Shortened-Duration Immunosuppressive Therapy after Nonmyeloablative, Related HLA-Haploidentical or Unrelated Peripheral Blood Grafts and Post-Transplantation Cyclophosphamide.

With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative (NMA) HLA-haploidentical (haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Previous reports have shown that discontinuation of immunosuppression (IS) as early as day 60 after infusion of a bone marrow (BM) haplo allograft with PTCy is feasible. There are certain diseases in which peripheral blood (PB) may be favored over BM, but given the higher rates of GVHD with PB, excessive GVHD is of increased concern. We report a completed, prospective single-center trial of stopping IS at days 90 and 60 after NMA PB stem cell transplantation (PBSCT). Between 12/2015-7/2018, 117 consecutive patients with hematologic malignancies associated with higher rates of graft failure after NMA conditioned BMT and PTCy, received NMA PB allografts on trial. The primary objective of this study was to evaluate the safety and feasibility of reduced-duration IS (from day 5 through day 90 in the D90 cohort and through day 60 in the D60 cohort). Of the 117 patients (median age, 64 years; range, 22 to 78 years), the most common diagnoses were myelodysplastic syndrome (33%), acute myelogenous leukemia (with minimal residual disease or arising from an antecedent disorder) (32%), myeloproliferative neoplasms (19%), myeloma (9%), and chronic lymphoblastic leukemia (7%). Shortened IS was feasible in 75 patients (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 patients), followed by early relapse (11 patients), nonrelapse mortality (NRM) (7 patients), patient/ physician preference (4 patients) or graft failure (3 patients). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned, and among the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV acute GVHD was 21 days in the D90 cohort and 32 days in the D60 cohort, with almost all cases developing within 40 days. Approximately one-third of these patients resumed IS. All outcome measures were similar in the 2 cohorts and our historical outcomes with 180 days of IS. The cumulative incidence of grade III-IV acute GVHD was low, 2% in the D90 cohort and 7% in the D60 cohort. The incidence of severe chronic GVHD at 2 years was 9% in the D90 cohort and 5% in the D60 cohort. The 2-year overall survival was 67% for both the D90 and D60 cohorts. The 2-year progression-free survival was 47% for the D90 cohort and 52% for the D60 cohort, and the GVHD-free, relapse-free survival was <35% for both cohorts. These data suggest that reduced-duration IS in patients undergoing NMA PBSCT with PTCy is feasible and has an acceptable safety profile. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Novel Disease Risk Model for Patients with Acute Myeloid Leukemia Receiving Allogeneic Hematopoietic Cell Transplantation.

Molecular data and minimal residual disease (MRD) have been shown to influence outcomes in acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (AHCT). Here we developed and validated a novel AML-specific disease risk group (AML-DRG) and revised our previously developed hematopoietic cell transplant-composite risk (HCT-CR) model by incorporating molecular data and MRD status to predict outcomes of patients with AML. The study included 1414 consecutively treated adult AML patients who received a first AHCT. Patients were randomly assigned into training (n = 944) and validation (n = 470) sets. To develop the AML-DRG model, the coefficient of all significant AML-related variables in multivariable Cox regression analysis in a training dataset was converted into scores, whereas the AML-HCT-CR was the sum of disease-related factors assessed by the AML-DRG model with the addition of weighted scores from patient-related factors. The AML-DRG was developed by assigning the following scores: 1 point to secondary AML, 1 point to the European LeukaemiaNet adverse genetic risk, 2 points to complete remission with MRD positive/unknown, and 4 points to active disease. These scores were used to generate 3 risk groups of the AML-DRG with significantly different overall survivals. By adding the score for significant patient-related factors (HCT-specific comorbidity index/age), we created 4 risk groups of AML-HCT-CR with distinct survival outcomes. Both the AML-DRG and AML-HCT-CR provided significantly better discriminative capacity compared with the disease risk index, European LeukaemiaNet genetic risk model, and cytogenetic risk model. Prognostic models incorporating molecular data and MRD status allow better stratification and improved survival estimates of AML patients post-transplant.

Allogeneic Hematopoietic Cell Transplantation for Older Patients: Prognosis Determined by Disease Risk Index.

The treatment of elderly patients with advanced hematological malignancies has expanded to include reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT) as a potentially curative option. We studied the association between Disease Risk Index (DRI) and clinical outcomes of 196 elderly patients (median age, 64.8; range, 60 to 75 years) with hematological malignancies receiving RIC alloHCT (2000 to 2014). Donors were related and unrelated adults (n = 100, 51.1%) or umbilical cord blood (n = 96, 48.9%). DRI classified 12 patients (6.1%) as low risk (LR), 146 patients (74.5%) as intermediate risk (IR), and 38 patients (19.4%) as high risk (HR). Two-year overall survival (OS) was 47% (52% for LR/IR versus 29% for HR, P < .01) and 2-year disease-free survival was 39% (44% for LR/IR versus 21% for HR, P < .01). Relapse incidence was 30% (26% for LR/IR versus 44% for HR, P < .01). Treatment-related mortality was 29% at 2 years; this was similar for all DRI groups. In multiple regression analysis, HR DRI was associated with increased risk of relapse (hazard ratio, 2.07; 95% confidence interval [CI], 1.34 to 3.33; P = .02) and treatment failure (hazard ratio, 2.07; 95% CI, 1.35 to 3.18; P < .01) and decreased OS (hazard ratio, 2.11; 95% CI, 1.34 to 3.33; P < .01). In elderly patients, DRI is a significant prognostic factor for post-transplantation relapse, treatment failure, and mortality. Because of increased risk of relapse leading to poor survival in HR DRI, participation in clinical trials offering relapse prevention strategies after RIC alloHCT should be encouraged when available.

Impact of Pretransplantation Indices in Hematopoietic Stem Cell Transplantation: Knowledge of Center-Specific Outcome Data Is Pivotal before Making Index-Based Decisions.

Outcome after allogeneic hematopoietic stem cell transplantation is influenced by patient comorbidity, disease type, and status before treatment. We performed a retrospective study involving 521 consecutive adult hematopoietic stem cell transplantation patients who underwent transplantation for hematological malignancy at our center from 2000 to 2012 to compare the predictive value of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and the disease risk index (DRI) for overall survival and transplantation-related mortality. Patients in the highest HCT-CI risk group (HCT-CI score ≥3) had a lower 5-year overall survival rate (50%) than the low-risk group (63%; P < .01). Subset analysis of donor origin showed greater 5-year overall survival in siblings than in matched unrelated donors, regardless of HCT-CI score (eg, 67% 5-year overall survival in siblings despite an HCT-CI score of >6 [n = 9]). Five-year overall survival in the highest DRI risk group was significantly poorer (44%) than in the low-risk group (63%; P < .01). Both indices failed to predict differences in transplantation-related mortality (HCT-CI, P = .54; DRI, P = .17). We conclude that HCT-CI and DRI were predictive of overall survival in our patient population. Even so, our data show that different patient groups may have different outcomes despite sharing the same index risk group and that indices should, therefore, be evaluated according to local data before clinical implementation at the single-center level.

Evaluation of a disease risk index for adult patients undergoing umbilical cord blood transplantation for haematological malignancies.

A disease risk index (DRI) has been defined for stratifying heterogeneous cohorts of patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT). This index defines 4 distinct groups with different outcomes, dividing patients by disease type and status and considering cytogenetics for acute myeloid leukaemia and myelodysplastic syndromes (MDS). Recently, the DRI has been refined to include rare diseases and improve MDS stratification by blast percentage and response to prior therapy. Previous reports on DRI include only a small number of UCBT recipients. The current study aims to determine the applicability of the DRI for patients undergoing unrelated cord blood transplantation (UCBT). We retrospectively analysed 2530 adults receiving UCBT between 2004 and 2014. Diagnosis was acute leukaemia (AL) in 66% of the cases. Overall survival (OS) at 2 years was 56 ± 3% for patients with low DRI (n = 352), 46 ± 1% for intermediate DRI (n = 1403), 28 ± 2% for high (n = 489) and 20 ± 4% for very high DRI (n = 109) (P < 0·001). In the multivariate model, DRI remained an independent risk factor for OS. Similar findings were observed for PFS and DRI. Our results show the applicability of DRI for stratifying UCBT recipients and confirm the prognostic value of this simple and robust tool in this setting.

Impact of Donor Type on Outcome after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia.

Allogeneic hematopoietic cell transplantation (alloHCT) is considered the most potent postremission antileukemic therapy in adults with acute leukemia. We analyzed 172 consecutive acute leukemia patients transplanted in complete remission after a T cell-replete alloHCT from either a matched related (MRD, n = 54), unrelated (MUD, n = 67), or haploidentical (haplo, n = 51) donor to look for patient-, disease-, and transplant-related factors associated with post-transplant outcomes. Patients included 123 acute myeloid leukemia patients (first complete remission [CR], n = 94; second CR, n = 28; third CR, n = 1) and 49 acute lymphoblastic leukemia (ALL) patients (first CR, n = 39; second CR, n = 9; third CR, n = 1) with a median age of 50 years (range, 19 to 74). Median follow-up for surviving patients was 38 months. Cumulative incidence of nonrelapse mortality at 1 and 3 years was 6% and 17%, respectively. The estimated rates of 3-year overall survival, disease-free survival, and relapse incidence were 59%, 50%, and 33%, respectively. In multivariate analysis, risk factors for inferior survival included diagnosis of ALL, high risk disease risk index, and use of a female donor for a male recipient. Donor type (MRD, MUD, haplo) had no impact on any transplant outcome. Given the favorable outcomes associated with alloHCT in acute leukemia and lack of effect of donor type, a strong case can be made for transplanting acute leukemia patients in remission as soon as any donor becomes available.

Validation of the disease risk index for outcome of patients undergoing allogeneic hematopoietic stem cell transplantation after T cell depletion.

Identification of pretransplantation risk factors is important in evaluating patient outcomes after hematopoietic stem cell transplantation. Current scoring schemes, such as the European Group for Blood and Marrow Transplantation risk score or the Hematopoietic Cell Transplantation-Specific Comorbidity Index, may under-rate disease and disease status at the time of transplantation. The recently published Disease Risk Index (DRI) specifically investigates these aspects by defining 4 risk groups (low, intermediate, high, very high) with significant differences in overall survival (OS). We retrospectively investigated whether the DRI could be applied at the transplantation center of Geneva's University Hospitals (Geneva, Switzerland), where 64% of patients are underwent transplantation with T cell-depleted grafts (TDEP). We analyzed 409 patients with various hematological malignancies who underwent transplantation between January 1998 and October 2012. Using the DRI, the 4-year OS for the low, intermediate, high, and very high groups was 82%, 53%, 27%, and 31%, respectively (P < .0001). For TDEP patients, the 4-year OS for low, intermediate, and high overall risk groups was 86%, 53%, and 33%, respectively (P < .0001). As patients in the very high overall risk group are usually not eligible for TDEP, our group comprised too few patients (n = 3) for meaningful analysis. For non-TDEP patients, the 4-year OS for low, intermediate, high, and very high overall risk groups was 63%, 54%, 22%, and 18%, respectively (P < .0001). Our results confirm the prognostic value of the DRI in a cohort with a majority of TDEP patients.

Development of a novel dementia risk prediction model in the general population: A large, longitudinal, population-based machine-learning study.

Background: The existing dementia risk models are limited to known risk factors and traditional statistical methods. We aimed to employ machine learning (ML) to develop a novel dementia prediction model by leveraging a rich-phenotypic variable space of 366 features covering multiple domains of health-related data. Methods: In this longitudinal population-based cohort of the UK Biobank (UKB), 425,159 non-demented participants were enrolled from 22 recruitment centres across the UK between March 1, 2006 and October 31, 2010. We implemented a data-driven strategy to identify predictors from 366 candidate variables covering a comprehensive range of genetic and environmental factors and developed the ML model to predict incident dementia and Alzheimer's Disease (AD) within five, ten, and much longer years (median 11.9 [Interquartile range 11.2-12.5] years). Findings: During a follow-up of 5,023,337 person-years, 5287 and 2416 participants developed dementia and AD, respectively. A novel UKB dementia risk prediction (UKB-DRP) model comprising ten predictors including age, ApoE ε4, pairs matching time, leg fat percentage, number of medications taken, reaction time, peak expiratory flow, mother's age at death, long-standing illness, and mean corpuscular volume was established. Our prediction model was internally evaluated based on five-fold cross-validation on discrimination and calibration, and it was further compared with existing prediction scales. The UKB-DRP model can achieve high discriminative accuracy in dementia (AUC 0.848 ± 0.007) and even better in AD (AUC 0.862 ± 0.015). The model was well-calibrated (Hosmer-Lemeshow goodness-of-fit p-value = 0.92), and the predictive power was solid in different incidence time groups. More importantly, our model presented an apparent superiority over existing models like Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (AUC 0.705 ± 0.008), the Dementia Risk Score (AUC 0.752 ± 0.007), and the Australian National University Alzheimer's Disease Risk Index (AUC 0.584 ± 0.017). The model was internally validated in the general population of European ancestry and White ethnicity; thus, further validation with independent datasets is necessary to confirm these findings. Interpretation: Our ML-based UKB-DRP model incorporated ten easily accessible predictors with solid predictive power for incident dementia and AD within five, ten, and much longer years, which can be used to identify individuals at high risk of dementia and AD in the general population. Funding: This study was funded by grants from the Science and Technology Innovation 2030 Major Projects (2022ZD0211600), National Key R&D Program of China (2018YFC1312904, 2019YFA070950), National Natural Science Foundation of China (282071201, 81971032, 82071997), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), Research Start-up Fund of Huashan Hospital (2022QD002), Excellence 2025 Talent Cultivation Program at Fudan University (3030277001), Shanghai Rising-Star Program (21QA1408700), Medical Engineering Fund of Fudan University (yg2021-013), and the 111 Project (No. B18015).

Early Post-Transplantation Serum Ferritin Level Predicts Survival in Recipients of Haploidentical Stem Cell Transplantation Using Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis.

The negative impact of high serum ferritin level (SFL) before and after allogeneic hematopoietic cell transplantation (allo-HSCT) on outcomes is well recognized. However, it is poorly documented in adults undergoing haploidentical HSCT (haplo-HSCT) with post-transplantation cyclophosphamide (PTCY) for hematologic malignancies. The main objective was to assess the impact of pretransplantation and post-transplantation SFL on overall survival (OS), disease-free survival (DFS), and nonrelapse mortality (NRM) in patients undergoing haplo-HSCT with PTCY. The secondary objective was to identify factors associated with outcomes after transplantation by comparing SFL with other parameters related to the status of patients or donors. This multicentric retrospective study included 223 consecutive patients who underwent haplo-HSCT with PTCY in 4 French centers (Nantes, Angers, Besançon, and Brest) between October 2013 and January 2020. The impact of SFL on OS, DFS, and NRM at different time points was assessed based on receiver operating characteristic curves. With a median follow-up of 37.6 months (interquartile range, 23.5 to 51.0 months), 3-year OS, DFS, and NRM were 48.1 ± 4%, 46.3 ± 4%, and 30.0 ± 3%, respectively. Pretransplantation SFL had no impact on outcomes irrespective of the cutoff tested. Considering patients alive at 3 months post-transplantation, an SFL ≥3500 µg/L at 3 months was statistically significantly associated with worse 3-year OS (32.7 ± 8.7% versus 53.4 ± 7.2%; P = .01) and DFS (30.1 ± 8.2% versus 53.1 ± 7.1%; P = .008), with a trend toward higher NRM (33.2 ± 8.6% versus 17.6 ± 5.4%; P = .10). Similarly, high SFL (≥2700 µg/L) at 6 months post-transplantation was associated with worse 3-year OS (56.1 ± 9.1% versus 79.2 ± 6.0%; P = .02) and DFS (53.6 ± 8.7% versus 74.9 ± 6.2%; P = .01), with a trend toward higher NRM (21.4 ± 7.4% versus 8.2 ± 4.0%; P = .10). In multivariate analysis, high 3-month and 6-month FL remained associated with lower OS and DFS, with a trend toward higher NRM. Pretransplantation SFL appears to have no impact on outcomes in haplo-HSCT with PTCY, in contrast to what is documented in the matched allo-HSCT setting. In contrast, in the haplo-HSCT setting, high SFL early post-transplantation is associated with lower survival and a trend toward higher NRM.

Use of Resistant Cultivars and Reduced Fungicide Programs to Manage Peanut Diseases in Irrigated and Nonirrigated Fields.

Field experiments were conducted in 2004 and 2005 to evaluate the response of several peanut cultivars to standard and reduced-input fungicide programs under production systems which differed in the duration of crop rotation, disease history within a field, or in the presence or absence of irrigation. Effects on early leaf spot (caused by Cercospora arachidicola), late leaf spot (caused by Cercosporidium personatum), and southern stem rot (caused by Sclerotium rolfsii), pod yields, and economic returns were assessed. Standard fungicide programs were similar for both sets of experiments and included applications of pyraclostrobin, tebuconazole, azoxystrobin, or chlorothalonil. Reduced-fungicide programs, comprising combinations of the aforementioned fungicides, resulted in two and four applications for the cultivar and irrigation experiment, respectively. Two additional programs (a seven-spray chlorothalonil and a nontreated control) were included in the cultivar experiment. Fungicide programs provided adequate levels of leaf spot suppression, and stem rot incidence was similar among fungicide programs within the two management systems. In the cultivar experiment, returns were significantly lower for the reduced program compared with the full program and seven-spray chlorothalonil program; however, they were significantly higher than the nontreated control. Significant differences in leaf spot, stem rot, and yield were observed among cultivars in both experiments. Overall, leaf spot intensity was lowest for the cvs. Georgia-03L and Georgia-01R and greatest for Georgia Green and Georgia-02C. Georgia-03L, Georgia-02C, and AP-3 consistently had lower incidence of stem rot than the other cultivars. Pod yields for all cultivars were equivalent to or greater than Georgia Green in both experiments; however, the performance of reduced-fungicide programs was inconsistent.

Allogeneic hematopoietic stem cell transplantation in adults with myelodysplastic syndrome: Experience of the Argentinean Group of Bone Marrow Transplantation (GATMO).

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative approach for patients with myelodysplastic syndrome (MDS). METHODS: In this multicenter retrospective study, we analyzed the outcome of adult patients with MDS who underwent AHSCT in Argentina and evaluated the prognostic factors associated with progression-free survival (PFS), overall survival (OS), cumulative incidence (CI) of relapse, and non-relapse mortality (NRM). RESULTS: We analyzed data from 87 adults (median age: 43 years, range 18-66) who underwent SCT after myeloablative (n = 60) or non-myeloablative conditioning (n = 27), and from related (n = 62) or unrelated (n = 25) donors. For all patients, unadjusted 4-year PFS and OS were 37% and 38%, respectively; no significant differences were found between recipients of related or unrelated donors. One-year CI of relapse and NRM were 21% and 20%, respectively. In the multivariate analysis, intermediate disease risk index (DRI) and acute graft versus host disease AGVHD of all grades (I-IV) were independent variables associated with better PFS and lower relapse CI; only intermediate DRI was associated with better OS. CONCLUSIONS: AHSCT is a feasible procedure in Argentina, with more than 30% of the patients achieving long-term survival. Recipients with unrelated donors had at least similar outcome than those with related donors. DRI may be useful to identify patients at higher risk of relapse after transplantation.