiple Organ Failure/chemically inducedABSTRACT
PURPOSE: Prior research has suggested that art-based interventions may reduce anxiety in cancer patients and enhance dialogue in the healthcare setting. Through implementing Art at the Bedside, an art-based hospital visitation program, we sought to examine whether dedicated art observation sessions, and varying formats (with and without guided discussion), could have therapeutic effects on cancer patients' mental wellbeing. METHODS: This randomized controlled pilot study evaluated the effects of bedside art observation on anxiety in a sample of 73 hematologic cancer inpatients. We compared state anxiety, as measured by an abbreviated form of the Spielberger State-Trait Anxiety Inventory (STAI Y-6), across three groups (participants who observed an electronic selection of artwork with and without guided discussion, and a control group that did not engage in either dedicated art observation activity). RESULTS: We found that mean anxiety scores were significantly lower among those who participated in guided art observation, compared to those who did not (8.92 versus 12.1, scored on a scale of 6 to 24, p = 0.009, with a medium effect size (η2 = 12.7)). The majority of participants who engaged in art observation felt that the activity provided positive distraction (85.7%) and decreased boredom (79.6%), and many noted that it reduced feelings of anxiety (46.9%) and depression (24.5%). CONCLUSION: These findings suggest that bedside art observation, particularly with guided discussion, may be a promising complementary therapy for reducing cancer-related anxiety and improving the patient experience in the inpatient hematology/oncology setting, and would benefit from further inquiry.
Subject(s)
Hematologic Neoplasms , Inpatients , Anxiety/etiology , Anxiety/therapy , Anxiety Disorders , Hematologic Neoplasms/therapy , Humans , Pilot ProjectsABSTRACT
Stem cell homing is a multistep endogenous physiologic process that is also used by exogenously administered hematopoietic stem and progenitor cells (HSPCs). This multistep process involves cell migration and is essential for hematopoietic stem cell transplantation. The process can be manipulated to enhance ultimate engraftment potential, and understanding stem cell homing is also important to the understanding of stem cell mobilization. Homing is also of potential importance in the recruitment of marrow mesenchymal stem and stromal cells (MSCs) to sites of injury and regeneration. This process is less understood but assumes importance when these cells are used for repair purposes. In this review, the process of HSPC and MSC homing is examined, as are methods to enhance this process.
Subject(s)
Stem Cell Transplantation , Stem Cells/cytology , Animals , Bone Marrow Cells/cytology , Cell Movement , Embryonic Development , Hematopoietic Stem Cell Mobilization , HumansABSTRACT
Hematopoietic cell transplantation (HCT) is an effective treatment for many hematologic malignancies, and its utilization continues to rise. However, due to the difficult logistics and high cost of HCT, there are significant barriers to accessing the procedure; these barriers are likely greater for older patients. Although numerous factors may influence HCT access, no formal analysis has detailed the cumulative barriers that have been studied thus far. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to better categorize the barriers to access and referral to HCT, with a focus on the subgroup of older patients. We searched for articles published in English from PubMed, Embase, Cumulative Index for Nursing and Allied Health, and Cochrane Central Register of Controlled Trials between the database inception and January 31, 2020. We selected articles that met the following inclusion criteria: (1) study design: qualitative, cross-sectional, observational cohort, or mixed-method study designs; (2) outcomes: barriers related to patient and physician access to HCT; and (3) population: adults aged ≥18 years with hematologic malignancies within the United States. Abstracts without full text were excluded. QUALSYST methodology was used to determine article quality. Data on the barriers to access and referral for HCT were extracted, along with other study characteristics. We summarized the findings using descriptive statistics. We included 26 of 3859 studies screened for inclusion criteria. Twenty studies were retrospective cohorts and 4 were cross-sectional. There was 1 prospective cohort study and 1 mixed-method study. Only 1 study was rated as high quality, and 16 were rated as fair. Seventeen studies analyzed age as a potential barrier to HCT referral and access, with 16 finding older age to be a barrier. Other consistent barriers to HCT referral and access included nonwhite race (n = 16/20 studies), insurance status (n = 13/14 studies), comorbidities (n = 10/11 studies), and lower socioeconomic status (n = 7/8 studies). High-quality studies are lacking related to HCT barriers. Older age and nonwhite race were consistently linked to reduced access to HCT. To produce a more just health care system, strategies to overcome these barriers for vulnerable populations should be prioritized. Examples include patient and physician education, as well as geriatric assessment guided care models that can be readily incorporated into clinical practice.
Subject(s)
Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Adolescent , Adult , Aged , Cross-Sectional Studies , Hematologic Neoplasms/therapy , Humans , Prospective Studies , Retrospective Studies , United StatesABSTRACT
It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (nâ¯=â¯89) compared with no TKI maintenance (nâ¯=â¯301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (nâ¯=â¯240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (nâ¯=â¯50), imatinib (nâ¯=â¯27), and nilotinib (nâ¯=â¯27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; Pâ¯=â¯.11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; Pâ¯=â¯.65), or overall survival (maintenance, 61% versus no maintenance, 57%; Pâ¯=â¯.61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Adult , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Protein Kinase Inhibitors/therapeutic useABSTRACT
Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potentially curative option for myelodysplastic syndromes (MDS). Mortality after HCT is high, with deaths related to relapse or transplant-related complications. Thus, identifying patients who may or may not benefit from HCT is clinically important. We identified 1514 patients with MDS enrolled in the Center for International Blood and Marrow Transplant Research Registry and had their peripheral blood samples sequenced for the presence of 129 commonly mutated genes in myeloid malignancies. A random survival forest algorithm was used to build the model, and the accuracy of the proposed model was assessed by concordance index. The median age of the entire cohort was 59 years. The most commonly mutated genes were ASXL1(20%), TP53 (19%), DNMT3A (15%), and TET2 (12%). The algorithm identified the following variables prior to HCT that impacted overall survival: age, TP53 mutations, absolute neutrophils count, cytogenetics per International Prognostic Scoring System-Revised, Karnofsky performance status, conditioning regimen, donor age, WBC count, hemoglobin, diagnosis of therapy-related MDS, peripheral blast percentage, mutations in RAS pathway, JAK2 mutation, number of mutations/sample, ZRSR2, and CUX1 mutations. Different variables impacted the risk of relapse post-transplant. The new model can provide survival probability at different time points that are specific (personalized) for a given patient based on the clinical and mutational variables that are listed above. The outcomes' probability at different time points may aid physicians and patients in their decision regarding HCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Middle Aged , Mutation , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/therapy , Neoplasm Recurrence, Local , Transplantation ConditioningABSTRACT
Peripheral blood stem cells (PBSCs) have been increasingly used for allogeneic hematopoietic cell transplantation instead of bone marrow stem cells. Current National Marrow Donor Program policy recommends 5 days of daily filgrastim, followed by either 1 or 2 days of apheresis for unrelated donors, depending on collection center choice. To date, there are no published studies comparing the differences in donor experience between 1 day and 2 days of apheresis. We examined 22,348 adult unrelated donor collections in 184 centers between 2006 and 2016. Of these 22,348 donors, 20,004 (89.5%) had collection on 1 day, and the other 2344 (9.5%) had collection over 2 days. Information on why donors underwent apheresis in 1 day or 2 days was not available. Donors who underwent apheresis in 1 day were more likely to be male (67% versus 46%; P < .001), younger (age <30 years, 48% versus 36%; P < .001), and have a higher body weight (83.0 kg versus 75.9 kg; P< .001) and body mass index (BMI; >30, 30% versus 22%; P < .001). Successful collection of the requested CD34+ cell count was achieved on the first day in 82% of 1-day collections and in 16% of 2-day collections. Despite not administering filgrastim the evening after the first day of collection in patients who underwent 2 days of apheresis, the median concentration of CD34+ cells/L in the product was higher on the second day of apheresis compared with the first day (23.8 × 106 CD34+/L on day 1 versus 28.7 × 106 CD34+/L on day 2; P< .001). Donors who underwent collection in 1 day were less likely to experience citrate toxicity (36% versus 52%; P< .001), hospitalization (1% versus 6%; P< .001), and other side effects related to apheresis (Modified Toxicity Criteria incidence: 20% versus 26%; P < .001). Female sex, older age, collection via central lines, and higher BMI were factors associated with greater likelihood for the development of toxicity, whereas less toxicity was noted in those with higher CD34+ counts and more blood processed on the first day of collection. We conclude that although unrelated donors can be successfully collected in 1 day or 2 days, 1-day apheresis procedures were associated with less overall toxicity, and thus we recommend single-day collections, especially if the requested number of cells have been collected in 1 day.
Subject(s)
Peripheral Blood Stem Cells , Unrelated Donors , Adult , Aged , Antigens, CD34 , Blood Donors , Female , Granulocyte Colony-Stimulating Factor , Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cells , Humans , MaleABSTRACT
BACKGROUND: We have previously shown that SLE BMSC have decreased proliferation, increased ROS, increased DNA damage and repair (DDR), a senescence associated secretory phenotype, and increased senescence-associated ß-galactosidase. We have also shown SLE BMSC produce increased amounts of interferon beta (IFNß), have increased mRNA for several genes induced by IFNß, and have a pro-inflammatory feedback loop mediated by a MAVS. To better understand the phenotype of SLE BMSC we conducted mRNA sequencing. METHODS: Patients fulfilling SLE classification criteria and age and sex matched healthy controls were recruited under an Institutional Review Board approved protocol. Bone marrow aspirates and peripheral blood samples were obtained. BMSC were isolated and grown in tissue culture. Early passage BMSC were harvested and mRNA samples were sent for RNAseq. Serum samples were assayed for IFNß by ELISA. RESULTS: On the basis of top differentially expressed genes between SLE and healthy controls, SLE patients with high levels of serum IFNß clustered together while SLE patients with low levels of IFNß clustered with healthy controls. Those genes differentially expressed in SLE patients generally belonged to known IFN pathways, and showed a strong overlap with the set of genes differentially expressed in IFNß high subjects, per se. Moreover, gene expression changes induced by treating healthy BMSC with exogenous IFNß were remarkably similar to gene expression differences in SLE IFNß high vs low BMSC. CONCLUSIONS: BMSCs from SLE patients are heterogeneous. A subgroup of SLE BMSC is distinguished from other SLE BMSC and from controls by increased levels of mRNAs induced by type I interferons. This subgroup of SLE patients had increased levels of IFNß in vivo.
Subject(s)
Bone Marrow Cells/metabolism , Interferon-beta/physiology , Lupus Erythematosus, Systemic/metabolism , Mesenchymal Stem Cells/metabolism , Cells, Cultured , Humans , Interferon-beta/blood , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/genetics , RNA-SeqABSTRACT
BACKGROUND: Bone marrow mesenchymal stem cells are multipotent adult stem cells that can differentiate into osteoblasts, adipocytes, and chondrocytes. Our recently published data demonstrate that systemic lupus erythematous bone marrow mesenchymal stem cells produce increased quantities of interferon ß based on a positive feedback loop involving the innate signaling molecule mitochondrial antiviral signaling protein. Moreover, this pathway contributes to human systemic lupus erythematous bone marrow mesenchymal stem cell senescence-like features. Here we investigate the differentiation defects of systemic lupus erythematous bone marrow mesenchymal stem cells and the potential for therapeutic interventions. METHODS: The six systemic lupus erythematous patients recruited in this study satisfy the American College of Rheumatology 1997 classification criteria for systemic lupus erythematous. Systemic Lupus Erythematous Disease Activity Index-2K was used to determine disease activity. Systemic lupus erythematous bone marrow mesenchymal stem cells were isolated with Ficoll centrifugation and phenotyped using flow cytometry. In vitro studies included real-time polymerase chain reaction and western blotting. RESULTS: We compared six age-paired bone marrow aspirates from healthy controls and systemic lupus erythematous patients. Systemic lupus erythematous bone marrow mesenchymal stem cells display significantly reduced alkaline phosphatase staining, as well as reduced expression of osteogenic markers alkaline phosphatase, Runt-related transcription factor 2, and bone sialoprotein. When healthy bone marrow mesenchymal stem cells were treated with interferon ß for 6 hours, expression of these same osteogenic markers was markedly reduced. Conversely the application of interferon ß neutralizing antibody enhanced the expression of osteoblastogenesis markers. When the underlying mechanisms for interferon ß inhibition of osteoblastogenesis were investigated, we found that IFNß pre-treatment activates the inhibitory Smad6 and Smad7 expression through JAK1/STAT1, leading to reduced Smad1 phosphorylation and nuclear translocation. CONCLUSIONS: Our present work suggests that interferon ß affects osteogenesis. By revealing the essential role of interferon ß on systemic lupus erythematous bone marrow mesenchymal stem cell differentiation, our study sheds light on systemic lupus erythematous pathogenesis and provides a new potential therapeutic target for the bone complications found in systemic lupus erythematous.
Subject(s)
Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Interferon-beta/pharmacology , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/pathology , Osteogenesis , Cell Differentiation/drug effects , Cells, Cultured , Core Binding Factor Alpha 1 Subunit/drug effects , Humans , Mesenchymal Stem Cells/cytology , Phosphorylation/drug effects , Signal Transduction/drug effectsABSTRACT
Bone marrow (BM) is an essential source of hematopoietic stem cell grafts for many allogeneic hematopoietic cell transplant (HCT) recipients, including adult patients (for specific diseases and transplantation strategies) and the majority of pediatric recipient. However, since the advent of granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (PBSC) grafts, there has been a significant decrease in the use of BM in HCT, thought to be due mainly to the increased logistical challenges in harvesting BM compared with PBSCs, as well as generally no significant survival advantage of BM over PBSCs. The decreased frequency of collection has the potential to impact the quality of BM harvests. In this study, we examined >15,000 BM donations collected at National Marrow Donor Program centers between 1994 and 2016 and found a significant decline in the quality of BM products, as defined by the concentration of total nucleated cells (TNCs). The mean TNC concentration in BM donations dropped from 21.8â¯×â¯106 cells/mL in the earliest era (1994 to 1996) to 18.7â¯×â¯106 cells/mL in the most recent era (2012 to 2016) (means ratio, .83; P < .001). This decline in BM quality was seen despite the selection of more donors perceived to be optimal (eg, younger and male). Multivariate regression analysis showed that higher-volume centers (performing >30 collections per era) had better-quality harvests with higher concentrations of TNCs collected. In conclusion, we have identified a significant decrease in the quality of BM collections over time, and lower-volume collection centers had poorer-quality harvests. In this analysis, we could not elucidate the direct cause for this finding, suggesting the need for further studies to investigate the key factors responsible and to explore the impact on transplant recipients.
Subject(s)
Bone Marrow Cells/cytology , Hematopoietic Stem Cell Transplantation , Adolescent , Adult , Cell Count , Female , Humans , Male , Middle AgedABSTRACT
The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59â¯×â¯106/L; age 41 to 60, 81â¯×â¯106/L; age 18 to 40, 121â¯×â¯106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50â¯×â¯109/L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.
Subject(s)
Peripheral Blood Stem Cell Transplantation/methods , Peripheral Blood Stem Cells/metabolism , Adolescent , Adult , Aged , Blood Donors , Comorbidity , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P < .001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.
Subject(s)
Hematopoietic Stem Cell Transplantation , Immunosuppression Therapy/adverse effects , Infections/mortality , Leukemia, Myeloid, Acute , Adolescent , Adult , Age Factors , Aged , Allografts , Child , Child, Preschool , Chronic Disease , Female , Humans , Incidence , Infant , Infant, Newborn , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Time FactorsABSTRACT
Systemic lupus (SLE) is characterized by a break of B cell tolerance that plays a central role in disease pathophysiology. An early checkpoint defect occurs at the transitional stage leading to the survival of autoreactive B cells and consequently the production of pathogenic autoantibodies. The main purpose of our work was to determine whether transitional B cells, as the most immature naïve B cell subset upstream of pathogenic B cells, display specific features compared to healthy non SLE subjects. Through extensive analysis of transitional B cells from untreated or low treated, mostly Caucasian, SLE patients, we demonstrated that transitional (T1 and T2) B cell frequencies were increased in SLE and positively correlated with disease activity. SLE transitional B cells displayed defects in two closely inter-related molecules (i.e. TLR9 defective responses and CD19 downregulation). RNA sequencing of sorted transitional B cells from untreated patients revealed a predominant overexpression of interferon stimulated genes (ISGs) even out of flares. In addition, early transitional B cells from the bone marrow displayed the highest interferon score, reflecting a B cell interferon burden of central origin. Hence, the IFN signature in transitional B cells is not confined to African American SLE patients and exists in quiescent disease since the medullary stage. These results suggest that in SLE these 3 factors (i.e. IFN imprintment, CD19 downregulation and TLR9 responses impairment) could take part at the early transitional B cell stage in B cell tolerance by-pass, ultimately leading in periphery to the expansion of autoantibodies-secreting cells.
Subject(s)
Antigens, CD19/biosynthesis , Interferons/immunology , Lupus Erythematosus, Systemic/immunology , Precursor Cells, B-Lymphoid/immunology , Toll-Like Receptor 9/immunology , Adult , Aged , Autoantibodies/immunology , B-Lymphocyte Subsets/immunology , Female , Humans , Middle Aged , Transcriptome/geneticsABSTRACT
Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P<0.001] and severe (OR 8.91; P<0.001) pain and toxicities (OR 1.84; P<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56; P=0.021) and non-recovery from pain (OR 1.42; P=0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors reporting grade ≥2 pain had significant decreases in Health-Related Quality of Life (HR-QoL) scores at one month and one year post donation (P=0.004). In conclusion, related PBSC donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at one year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Registered at clinicaltrials.gov identifier:00948636.
Subject(s)
Living Donors , Peripheral Blood Stem Cell Transplantation , Peripheral Blood Stem Cells , Quality of Life , Unrelated Donors , Adolescent , Adult , Female , Humans , Male , Middle Aged , Prospective Studies , Young AdultABSTRACT
Chronic graft-versus-host disease (cGVHD) frequently affects the oral mucosa and is generally responsive to topical immunomodulatory therapies. Clinicians may benefit from guidance in choosing the most appropriate therapy with respect to practicality and cost. To assess the economic considerations related to topical immunomodulatory treatments for management of oral mucosal cGVHD and their practical implications. Topical treatments used for management of oral cGVHD were obtained from the National Institutes of Health Consensus document for ancillary and supportive care. Cost data for a standard 1-month prescription was obtained from national databases for commercially available formulations and from compounding pharmacies for formulations requiring compounding. There are numerous topical preparations used for the management of oral cGVHD, many of which require compounding. The average wholesale price of the commercially available agents ranges from $5 to $277/month, and the cost of the compounded preparations ranges from $43 to $499/month. Costs can be influenced by drug-, patient-, and pharmacy-related factors. The costs associated with topical treatment of oral cGVHD are substantial, particularly because the disease is chronic and expenses accumulate over time. Rational prescribing according to a proposed algorithm, including de-escalation of therapy when indicated, can help to minimize associated costs. This has practical implications for patients, physicians, pharmacies, and insurance providers.