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Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.

Background : Higher CD34 cell dose is associated with improved engraftment after peripheral blood allogeneic hematopoietic stem cell transplantation (alloHCT), but may also increase the risk of long-term complications, such as graft-versus-host disease (GVHD). Prior studies examining the relationship between CD34 cell dose and long-term survival outcomes have yielded conflicting results. Objective : This study sought to clarify the prognostic impact of CD34 cell dose by examining a large, contemporary cohort of patients undergoing alloHCT with matched sibling peripheral blood stem cell (PBSC) donors. Study Design : We retrospectively examined the impact of CD34 cell dose on overall survival (OS), neutrophil engraftment, platelet engraftment, treatment-related mortality (TRM), relapse, acute GVHD grades II-IV and III-IV, and chronic GVHD in 377 consecutive patients undergoing alloHCT with PBSC graft source from matched sibling donors at the University of Minnesota from 2002-2015. Patients were classified into three groups based on tertile (T) of CD34 cell dose received (T1, Results : Multivariable analysis demonstrated that high CD34 cell dose was associated with superior 5-year OS (hazard ratio [HR] 0.57, P = 0.01) and more rapid platelet engraftment (HR 1.70, P Conclusion : Higher CD34 cell dose (>7.5 × 106/kg) is associated with superior OS at 5 years and improved engraftment but does carry an increased risk of chronic GVHD. These data support a target CD34 cell dose goal of 7.5 × 106/kg for peripheral blood sibling donors.

In young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front-line setting. Recently, time-to-event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post-autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six-month [hazard ratio (HR) = 7·68], 12-month (HR = 6·68), and 18-month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non-relapsing patients. Furthermore, early relapse (

As an alternative stem cell source, cord blood (CB) has many advantages. However, delayed engraftment, lack of transferred immunity, and a significant incidence of acute graft-versus-host disease renders CB transplant (CBT) recipients at high risk of infectious complications. This guidance written by CBT and infectious disease experts outlines evidence-based recommendations for the prevention and treatment of opportunistic infections in adult patients undergoing CBT. Topics addressed include bacterial, fungal, viral, pneumocystis jirovcii and toxoplasmosis prophylaxis, suggested PCR monitoring for viruses, therapy for the most commonly encountered infections after CBT. We review key concepts including the recent important role of letermovir in the prevention of CMV reactivation. In instances where there is a paucity of data, practice recommendations are provided, including the duration of antimicrobial prophylaxis.

For cord blood transplantation (CBT), appropriate patient and conditioning regimen selection is necessary to achieve long-term disease-free survival. This review aims to provide comprehensive guidelines on these issues using evidence from the literature and experience at dedicated CBT centers. Topics include patient and disease characteristics that make CBT a good or poor choice and a review of outcomes in commonly used conditioning regimens in CBT. This is accompanied with recommendations on regimen intensity based on disease, organ function, and patient performance status and age. In addition, the use of antithymocyte globulin in CBT is discussed, as is the choice of conditioning in aplastic anemia patients who have access to acceptable CB units.

Streptococcus pneumoniae is the main cause of community-acquired pneumonia worldwide; pneumonia occurs sporadically in most cases, but rare outbreaks have been reported. We describe an outbreak occurred in a 21-guests nursing home for elders in Aosta (Italy); outbreak occurred in april 2014 over a 2 weeks period, resulting in 12 out 20 guests affected (all with high fever and respiratory symptoms), two deaths (at home), nine patients referred to Hospital Emergency Room, and eight admissions. Urinary streptococcus antigen was positive in seven out of eight patient tested. None of the nursing home guests were vaccinated against Streptococcus pneumoniaeThe Hospital Medical Direction and Public Health Service gave support and adopted strategies to contain the outbreak spread.We underline the need for pneumococcal vaccination in nursing homes/ Long-term care facilities; accurate check of hygiene behaviours in those setting is also mandatory.

Human CD4+25− T cells cultured in interleukin 2 (IL-2), rapamycin, and transforming growth factor β (TGFβ) along with anti-CD3 monoclonal antibody–loaded artificial antigen-presenting cells generate FoxP3+ induced regulatory T cells (iTregs) with potent suppressive function. We performed a phase 1, single-center, dose-escalation study to determine the safety profile of iTregs in adults with high-risk malignancy treated with reduced-intensity conditioning and mobilized peripheral blood stem cells (PBSCs) from HLA-identical sibling donors. Sixteen patients were enrolled and 14 were treated (2 productions failed to meet desired doses). One patient each received 3.0 × 106/kg, 3.0 × 107/kg, and 3.0 × 108/kg iTregs with corresponding T-conventional-to-iTreg ratios of 86:1, 8:1, and 1:2. After 3 patients received 3.0 × 108/kg in the presence of cyclosporine (CSA) and mycophenolate mofetil (MMF) with no dose-limiting toxicities, subsequent patients were to receive iTregs in the presence of sirolimus/MMF that favors Foxp3 stability based on preclinical modeling. However, 2 of 2 developed grade 3 acute graft-versus-host disease (GVHD), resulting in suspension of the sirolimus/MMF. An additional 7 patients received 3.0 × 108/kg iTregs with CSA/MMF. In the 14 patients treated with iTregs and CSA/MMF, there were no severe infusional toxicities with all achieving neutrophil recovery (median, day 13). Of 10 patients who received 3.0 × 108/kg iTregs and CSA/MMF, 7 had no aGVHD, 2 had grade 2, and 1 had grade 3. Circulating Foxp3+ iTregs were detectable through day 14. In summary, iTregs in the context of CSA/MMF can be delivered safely at doses as high as 3 × 108/kg. This trial was registered at www.clinicaltrials.gov as #NCT01634217.

Results of two parallel phase II trials of transplantation of unrelated umbilical cord blood or bone marrow from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18-70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo cord blood (n=186) or haploidentical (n=182) transplant. Reduced intensity conditioning comprised total body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for cord blood transplantation was cyclosporine and mycophenolate mofetil and for haploidentical transplantation, post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil. The primary endpoint was 2-year progression-free survival. Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease and disease status at randomization. Two-year progression-free survival was 35% (95% CI, 28-42%) compared to 41% (95% CI, 34-48%) after cord blood and haploidentical transplants, respectively (p=0.41). Pre-specified analysis of secondary endpoints recorded higher 2-year non-relapse mortality after cord blood, 18% (95% CI, 13-24%) compared to haploidentical transplantation, 11% (95% CI, 6-16%), p=0.04. This led to lower 2-year overall survival after cord blood compared to haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49-64%), respectively (p=0.04). The trial did not demonstrate a statistically significant difference in the primary endpoint, 2-year progression-free survival, between the donor sources. While both donor sources extend access to reduced intensity transplantation, analyses of secondary endpoints, including overall survival, favor haploidentical bone marrow donors. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute; ClinicalTrials.gov number, NCT01597778).

We compared chronic graft-versus-host disease (cGvHD) following umbilical cord blood (UCBT) and matched sibling donor peripheral blood transplant (MSD). 145 patients (2010–2017) with cGvHD after MSD (n = 104) and UCBT (n = 41) were included. Prior acute GvHD was less frequent in MSD (55% vs. 85%; p = 0.01). Severe cGvHD (32% vs. 15%, p = 0.01) and de-novo onset (45% vs. 15%, p < 0.01) were more frequent following MSD. Liver was more frequently involved in MSD recipients (38% vs. 6%); and GI in UCBT (33% vs. 63%), both p < 0.01. Overall response (CR + PR) was similar between both cohorts. 2-year CR was higher in UCBT (14% vs 33%, p = 0.02). Karnofsky score (KPS) ≥ 90 at cGvHD diagnosis was associated with higher odds of response (95%CI: 1.42–10, p < 0.01). The cumulative incidence of durable discontinuation of immune-suppressive therapy, failure-free survival (FFS) and NRM at 2-years were similar between cohorts. KPS < 90 (95%CI: 3.1–24.9, p < 0.01) and platelets

Optimal cord blood (CB) unit selection is critical to maximize the likelihood of successful engraftment and survival after CB transplantation (CBT). However, unit selection can be complex because multiple characteristics must be considered including unit cell dose, donor-recipient human leukocyte antigen (HLA) match, and unit quality. This review provides evidence-based and experience-based comprehensive guidelines for CB unit selection. Topics addressed include the use of both the TNC and the CD34+ cell dose, as well as the CD34+ cell to TNC content ratio to evaluate unit progenitor cell content and engraftment potential, the acceptable TNC and CD34+ cell dose criteria that define an adequate single-unit graft, and the indication and acceptable cell dose criteria for double-unit grafts. The acceptable criteria for 6-loci (HLA-A, -B antigen, -DRB1 allele) and 8-allele (HLA-A, -B, -C, -DRB1) donor-recipient HLA match, the evaluation of patients with donor-specific HLA antibodies, and the multiple determinants of unit quality are also reviewed in detail. Finally, a practical step-by-step guide to CB searches and the principles that guide ultimate graft selection are outlined.

Prognostic factors associated with clinical outcomes of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients with central nervous system (CNS) involvement are unknown. We retrospectively studied the characteristics and outcomes of 66 (18 pediatric and 48 adult) patients with CNS leukemia with ALL (n = 41) or AML (n = 25). The median age of patients at diagnosis of CNS leukemia was 30 (range, 1–69) years. Nearly two-third patients had CNS involvement at the initial diagnosis of leukemia. Complete remission of CNS leukemia was attained in 58 (88%) patients, and probability of overall survival at 36 months after the diagnosis of CNS leukemia was 43% for the entire cohort. We identified that achieving remission of systemic leukemia and having CNS leukemia diagnosed and treated before allogeneic transplantation were the factors associated with CNS leukemia remission. Prognostic factors associated with better overall survival in patients with CNS leukemia included pediatric age, diagnosis of CNS leukemia before receiving allogenic transplantation, achieving clearance of systemic or CNS leukemia, receiving no cranial radiation in conjunction with intrathecal chemotherapy (IT), and receiving IT consolidation after achieving remission of CNS leukemia. Our findings show that patients with CNS leukemia are at considerable risk of mortality. Awareness of modifiable prognostic factors such as avoidance of cranial radiation whenever possible and use of IT consolidation can result in improved outcomes in subset of patients with CNS leukemia.

Introduction: Since photobiomodulation therapy (PBMT) favors in vitro mesenchymal stem cell (MSC) preconditioning before MSC transplantation, increasing the proliferation of these cells without molecular injuries by conserving their characteristics, in the present in vitro study we analyzed the effect of PBMT on the proliferation and osteogenic differentiation of human umbilical cord mesenchymal stem cells (hUCMSCs). Methods: Irradiation with an InGaAIP Laser (660 nm, 10 mW, 2.5 J/cm(2) , 0.08 cm(2) spot size, and 10 s) was carried out. The cells were divided into four groups: CONTROL [cells grown in Dulbecco’s Modified Eagle Medium (DMEM)], OSTEO (cells grown in an osteogenic medium); PBMT (cells grown in DMEM+PBMT), and OSTEO+PBMT (cells grown in an osteogenic medium plus PBMT). The cell proliferation curve was obtained over periods of 24, 48 and 72 hours using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Osteogenic differentiation was analyzed by the formation of calcium nodules over periods of 7, 14 and 21 days. Morphometric analysis was performed to quantify the total area of nodular calcification. Results: The highest cell proliferation and cell differentiation occurred in the OSTEO+PBMT group, followed by the PBMT, OSTEO and CONTROL groups respectively, at the observed times (P

The utility of surveillance imaging after autologous hematopoietic cell transplantation (AHCT) in relapsed/refractory diffuse large B cell lymphoma (DLBCL) remains unclear. The purpose of this study was to determine whether surveillance imaging predicts survival after AHCT. At the University of Minnesota, serial imaging for early relapse detection has been used prospectively for all consecutive AHCT recipients treated since 2010. The present analysis included 91 AHCT recipients with DLBCL who underwent 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scan at day +100 post-AHCT. 18F-FDG-PET parameters included the Deauville (D) 5-point scale, peak standardized uptake values (SUVmax), total legion glycolysis (TLG), and total metabolic tumor volume (TMTV). Survival of patients with clinically symptomatic versus asymptomatic radiographically detected relapsed DLBCL after AHCT was compared. Sixty patients experienced relapse; 35% was detected on day +100 surveillance PET scan. 5-year overall survival (OS) by 18F-FDG-PET scan at day +100 post-AHCT was significantly lower in D4 and D5 patients (37%; 95% confidence interval [CI], 14% to 100% versus 25%; 95% CI, 43% to 89%) compared with patients with D1 and D2 (62%; 95% CI, 43% to 89% versus 62%; 95% CI, 46% to 84%). TLG and TMTV were not prognostic. SUVmax at day +100 varied from 1.5 (D1) to 17.9 (D5). In multivariate analysis, only SUVmax was predictive of relapse and OS; mortality increased 1.8-fold with each SUVmax doubling (hazard ratio [HR], 1.8; 95% CI, 1.3 to 2.3; P

BACKGROUND: The CFU assay is considered the only in vitro assay that assesses the biologic function of hematopoietic stem and progenitor cells (HSPC). STUDY DESIGN AND METHODS: To investigate the impact of post-thaw CFU-GM counts on the quality of umbilical cord blood (UCB), we studied transplant outcomes in 269 patients receiving single UCB transplant. We also correlated the post-thaw CFU-GM counts of 1912 units with the pre-freeze and post-thaw graft characteristics, hoping to optimize selection criteria of UCB. Data analysis included: total nucleated cells, viability, CD34+, nucleated red blood cells (NRBC), hematocrit, frozen storage time, and cord blood bank (CBB). RESULTS: We demonstrated an association between post-thaw CFU-GM dose and the speed of neutrophil and platelet engraftment (p < 0.01). Higher post-thaw CFU-GM dose showed an increased benefit for neutrophil and platelet engraftment (p < 0.01). Post-thaw CD34+ cell dose and CFU-GM dose were strongly correlated (r = 0.78). However, CFU-GM dose showed additional benefit for patients receiving the lowest quartile of CD34+ dose. HLA disparity did not adversely impact either neutrophil or platelet engraftment. Post-thaw CFU-GM/million nucleated cells plated showed moderate correlation with pre-freeze and postthaw CD34+ and weak correlation with other parameters. Post-thaw CFU-GM was not influenced by storage time, but was impacted by the CBB from which the unit is obtained (p < 0.01). CONCLUSION: Post-thaw CFU-GM is an effective measure of the quality and efficacy of the UCB graft, particularly adding valuable clinical information when the CD34+ cell dose is low. Consideration of pre-freeze CD34+ cell content and CBB as additional selection criteria is warranted.

The in vivo depletion of recipient and donor T lymphocytes using antithymocyte globulin (ATG; Thymoglobulin) is widely adopted in allogeneic hematopoietic stem cell transplantation (HCT) to reduce the incidence of both graft failure and graft-versus-host disease (GVHD). However, excess toxicity to donor lymphocytes may hamper immune reconstitution, compromising antitumor effects and increasing infection. Granulocyte-colony stimulating factor (G-CSF) administered early after HCT may increase ATG-mediated lymphotoxicity. This study aimed to investigate the effect of an interaction between ATG and post-transplantation granulocyte colony-stimulating factor (G-CSF) on allogeneic HCT outcomes, using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. We studied patients age ≥18 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who received Thymoglobulin-containing preparative regimens for HLA-matched sibling/unrelated or mismatched unrelated donor HCT between 2010 and 2018. The effect of planned G-CSF that was started between pretransplantation day 3 and post-transplantation day 12 was studied in comparison with transplantations that did not include G-CSF. Cox regression models were built to identify risk factors associated with outcomes at 1 year after transplantation. A total of 874 patients met the study eligibility criteria, of whom 459 (53%) received planned G-CSF. HCT with planned G-CSF was associated with a significantly increased risk for nonrelapse mortality (NRM) (hazard ratio [HR] 2.03; P.0001; 21% versus 12%) compared to HCT without G-CSF. The 6-month incidence of viral infection was higher with G-CSF (56% versus 47%; P = .007), with a particular increase in Epstein-Barr virus infections (19% versus 11%; P = .002). The observed higher NRM with planned G-CSF led to lower overall survival (HR, 1.52; P = .0005; 61% versus 72%). There was no difference in GVHD risk between the treatment groups. We performed 2 subgroup analyses showing that our findings held true in patients age ≥50 years and in centers where G-CSF was used in some, but not all, patients. In allogeneic peripheral blood HCT performed with Thymoglobulin for AML and MDS, G-CSF administered early post-transplantation resulted in a 2-fold increase in NRM and a 10% absolute decrement in survival. The use of planned G-CSF in the early post-transplantation period should be carefully considered on an individual patient basis, weighing any perceived benefits against these risks.

Maternal near-miss (MNM) is a maternal quality care indicator. The World Health Organization (WHO) defines it as a state in which a woman nearly dies but survives due to a complication during pregnancy, birth, or puerperium. The Latin American Federation of Obstetrics and Gynecology (FLASOG) and the Colombian National Health Institute (INS) established recommendations for the event's epidemiological surveillance; nonetheless, the operational definitions of the cases are different. This retrospective study examined the approaches of FLASOG and INS versus the WHO approach (gold standard) for the assessment of MNM in a high obstetric risk unit. Patients admitted with at least one criterion of the WHO, FLASOG, or INS approach for the definition of MNM from March 2016 to March 2017 were included. Sensitivity, specificity, positive and negative predictive value (PPV, NPV) were evaluated, as well as the Receiver Operating Characteristics (ROC) curve of the FLASOG and INS. MNM classification compared to WHO system as reference. The results highlight that the WHO classification establishes very high boundaries for some of the diagnostic criteria and the lack of standardization of the MNM criteria among the different proposals in Latin America hinders the applicability in Colombia and other countries with a similar situation.

To improve accrual to a randomized clinical trial of double unrelated cord blood (dUCB) versus HLA-haploidentical bone marrow (haplo-BM) transplantation, patients with less previous therapy and potentially greater immunocompetence were enrolled. To reduce the risk of graft rejection, patients randomized to receive dUCB received a higher dose of total body irradiation (TBI) (300 cGy versus 200 cGy). In this study, we investigated whether the inclusion of recipients of 300 cGy TBI influenced the trial outcomes. This was a secondary analysis of dUCB recipients, 161 who received TBI 200 cGy and 18 who received TBI 300 cGy. Fine and Gray regression was used to evaluate the effect of TBI dose on relapse and nonrelapse mortality (NRM). Cox regression was used for evaluation of neutrophil engraftment and overall survival. Patient characteristics were similar in the 2 TBI dose subgroups. The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy (P = .64), which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality. We conclude that inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.

Background: Limited studies report a wide range of venous thromboembolism (VTE) incidence among allogeneic hematopoietic cell transplant (alloHCT) recipients. Chronic GVHD (cGVHD) is an immune mediated complication after alloHCT associated with vascular endothelial damage and prolonged systemic inflammation. We hypothesized that patients developing cGVHD are a subgroup at particularly high risk for VTE. Aims: To assess VTE incidence, sites of involvement, and risk factors in patients with cGVHD and to examine the impact of VTE on clinical outcomes after alloHCT. Methods: We performed a retrospective cohort study of all 145 patients who developed cGVHD after a matched sibling (MSD) and umbilical cord blood (UCB) donor alloHCT from 2010 to 2018. VTE was defined as a new confirmed event by imaging at any time after cGVHD diagnosis. VTE sites were categorized as upper extremity (UE), lower extremity (LE) deep vein thrombosis (DVT) or pulmonary embolus (PE). We assessed the cumulative incidence of VTE treating non-VTE mortality as a competing risk. Multivariate regression was used to evaluate the independent association of risk factors with the incidence of VTE using predefined factors in our model including gender, age, DRI, cGVHD severity, days to cGVHD from transplant and platelet level. We accounted for multiple events of VTE using PWP regression. Cox and Fine and Gray regressions were used to evaluate the independent association of time-dependent VTE on overall survival (OS) and non-relapse mortality (NRM), respectively using propensity scoring to control for confounding.. Results: Median age at time of cGVHD diagnosis was 52 years (range 19-74). 104 (72%) patients received MSD and 41 (28%) UCB alloHCT. Of the 145 patients with cGVHD, 32 (22%) developed either 1 or 2 VTE events and 14 (10%) developed 2 VTE events. The first VTE events were PE (n=6, 19%), and DVT (n=26, 81%; n=17 LE, n= 8 UE and n=5 catheter related UE DVT); one patient developed an IVC thrombus. The second VTE events were PE (n=2, 14%), and DVT (n=12, 86%; n=5 LE, n= 7 UE and n=4 catheter related UE DVT). Most patients were on corticosteroids at the first (n=28, 88%) and second (n=10, 71%) VTE with a median dose of (0.3 and 0.2 mg/kg/day, respectively) ± additional immunosuppression therapies. The cumulative incidence of VTE through 5 years post cGVHD diagnosis was estimated at 22% (95% CI: 15-29%) with median time from cGVHD diagnosis to VTE of 234 days (IQR 85-599). Median time to the development of LE DVT or PE was shorter than UE DVT (107 vs 450 days, respectively). Incidence was higher in males (24% vs 18%), and was not significantly different by age (< or ≥50), BMI (< or ≥30), HCT- comorbidity index, donor type, conditioning regimen and GVHD prophylaxis. Cumulative incidence was higher (50%) in patients with high/very high risk DRI compared to 19% in those with low and intermediate risk DRI. VTE incidence was highest in patients with de novo cGVHD (25%) compared to quiescent (20%) and progressive type (17%). Cumulative incidence was 9%, 17% and 38% in those with mild, moderate and severe GVHD respectively. Patients with lung, gastrointestinal, genitourinary and liver cGVHD had a higher incidence of VTE. Patients developing cGVHD >6 months from HCT had a higher incidence of VTE (24% vs 19%). In multivariate analysis, high/very high risk DRI was associated with higher risk of VTE (HR 2.5; 95% CI; 1.2-5.3) (Figure 2). VTE was not associated with a significantly higher 2-year NRM (HR 1.2; 95% CI; 0.4-3.6) or 5 year OS (HR 1.4; 95% CI; 0.7-3.0). Conclusion: Patients who develop cGVHD after alloHCT have a high incidence VTE. Identifying a subgroup at a particularly high risk for VTE could inform thromboprophylaxis and other supportive care strategies for prevention of such events. Disclosures Bachanova: Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Blazar:Tmunity: Other: Co-founder; Magenta Therapeutics: Consultancy; KidsFirst Fund: Research Funding; Fate Therapeutics Inc.: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeuetic: Consultancy; BlueRock Therapeutics: Research Funding. Brunstein:Astex: Research Funding; AlloVir: Other: Advisory board; Magenta: Research Funding; Gamida: Research Funding. Holtan:CSL Behring: Other: Clinical trial data adjudication; BMS: Consultancy; Generon: Consultancy; Incyte: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Gangaraju:Sanofi Genzyme, Consultant for Cold Agglutinin Disease: Consultancy. MacMillan:Talaris Therapeutics, Inc: Consultancy; Angiocrine Biosciences, Inc.: Consultancy; Equillium, Inc.: Consultancy; Fate Therapeutics, Inc.: Consultancy; Mesoblast: Consultancy. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Arora:Pharmacyclics: Research Funding; Fate Therapeutics: Consultancy; Kadmon: Research Funding; Syndax: Research Funding.

Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning is currently the standard of care for young and fit patients; however, graft-versus-host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one combining strategies that reduce incidence and severity of GVHD, without compromising graft-versus-tumor effect. We hypothesized that GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) will reduce the incidence of chronic GVHD in patients receiving a standard hematopoietic myeloablative HCT without an increase in risk of malignant relapse. Methods This is an interim analysis of a phase II study using a myeloablative preparative regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 µmol/min/L) plus fludarabine 160mg/m 2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Patient and disease characteristics are detailed in Table 1. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. Results Through October 2020 we treated 63 patients with a median follow up of 502 days post-transplant. Of those, 48% were female and n=11 (17%) younger than 18 with median age at HCT of 36 years (range, 2-55; Interquartile range [IQR], 20-48). Donor source was 8/8 MRD in 44 patients (70%), 8/8 MUD in 18 (29%), and one with 7/8 MUD. Graft source was BM in n=28 (44%) and PB in n=35 (56%). Preparative regimen was TBI in 94% of patients. All patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-27). Overall, 94% achieved platelet engraftment by 6 months, median 25 days (range, 16-98). At day 100, 48 patients (86%) achieved full donor bone marrow chimerism (>95% donor DNA); 29 (52%) and 52 (95%) achieved full donor peripheral blood CD3 and CD33 chimerism (defined as >95% donor). 42 patients (66%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by 100 days post-transplant was 14% overall (95% confidence interval CI: 6-23%), 7% for MRD and 32% for the MUD group; Grade III-IV acute GVHD was 5% overall (CI: 0-10%), similar for both MRD and MUD group. At 1 year, only two patients receiving a PBSC graft developed chronic GVHD requiring immune suppression, for a cumulative incidence of 3% overall, one in the MRD group and one in the MUD group. Two-year cumulative incidence of relapse was estimated at 21% overall, 22% and 16% for the MRD and MUD groups, respectively. Two year cumulative incidence of non-relapse mortality was 13% overall, 15% and 5% for MRD and MUD, respectively. Estimated 2-year overall survival was 79% overall (CI: 65-88%), 75% for the MRD group and 95% for MUD. Estimated 2-year GVHD-free relapse free survival (GRFS) was 57% overall (CI: 42-69%), 56% and 63% in the MRD and MUD groups, respectively. Discussion Myeloablative transplantation with a TBI preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in very low incidence of chronic GVHD. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes can be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1 Figure 1. Disclosures Arora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Janakiram: Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria; FATE, Nektar Therapeutics: Research Funding. Smith: Astellas Gene Therapies: Current Employment. Bachanova: Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brunstein: BlueRock: Research Funding; AlloVir: Consultancy; FATE: Research Funding; NANT: Research Funding; GamidaCell: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Miller: Sanofi: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: Mitobridge, an Astellas Company: Consultancy, Research Funding; CSL Behring: Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Holtan: Generon: Consultancy; Incyte: Consultancy, Research Funding.

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with systemic inflammation and endothelial dysfunction, increasing risk for thromboembolic events (TEE). In 145 adult recipients who developed cGVHD after a matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 32(22%) developed at least 1 TEE event, and 14(10%) developed 2 TEE events. The 5-year cumulative incidence of TEE was 22% (95% CI, 15–29%) with a median time from cGVHD to TEE of 234 days (range, 12–2050). Median time to the development of LE DVT or PE was 107 (range, 12–1925) compared to 450 days (range, 158–1300) for UE DVT. Cumulative incidence of TEE was 9% (95% CI, 0–20%), 17% (95% CI, 9–25%), and 38% (95% CI, 22–55%) in those with mild, moderate, and severe GVHD, respectively. Higher risk for TEE was associated with cGVHD severity (hazard ratio [HR] 4.9, [95% CI, 1.1–22.0]; p = 0.03), non-O-donor to recipient ABO match compared to O-donor to O-recipient match (HR 2.7, [95% CI, 1.0–7.5]; p = 0.053), and personal history of coronary artery disease (HR 2.4, [95% CI, 1.1–5.3]; p = 0.03). TEE was not associated with 2-year non-relapse mortality or 5-year overall survival., Key points Patients with chronic GVHD after allogeneic hematopoietic cell transplantation are at high risk for thromboembolic events occurring years after diagnosis. More severe chronic GVHD, non-O donor-recipient ABO compared to O-O match and personal history of coronary artery disease are associated with higher risk of thromboembolic events.

Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain partially elusive. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who beared biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein–protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4(+) CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity and provides the molecular pathomechanism behind the identified here and previously unreported genetically determined form of HLH.

Post transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has allowed haploidentical (Haplo) transplantation to be performed with results similar to that after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD versus Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate containing GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults between 2011 and 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced intensity regimens were analyzed separately. Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70, p=0.022), acute grade III-IV GVHD (HR 0.41, p=0.016) and non-relapse mortality (HR 0.43, p=0.0008) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74, p=0.008; 55% versus 41%) and overall survival (HR 0.65, p=0.001; 67% versus 54%) were higher after MUD compared to Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% versus 88%) was higher and grade III-IV acute (HR 0.39, p=0.07) and chronic GVHD (HR 0.66, p=0.05) were lower after MUD compared to Haplo transplantation. There were no differences in graft failure, relapse, non-relapse mortality, disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced intensity conditioning regimens.

BACKGROUND Transfusions are essential for allogeneic hematopoietic cell transplant (HCT), yet they are influenced by graft, donor, and other factors. STUDY DESIGN We analyzed transfusions in 165 adult reduced intensity HCTs (2016-2019): HLA matched sibling donor (MSD) (n = 59), matched URD (n = 25), UCB (n = 33), and haploidentical (haplo, n = 48) detailing the cumulative incidence of platelet and RBC transfusion independence, total transfusions (day-10 to day+100) plus transfusion densities (per week) over 110 days. RESULTS Platelet recovery to 20 × 109 /L by 6 months occurred in 39/48 (81.25%) haplo recipients (median 33 [range, 0-139]) days vs. 58/59 (98.3%) MSD (median 10 [0-37]), 21/25 (84%) matched URD (median 20 [0-153]), and 29/33 (87.87%) UCB (median 48 [29-166]) days, p

The COVID19 pandemic requires no introduction anymore with a total of 12.5 million cases reported worldwide and more than 500,000 deaths as of July 30, 2020 [1]. Of particular interest to the audience of this journal is the impact of SARS-CoV2 infection in immunosuppressed patients and patients with hematological malignancies. The COVID19 and Cancer Consortium database (CCC19) is an ongoing clinical trial investigating the impact of SARS-CoV2 infection in patients with malignancies. They have reported an increased mortality (13%) among ~1000 patients with different cancer types [2]. Hematopoietic stem cell transplant (HCT) programs have all adapted and gradually adopted workflow modifications to mitigate infectious risk on both patients and staff. The National Marrow Donor Program (NMDP) has also adjusted its workflow by screening donors of HCT prior to collection of hematopoietic stem cells (HSC) followed by cryopreservation of the graft. Most transplant centers have also adopted a policy of not initiating conditioning regimens prior to receipt of the cryopreserved HSCs given the possibility of delays in air travel and shipping [3]. We herein report the first occurrence of an unrelated HSC donor who tested positive for SARS-CoV2 shortly after donating HSCs, our approach to management, and short-term follow-up. We review the literature about transmission of SARS-CoV2 in blood and end with a brief set of recommendations about lessons learned. Our index patient is a 53-year-old woman with therapy-related acute myeloid leukemia with a TP53 mutation. She was in complete remission but had evidence of minimal residual disease by next generation sequencing (NGS). She was set to receive a total-body irradiation-based, myeloablative transplant from a HLA-matched donor (11/12; DP permissive mismatch), who was an ABO major mismatch. The donor was tested negative for SARS-CoV2 48 h prior to undergoing HSC harvest from the bone marrow per what is currently standard of practice of the donor center. Two days following the harvest, he reported symptoms of a sore throat and fatigue. He also reported that one of the members of his household was diagnosed with COVID19. After the close contact tested positive, the donor was retested for SARS-CoV2 and found to be positive. He displayed mild symptoms that spontaneously resolved. At the time of confirmed positive testing, the patient had completed 80% of her scheduled TBI and the decision was made to move forward with the transplant given the myeloablative conditioning already administered. High-efficiency particulate-air (HEPA) filtration was activated in the patient’s room. A segment from the bone marrow product, cryopreserved at −80°C was tested for SARS-CoV2 using qRT-PCR to viral targets N1 and N2 (as per the CDC 2019 Novel Coronavirus (2019-nCoV) Real-Time Reverse Transcriptase (RT)–PCR Diagnostic Panel) and was negative [4]. Given the negative result on the bone marrow product and the lack of evidence for blood transmission of coronavirus, we used standard precautions and did not isolate the patient. The patient did not display any infectious signs or symptoms during the first 14 days of her post-transplant course and is currently recovering almost one month from her transplant. The medical community responded in a swift and nimble manner to the COVID19 pandemic by instituting policies to minimize both staff and patient exposure and to account for the logistic barriers that have arisen. The NMDP was among those early responders when they rallied to get flight exemptions for couriers carrying stem cell products, rapidly analyzed and the CIBMTR made available data regarding the safety of cryopreservation in different disease states, instituted policies and communicated with transplant centers about the procurement and transportation of stem cell products. Donors were routinely screened with the questionnaire. Once testing became widely available, it was added, whenever possible, prior to donation to ensure utmost safety. Our transplant center, along with others, instituted policies where conditioning of the patient is delayed until the product has safely arrived. Despite all these measures, new challenges continue to arise despite our best efforts to predict and mitigate them. We herein presented a patient who was set to receive a product that potentially could have been contaminated with SARS-CoV2. When we learned of the donor testing, it would have been difficult to delay the transplant. After discussing the risks and benefits of proceeding versus aborting the transplant, we proceeded as scheduled. SARS-CoV2 ribonucleic acid (RNA) has been detected in the blood of patients with SARS-CoV2 [5,6,7]. However, there is no reported evidence that SARS-CoV2 is transmissible in the blood. In fact, there is evidence that it is unlikely to be transmitted. A report of 18 patients with SARS-CoV2 infection and varying levels of symptoms examined the rate of positivity of RNA qRT-PCR in whole blood, serum, and plasma. Testing was repeated between 1 and 8 times on each individual patient for a total of 77 samples. Only one sample had weak positivity (179 copies/ml) [8]. The mere detection of RNA in the blood of donors does not imply transmissibility of the infectious virus itself. In another study examining SARS-CoV2 virology, RNA was consistently recovered from stool, but no viral particles were isolated in cultures, highlighting the discrepancy between RNA detection and infectivity [9]. In fact, respiratory viruses are generally not considered to be transmissible by blood. The two most commonly cited examples are Severe Acute Respiratory Syndrome (SARS) virus and the Middle East Respiratory Syndrome (MERS) coronavirus that have caused epidemics in recent history but have not been reported to be transported by blood products [10]. There is also no evidence that respiratory viruses, including SARS-CoV2, survive cryopreservation or other...

Graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents complete, ideal recovery after allogeneic hematopoietic cell transplantation (HCT). However, as originally proposed, this composite endpoint does not account for the possibility that HCT complications may improve after treatment. To more accurately estimate survival with response to GVHD and relapse after HCT, we developed a dynamic multistate GRFS (dGRFS) model with outcomes data from 949 patients undergoing their first allogeneic HCT for hematologic malignancy at the University of Minnesota. Because some patients were successfully treated for GVHD and relapse, dGRFS was higher than the originally defined time-to-event GRFS at 1 year (37.0 versus 27.6%) through 4 years (37.4% versus 22.2%). Mean survival without failure events was .52 years (95% confidence interval, .45 to .58 year) greater in dGRFS compared with the originally defined GRFS. Patient age (P< .001 ), disease risk (P < .001 ), conditioning intensity (P = .007), and donor type (P = .003) all significantly influenced dGRFS. The multistate model of dGRFS closely estimates the continuing and prevalent severe morbidity and mortality of allogeneic HCT. To serve the greater HCT community in more accurately modeling recovery from transplantation, we provide our R code for determination of dGRFS with annotations in Supplementary Materials.

Key Points CMV reactivation was associated with the maturation of reconstituting NK cells from BM, but not PB, unrelated donor grafts. CMV reactivation was associated with CD8+, but not CD4+, T-cell recovery, more so after BM than PB unrelated donor grafts.

Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) >= 30 kg/m(2). Dose adjustment was defined as a reduction in standard dosing >= 20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) who received carmustine, etoposide, cytarabine, and melphalan conditioning. Chemotherapy dose was adjusted in 1324 patients (78%) with MM and 608 patients (78%) with lymphoma. Age, sex, BMI, race, performance score, comorbidity index, and disease features (stage at diagnosis, disease status, and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (P = .894) and treatment-related mortality (TRM) (P = .62), progression (P = .12), and progression-free survival (PFS; P= .178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (P = .176), TRM (P = .802), relapse (P = .633), or PFS (P = .812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose before autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population. (C) 2018 American Society for Blood and Marrow Transplantation.

PURPOSE Single-cycle melphalan 200 mg/m2 and autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide (len) maintenance have improved progression-free survival (PFS) and overall survival (OS) for transplantation-eligible patients with multiple myeloma (MM). We designed a prospective, randomized, phase III study to test additional interventions to improve PFS by comparing AHCT, tandem AHCT (AHCT/AHCT), and AHCT and four subsequent cycles of len, bortezomib, and dexamethasone (RVD; AHCT + RVD), all followed by len until disease progression. PATIENTS AND METHODS Patients with symptomatic MM within 12 months from starting therapy and without progression who were age 70 years or younger were randomly assigned to AHCT/AHCT + len (n = 247), AHCT + RVD + len (n = 254), or AHCT + len (n = 257). The primary end point was 38-month PFS. RESULTS The study population had a median age of 56 years (range, 20 to 70 years); 24% of patients had high-risk MM, 73% had a triple-drug regimen as initial therapy, and 18% were in complete response at enrollment. The 38-month PFS rate was 58.5% (95% CI, 51.7% to 64.6%) for AHCT/AHCT + len, 57.8% (95% CI, 51.4% to 63.7%) for AHCT + RVD + len, and 53.9% (95% CI, 47.4% to 60%) for AHCT + len. For AHCT/AHCT + len, AHCT + RVD + len, and AHCT + len, the OS rates were 81.8% (95% CI, 76.2% to 86.2%), 85.4% (95% CI, 80.4% to 89.3%), and 83.7% (95% CI, 78.4% to 87.8%), respectively, and the complete response rates at 1 year were 50.5% (n = 192), 58.4% (n = 209), and 47.1% (n = 208), respectively. Toxicity profiles and development of second primary malignancies were similar across treatment arms. CONCLUSION Second AHCT or RVD consolidation as post-AHCT interventions for the up-front treatment of transplantation-eligible patients with MM did not improve PFS or OS. Single AHCT and len should remain as the standard approach for this population.

Catheter-related thrombosis (CRT) occurs frequently during autologous hematopoietic cell transplantation (AHCT) and data regarding the incidence, risk factors, and management are understudied. We evaluated 789 consecutive patients with lymphoma and myeloma that underwent AHCT over 10 years (2006 to 2016) and detected the incidence of CRT was 6.3%; only 32% of CRT were symptomatic. The majority occurred within 100 days of AHCT (86%) and median time from tunneled line placement to CRT was 44 days (range, 11 to 89 days). Outcomes of these 50 patients with CRT were compared with age- and disease-matched AHCT control subjects to identify risk factors. History of prior venous thromboembolism (VTE) (20.9% versus 7.0%, P = .02) was the only significant risk factor. Treatment with low-molecular-weight heparin was tolerated with rare minor bleeding (4%), although CRT recurrence or extension (10%) and subsequent VTE (12%) were common. CRT did not impact on nonrelapse mortality or risk of relapse; 2-year progression-free survival was 55% in CRT cases versus 54% in control subjects (P = .42). CRT appears to be common in patients with lymphoma and myeloma undergoing AHCT and significantly contributes to morbidity. Further study to determine mitigating strategies and modify risk factors for CRT is warranted.

Universities across the world are contributing greatly to production and operations management (POM) research and playing significant roles in social and economic development. This article analyzes the performance of universities in POM research and development between 1990 and 2014. The Web of Science core collection database is used to collect all the necessary data. The results show a wide diversity among the countries of origin of the top universities, with some of them being in Asia, Europe, and North America. These results are quite different from many other management areas where English-speaking countries, especially the USA, tend to be dominant. Hong Kong Polytechnic University is the most productive university, while Michigan State University is the most influential one. Time-based evolution reveals that the USA previously had a more dominant position, while now there is more distribution of top universities around the world. The analysis of selected journals indicates that many journals tend to be more influenced by their respective countries of origin. However, other journals show a more general profile by publishing papers from most of the countries around the world.

Platelet recovery is delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that has the potential to improve platelet engraftment after UCBT. The purpose of this study was to determine the safety profile and maximum tolerated dose (MTD) of romiplostim and to investigate whether romiplostim accelerates platelet recovery post-UCBT. It was a single-center, dose-finding, safety and tolerability phase I trial of weekly romiplostim in 20 adult patients who failed to achieve an un-transfused platelet count of 20 × 109/L by day +28 post-UCBT. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post-UCBT. Four dose levels (4, 6, 8, and 10 µg/kg per dose) were evaluated. The MTD of romiplostim was determined by the continual reassessment method, with a goal to identify a dose level with desired toxicity rate of ≤20%. Median age of the patients was 59.5 years, and 60% were female. Eleven patients received nonmyeloablative (NMA) double UCBT, seven patients received myeloablative single UCBT, and two patients received NMA single UCBT. Two patients received 4 µg/kg per dose, two received 6 µg/kg per dose, four received 8 µg/kg per dose, and the remaining 12 received 10 µg/kg per dose. Only five patients completed the full six doses of treatment. Of the 15 patients who received fewer than six doses, 12 were due to a platelet count of >100 × 109/L, two were due to platelet count of >400 × 109/L, and one was due to right upper extremity edema without thrombosis. All romiplostim-treated patients achieved platelet engraftment to 20 × 109/L at a median of 45 days post-UCBT compared to 90% of controls at a median of 45 days (P = .08). Similarly, 90% of romiplostim-treated patients achieved platelet engraftment to 50 × 109/L at a median of 48 days compared to 75% of controls at a median of 52 days (P = .09). All dose levels were effective with low toxicity; therefore, the MTD of romiplostim was 10 µg/kg per dose, and romiplostim is a safe and potentially effective therapy to counter delayed platelet recovery post-UCBT.

This chapter describes the new wave of modern family businesses created by family entrepreneurs who have known to globalize their business through information technologies, social networks, and megatrends since the 2000s to the present in Latin America. Likewise, we describe the meaning of family entrepreneurship, its triggers in Latin America, and the challenges of entrepreneurial families.

[Importance] Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm., [Objective] To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes., [Data Sources] Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts., [Study Selection] Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria., [Data Extraction and Synthesis] In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance–weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality., [Main Outcomes and Measures] The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days., [Results] A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P, [Conclusions and Relevance] In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality., [Trial Registration] PROSPERO Identifier: CRD42021230155., Funding for administrative and communications support was provided by the World Health Organization.

During the last two decades, there has been a growing interest in the study of family businesses and their interrelation with other specialties and sciences, such as anthropology and sociology, and this incorporation is undoubtedly a relevant contribution to the knowledge we have of this ownership structure. Much of the current research has focused on comparing family businesses with non-family businesses; in other cases, on the dynamics of family businesses according to their size, or on analyzing them as individual businesses, not as a more homogeneous group.

Objective To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19). Design Randomised, open label trial. Setting Nine hospitals in Brazil, 8 May to 17 July 2020. Participants Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group. Interventions Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64). Main outcome measure The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met. Results A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab. Conclusions In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality. Trial registration ClinicalTrials.gov NCT04403685 .

Omidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase 3 trial to evaluate the efficacy of omidubicel compared with standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients age 13 to 65 years with hematologic malignancies were randomly assigned to omidubicel vs standard UCBT. Patients received myeloablative conditioning and prophylaxis with a calcineurin inhibitor and mycophenolate mofetil for graft-versus-host disease (GVHD). The primary end point was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% confidence interval [CI], 10-14 days) for the omidubicel arm and 22 days (95% CI, 19-25 days) for the control arm (P < .001). The cumulative incidence of neutrophil engraftment was 96% for patients receiving omidubicel and 89% for patients receiving control transplants. The omidubicel arm had faster platelet recovery (55% vs 35% recovery by 42 days; P = .028), had a lower incidence of first grade 2 to 3 bacterial or invasive fungal infection (37% vs 57%; P = .027), and spent more time out of hospital during the first 100 days after transplant (median, 61 vs 48 days; P = .005) than controls. Differences in GVHD and survival between the 2 arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduces early transplant-related complications compared with standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT. The trial was registered at www.clinicaltrials.gov as #NCT02730299.

BACKGROUND: Randomized clinical trials offer the highest quality data for modifying clinical practice. Results of a phase III randomized trial of non-myeloablative transplantation for adults with high-risk hematologic malignancies with two umbilical cord blood (UCB) units (n=183) or HLA-haploidentical relative bone marrow (Haplo-BM) (n=154) revealed 2-year progression-free survival (PFS) of 41% and 35% after Haplo-BM and two-unit UCB transplantation, respectively (p=0.41); overall survival was 57% and 46%, respectively (p=0.04), BMT CTN 1101; NCT01597778. OBJECTIVES: We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial’s pre-specified 2-year outcomes. All transplantation occurred between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial will be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM to those after haploidentical peripheral blood (Haplo-PB). STUDY DESIGN: The trial’s broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select non-trial subjects. Extended follow up of trial subjects was obtained from this data source. Three separate analyses were performed: 1) trial subjects beyond the trial’s 2-year endpoint 2) comparison of trial subjects to a contemporaneous cohort of non-trial subjects (195 two-unit UCB, 358 Haplo-BM, 403 Haplo-PB) and 3) comparison of non-trial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups. RESULTS: With longer follow up of the trial cohorts, 5-year PFS (37% versus 29%, p=0.08) and overall survival (42% versus 36%, p=0.06) were not significantly different between treatment groups. We then compared the trial results to comparable real-world transplantations. Five-year overall survival after trial and non-trial two-unit UCB (36% versus 41%, p=0.48) and trial and non-trial Haplo-BM (42% versus 47%, p=0.80) transplantation were not different confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in progression-free survival. With substantially larger numbers of non-trial Haplo-BM transplantations, 5-year survival was higher after non-trial Haplo-BM compared to trial two-unit UCB (47% versus 36%, p=0.012). Non-trial patients who received Haplo-PB transplantation had higher 5-year survival (54%) compared to trial (HR 0.76, p=0.044) and non-trial (HR 0.78, p=0.026) Haplo-BM. Similarly, survival was higher after Haplo-PB compared to trial (HR 0.57, p

The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n = 114) and younger (40 to 64 years; n = 240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day −14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3–4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR, .98; 95% confidence interval [CI], .90 to 1.06; P = .65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P < .01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P = .03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P = .02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P < .01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P = .02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P = .02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P = .01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P < .01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P = .01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P = .05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3–4 toxicities (P = .04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3–4 toxicities. Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs.

Recipients of allogeneic hematopoietic cell transplantation (HCT) experience a substantial health care burden, with potentially differing patterns of long-term health care requirements using peripheral blood stem cells, bone marrow, and umbilical cord blood (UCB) grafts. We analyzed data from 1077 consecutive adult allogeneic HCT recipients who underwent transplant at the University of Minnesota between 2000 and 2016. To estimate health care burden over time, we compared the number of visits, laboratory studies, medications, and relative value units billed. Health care elements were analyzed both individually and together (ie, total health care elements used per patient days into a density composite score). UCB had the lowest density health care burden composite score from the time of transplant through year 5 (median score 64.0 vs 70.5 for peripheral blood stem cells and 88.0 for bone marrow; P < .01). In multivariate analysis of health care burden between years 1 and 5, recipients of either bone marrow (odds ratio [OR] 0.49 [95% confidence interval (CI) 0.29-0.84]) or peripheral blood stem cells (OR 0.49 [95% CI 0.36-0.67]) were half as likely to experience low health care burden compared with UCB. Adult recipients of UCB have a lower long-term health care burden compared with other graft sources, possibly reflecting a better quality of life.

OBJECTIVES Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT. METHODS MMF was combined with cyclosporine (n = 599) or sirolimus (n = 81). We divided MMF dose/kg/day in quartiles. RESULTS The median time to grade II-IV acute GVHD was 32 days. The incidence of grade II-IV acute GVHD at day 30 was 30% in 1st (

Compared with reduced-intensity conditioning (RIC), myeloablative conditioning (MAC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). However, disease-specific risk factors in AML/MDS can further inform when MAC and RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the Disease Risk Index (DRI) in 4387 adults (age 40 to 65 years) to identify the impact of conditioning intensity. In the low/ intermediate-risk DRI cohort, RIC was associated with lower nonrelapse mortality (NRM) (hazard ratio [HR],.74; 95% confidence interval [CI],.62 to.88; P

Although hematopoietic cell transplantation from an HLA-matched unrelated donor is potentially curative for hematologic malignancies, survival is lower for African Americans compared with Caucasians. Because only approximately 20% of African Americans will have an HLA-matched unrelated donor, many of these patients undergo HLA-haploidentical relative or umbilical cord blood transplantation. In this study, we analyzed outcomes after HLA-haploidentical related donor (n = 249) and umbilical cord blood (n = 118) transplantations in African American patients with hematologic malignancy between 2008 and 2016. The predominant disease was acute myelogenous leukemia for recipients of both types of donor grafts. The incidences of grade II-IV and III-IV acute graft-versus-host disease were higher after umbilical cord blood transplantation compared with HLA-haploidentical relative transplantation (56% and 29%, respectively, versus 33% and 11%, respectively; P

There is a growing population of transplant survivors receiving both a solid organ transplantation (SOT) and a hematopoietic cell transplantation (HCT). This group remains underreported and not well described. We conducted a single-center retrospective study aimed at assessing safety and long-term survival outcomes of 40 patients receiving both HCT and SOT at the University of Minnesota. Twenty-seven patients underwent HCT followed by SOT (13 kidney, 10 lung, 2 liver, 1 heart, 1 heart/kidney) with a median age of 40 years (range, 5 to 72) at the time of SOT at a median of 88 months (range, 24 to 302) following the HCT. The 1-, 5-, and 10-year overall survival (OS) from the SOT was 93%, 76%, and 49%, respectively, with only 4 organ failures reported. Thirteen other patients received a HCT following a prior kidney (n = 8), liver (n = 4), or pancreas/kidney (n = 1) SOT with a median age of 42 years (range, 3 to 66) at the time of the HCT and a median 154 months (range, 1 to 304) from the SOT. The 1-, 5-, and 10-year OS from HCT were 46%, 46%, and 17% respectively. In patients receiving SOT followed by HCT, survival outcomes were better in kidney transplant recipients and patients subsequently requiring an autologous rather than an allogeneic HCT. There were no HCT engraftment failures. Our findings show that in a select patient population, undergoing a second transplant at a specialized center can lead to favorable outcomes with long-term survival and low incidence of graft rejection, organ failure, and malignant disease relapse. A large-scale study is needed to determine the incidence and risk factors preferred for a successful subsequent SOT or HCT. Those studies are crucial to further guide selection and management of patients who would benefit most from a second transplant.

The functions of mast cells in human graft-versus-host disease (GVHD) are unknown. We studied 56 patients who had an allogeneic hematopoietic cell transplantation (alloHCT) with a biopsy for diagnosis of gastrointestinal tract (GIT) GVHD before any treatment (including steroids): 35 with GIT GVHD, 21 HCT recipients whose biopsies did not confirm GVHD, and 9 with a new diagnosis of inflammatory bowel disease (IBD) as a comparison. the median number of mast cells (mean of CD117(+) cells, counted in 3 selected spots under 40x magnification) was similar between patients with GVHD (59 cells) and those without GVHD (60 cells). However, the median number of mast cells was significantly associated with maximum clinical stage of GIT GVHD; the lowest counts of mast cells were observed in the highest clinical stage of GIT GVHD (stage 1, 80; stage 2, 69; stage 3, 54; stage 4, 26; P = .01). Moreover, every decrease by 10 mast cells was associated with increased nonrelapse mortality through 1 year (hazard ratio, 0.77; 95% confidence interval, 0.59-1.00; P = .05). AlloHCT recipients all had significantly fewer mast cells, even those without GVHD compared with those with IBD (median, 59 vs 119; P < .01). the median number of GIT mast cells was also significantly lower in patients who received myeloablative conditioning (61.5 cells) than in those who received reduced intensity conditioning (78 cells) in the entire study population (P = .02). We conclude that GIT mast cells are depleted in all alloHCT patients, more prominently in those receiving myeloablative conditioning and those with severe GIT GVHD. Our novel findings warrant further investigation into the biological effects of mast cells in GIT GVHD., NCATS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1 TR002494] Funding Source: Medline; NCI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30 CA077598] Funding Source: Medline; NHLBI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01 HL056067] Funding Source: Medline

Human settlement of Madagascar traces back to the beginning of the first millennium with the arrival of Austronesians from Southeast Asia, followed by migrations from Africa and the Middle East. Remains of these different cultural, genetic, and linguistic legacies are still present in Madagascar and other islands of the Indian Ocean. The close relationship between human migration and the introduction and spread of infectious diseases, a well-documented phenomenon, is particularly evident for the causative agent of leprosy, Mycobacterium leprae. In this study, we used whole-genome sequencing (WGS) and molecular dating to characterize the genetic background and retrace the origin of the M. leprae strains circulating in Madagascar (n = 30) and the Comoros (n = 3), two islands where leprosy is still considered a public health problem and monitored as part of a drug resistance surveillance program. Most M. leprae strains (97%) from Madagascar and Comoros belonged to a new genotype as part of branch 1, closely related to single nucleotide polymorphism (SNP) type 1D, named 1D-Malagasy. Other strains belonged to the genotype 1A (3%). We sequenced 39 strains from nine other countries, which, together with previously published genomes, amounted to 242 genomes that were used for molecular dating. Specific SNP markers for the new 1D-Malagasy genotype were used to screen samples from 11 countries and revealed this genotype to be restricted to Madagascar, with the sole exception being a strain from Malawi. The overall analysis thus ruled out a possible introduction of leprosy by the Austronesian settlers and suggests a later origin from East Africa, the Middle East, or South Asia.

We demonstrate a chip-scale quantum emitter-metamaterial device that emits highly directional photons. Our device opens the door for quantum imaging of yveak sources by adding photon(s) to manipulate the photon statistics for improved signal-to-noise ratio.

Highlights • In post-transplantation cyclophosphamide-based allogeneic hematopoietic stem cell transplantation, graft cryopreservation was not associated with significantly higher mortality. • Cryopreserved grafts were not associated with significantly delayed hematopoietic recovery or increased risk of acute graft-versus-host disease (GVHD). • Cryopreserved grafts were associated with lower risk of chronic GVHD and inferior disease-free survival, but these differences were of only borderline statistical significance., The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values

Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation that fails to improve with intense immunosuppression in some patients. We hypothesized that urinary-derived human chorionic gonadotropin (uhCG) could help facilitate resolution of life-threatening aGVHD when added as supportive care via 2 potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF; to aid in epithelial repair). In a phase 1 study, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 receiving initial therapy for high-risk aGVHD [according to the Minnesota criteria] and 13 receiving second-line therapy). Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study. uhCG was well tolerated, with no dose-limiting toxicities. Sixty-two percent of patients in the high-risk cohort and 54% of patients in the second-line cohort had a complete response at study day 28. Plasma EGF was elevated sixfold (from 4 to 24 pg/mL; P = .02) at 6 hours postdose in the high-risk cohort, in contrast to no peak in plasma EGF in the more severe second-line cohort. After 1 week of uhCG, patients reported a twofold increase in the regulatory T cell to conventional T-cell ratio, suggesting immune modulation despite high-dose steroids. Responding patients reported significantly lower plasma amphiregulin and higher plasma butyrate levels at study completion, suggesting improvement in mucosal damage over time. uhCG is a novel, safe, supportive therapy, proceeding to phase 2 testing at 2000 units/m2 in high-risk aGVHD. This study was registered at www.clinicaltrials.gov as #NCT02525029.

In the absence of prospective studies that examine the effect of conditioning regimen intensity after T-cell–replete haploidentical transplant for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS), a retrospective cohort analysis was performed. Of the 1325 eligible patients (AML, n = 818; ALL, n = 286; and MDS, n = 221), 526 patients received a myeloablative regimen and 799 received a reduced-intensity regimen. Graft-versus-host disease prophylaxis was uniform with posttransplant cyclophosphamide, a calcineurin inhibitor, and mycophenolate mofetil. The primary end point was disease-free survival. Cox regression models were built to study the effect of conditioning regimen intensity on transplant outcomes. For patients aged 18 to 54 years, disease-free survival was lower (hazard ratio [HR], 1.34; 42% vs 51%; P = .007) and relapse was higher (HR, 1.51; 44% vs 33%; P = .001) with a reduced-intensity regimen compared with a myeloablative regimen. Nonrelapse mortality did not differ according to regimen intensity. For patients aged 55 to 70 years, disease-free survival (HR, 0.97; 37% vs 43%; P = .83) and relapse (HR, 1.32; 42% vs 31%; P = .11) did not differ according to regimen intensity. Nonrelapse mortality was lower with reduced-intensity regimens (HR, 0.64; 20% vs 31%; P = .02). Myeloablative regimens are preferred for AML, ALL, and MDS; reduced-intensity regimens should be reserved for those unable to tolerate myeloablation.

PRIMeR is the first U.S.-based ancillary study of MRD assessment by multiparameter flow cytometry (MFC). Patients were enrolled on a national 3-arm RCT (BMT CTN 0702, STAMiNA trial, ClinicalTrials.gov Identifier: NCT01109004) comparing 1) tandem auto-HCT, 2) single auto-HCT and 3) single auto-HCT, 4 cycles of lenalidomide, bortezomib, dexamethasone consolidation (auto+RVD); all 3 treatment arms included continuous lenalidomide maintenance until MM progression. STAMiNA opened to accrual before PRIMeR initiated, therefore 437 of 758 patients enrolled in STAMiNA provided consent and at least one analyzable sample for MRD by MFC to PRIMeR. Disease responses and progressions were adjudicated by an independent review committee. All analyses of treatment arm were performed using intent-to-treat. The MFC panel included 10 monoclonal antibodies (CD38, CD138, CD45, CD56, CD19, CD20, CD27, CD28, kappa, lambda) measured via 3 tubes of 6 colors each with a target of analyzing 2.5 × 105-1.5 × 106 events, depending on sample quality and quantity, yielding a sensitivity of 10−5 to 10−6. All samples were interpreted by two experienced flow cytometrists who were blinded to treatment arm and other patient, disease and treatment characteristics. MRD was assessed at Baseline/pre-AutoHCT (BL), Pre-maintenance (PM), and 1 year (Y1) post AutoHCT with the primary endpoint of MRD negative at Y1. At a median follow-up of 38 months, there was no significant difference in PFS or OS by treatment arm in the subset of PRIMeR patients. Univariate analysis demonstrated that being MRD negative at PM and Y1 was associated with better PFS, and at Y1, patients who were MRD negative also had longer OS (Table 1, Figures). Multivariate analysis of time to progression or death, adjusting for disease risk, demonstrated hazard ratios (HR) in MRD negative patients compared to MRD positive patients at BL, PM and Y1 were 0.66 (p=0.07), 0.48 (0