Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease.
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ABSTRACT:
SUBMITTER: Brazauskas R
PROVIDER: S-EPMC7393258 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Publications
Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease.
Brazauskas Ruta R Scigliuolo Graziana M GM Wang Hai-Lin HL Cappelli Barbara B Ruggeri Annalisa A Fitzhugh Courtney D CD Hankins Jane S JS Kanter Julie J Meerpohl Joerg J JJ Panepinto Julie A JA Rondelli Damiano D Shenoy Shalini S Walters Mark C MC Wagner John E JE Tisdale John F JF Gluckman Eliane E Eapen Mary M
Blood 20200701 5
We developed a risk score to predict event-free survival (EFS) after allogeneic hematopoietic cell transplantation for sickle cell disease. The study population (n = 1425) was randomly split into training (n = 1070) and validation (n = 355) cohorts. Risk factors were identified and validated via Cox regression models. Two risk factors of 9 evaluated were predictive for EFS: age at transplantation and donor type. On the basis of the training cohort, patients age 12 years or younger with an HLA-ma ...[more]
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Project description:Intestinal microbiota is an important prognostic factor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its role in predicting survival has not been determined. Here, stool samples at day 15 ± 1 posttransplant were obtained from 209 patients at two centers. Microbiota was examined using 16S rRNA sequencing. The microbiota diversity and abundance of specific bacteria (including Lachnospiraceae, Ruminococcaceae, Erysipelotrichaceae, and Enterobacteriaceae) were assigned a value of 0 or 1 depending on whether they were positive or negative associated with survival, respectively. An accumulated intestinal microbiota (AIM) score was generated, and patients were divided into low- and high-score groups. A low score was associated with a better 3-year cumulative overall survival (OS) as well as lower mortality than a high score (88.5 vs. 43.9% and 7.1 vs. 35.8%, respectively; both P < 0.001). In multivariate analysis, a high score was found to be an independent risk factor for OS and transplant-related mortality (hazard ratio = 5.68 and 3.92, respectively; P < 0.001 and 0.003, respectively). Furthermore, the AIM score could serve as a predictor for survival (area under receiver operating characteristic curve = 0.836, P < 0.001). Therefore, the intestinal microbiota score at neutrophil recovery could predict survival following allo-HSCT.
| S-EPMC9072276 | biostudies-literature
Project description:Hematopoietic cell transplant for sickle cell disease is curative but is associated with life threatening complications most of which occur within the first 2 years after transplantation. In the current era with interest in gene therapy and gene editing we felt it timely to report on sickle cell disease transplant recipients who were alive for at least 2-year after transplantation, not previously reported. Our objectives were to (1) report the conditional survival rates of patients who were alive for 2 or more years after transplantation (2) identify risk factors for death beyond 2 years after transplantation and (3) compare all-cause mortality risks to those of an age-, sex- and race-matched general population in the United States. By limiting to 2-year survivors, we exclude deaths that occur as a direct consequence of the transplantation procedure. De-identified records of 1149 patients were reviewed from a publicly available data source and 950 patients were eligible (https://picsure.biodatacatalyst.nhlbi.nih.gov). All analyses were performed in this secure cloud environment using the available statistical software package(s). The validity of the public database was confirmed by reproducing results from an earlier publication. Conditional survival estimates were obtained using the Kaplan-Meier method for the sub-cohort that had survived a given length (x) of time after transplantation. Cox regression models were built to identify risk factors associated with mortality beyond 2 years after transplantation. The standardized relative mortality risk (SMR) or the ratio of observed to expected number of deaths, was used to quantify all-cause mortality risk after transplantation and compared to age, race and sex-matched general population. Person-years at risk were calculated from an anchor date (i.e., 2-, 5- and 7-years) after transplantation until date of death or last date known alive. The expected number of deaths was calculated using age, race and sex-specific US mortality rates. The median follow up was 5 years (range 2-20) and 300 (32%) patients were observed for more than 7 years. Among those who lived for at least 7 years after transplantation the 12-year probability of survival was 97% (95% CI, 92%-99%). Compared to an age-, race- and sex-matched US population, the risk for late death after transplantation was higher as late as 7 years after transplantation (hazard ratio (HR) 3.2; P= .020) but the risk receded over time. Risk factors for late death included age at transplant and donor type. For every 10-year increment in patient age, an older patient was 1.75 times more likely to die than a younger patient (P= .0004). Compared to HLA-matched siblings the use of other donors was associated with higher risk for late death (HR 3.49; P= .003). Graft failure (beyond 2-years after transplantation) was 7% (95% CI, 5%-9%) and graft failure was higher after transplantation of grafts from donors who were not HLA-matched siblings (HR 2.59, P< .0001). Long-term survival after transplantation is excellent and support this treatment as a cure for sickle cell disease. The expected risk for death recedes over time but the risk for late death is not negligible.
| S-EPMC9198002 | biostudies-literature
Project description:ImportanceInduction chemotherapy followed by high-dose therapy with autologous stem cell transplant and subsequent antidisialoganglioside antibody immunotherapy is standard of care for patients with high-risk neuroblastoma, but survival rate among these patients remains low.ObjectiveTo determine if tandem autologous transplant improves event-free survival (EFS) compared with single transplant.Design, setting, and participantsPatients were enrolled in this randomized clinical trial from November 2007 to February 2012 at 142 Children's Oncology Group centers in the United States, Canada, Switzerland, Australia, and New Zealand. A total of 652 eligible patients aged 30 years or younger with protocol-defined high-risk neuroblastoma were enrolled and 355 were randomized. The final date of follow-up was June 29, 2017, and the data analyses cut-off date was June 30, 2017.InterventionsPatients were randomized to receive tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan (n = 176) or single transplant with carboplatin/etoposide/melphalan (n = 179).Main outcomes and measuresThe primary outcome was EFS from randomization to the occurrence of the first event (relapse, progression, secondary malignancy, or death from any cause). The study was designed to test the 1-sided hypothesis of superiority of tandem transplant compared with single transplant.ResultsAmong the 652 eligible patients enrolled, 297 did not undergo randomization because they were nonrandomly assigned (n = 27), ineligible for randomization (n = 62), had no therapy (n = 1), or because of physician/parent preference (n = 207). Among 355 patients randomized (median diagnosis age, 36.1 months; 152 [42.8%] female), 297 patients (83.7%) completed the study and 21 (5.9%) were lost to follow-up after completing protocol therapy. Three-year EFS from the time of randomization was 61.6% (95% CI, 54.3%-68.9%) in the tandem transplant group and 48.4% (95% CI, 41.0%-55.7%) in the single transplant group (1-sided log-rank P=.006). The median (range) duration of follow-up after randomization for 181 patients without an event was 5.6 (0.6-8.9) years. The most common significant toxicities following tandem vs single transplant were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%).Conclusions and relevanceAmong patients aged 30 years or younger with high-risk neuroblastoma, tandem transplant resulted in a significantly better EFS than single transplant. However, because of the low randomization rate, the findings may not be representative of all patients with high-risk neuroblastoma.Trial registrationClinicalTrials.gov Identifier: NCT00567567.
| S-EPMC6714031 | biostudies-literature
Project description:A risk score identifying patients at high risk for veno-occlusive disease (VOD) may aid efforts to study preventive strategies for this uncommon complication of hematopoietic cell transplantation (HCT). Patients receiving a first allogeneic HCT between 2008 and 2013 as reported to the Center for International Blood and Marrow Transplant Research (N = 13,097) were randomly divided into training and validation sets. Independent prognostic factors for development of VOD by day +100 after HCT were identified with a multivariate logistic regression model. A risk score was constructed in the training set using the significant factors and confirmed in the validation set. Baseline characteristics of the training and validation sets were balanced. In total, 637 patients (4.9%) developed VOD by day +100. Younger age, positive hepatitis B/C serology, lower Karnofsky performance scale score, use of sirolimus, disease, disease status at transplant, and conditioning regimen were independent prognostic factors. Myeloablative conditioning regimens were associated with higher risk of VOD. Busulfan-based myeloablative conditioning regimens guided by pharmacokinetic monitoring were associated with higher risk than those without pharmacokinetic monitoring. Patients were stratified into 4 distinct, statistically significantly different groups by their risk score percentile. This pretransplant risk score successfully stratified allogeneic HCT patients by risk of developing VOD, was validated in an independent set, and demonstrated strong discriminatory ability to identify a high-risk cohort.
| S-EPMC6239945 | biostudies-literature
Project description:BackgroundAdvances in allogeneic hematopoietic stem cell transplant (HSCT) have increased patient survival, although substantial treatment-related toxicity remains, including chronic kidney disease (CKD). We assessed the association between CKD and survival and transplant-specific outcomes in HSCT recipients.MethodsWe conducted a retrospective study of all 408 adult patients with allogenic HSCT at Princess Margaret Cancer Centre (Toronto, Canada, 2015-18). We used logistic regression to identify risk factors for CKD at 1 year post-transplant. Associations between CKD at 1 year and overall survival, relapse-free survival, graft-versus-host-disease (GVHD)-free/relapse-free survival, relapse and transplant-related mortality were examined using extended time-varying Cox models. In a sensitivity analysis, we restricted the cohort to survivors at 1 year, using standard Cox proportional hazard models to examine associations between CKD and overall survival, relapse-free survival and GVHD-free/relapse-free survival, and Fine and Gray's competing risk models to determine associations between CKD and relapse/transplant-related mortality.ResultsThe prevalence of CKD at 1 year was 19% (46 patients) with median follow-up of 23 months. Multivariable regression identified age at transplant [adjusted OR (aOR) 1.09, 95% confidence interval (95% CI) = 1.05-1.14; P < 0.0001), female gender (aOR 2.83, 95% CI = 1.34-5.97; P = 0.006) and acute kidney injury during the first 100 days (aOR 3.86, 95% CI = 1.70-8.73; P = 0.001) as risk factors for CKD at 1 year. Patients with CKD at 1 year had significantly poorer overall survival than those without CKD, when adjusted for relevant covariates [adjusted HR (aHR) 1.93, 95% CI = 1.02-3.66; P = 0.04 in the time-varying Cox model, and aHR 2.06, 95% CI = 1.04-4.07; P = 0.04 using the standard Cox model]. CKD at 1 year was also associated with worse GVHD-free/relapse-free survival (aHR 1.65, 95% CI = 1.04-2.61; P = 0.03).ConclusionsCKD adversely affects the long-term prognosis for allogeneic HSCT recipients, with increased mortality risk and worse GVHD-free/relapse-free survival.
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Project description:Hematopoietic stem cell transplant (HSCT) is the only cure for patients with sickle cell disease (SCD). Although most SCD patients experience progressive end-organ damage and shortened lifespans, not all patients follow the same disease course, tempo, or outcome. Therefore, the dilemma facing physicians is weighing the selection of patients and timing for the procedure against donor type and transplant-related mortality and morbidity that go up with increasing age. On the other hand, the dilemma facing the patients and families is how acceptable HSCT that carries some mortality risks to them. We have analyzed the chronic conditions due to SCD in 449 patients to determine whether SCD-related multiple chronic conditions (MCC) can be risk-stratified to identify the group of patients predicted to not only have shortened lifespans but also functional limitation and poor quality of life so that these at-risk patients can be offered HSCT early and before MCC develops. We identified that the age of onset of the first SCD-related chronic conditions strongly predicted for the risks for disease-related MCC. SCD patients who suffered their first disease-related chronic condition before age 30 years developed MCC at a rate of 19.1 times faster than those at a later age. These patients are therefore high-risk patients and should be offered HSCT early in the course of their disease before multiple organ damage intervenes, even if matched-related donors are not available. This patient selection and timing approach provides a forum for an easy-to-understand and real-time discussion, including the choice of donor type, with SCD patients and families when considering HSCT.
| S-EPMC8504222 | biostudies-literature
Project description:Hematopoietic stem cell transplantation (HSCT) may be used to consolidate chimeric antigen receptor (CAR) T cell therapy-induced remissions for patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL), but little is known about the factors impacting overall survival (OS) and event-free survival (EFS) for post-CAR hematopoietic stem cell transplantation (HSCT). The present study's primary objective was to identify factors associated with OS and EFS for consolidative HSCT following CAR-induced complete remission (CR) in transplantation-naïve patients. Secondary objectives included evaluation of OS/EFS, relapse-free survival and cumulative incidence of relapse for all patients who proceeded to HSCT, stratified by first and second HSCT, as well as the tolerability of HSCT following CAR-induced remission. This was a retrospective review of children and young adults enrolled on 1 of 3 CAR T cell trials at the National Cancer Institute targeting CD19, CD22, and CD19/22 (ClinicalTrials.gov identifiers NCT01593696, NCT02315612, and NCT03448393) who proceeded directly to HSCT following CAR T cell therapy. Between July 2012 and February 2021, 46 children and young adults with pre-B ALL went directly to HSCT following CAR therapy. Of these patients, 34 (74%) proceeded to a first HSCT, with a median follow-up of 50.8 months. Transplantation-naïve patients were heavily pretreated prior to CAR T cell therapy (median, 3.5 lines of therapy; range, 1 to 12) with significant prior immunotherapy exposure (blinatumomab, inotuzumab, and/or CAR T cell therapy in patients receiving CD22 or CD19/22 constructs (88%; 15 of /17)). Twelve patients (35%) had primary refractory disease, and the median time from CAR T cell infusion to HSCT Day 0 was 54.5 days (range, 42 to 127 days). The median OS following first HSCT was 72.2 months (95% confidence interval [CI], 16.9 months to not estimable [NE]), with a median EFS of 36.9 months (95% CI, 5.2 months to NE). At 12 and 24 months, the OS was 76.0% (95% CI, 57.6% to 87.2%) and 60.7% (95% CI, 40.8% to 75.8%), respectively, and EFS was 64.6% (95% CI, 46.1% to 78.1%) and 50.9% (95% CI, 32.6% to 66.6%), respectively. The individual factors associated with both decreased OS and EFS in univariate analyses for post-CAR consolidative HSCT in transplantation-naïve patients included ≥5 prior lines of therapy (not reached [NR] versus 12.4 months, P = .014; NR versus 4.8 months, P = .063), prior blinatumomab therapy (NR versus 16.9 months, P = .0038; NR versus 4.4 months, P = .0025), prior inotuzumab therapy (NR versus 11.5 months, P = .044; 36.9 months versus 2.7 months, P = .0054) and ≥5% blasts (M2/M3 marrow) pre-CAR T cell therapy (NR versus 17 months, P = .019; NR versus 12.2 months, P = .035). Primary refractory disease was associated with improved OS/EFS post-HSCT (NR versus 21.9 months, P = .075; NR versus 12.2 months, P = .024). Extensive prior therapy, particularly immunotherapy, and high disease burden each individually adversely impacted OS/EFS following post-CAR T cell consolidative HSCT in transplantation-naïve patients, owing primarily to relapse. Despite this, HSCT remains an important treatment modality in long-term cure. Earlier implementation of HSCT before multiply relapsed disease and incorporation of post-HSCT risk mitigation strategies in patients identified to be at high-risk of post-HSCT relapse may improve outcomes.
| S-EPMC10292107 | biostudies-literature
Project description:Importance:Studies demonstrating improved survival after allogeneic hematopoietic cell transplant generally exclude infants. Objective:To analyze overall survival trends and other outcomes among infants who undergo allogeneic hematopoietic cell transplant. Design, Setting, and Participants:In this cohort study, we used time-trend analysis to evaluate 3 periods: 2000 through 2004, 2005 through 2009, and 2010 through 2014. The study was conducted in a multicenter setting through the Center for International Blood and Marrow Transplant Research, which is made up of a voluntary working group of more than 450 transplant centers worldwide. Two groups of infants aged 1 year or younger in 2 cohorts were included: those with malignant conditions, such as leukemia, and those with nonmalignant disorders, including immunodeficiencies. Data analysis was conducted from July 2017 to December 2018. Exposures:Allogeneic hematopoietic cell transplant. Main Outcomes and Measures:Survival trends, disease relapse, and toxicity. Results:A total of 2498 infants with a median age of 7 months (range, <1-12 months) were included. In the nonmalignant cohort (n = 472), survival rates improved from the first to the second period (hazard ratio, 0.77 [95% CI, 0.63-0.93]; P = .007) but did not change after 2004. Compared with infants with nonmalignant diseases (n = 2026; 3-year overall survival: 2000-2004, 375/577 [65.0%]; 2005-2009, 503/699 [72.0%]; and 2010-2014, 555/750 [74.0%]), those with malignant conditions had poorer survival rates, without improvement over time (3-year overall survival: 2000-2004, 109/199 [54.8%]; 2005-2009, 104/161 [64.6%]; and 2010-2014, 66/112 [58.9%]). From 2000 through 2014, relapse rates increased in infants with malignant conditions (3-year relapse rate: 2000-2004, 19% [95% CI, 14%-25%]; 2005-2009, 23% [95% CI, 17%-30%]; 2010-2014, 36% [95% CI, 27%-46%]; P = .01). Sinusoidal obstruction syndrome was frequent, occurring with a cumulative incidence of 13% (95% CI, 11%-16%) of infants with nonmalignant diseases and 32% (95% CI, 22%-42%) of those with malignant diseases. Generally, recipients of human leukocyte antigen-identical sibling bone marrow grafts had the best outcomes. Conclusions and Relevance:Survival rates have not improved for infants with malignant diseases over the 15-year study period. Infants with nonmalignant diseases had improved survival rates in the earlier but not the later study period. Higher relapses for the malignant cohort and toxicities for all infants remain significant challenges. Strategies to reduce relapse and toxicity and optimize donor and graft selection may improve outcomes in the future.
| S-EPMC6503511 | biostudies-literature
Project description:Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (-19.4 mL/100 g/min) and OEF (-8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, -0.9 mL/100 g/min; P = .024; OEF, -3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.
| S-EPMC9936296 | biostudies-literature
Project description:AbstractPreliminary evidence from a series of 4 adults with sickle cell disease (SCD) suggests that hematopoietic stem cell transplant (HSCT) improves cerebral hemodynamics. HSCT largely normalizes cerebral hemodynamics in children with SCD. We tested the hypothesis in adults with SCD that cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) measured using magnetic resonance imaging, normalized to healthy values, comparing measurements from ∼1 month before to 12 to 24 months after HSCT (n = 11; age, 33.3 ± 8.9 years; 389 ± 150 days after HSCT) with age-, race- and sex-matched values from healthy adults without sickle trait (n = 28; age, 30.2 ± 5.6 years). Before transplant, 7 patients had neurological indications for transplant (eg, overt stroke) and 4 had nonneurological reasons for haploidentical bone marrow transplant (haplo-BMT). All received haplo-BMT from first-degree relatives (parent, sibling, or child donor) with reduced-intensity preparation and maintained engraftment. Before transplant, CBF was elevated (CBF, 69.11 ± 24.7 mL/100 g/min) compared with that of controls (P = .004). Mean CBF declined significantly after haplo-BMT (posttransplant CBF, 48.2 ± 13.9 mL/100 g/min; P = .003). OEF was not different from that of controls at baseline and did not change significantly after haplo-BMT (pretransplant, 43.1 ± 6.7%; posttransplant, 39.6 ± 7.0%; P = .34). After transplant, CBF and OEF were not significantly different from controls (CBF, 48.2 ± 13.4 mL/100 g/min; P = .78; and OEF, 39.6 ± 7.0%; P > .99). CMRO2 did not change significantly after haplo-BMT (pretransplant, 3.18 ± 0.87 mL O2/100 g/min; posttransplant, 2.95 ± 0.83; P = .56). Major complications of haplo-BMT included 1 infection-related death and 1 severe chronic graft-versus-host disease. Haplo-BMT in adults with SCD reduces CBF to that of control values and maintains OEF and CMRO2 on average at levels observed in healthy adult controls. The trial was registered at www.clinicaltrials.gov as #NCT01850108.
| S-EPMC10838697 | biostudies-literature