Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial.

Results of 2 parallel phase 2 trials of transplantation of unrelated umbilical cord blood (UCB) or bone marrow (BM) from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo UCB (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 UCB transplantation was cyclosporine and mycophenolate mofetil (MMF) and for haploidentical transplantation, posttransplant cyclophosphamide, tacrolimus, and MMF. The primary end point was 2-year progression-free survival (PFS). Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease, and disease status at randomization. Two-year PFS was 35% (95% confidence interval [CI], 28% to 42%) compared with 41% (95% CI, 34% to 48%) after UCB and haploidentical transplants, respectively (P = .41). Prespecified analysis of secondary end points recorded higher 2-year nonrelapse mortality after UCB, 18% (95% CI, 13% to 24%), compared with haploidentical transplantation, 11% (95% CI, 6% to 16%), P = .04. This led to lower 2-year overall survival (OS) after UCB compared with haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49% to 64%), respectively (P = .04). The trial did not demonstrate a statistically significant difference in the primary end point, 2-year PFS, between the donor sources. Although both donor sources extend access to reduced-intensity transplantation, analyses of secondary end points, including OS, favor haploidentical BM donors. This trial was registered at www.clinicaltrials.gov as #NCT01597778.

Differences in Graft-versus-Host Disease Characteristics between Haploidentical Transplantation Using Post-Transplantation Cyclophosphamide and Matched Unrelated Donor Transplantation Using Calcineurin Inhibitors.

We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic graft-versus-host disease (GVHD) after receiving their first allogeneic transplantation (HSCT) from a 10/10 HLA allele-matched unrelated donor (MUD; n = 179) using calcineurin inhibitors or a T cell-replete haploidentical donor (haplo; n = 215) and post-transplantation cyclophosphamide at our center between 2005 and 2017. The median duration of follow-up for survivors was 52.5 months. The cumulative incidences for grade II-IV and grade III-IV acute GVHD at day 180 post HCT were similar, at 39% and 14%, respectively, for haplo-HSCT compared with 50% and 16% for MUD HSCT (P not significant). Haplo-HSCT recipients had a lower cumulative incidence of moderate to severe chronic GVHD, at 22% (severe, 19%), compared with 31% (severe, 29%) for MUD HSCT recipients (P = .026). The time to onset of moderate to severe chronic GVHD was faster for haplo-HSCT recipients (213 days versus 280 days; P = .011). Among patients with grade II-IV acute GVHD, there was no significant between-group difference in organ involvement, with skin the most affected (75% for haplo-HSCT versus 70% for MUD HSCT), followed by the gastrointestinal tract (71% versus 69%) and liver (14% versus 17% MUD). For chronic GVHD, haplo-HSCT recipients had less involvement of the eyes (46% versus 75% for MUD; P < .001) and of the joints/fascia (12% versus 36%; P = .001). Also for cGVHD patients, haplo-HSCT recipients and MUD HSCT recipients had similar all-cause mortality (22% versus 18%; P = .89), but the former were more likely to be off immunosuppression at 2 years post-HCT (63% versus 43%; P = .03) compared with MUD.

Accumulation of six PFAS compounds by woody and herbaceous plants: potential for phytoextraction.

Per and polyfluoroalkyl substances (PFAS) consist of a large group of compounds used to make products more resistant to stains, grease, and water and for fire suppression. They have been widely detected in the environment and exposure has been linked to adverse human health effects. Phytoremediation could be used to remediate PFAS-impacted sites, but there is little information on herbaceous and woody plant species uptake of PFAS compounds from soil. A greenhouse study evaluated the potential for eight herbaceous and seven woody plant species to absorb PFAS compounds. Six PFAS compounds: PFPeA, PFHxA, PFOA, PFBS, PFHxS, and PFOS were added weekly to irrigation water, and the plants grown for up to 14 weeks after an initial establishment period. Significant accumulation of all PFAS compounds occurred in at least one plant species. Mass recovery in above-ground tissue by the best performing plant ranged from a low of 3.8% for PFOS by Festuca rubra to a high of 42% for PFPeA by Schedonorus arundinaceus. Hyperaccumulation, defined as tissue/soil concentrations >10/1, was observed for all six PFAS compounds in at least one plant species. These results demonstrate the potential use of phytoremediation as a tool for remediating PFAS-contaminated sites.

Fludarabine and Total-Body Irradiation Conditioning before Ablative Haploidentical Transplantation: Long-Term Safety and Efficacy.

Although myeloablative conditioning (MAC) before haploidentical donor transplant (HIDT) with post-transplant cyclophosphamide is being increasingly used, the optimal preparative regimen remains unclear. In our initial trial, the feasibility of HIDT following a MAC preparative regimen using fludarabine and 12 Gy of total-body irradiation was demonstrated in 30 patients. We now present long-term outcome results, including an additional 52 patients, now with 47 months (16 to 96) median follow-up. Median patient age was 42 (19 to 61) years. The most common diagnoses were acute myelogenous leukemia (51%) and acute lymphoblastic leukemia (33%), and 39% had a high/very high disease risk index (DRI). Engraftment was universal with no cases of primary or secondary graft failure. Grade 3 to 4 acute graft-versus-host disease (GVHD) and moderate to severe chronic GVHD occurred in 17% and 23%, respectively. Nonrelapse mortality (NRM) was 7% at 1 year and 13% at 4 years. Estimated 4-year overall survival (OS), disease-free survival, and cumulative incidence of relapse (CIR) were 67%, 60%, and 27%, respectively. CIR was significantly higher in patients with high/very high- versus low/intermediate-risk DRI (38% versus 20%, P= .032), which led to inferior 4-year OS (50% versus 77%, P = .001). Median time to systemic immunosuppressive therapy (IST) discontinuation was 7.8 months, with 84% of patients off IST at 2 years post-transplant. Current GHVD-free, relapse-free survival (CGRFS) at 2, 3, and 4 years was 60%, 57%, and 60%, respectively. This approach to MAC HIDT results in universal engraftment; low rates of NRM, infection, and clinically significant GVHD; and relatively rapid IST discontinuation, resulting in high rates of CGRFS and survival.

The Dilemma of Conditioning Intensity: When Does Myeloablative Conditioning Improve Outcomes for Allogeneic Hematopoietic Cell Transplantation.

The impact of conditioning intensity on different disease risk index (DRI) groups has not been evaluated. We retrospectively analyzed acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) hematopoietic cell transplantation (HCT) recipients in 2 groups based on DRI, to assess the impact of conditioning intensity on overall survival (OS), disease free survival (DFS), relapse, and nonrelapse mortality (NRM). A total of 380 patients with either high/very high (n = 148) or low/intermediate DRI (n = 232) myeloid malignancy (AML, n = 278; MDS, n = 102) were included in the analysis. Median follow-up for survivors was 35 months. Median age was 58years (range, 18 to 75). Patient and transplant-related characteristics were 41% reduced-intensity conditioning (RIC), 59% myeloablative conditioning (MAC), 13% bone marrow graft, 29% matched related donor, 49% matched unrelated donor, 22% haploidentical donor, and 52% HCT-specific comorbidity index ≥ 3. Among patients with high/very high DRI, there was no difference in OS, DFS, relapse, and NRM between RIC and MAC conditioning groups. For low/intermediate risk DRI recipients of MAC had better 3-year OS estimate (69% versus 57%, P = .001), DFS (65% versus 51%, P = .003), and lower relapse (3-year cumulative incidence, 17% versus 32%; P = .01) but similar NRM (19% versus 17%, P = .04) to RIC recipients. On multivariable analysis MAC was associated with better DFS (hazard ratio [HR], .58; 95% confidence interval [CI], .39-.88; P = .01), lower relapse (HR, .56; 95% CI, .32 to .97; P = .038), and similar NRM (HR, 1.11; 95% CI, .54 to 2.26; P = .781) compared with RIC in the low/intermediate DRI group. Intensity had no impact on HCT outcomes in the high/very high DRI group. MAC improves DFS and relapse compared with RIC among AML/MDS patients with low/intermediate DRI. The finding of no such benefit in high/very high DRI needs to be further explored in a larger cohort with a longer follow-up.

Who Is a Better Donor for Recipients of Allogeneic Hematopoietic Cell Transplantation: A Young HLA-Mismatched Haploidentical Relative or an Older Fully HLA-Matched Sibling or Unrelated Donor?

T cell replete HLA-mismatched haploidentical transplantation (HIDT) with post-transplant cyclophosphamide is increasingly becoming an acceptable treatment approach for patients lacking timely access to a suitably matched related donor transplant (MRDT) or matched unrelated donor transplant (MUDT). Multiple recent registry and single-center studies have shown comparable overall survival (OS) and disease-free survival (DFS) rates among HIDT, MRDT, and MUDT with a significantly lower risk of acute and chronic graft-versus-host disease (GVHD) among HIDT recipients. Candidates for allogeneic hematopoietic stem cell transplantation (HSCT) often have access to multiple donor sources, and a relevant question is whether outcomes can be improved with a younger HLA-mismatched haploidentical donor (≤35 years) rather than an older matched related donor (≥35 years) or matched unrelated donor (≥35 years). We analyzed 406 consecutive allogenic HSCT recipients, with a median age of 54 years (range, 19 to 77), after a MRDT with a donor age of ≥35 years (n = 222), MUDT with a donor age of ≥35 years (n = 91), and HIDT with a donor age of ≤35 years (n = 93). Median follow-up time for survivors was 51.5 months. Compared with MRDT and MUDT, HIDT recipients had a similar median age at time of HSCT, hematopoietic cell transplant comorbidity index, disease risk index distribution, and donor recipient sex matching. The survival estimates and relapse incidence at 3 years post-HSCT were OS (64% for MRDT, 54% for MUDT, and 62% for HIDT), DFS (55% for MRDT, 44% for MUDT, and 58% for HIDT), Transplant related mortality (TRM) (19% for MRDT, 16% for MUDT, and 18% for HIDT), and relapse (26% for MRDT, 37% for MUDT, and 24% for HIDT). HIDT recipients had better 3-year relapse rates compared with MUDT recipients (24% versus 37%, P= .048), with similar DFS and OS in a univariate analysis. MRDT recipients had a better relapse rate (26% versus 37%, P = .042) compared with MUDT recipients. Recipients of HIDT also had significantly lower rates of moderate to severe chronic GVHD compared with MRDT and MUDT recipients (P = .01). Multivariable analysis showed no effect of donor on OS, DFS, relapse, and TRM. Recipients of HIDT from a young donor ≤35 years had similar OS, lower rates of chronic GVHD, and better chronic GVHD-free, relapse-free survival compared with patients undergoing transplantation with an MRD or a MUD donor ≥35 years. This study suggests that given a situation where a choice between a young haploidentical relative and an older matched unrelated donor is to be made, one can achieve similar survival with a haploidentical donor and significantly lower rates of chronic GVHD.

Superior Survival of Black Versus White Patients Following Post-Transplant Cyclophosphamide-Based Haploidentical Transplantation for Adults with Hematologic Malignancy.

Available evidence from large registry studies has shown inferior survival for black adult patients following both unrelated donor and cord blood transplantation. Post-transplant cyclophosphamide (PTCy)-based haploidentical donor transplantation (HIDT) is being increasingly used in ethnic minorities. However, no studies of the impact of race on outcomes following HIDT have been reported. We analyzed 203 consecutive patients (123 white, 80 black) who underwent first HIDT using PTCy for hematologic malignancy at a single institution. Median recipient age was 53 (range, 19-75) years. Peripheral blood stem cells (PBSCs) were used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative (MA) in 41%. After a median follow-up of 36 months, the estimated 3-year overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR) were significantly better in black patients, compared with white patients (72% [95% confidence interval (CI), 60% to 81%], 65% [95% CI, 52% to 75%], and 25% [95% CI, 16% to 35] versus 50% [95% CI, 40% to 59%], 45% [95% CI, 36% to 54%], and 39% [95% CI, 31% to 47%], respectively; P < .001 for OS and DFS, P = .015 for CIR). In contrast, 3-year nonrelapse mortality was similar between black (11%) and white (16%) patients, as were the incidences of acute graft-versus-host disease (GVHD) and moderate-to-severe chronic GVHD. Improved survival was noted in all subgroups of black patients-younger versus older, male versus female, lower versus higher disease risk index, MA versus non-MA conditioning, or PBSC versus marrow stem cell source. In multivariate analysis, black race was independently associated with better OS (hazard ratio [HR], .47; P = .003), DFS (HR, .49; P = .003), and relapse (HR, .49; P = .01). Black patients achieve superior outcomes to their white counterparts following PTCy-based HIDT due to a decreased incidence of disease relapse.

Selecting the Best Donor for Haploidentical Transplant: Impact of HLA, Killer Cell Immunoglobulin-Like Receptor Genotyping, and Other Clinical Variables.

The use of post-transplant cyclophosphamide (PTCy)-based haploidentical (haplo) transplant is increasing worldwide. However, because multiple potential haplo donors are usually available, data-driven guidance is clearly needed to help transplant centers prioritize donors. To that end, we retrospectively analyzed 208 consecutive donor-recipient pairs receiving PTCy-based haplo transplant at a single institution. Median recipient and donor age were 52 years (range, 19 to 75) and 38 years (range, 15 to 73), peripheral blood stem cell was the stem cell source in 66%, and myeloablative conditioning was used in 41%. Median follow-up for surviving patients was 33 months (range, 7 to 130). Donor variables analyzed included age, sex, relationship, cytomegalovirus (CMV) status, ABO compatibility, HLA disparity, and several natural killer (NK) alloreactivity models. Multivariate Cox analysis was used to adjust for known patient, disease, and transplant covariates. Donor characteristics independently associated with improved survival included presence of HLA-DR mismatch, HLA-DP nonpermissive mismatch, killer cell immunoglobulin-like receptor (KIR) receptor-ligand mismatch, and KIR B/x haplotype with KIR2DS2. Donor characteristics associated with inferior survival included parental donor relationship and the use of a CMV-seronegative donor for a CMV-seropositive patient. Increased HLA disparity (≥4/10 HLA allelic mismatches [graft-versus-host direction]) resulted in relapse protection at the expense of increased nonrelapse mortality with no associated survival effect. We further propose a donor risk factor scoring system to permit a more evidence-based selection algorithm for potential haplo donors. This large, single-institution analysis demonstrates the importance of HLA-DR/HLA-DP disparity, NK alloreactivity, and other clinical variables in the haplo donor selection process and suggests that KIR and HLA-DP genotyping should be performed routinely for haplo donor selection.

Easy-to-Read Informed Consent Form for Hematopoietic Cell Transplantation Clinical Trials: Results from the Blood and Marrow Transplant Clinical Trials Network 1205 Study.

Because of the complexity of hematopoietic cell transplant trial treatments, informed consent forms are often long and difficult to read. We evaluated a 2-column easy-to-read informed consent (ETRIC) form that incorporates elements of health literacy and readability in participants and centers participating in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) clinical trials. In a randomized study 198 adult patients from 25 centers potentially eligible to participate in 4 BMT CTN interventional trials were randomized to the ETRIC form or a standard consent form for that trial. Both forms were written at no more than an eighth-grade reading level. The primary endpoint was objective comprehension score on the Quality of Informed Consent, part A (QuIC-A) instrument. In a parallel evaluation study, 2 moderators conducted semistructured interviews of 49 investigators, research staff, and institutional review board (IRB) members at 9 BMT CTN trial sites. The mean QuIC-A scores were comparable in 152 patients (77%) assessable for the primary endpoint (ETRIC form, 80.5; standard form, 81.8; P = .37). In regression analysis there was no significant association between the consent type and QuIC-A score. In the evaluation study dominant themes identified on qualitative analyses included general comfort and willingness to use the ETRIC template and that its formatting and layout enhancements would offer additional value to research participants, investigators, and IRBs. IRB language preferences and requirements, length, and prior experience with alternative consent formats were perceived as barriers. Among patients considering participation in BMT CTN clinical trials, the formatting enhancements of the ETRIC form did not alter comprehension of the trial. Despite local challenges to implementation, trial sites generally viewed the ETRIC form favorably and expressed willingness to use it over standard consent form.

Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of the BMT CTN 0803/AMC 071 trial.

Autologous hematopoietic cell transplant (AHCT) for HIV-infected patients is largely limited to centers with HIV-specific expertise. The Blood and Marrow Transplant Clinical Trials Network 0803/AIDS Malignancy Consortium 071 trial is a multicenter phase 2 study of AHCT for patients with HIV-related lymphoma (HRL). Eligible patients had chemotherapy-sensitive relapsed/persistent HRL, were >15 years of age, and had treatable HIV infection. Patients were prepared using carmustine, etoposide, cytarabine, and melphalan and received consistent management of peritransplant antiretroviral treatment. The primary endpoint was 1-year overall survival. Forty-three patients were enrolled; 40 underwent AHCT. Pretransplant HIV viral load was undetectable (<50 copies/mL) in 32 patients (80%); the median CD4 count was 249/µL (range, 39-797). At a median follow-up of 24.8 months, 1-year and 2-year overall survival probabilities were 87.3% (95% confidence interval [CI], 72.1-94.5) and 82% (95% CI, 65.9-91), respectively. The probability of 2-year progression-free survival was 79.8% (95% CI, 63.7-89.4). One-year transplant-related mortality was 5.2%. Median time to neutrophil and platelet recovery was 11 days and 18 days, respectively. Nine patients experienced a total of 13 unexpected grade 3-5 adverse events posttransplant (10 grade 3 and 3 grade 4 events). Twenty-two patients had at least 1 infectious episode posttransplant. At 1 year post-AHCT, median CD4(+) T-cell count was 280.3 (range, 28.8-1148.0); 82.6% had an undetectable HIV viral load. Trial patients were compared with 151 matched Center for International Bone Marrow Transplant Research controls. Outcomes between HIV-infected patients and controls were not statistically significantly different. HRL patients should be considered candidates for AHCT if they meet standard transplant criteria. The trial was registered at www.clinicaltrials.gov as #NCT01141712.

Release of Electron Donors during Thermal Treatment of Soils.

Thermal treatment of soil and groundwater may provide an in situ source of soluble organic compounds and hydrogen (H2) that could stimulate microbial reductive dechlorination (MRD) at sites impacted by chlorinated solvents. The objectives of this study were to identify and quantify the release of electron donors and fermentable precursors during soil heating and to estimate availability of these compounds following thermal treatment. Fourteen solid materials containing <0.01 to 63.81 wt % organic carbon (OC) were incubated at 30, 60, or 90 °C for up to 180 d, leading to the release of direct electron donors (i.e., H2 and acetate) and fermentable volatile fatty acids (VFAs). Total VFA release ranged from 5 ± 0 × 10-9 carbon per gram solid (mol C/gs) during 30 °C incubation of quartz sand to 820 ± 50 × 10-6 mol C/gs during 90 °C incubation of humic acid, and was positively impacted by incubation time, temperature, and solid-phase OC content. H2 gas was detected at a maximum of 180 ± 50 × 10-9 mol H2/gs, accounting for less than 0.3% of reducing equivalents associated with VFAs released under the same conditions. These findings will allow for more reliable prediction of substrate release during thermal treatment, supporting the implementation of coupled thermal and biological remediation strategies.

Sediment pollution in an urban water supply lake in southern Brazil.

Urbanization and anthropogenic activities create many environmental issues in urban water supply reservoirs, especially in metropolitan regions. Thus, this study was carried out aiming to evaluate the variance in the physical-chemical characteristics of bottom sediment along the Lake Guaíba, Brazil. Lake Guaíba is a freshwater lake situated in a metropolitan region in southern Brazil, being the main water supply to the region. Surface sediment was evaluated to pH, electrical conductivity, particle-size, total organic carbon and nitrogen, metals and inorganic elements (Fe, Al, Ca, Ba, Sr, Co, Tl, Zn, Cu, Cr, Ni, Pb, Cd, and Hg), and organic compounds. The sediments in the Lake Guaíba show a wide range in the physical-chemical characteristics. Metals Zn, Cu, Cr, and Ni appear in higher concentrations near to the margin of southern Porto Alegre, where there was also more clay plus silt. Sediments of Lake Guaíba have physical-chemical variability by the settle tendency and water flow from the riverine to lacustrine areas. The sediment in Lake Guaíba had a median of: Zn, 132; Cu, 78; Cr, 42; Ni, 28; Pb, 33; Cd, 0.3; and Hg, 0.07 µg/g. Bed sediments of Lake Guaíba are polluted with Zn, Cu, Cr, and Ni, major in the east margin (near to Porto Alegre). The potential toxic metals and organic compounds found in Lake Guaíba are commonly reported in urban regions around the world. Those elements and compounds derive from many anthropic activities, as industries, sewage, and vehicles. With diffuse sources in the region, the pollution control in Lake Guaíba is very complex.

Current Graft-versus-Host Disease-Free, Relapse-Free Survival: A Dynamic Endpoint to Better Define Efficacy after Allogenic Transplant.

An accurate measure of allogeneic transplant efficacy should take into account quality-of-life issues associated with graft-versus-host disease (GVHD). However, unlike death and relapse, GVHD morbidity is temporary in many patients, and this fact must be reflected in such an outcome measure. Therefore, we have defined a new composite endpoint, called current GVHD-free, relapse-free survival (CGRFS), which is the probability, at any time post-transplant, of being alive, in remission, and without clinically significant chronic GVHD, defined as moderate-severe by the National Institutes of Health consensus criteria. Chronic GVHD is considered a dynamic event, which can resolve once manifestations are quiescent and systemic immunosuppression discontinued. CGRFS is achieved through linear combination of relevant Kaplan-Meier estimates. We evaluated 422 consecutive patients receiving an allogeneic transplant at a single institution between January 2010 and July 2015. With a median follow-up of 36 months, estimated 3-year overall and disease-free survival was 60% and 54%, respectively. Conventionally defined GRFS at 1, 2, 3, and 4 years was 33%, 26%, 23%, and 22%, respectively. In contrast, the corresponding rates of CGRFS were 45%, 46%, 47%, and 49%, respectively. Patients living with active moderate-severe chronic GVHD decreased over time, quantitated at 23%, 14%, 7%, and 4%, respectively, at 1, 2, 3, and 4 years post-transplant. Whereas only approximately one-fourth of patients achieve transplant success as defined by conventional GRFS, nearly half of patients, by CGRFS, are considered cured without the morbidity of ongoing GVHD. We propose that CGRFS may represent a more dynamic and accurate estimate of long-term transplant effectiveness.

Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation: A Single-Center Analysis of 613 Adult Hematopoietic Cell Transplantation Recipients Using a Modified Composite Endpoint.

The composite endpoint graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) has recently been introduced as a tool to assess the success of allogeneic hematopoietic stem cell transplantation (HSCT) and has been incorporated into recent randomized trials of GVHD prophylaxis by the Blood and Marrow Transplant Clinical Trials Network. As developed, GRFS incorporates "chronic GVHD requiring systemic immunosuppression" as a measure of clinically significant chronic GVHD (cGVHD). However, the decision to start patients on immunosuppressive therapy for cGVHD is subjective and physician-dependent. We elected to assess a modification of the GRFS (m-GRFS) that uses a potentially more objective measure of cGVHD, specifically the development of National Institutes of Health grade moderate or severe cGVHD. A total of 613 patients who underwent a first allogeneic HSCT after an HLA-identical sibling (matched related donor [MRD]; n = 212), an 8/8 matched unrelated donor (MUD; n = 251) or T cell-replete haploidentical donor (HID) transplant with post-transplantation cyclophosphamide (n = 150) were included in this analysis. In the HID group, 86 patients (54%) received peripheral blood stem cells as the graft source. The median duration of follow-up was 50.2 months. The unadjusted Kaplan-Meier estimates for 1- and 2-year m-GRFS were 36% (95% confidence interval [CI], 32% to 40%) and 28% (95% CI, 25% to 32%), respectively. The 2-year m-GRFS was 30% (95% CI, 24% to 36%) for MRD graft recipients, 24% (95% CI, 19% to 30%) for MUD graft recipients, and 33% (95% CI, 26% to 41%) for HID graft recipients. A multivariate Cox model for m-GRFS identified donor type, Disease Risk Index (DRI) risk, donor-recipient sex mismatch, and year of transplantation as significant predictors of m-GRFS. Patients who received a MUD graft had worse m-GRFS compared to MRD graft recipients (hazard ratio [HR], 1.39; P = .003), whereas HID graft recipients had a similar m-GRFS as MRD graft recipients (HR, 1.10; P = .43). HID was associated with better m-GRFS compared with MUD (HR, .79; P = .046). These data show that m-GRFS is significantly affected by several modifiable factors, including donor type, donor-recipient sex match, and DRI. Adjusting donor choice and earlier referral of patients for evaluation of transplantation to improve the DRI can potentially overcome the negative impact of these factors.

Factors Predicting Graft-versus-Host Disease-Free, Relapse-Free Survival after Allogeneic Hematopoietic Cell Transplantation: Multivariable Analysis from a Single Center.

The ideal outcome of allogeneic hematopoietic cell transplantation (allo-HCT) is based on survival that is free of morbidity. The most common causes of treatment failure and morbidity after HCT are relapse, graft-versus-host disease (GVHD), and nonrelapse death. A composite endpoint that measures survival free of clinically significant negative events may be a useful way to determine the success of allo-HCT. We assessed GVHD and relapse-free survival (GRFS) where the events were acute GVHD grades III to IV, chronic GVHD requiring immunosuppression, relapse, or death in 531 consecutive adult patients who received an allo-HCT between 2006 and 2014 at our center. Median follow-up of living patients was 46 months (range, 12 to 123). HLA matched related donor (MRD, n = 198, 37%), matched unrelated donor (MUD, n = 205, 39%), and haploidentical donor with post-transplant cyclophosphamide (HID, n = 128, 24%) were used. Thirty-six percent of patients had a high/very-high Dana Farber disease risk index (DRI). Estimated rates of GRFS at 1 and 2 years after MRD, MUD, and HID transplantations were 34% and 26%, 26% and 17%, and 33% and 31%, respectively, with MRD recipients having a better GRFS than MUD (P < .05). On multivariable analysis, peripheral blood stem cell source (HR, 1.34; P = .04), MUD (HR, 1.41; P = .003), and high/very high DRI (HR, 1.66; P = .001) were all associated with a worse GFRS post-HCT. These data suggest that GRFS can be predicted by patient disease risk, stem cell source, and donor type. Importantly, MUDs produce inferior GRFS to MRDs, whereas HIDs do not.

Comparison of Outcomes of Hematopoietic Cell Transplants from T-Replete Haploidentical Donors Using Post-Transplantation Cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 Allele-Matched Unrelated Donors and HLA-Identical Sibling Donors: A Multivariable Analysis Including Disease Risk Index.

Outcomes of 475 consecutive patients undergoing first allogeneic transplantation for hematologic malignancy performed using T-replete HLA-haploidentical donors and post-transplantation cyclophosphamide (HIDT; n = 116) were compared with contemporaneous patients transplanted from 10 of 10 HLA allele-matched unrelated donors (MUDT; n = 178) or HLA-identical sibling donors (MRDT; n = 181). Uniform supportive care measures and assessments were used. Median follow-up was 45 months. HIDT patients were more likely than MUDT patients to be black (44% versus 2%; P < .001). At 2 years after transplantation, estimates of overall survival were 57% for HIDT, 59% for MUDT, and 72% for MRDT (P not significant [NS] for HIDT versus MUDT; P = .02 for HIDT versus MRDT); corresponding disease-free survival rates were 54%, 50%, and 56% (P NS for both comparisons). The respective cumulative incidences (CIs) of nonrelapse mortality were 17%, 16%, 14%, and those of relapse were 29%, 34%, and 30% (P NS for all). The respective CIs of acute graft-versus-host disease (GVHD) grade II-IV were 41%, 48%, and 28% (P = NS for HIDT versus MUDT; P = .005 for HIDT versus MRDT). At 2 years, the respective CIs of moderate/severe chronic GVHD were 31%, 47%, and 44% (P = .004 for HIDT versus MUDT; P = .032 for HIDT versus MRDT) and 19% of HIDT recipients, 42% of MUDT recipients, and 35% of MRDT recipients were on systemic immunosuppressive treatment (P = .007 for HIDT versus MUDT). In recipients of peripheral blood stem cell grafts, the incidence of moderate-severe chronic GVHD was significantly lower in HIDT recipients compared with MUDT recipients (2-year CI, 25% versus 48%; P = .002). In a multivariate analysis incorporating Disease Risk Index and other significant covariates, survival (hazard ratio [HR], 1.31; P = .15) and disease-free survival (HR, 0.96; P = .79) were not significantly different between HIDT and MUDT recipients, but the incidence of chronic GVHD was lower in HIDT recipients (moderate-severe, HR, 0.59; P = .007). HIDT produced similar long-term survival with lower rates of chronic GVHD than optimally matched MUDT. HIDT should be considered a standard of care option for patients lacking a matched sibling donor.

T Cell-Replete HLA Haploidentical Donor Transplantation with Post-Transplant Cyclophosphamide Is an Effective Salvage for Patients Relapsing after an HLA-Matched Related or Matched Unrelated Donor Transplantation.

A second allogeneic hematopoietic stem cell transplantation (HSCT) using the same donor or another fully matched donor is an effective treatment approach for a subset of patients relapsing after a matched related (MRDT) or matched unrelated donor transplant (MUDT). There are limited data on the use of haploidentical transplantation (HIDT) with post-transplant cyclophosphamide in the setting of a second HSCT after an MRDT or MUDT. We analyzed the outcomes of 20 patients who received HIDT with post-transplant cyclophosphamide as a second HSCT after an MRDT (n = 10) or MUDT (n = 10). The median time from the first to the second HSCT was 20.7 months (range, 2.7 to 65.8). Ten patients had acute myelogenous leukemia/myelodysplastic syndrome, 6 had acute lymphoblastic leukemia, 2 had chronic lymphoblastic leukemia, and 2 had myeloproliferative neoplasms. All patients received cytoreductive therapy before HIDT, with 12 (60%) achieving complete remission and 8 (40%) with active disease at the time of transplant. All patients achieved sustained engraftment with median times to neutrophil and platelet engraftment of 17.5 days (range, 14 to 44) and 32 days (range, 15 to 99), respectively. Nineteen patients (95%) achieved full donor chimerism in both the T cell and myeloid lineages at day 30 post-HSCT. The cumulative incidences of grades II to IV and grades III to IV acute graft-versus-host disease at 180 days were 36% and 10%, respectively. The cumulative incidence of moderate to severe chronic graft-versus-host disease was 13% at 1 year post-HIDT. At a median follow-up of 38 months, the probability of overall survival, disease-free survival, nonrelapse mortality, and relapse post-HIDT were 52%, 39%, 29%, and 33% at 1 year and 34%, 31%, 29%, and 40% at 3 years, respectively. These data suggest that HIDT is an effective strategy to treat relapsed hematologic malignancies after MRDT or MUDT. Further studies to confirm these observations are warranted.

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.

Eucalyptus urograndis and Pinus taeda enhance removal of chlorobenzene and benzene in sand culture: A greenhouse study.

Contamination of soils and groundwater by chlorobenzene and benzene is a common problem at industrial sites worldwide. Since chemical remediation techniques are rarely completely effective, remnants of these contaminants often persist at levels that can still influence ecosystem health. We evaluated the potential of Pinus taeda and Eucalyptus urograndis to accelerate the removal of these compounds from sand/water systems using a completely randomized block greenhouse experiment with a no-plant control. At 2-day intervals, we added a solution containing both chlorobenzene and benzene with the same concentration of 50 mg L(-1) (25 mg pot(-1)), and we monitored leachate concentrations daily. The planted treatments showed greater decrease of contaminants over time. In the absence of plants, the contaminant mass decreased 50-60% during each 2-day cycle; whereas, in the planted treatments the contaminant mass decreased 91-98%. At the end of the experiment the plant roots, leaves, and the sand-substrate each contained less than 1 mg kg(-1) of contaminants, which is ∼1% of the total contaminant mass added. In addition, we observed no tree mortality even at concentrations exceeding the aqueous solubility limit of both compounds. Our results suggest both trees are good candidates for remediating chlorobenzene and benzene in soils and groundwater.

Corticosteroid-Free Primary Treatment of Chronic Extensive Graft-versus-Host Disease Incorporating Rituximab.

Chronic graft-versus-host disease (cGVHD) is a significant determinant of overall outcome and quality of life in survivors of allogeneic hematopoietic cell transplantation. Standard initial therapy of cGVHD is based on prolonged use of corticosteroids and a calcineurin inhibitor and has not changed for over 3 decades, despite limited efficacy and long-term toxicity. Rituximab is an attractive agent for the upfront treatment of cGVHD because of its favorable toxicity profile, efficacy in steroid-refractory cGVHD, and ability to serve as a steroid-sparing agent in autoimmune diseases. We hypothesized that a corticosteroid-free regimen incorporating rituximab would result in improved outcomes when used for the initial treatment of cGVHD. Twenty-five patients (median age, 56 years; range, 29 to 77) with extensive cGVHD were enrolled on a prospective phase II trial. Enrollment was limited to patients with first onset extensive cGVHD requiring systemic immunosuppression and without residual or concurrent acute graft-versus-host disease. cGVHD was classified as de novo, interrupted, and progressive in 12, 11, and 2 patients, respectively. cGVHD severity (National Institutes of Health grade) was mild, moderate, and severe in 3, 14, and 8 patients, respectively. All patients received rituximab 375 mg/m(2) × 4 weekly doses, then 1 dose every 3 months × 4 doses, in addition to mycophenolate mofetil and either tacrolimus or sirolimus. No other systemic immunosuppression was permitted, and only a short-course of steroids (≤4 weeks) was allowed at physician discretion; otherwise, treatment was deemed a failure and patients were treated off study. Twenty-two of 25 patients (88%) responded to treatment. Of the 22 responding patients, the median time to maximum response was 161 days (range, 35 to 300 days) with maximum response being complete in 21 of 22 patients and partial in 1 patient. Excluding the 3 patients taken off study for treatment failure, corticosteroids were used sparingly, with only 2 patients receiving any steroids for a median of 15 days (range, 13 to 18 days). Immunosuppression was discontinued in 17 of 22 evaluable patients (77%) with a median time to discontinuation of 300 days (range, 138 to 488 days). After immunosuppression discontinuation, cGVHD did recur in 7 patients after a median of 166 days (range, 21 to 393 days), requiring reinstitution of systemic immunosuppression (estimated cGVHD recurrence rate of 37%). With a median follow-up of 27 months, estimated 2-year overall survival is 82%. This regimen utilizing rituximab in the initial therapy of cGVHD is effective and avoids the use of corticosteroids in the majority of patients. In permitting early discontinuation of immunosuppression while obviating the need for prolonged exposure to systemic corticosteroids, this regimen may result in reduced treatment-related morbidity and mortality associated with cGVHD and its treatment.