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The α-emitter 211 At deposits a high amount of energy within a few cell diameters, resulting in irreparable DNA double-strand breaks while minimizing off-target toxicity. We investigated the use of the 211 At-labeled anti-CD45 monoclonal antibody (mAb) 211 At-CD45-B10 as a nonmyeloablative conditioning regimen for dog-leukocyte-antigen-haploidentical hematopoietic cell transplantation. Methods: Seventeen healthy dogs were injected with either a 0.50 ( n = 14) or 0.75 ( n = 3) mg/kg dose of anti-CD45 mAb labeled with 211 At (8.436-23.199 MBq [0.228-0.627 mCi/kg]) on day -3. Peripheral blood stem cells from dog-leukocyte-antigen-haploidentical donors were given on day 0. Peripheral blood chimerism was calculated by polymerase chain reaction assays, and blood clearance of the radioimmunoconjugate was studied using enzyme-linked immunosorbent assay and radioactivity measurements of serial blood samples. Results: All dogs achieved donor chimerism by day 28 (range, 27%-100%). The hematopoietic engraftment rate was 100%, though engraftment durability was variable. No difference in absorbed dose to blood was seen for the 2 mAb dosing levels studied. Neutropenia (0-29 cells/μL), lymphocytopenia (36-130 cells/μL), and thrombocytopenia (1.5-9 × 10 3 /μL) with prompt recovery were observed. The main adverse nonhematologic event related to 211 At-CD45-B10 was mild reversible transaminitis. Graft-versus-host disease was not seen. Twelve of the 17 dogs survived over 30 d, with donor chimerism ranging from 3% to 99%. Conclusion: The results suggest that nonmyeloablative conditioning with 211 At-CD45-B10 could be used in haploidentical hematopoietic cell transplantation though with variable engraftment., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Hematopoietic cell transplantation (HCT) has curative potential for myeloid malignancies, though many patients cannot tolerate myeloablative conditioning with high-dose chemotherapy alone or with total-body irradiation (TBI). Here we report long-term outcomes from a phase I/II study using iodine-131 (131I)-anti-CD45 antibody BC8 combined with nonmyeloablative conditioning prior to HLA-haploidentical HCT in adults with high-risk relapsed/ refractory acute myeloid or lymphoid leukemia (AML or ALL), or myelodysplastic syndrome (MDS; ClinicalTrials.gov, NCT00589316)., Patients and Methods: Patients received a tracer diagnostic dose before a therapeutic infusion of 131I-anti-CD45 to deliver escalating doses (12-26 Gy) to the dose-limiting organ. Patients subsequently received fludarabine, cyclophosphamide (CY), and 2 Gy TBI conditioning before haploidentical marrow HCT. GVHD prophylaxis was posttransplant CY plus tacrolimus and mycophenolate mofetil., Results: Twenty-five patients (20 with AML, 4 ALL and 1 high-risk MDS) were treated; 8 had ≥ 5% blasts by morphology (range 9%-20%), and 7 had previously failed HCT. All 25 patients achieved a morphologic remission 28 days after HCT, with only 2 patients showing minimal residual disease (0.002-1.8%) by flow cytometry. Median time to engraftment was 15 days for neutrophils and 23 days for platelets. Point estimates for overall survival and progression-free survival were 40% and 32% at 1 year, and 24% at 2 years, respectively. Point estimates of relapse and nonrelapse mortality at 1 year were 56% and 12%, respectively., Conclusions: 131I-anti-CD45 radioimmunotherapy prior to haploidentical HCT is feasible and can be curative in some patients, including those with disease, without additional toxicity., (©2023 American Association for Cancer Research.)

Objectives: We recently performed a single-arm phase II trial of DA-EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard Hyper-CVAD., Methods: We created a retrospective matched cohort of patients who received Hyper-CVAD (n = 69) at our center and otherwise met eligibility criteria for the DA-EPOCH trial (n = 53)., Results: Our outcomes support the use of Hyper-CVAD over DA-EPOCH in Ph- disease for both overall survival (OS; HR 0.18, p = .004) and event-free survival (EFS; HR 0.51, p = .06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97, p = .96; EFS HR 0.65, p = .21). Rates of morphologic remission and measurable residual-disease negativity were similar between the regimens. Hyper-CVAD was associated with significantly more febrile neutropenia (OR 1.9, p = .03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (p < .001) and platelets (p < .001) were five-fold higher with Hyper-CVAD., Conclusions: Our findings support continued use of Hyper-CVAD for Ph- ALL but suggest that DA-EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA-EPOCH in resource-limited settings or when more intense therapy is not feasible., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease-negative complete remission (MRD- CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD- CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Burnout syndrome (BS) is the result of chronic stress in the workplace. Moreover, chronic stress can affect sleep. A unidirectional relationship has been established between burnout and sleep, and it is known that white-collar workers with burnout syndrome have sleep fragmentation and marked daytime sleepiness., Objective: The aim of this study was to assess the relationships between burnout and sleep quality in elementary school teachers in Mexico., Methods: We collected data from more than 400 teachers who completed tests. Correlation analyses controlled for anxiety and depression, and Poisson logistic regression analyses were performed to examine the relationships of burnout with sleep quality, depression, and anxiety., Results: There was a significant correlation between burnout syndrome (mainly in the dimension of emotional exhaustion) and sleep disturbances; significant correlations were also observed with other burnout, depression, and anxiety dimensions. The strength of the correlations decreased after controlling for depression and anxiety., Conclusions: The symptoms of burnout syndrome in teachers can overlap with sleep disorders, so it is necessary to make a differential diagnosis to differentiate burnout syndrome from depression and anxiety, among others.

Treatments for adults with newly-diagnosed acute lymphoblastic leukemia (ALL) may be prohibitively toxic and/or resource-intense. To address this, we performed a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH). Imatinib or dasatinib was added for Ph + disease; rituximab was added when CD20+. Fifty-three patients were evaluable: 28 with Ph + disease, and 25 with Ph-. All patients had ≥1 high-risk clinical feature. Measurable residual disease-negativity by multiparameter flow cytometry within 4 cycles was achieved in 71% in patients with Ph + ALL and 64% in Ph - ALL. Median overall survival (OS) was 49 months, with a 2-year OS of 71%. Median relapse-free survival (RFS) in the 47 patients that attained morphologic remission was 24 months, with a 2-year RFS of 57%. Early mortality was 2%. In summary, DA-EPOCH yields deep and durable remissions in adults with ALL comparable to some resource-intense strategies but with a low rate of treatment-related death.

Background: Early intrahepatic recurrence is common after surgical resection of hepatocellular carcinoma (HCC) and leads to increased morbidity and mortality. Insensitive and nonspecific diagnostic imaging contributes to EIR and results in missed treatment opportunities. In addition, novel modalities are needed to identify targets amenable for targeted molecular therapy. In this study, we evaluated a zirconium-89 radiolabeled glypican-3 (GPC3) targeting antibody conjugate ( 89 Zr-αGPC3) for use in positron emission tomography (PET) for detection of small, GPC3 + HCC in an orthotopic murine model. Athymic nu/J mice received hepG2, a GPC3 + human HCC cell line, into the hepatic subcapsular space. Tumor-bearing mice were imaged by PET/computerized tomography (CT) 4 days after tail vein injection of 89 Zr-αGPC3. Livers were then excised for the tumors to be identified, measured, bisected, and then serially sectioned at 500 μm increments. Sensitivity and specificity of PET/CT for 89 Zr-αGPC3-avid tumors were assessed using tumor confirmation on histologic sections as the gold standard., Results: In tumor-bearing mice, 89 Zr-αGPC3 avidly accumulated in the tumor within four hours of injection with ongoing accumulation over time. There was minimal off-target deposition and rapid bloodstream clearance. Thirty-eight of 43 animals had an identifiable tumor on histologic analysis. 89 Zr-αGPC3 immuno-PET detected all 38 histologically confirmed tumors with a sensitivity of 100%, with the smallest tumor detected measuring 330 μm in diameter. Tumor-to-liver ratios of 89 Zr-αGPC3 uptake were high, creating excellent spatial resolution for ease of tumor detection on PET/CT. Two of five tumors that were observed on PET/CT were not identified on histologic analysis, yielding a specificity of 60%., Conclusions: 89 Zr-αGPC3 avidly accumulated in GPC3 + tumors with minimal off-target sequestration. 89 Zr-αGPC3 immuno-PET yielded a sensitivity of 100% and detected sub-millimeter tumors. This technology may improve diagnostic sensitivity of small HCC and select GPC3 + tumors for targeted therapy. Human trials are warranted to assess its impact., (© 2023. The Author(s).)

A patient with B-cell acute lymphoblastic leukemia (ALL) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had persistent, progressive pneumonia with viremia after 5 months of infection despite monoclonal antibodies, intravenous (IV) remdesivir and prolonged oral steroids. Twenty days of nirmatrelvir/ritonavir and 10 days of IV remdesivir led to full recovery., Competing Interests: Potential conflicts of interest. J. H., J. M. R., and M. D. are employees of Pfizer. M. B. receives research support from GlaxoSmithKline and Gilead, and research support and consulting fees from Vir Biotechnology. A. L. G. reports contract testing to University of Washington (UW) from Abbott, Cepheid, Novavax, Pfizer, Janssen and Hologic and research support to UW from Gilead and Merck, outside of the described work. P. R. received speaking fees from Gates Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide, with limited therapeutic options for advanced disease. Targeted α-therapy is an emerging class of targeted cancer therapy in which α-particle-emitting radionuclides, such as 227 Th, are delivered specifically to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and in vivo efficacy of a 227 Th-labeled GPC3-targeting antibody conjugate ( 227 Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. Methods: The chelator p -SCN-Bn-H 4 octapa-NCS (octapa) was conjugated to a GPC3-targeting antibody (αGPC3) for subsequent 227 Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of 227 Th. In vitro stability was evaluated by measuring the percentage of protein-bound 227 Th by γ-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2-Red-FLuc cells was developed. Biodistribution and blood clearance of 227 Th-octapa-αGPC3 were evaluated in tumor-bearing mice. The efficacy of 227 Th-octapa-αGPC3 was assessed in tumor-bearing animals with serial measurement of serum α-fetoprotein at 23 d after injection. Results: Octapa-conjugated αGPC3 provided up to 70% 227 Th labeling yield in 2 h at room temperature. In the presence of ascorbate, at least 97.8% of 227 Th was bound to αGPC3-octapa after 14 d in phosphate-buffered saline. In HepG2-Red-FLuc tumor-bearing mice, highly specific GPC3 targeting was observed, with significant 227 Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. Twenty-three days after treatment, a significant reduction in tumor burden was observed in mice receiving a 500 kBq/kg dose of 227 Th-octapa-αGPC3 by tail-vein injection. No acute off-target toxicity was observed, and no animals died before termination of the study. Conclusion: 227 Th-octapa-αGPC3 was observed to be stable in vitro; maintain high specificity for GPC3, with favorable biodistribution in vivo; and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Radioimmunotherapy (RIT) has long been pursued to improve outcomes in acute leukemia and higher-risk myelodysplastic syndrome (MDS). Of increasing interest are alpha-particle-emitting radionuclides such as astatine-211 ( 211 At) as they deliver large amounts of radiation over just a few cell diameters, enabling efficient and selective target cell kill. Here, we developed 211 At-based RIT targeting CD123, an antigen widely displayed on acute leukemia and MDS cells including underlying neoplastic stem cells. We generated and characterized new murine monoclonal antibodies (mAbs) specific for human CD123 and selected four, all of which were internalized by CD123+ target cells, for further characterization. All mAbs could be conjugated to a boron cage, isothiocyanatophenethyl-ureido-closo-decaborate(2-) (B10), and labeled with 211 At. CD123+ cell targeting studies in immunodeficient mice demonstrated specific uptake of 211 At-labeled anti-CD123 mAbs in human CD123+ MOLM-13 cell tumors in the flank. In mice injected intravenously with MOLM-13 cells or a CD123 NULL MOLM-13 subline, a single dose of up to 40 µCi of 211 At delivered via anti-CD123 mAb decreased tumor burdens and substantially prolonged survival dose dependently in mice bearing CD123+ but not CD123- leukemia xenografts, demonstrating potent and target-specific in vivo anti-leukemia efficacy. These data support the further development of 211 At-CD123 RIT toward clinical application., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Matrix metalloproteinases (MMPs) are involved in remodeling the extracellular matrix, but also participate in the development of physiopathologic processes. As they are overexpressed in different types of epithelial cancers, it has been suggested that their level expression could explain the different biological behavior between odontogenic cysts and tumors. Here, we compared the expression level and proteolytic activities of MMP-2 and MMP-9 in dental follicles, dentigerous cysts, odontogenic keratocysts and unicystic ameloblastomas. We found similar expression of MMP-2 in all tissues, but a higher activity in cystic and tumor lesions than follicles. On the other hand, MMP-9 expression and activity was greater in cysts and ameloblastoma than in follicles. However, no differences were found in expression or activity of both MMPs between cystic and tumor injuries, suggesting that they could participate in the growth of these lesions, but they cannot define their different biological behavior., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 Craniofacial Research Foundation. Published by Elsevier B.V. All rights reserved.)

Background: Potential involvement of the central nervous system (CNS) by acute lymphoblastic leukemia is typically evaluated by a conventional cytospin (CC) of cerebrospinal fluid (CSF). Multiparameter flow cytometry (MFC) is generally more sensitive and specific than morphology, but data to guide its use versus CC are limited., Methods: This study identified 92 patients who had MFC performed on their initial CSF specimen and received at least 4 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) as their initial treatment., Results: Eighteen (20%) were CSF+ by MFC at the baseline, and only 6 of these patients were positive by CC. In contrast, 0 of 51 patients who were negative by MFC and had CC available were positive by CC. Despite the receipt of significantly more intra-CSF chemotherapy (P < .001), the cumulative incidence of CNS relapse by MFC was 22% among CSF+ patients versus 5% among those who were CSF- (P = .044). No such association was observed between CNS relapse and CC results (P = .42). None of the 74 CSF- patients became CSF+ during their initial treatment despite being tested a median of 5 times (range, 2-10). CSF positivity by MFC was the factor most strongly associated with CNS relapse in a series of univariate Cox models (hazard ratio, 3.7; P = .067). The initial CSF status by MFC had no significant impact on overall or event-free survival., Conclusions: MFC of CSF is superior to CC of CSF in identifying adults at high risk for CNS relapse after treatment with hyperCVAD. Surveillance of CSF by MFC has limited utility., (© 2021 American Cancer Society.)

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCLs), although outcomes are worse in aggressive disease, and most patients will still experience relapse. Radioimmunotherapy using 90Y-ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that megadoses of 90Y-ibritumomab tiuxetan with reduced-intensity conditioning could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-ibritumomab tiuxetan (1.5 mCi/kg; maximum, 120 mCi), fludarabine, and then 2 Gy total body irradiation before HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy, including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y-ibritumomab tiuxetan activity of 113.6 mCi (range, 71.2-129.2 mCi) was administered, delivering a median of 552 cGy to the liver (range, 499-2411 cGy). The estimated 1- and 5-year progression-free survival was 55% (95% confidence interval [CI], 31-73) and 50% (95% CI, 27-69) with a median progression-free survival of 1.57 years. The estimated 1- and 5-year overall survival was 80% (95% CI, 54-92) and 63% (95% CI, 38-81) with a median overall survival of 6.45 years. Sixteen patients (80%) experienced grade 3 or higher toxicities, although nonrelapse mortality was 10% at 1 year. No patients developed secondary acute myeloid leukemia/myelodysplastic syndrome. Megadose 90Y-ibritumomab tiuxetan, fludarabine, and low-dose total body irradiation followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified end point while producing nonhematologic toxicities comparable to those of standard reduced-intensity conditioning regimens., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Organic and conventional production are common in horticulture crops and each system may exert a different influence on the soil ecosystem, particularly the nematode community. Crop nutrient rate is an important choice in both production systems. The objectives of this study were to assess the impacts of (i) organic and conventional production systems and (ii) nutrient rate in both systems on the nematode community in carrot production. To investigate these objectives, field studies in organic and conventional production - which included fumigation with 1,3-dichloropropene - were conducted in North-Central Florida. In both production systems, nutrient rate treatments were 168, 224, 280, 336, and 392 kg N/ha. Poultry litter was the nitrogen source in organic production whereas synthetic, inorganic fertilizer was used in conventional production. All nematode trophic groups were consistently more abundant in organic than conventional production. The nematode community was more diverse and had greater trophic structure in organic production. Greater rates of organic nutrients increased enrichment opportunists (bacterivores and fungivores), but inconsistently across years. Conventional production had similar results except that only moderate nutrient rates increased fungivore abundances. Extreme enrichment opportunists ( Rhabditis spp.) drove bacterivore trends in organic production whereas moderate enrichment opportunists ( Cephalobus spp.) drove trends in conventional production. Nutrient rates did not affect omnivore-predators, herbivores, nematode community diversity, or structure in either system. In summary, type of production system, organic or conventional, exerts a strong influence on the nematode community, but nutrient rate has less consistent effects in horticulture production., (© 2021 Authors.)

Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 ( 89 Zr) and yttrium-90 ( 90 Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with 89 Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with 90 Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUV max by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R 2  = 0.90). Serum AFP was significantly lower 30 days after RIT in 90 Y-αGPC3 treated animals compared to those untreated (p = 0.01) or treated with non-radiolabeled αGPC3 (p = 0.02). Immuno-PET GTV measurements strongly correlated with tumor burden after RIT (R 2  = 0.87), and GTV of animals treated with 90 Y-αGPC3 was lower than in animals who did not receive treatment or were treated with non-radiolabeled αGPC3, although this only trended toward statistical significance. A theranostic platform utilizing GPC3 targeted 89 Zr and 90 Y effectively imaged, treated, and assessed response after radioimmunotherapy in a GPC3-expressing HCC xenograft model.

To improve disease control without increasing the toxicity of a reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM), a phase I trial was performed using an antibody-radionuclide conjugate targeting CD45 ( 90 Y-DOTA-BC8) as conditioning. 90 Y-DOTA-BC8 was combined with fludarabine and low-dose TBI followed by allogeneic HCT in patients with MM and ≥1 adverse risk characteristic at diagnosis, relapse after autologous transplant, or plasma cell leukemia (PCL). The primary objective was to estimate the maximum tolerated radiation absorbed dose. Fourteen patients were treated (one with PCL, nine failed prior autologous HCT, and nine with ≥1 adverse cytogenetics). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Non-hematologic toxicities were manageable and included primarily gastrointestinal (43%) and metabolic/electrolyte disturbances (36%). Treatment-related mortality at 100 days was 0%. At a median follow-up of 5 years, the overall survival was 71% (median not reached) and the progression-free survival was 41% (median 40.9 months). The incorporation of CD45-targeted radioimmunotherapy (RIT) into a reduced-intensity allogeneic HCT is well-tolerated and may induce long-term remissions among patients with poor-risk MM, supporting further development of RIT-augmented conditioning regimens for HCT.

Pretargeted radioimmunotherapy (PRIT) has been investigated as a multi-step approach to decrease relapse and toxicity for high-risk acute myeloid leukemia (AML). Relevant factors including endogenous biotin and immunogenicity, however, have limited the use of PRIT with an anti-CD45 antibody streptavidin conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine and anti-human CD45 bispecific antibody constructs using 30F11 and BC8 antibodies, respectively, combined with an anti-yttrium (Y)-DOTA single-chain variable fragment (C825) to capture a radiolabeled ligand. The bispecific construct targeting human CD45 (BC8-Fc-C825) had high uptake in leukemia HEL xenografts [7.8 ± 0.02% percent injected dose/gram of tissue (% ID/g)]. Therapy studies showed that 70% of mice with HEL human xenografts treated with BC8-Fc-C825 followed by 44.4 MBq (1,200 μCi) of 90 Y-DOTA-biotin survived at least 170 days after therapy, while all nontreated controls required euthanasia because of tumor progression by day 32. High uptake at sites of leukemia (spleen and bone marrow) was also seen with 30F11-IgG1-C825 in a syngeneic disseminated SJL murine leukemia model (spleen, 9.0 ± 1.5% ID/g and bone marrow, 8.1 ± 1.2% ID/g), with minimal uptake in all other normal organs (<0.5% ID/g) at 24 hours after 90 Y-DOTA injections. SJL leukemia mice treated with the bispecific 30F11-IgG1-C825 and 29.6 MBq (800 μCi) of 90 Y-DOTA-biotin had a survival advantage compared with untreated leukemic mice (median, 43 vs. 30 days, respectively; P < 0.0001). These data suggest bispecific antibody-mediated PRIT may be highly effective for leukemia therapy and translation to human studies., (©2020 American Association for Cancer Research.)

Outcomes of patients with persistent high-risk leukemia or myelodysplasia prior to allogeneic hematopoietic cell transplantation are dismal. We therefore conducted a phase I trial evaluating the use of CD45-targeted radiotherapy preceding hematopoietic cell transplantation with the goal of improving outcomes for this high-risk scenario. Fifteen patients, median age 62 (range 37-76) years, were treated: ten with advanced acute myeloid leukemia, five with high-risk myelodysplastic syndrome. All patients had evidence of disease prior to treatment including nine with marrow blast counts ranging from 7-84% and six with minimal residual disease. Patients received escalating doses of yttrium-90-labeled anti-CD45 antibody followed by fludarabine and 2 Gy total body irradiation prior to human leukocyte antigen-matched, related or unrelated hematopoietic cell transplantation. Although a maximum dose of 30 Gy was delivered to the liver, no dose-limiting toxicity was observed. Therefore, the maximum-tolerated dose could not be estimated. Treatment led to complete remission in 13 patients (87%). All patients engrafted by day 28. Six patients relapsed, median of 59 (range 6-351) days, after transplantation. The 1-year estimate of relapse was 41%. Eight patients (53%) are surviving with median follow up of 1.8 (range 0.9-5.9) years. Estimated overall survival at one and two years was 66% and 46%, respectively, with progression-free survival estimated to be 46% at each time point. In conclusion, the combination of 90 Y-DOTA-BC8 with an allogeneic hematopoietic cell transplantation regimen was feasible and tolerable. This approach appears promising in this high-risk leukemia/myelodysplasia patient population with active disease. (Trial registered at clinicaltrials.gov identifier: NCT01300572 )., (Copyright© 2020 Ferrata Storti Foundation.)

Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients., (© 2019 by The American Society of Hematology.)

The objective of this study was to translate reaction conditions and quality control methods used for production of an astatine-211(211At)-labeled anti-CD45 monoclonal antibody (MAb) conjugate, 211At-BC8-B10, from the laboratory setting to cGMP production. Five separate materials were produced in the preparation of 211At-BC8-B10: (1) p-isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS), (2) anti-CD45 MAb, BC8, (3) BC8-B10 MAb conjugate, (4) [211At]NaAt, and (5) 211At-BC8-B10. The 211At-labeling reagent, B10-NCS, was synthesized as previously reported. BC8 was produced, then conjugated with B10-NCS under cGMP conditions to form BC8-B10. [211At]NaAt was produced by α-irradiation of Bi targets, followed by isolation of the 211At using a "wet chemistry" method. The clinical product, 211At-BC8-B10, was prepared by reacting [211At]NaAt with BC8-B10 in NH4OAc buffer (pH 5.5) for 2 min at room temperature, followed by size-exclusion chromatography purification. Quality control tests conducted on the 211At-BC8-B10 included evaluations for purity and identity, as well as pyrogen and sterility tests. Stability of the 211At-BC8-B10 in 25 mg/mL sodium ascorbate solution was evaluated at 1, 2, 4, 6 and 21 h post isolation. For qualification, three consecutive 211At-BC8-B10 clinical preparations were successfully conducted in the cGMP suite, and an additional cGMP clinical preparation was carried out to validate each step required to deliver 211At-BC8-B10 to a patient. These cGMP preparations provided 0.80-1.28 Gbq (21.5-34.5 mCi) of 211At-BC8-B10 with radiochemical purity of >97%. The preparations were found to be sterile and have a pyrogen level <0.50 EU/mL. Cell binding was retained by the 211At-BC8-B10. 211At-BC8-B10 in ascorbic acid solution demonstrated a radiochemical stability of >95% for up to 21 h at room temperature. The experiments conducted have defined conditions for translation of 211At-BC8-B10 production from the laboratory to cGMP suite. This study has allowed the initiation of a phase I/II clinical trial using 211At-BC8-B10 (NCT03128034)., Competing Interests: The authors have declared that no competing interests exist.

Pretargeted radioimmunotherapy (PRIT) has demonstrated remarkable efficacy targeting tumor antigens, but immunogenicity and endogenous biotin blocking may limit clinical translation. We describe a new PRIT approach for the treatment of multiple myeloma (MM) and other B-cell malignancies, for which we developed an anti-CD38-bispecific fusion protein that eliminates endogenous biotin interference and immunogenic elements. In murine xenograft models of MM and non-Hodgkin lymphoma (NHL), the CD38-bispecific construct demonstrated excellent blood clearance and tumor targeting. Dosimetry calculations showed a tumor-absorbed dose of 43.8 Gy per millicurie injected dose of 90 Y, with tumor-to-normal organ dose ratios of 7:1 for liver and 15:1 for lung and kidney. In therapy studies, CD38-bispecific PRIT resulted in 100% complete remissions by day 12 in MM and NHL xenograft models, ultimately curing 80% of mice at optimal doses. In direct comparisons, efficacy of the CD38 bispecific proved equal or superior to streptavidin (SA)-biotin-based CD38-SA PRIT. Each approach cured at least 75% of mice at the highest radiation dose tested (1200 µCi), whereas at 600- and 1000-µCi doses, the bispecific outperformed the SA approach, curing 35% more mice overall ( P < .004). The high efficacy of bispecific PRIT, combined with its reduced risk of immunogenicity and endogenous biotin interference, make the CD38 bispecific an attractive candidate for clinical translation. Critically, CD38 PRIT may benefit patients with unresponsive, high-risk disease because refractory disease typically retains radiation sensitivity. We posit that PRIT might not only prolong survival, but possibly cure MM and treatment-refractory NHL patients., (© 2018 by The American Society of Hematology.)

Objectives: Invasive Aspergillosis (IA) is a serious problem among hematological patients and it is associated with high mortality. This situation can worsen at times of hospital construction, however there are several preventive measures available. This work aims to define the cost-effectiveness of some of these interventions., Patients and Methods: A decision tree model was used, it was divided into four arms according to each 1 of the interventions performed. A cost-effectiveness incremental analysis comparing environmental control measures, high efficiency particulate absorption (HEPA) filter installation and prophylaxis with posaconazole was done. Probabilistic and deterministic sensitivity analyses were also carried out., Results: Among 86 patients with 175 hospitalization episodes, the incidence of IA with environmental protection measures, antifungal prophylaxis and hospitalization in rooms with HEPA filters was 14.4%, 6.3% and 0%, respectively. An Incremental Cost Effectiveness Ratio analysis was performed and it was found that HEPA filtered rooms and environmental protection measures are cost saving interventions when compared with posaconazole prophylaxis (-$2665 vs -$4073 vs $42 531 US dollars, respectively) for IA episode prevented., Conclusion: The isolation of inpatients with acute leukemia during hospital construction periods in HEPA filtered rooms could reduce the incidence of IA and might be a cost-effective prevention strategy., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Invasive aspergillosis (IA) is a significant problem in acute leukaemia patients. Construction work near hospital wards caring for immunocompromised patients is one of the main risk factors for developing invasive pulmonary aspergillosis (IPA)., Aim: To assess the impact of environmental control measures used during hospital construction for the prevention of IA in acute leukaemia patients., Methods: A retrospective cohort study was developed to evaluate the IA incidence in acute leukaemia patients with different environmental control measures employed during hospital construction. We used European Organisation for the Research and Treatment of Cancer (EORTC) criterial diagnosis parameters for definition of IA., Findings: A total of 175 episodes of inpatient care were evaluated, 62 of which did not have any environmental control measures (when an outbreak occurred), and 113 that were subject to environmental control measures directed to preventing IA. The study showed an IA incidence of 25.8% for the group without environmental control measures vs 12.4% for those who did receive environmental control measures (P=0.024). The relative risk for IA was 0.595 (95% confidence interval: 0.394-0.897) for the group with environmental control measures., Conclusion: The current study suggests that the implementation of environmental control measures during a hospital construction has a positive impact for prevention of IA in patients hospitalized with acute leukaemia., (Copyright © 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation. We tested B-NHL responses to venetoclax combined with either external beam radiotherapy or radioimmunotherapy (RIT), which joins the selectivity of antibody targeting with the effectiveness of irradiation. We first tested cytotoxicity of cesium-137 irradiation plus venetoclax in 14 B-NHL cell lines representing five lymphoma subtypes. Combination treatment synergistically increased cell death in 10 of 14 lines. Lack of synergy was predicted by resistance to single-agent venetoclax and high BCL-XL expression. We then assessed the efficacy of external beam radiotherapy plus venetoclax in murine xenograft models of mantle cell (MCL), germinal-center diffuse large B-cell (GCB-DLBCL), and activated B-cell (ABC-DLBCL) lymphomas. In each model, external beam radiotherapy plus venetoclax synergistically increased mouse survival time, curing up to 10%. We finally combined venetoclax treatment of MCL and ABC-DLBCL xenografts with a pretargeted RIT (PRIT) system directed against the CD20 antigen. Optimal dosing of PRIT plus venetoclax cured 100% of mice with no detectable toxicity. Venetoclax combined with radiotherapy may be a promising treatment for a wide range of lymphomas Cancer Res; 77(14); 3885-93. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7), with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hours. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared with 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (P < 0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (P < 0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90 Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression, and superior efficacy. Cancer Res; 76(22); 6669-79. ©2016 AACR., (©2016 American Association for Cancer Research.)

Objective: To assess the long-term clinical and economic impact of integrated pump/CGM technology therapy as compared to multiple daily injections (MDI), for the treatment of type 1 diabetes (T1D) in Colombia., Methods: The CORE Diabetes Model was used to simulate a hypothetical cohort of patients with T1D. Mean baseline characteristics were taken from a clinical study conducted in Colombia and a healthcare payer perspective was adopted, with a 5% annual discount rate applied to both costs and outcomes., Results: The integrated pump/CGM improved mean life expectancy by 3.51 years compared with MDI. A similar increase occurred in mean quality-adjusted life expectancy with an additional 3.81 quality-adjusted life years (QALYs). Onset of diabetes-related complications was also delayed as compared to MDI, and mean survival time free of complication increased by 1.74 years with integrated pump/CGM. Although this increased treatment costs of diabetes as compared to MDI, savings were achieved thanks to reduced expenditure on diabetes-related complications. The estimated incremental cost-effectiveness ratio (ICER) for SAP was Colombian Pesos (COP) 44,893,950 (approximately USD$23,200) per QALY gained., Conclusions: Improved blood glucose control associated to integrated pump/CGM results in a decreased incidence of diabetes-related complications and improves life expectancy as compared to MDI. Using recommended thresholds from the World Health Organization and previous coverage decisions about health technologies in Colombia, it is a cost-effective alternative to MDI for the treatment of type 1 diabetes in Colombia., (Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.)

Autologous stem cell transplantation (ASCT) is standard therapy for mantle cell lymphoma (MCL) in remission after induction chemotherapy, with the best results for patients in complete remission (CR). We hypothesized that evaluation of minimal residual disease (MRD) before ASCT could further stratify outcomes for these patients. Patients with MCL who underwent ASCT in clinical CR between 1996 and 2011 with pretransplantation MRD testing were eligible. Presence of a clonal IgH rearrangement, t(11; 14) by PCR or positive flow cytometry from blood or bone marrow, was considered positive. An adjusted proportional hazards model for associations with progression-free (PFS) and overall survival (OS) was performed. Of 75 MCL patients in CR, 8 (11%) were MRD positive. MRD positivity was associated with shorter OS and PFS. The median OS for MRD-negative patients was not reached, with 82% survival at 5 years, whereas for the MRD-positive patients, median OS was 3.01 years (hazard ratio [HR], 4.04; P = .009), with a median follow-up of 5.1 years. The median PFS for MRD-negative patients was not reached with 75% PFS at 5 years, whereas for MRD-positive patients, it was 2.38 years (HR, 3.69; P = .002). MRD positivity is independently associated with poor outcomes after ASCT for MCL patients in CR., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Many patients with hematologic malignancies cannot tolerate hematopoietic cell transplantation (HCT), whereas others may not have a compatible human leukocyte antigen-matched donor. To overcome these limitations, we optimized a conditioning regimen employing anti-CD45 radioimmunotherapy (RIT) replacing total body irradiation (TBI) before haploidentical HCT in a murine model. Mice received 200 to 400 μCi (90)Y-anti-CD45 antibody (30F11), with or without fludarabine (5 days starting day -8), with cyclophosphamide (CY; days -2 and +2) for graft-versus-host disease prophylaxis, and 1.5 × 10(7) haploidentical donor bone marrow cells (day 0). Haploidentical bone marrow transplantation (BMT) with 300 μCi (90)Y-anti-CD45 RIT and CY, without TBI or fludarabine, led to mixed chimeras with 81.3 ± 10.6% mean donor origin CD8(+) cells detected 1 month after BMT, and remained stable (85.5 ± 11% mean donor origin CD8(+) cells) 6 months after haploidentical BMT. High chimerism levels were induced across multiple hematopoietic lineages 28 days after haploidentical BMT with 69.3 ± 14.1%, 75.6 ± 20.2%, and 88.5 ± 11.8% CD3(+) T cells, B220(+) B cells, and CD11b(+) myeloid cells, respectively. Fifty percent of SJL leukemia-bearing mice treated with 400 μCi (90)Y-DOTA-30F11, CY, and haploidentical BMT were cured and lived >200 days. Mice treated with 200 μCi (90)Y-DOTA-30F11 had a median overall survival of 73 days, while untreated leukemic mice had a median overall survival of 34 days (P < .001, Mantel-Cox test). RIT-mediated haploidentical BMT without TBI may increase treatment options for aggressive hematologic malignancies., (© 2016 by The American Society of Hematology.)

Autologous stem cell transplant (ASCT) can improve outcomes for mantle cell lymphoma (MCL) patients, yet relapses are frequent. We hypothesized that high-dose anti-CD20 radioimmunotherapy (RIT)-based conditioning could improve results in this setting. We thus assessed 162 consecutive patients with MCL at our centre undergoing ASCT following high-dose RIT-based (n = 61) or standard (n = 101) conditioning. RIT patients were less likely to be in first remission (48% vs. 72%; P = 0·002), be in complete remission (CR) (26% vs. 61%; P < 0·001) and have chemosensitive disease (84% vs. 96%; P = 0·006). RIT-based conditioning was associated with a reduced risk of treatment failure [hazard ratio (HR) 0·40; P = 0·001] and mortality (HR 0·49; P = 0·01) after adjusting for these imbalances. This difference increased as disease status worsened (from CR to partial remission to stable/progressive disease), with respective HRs of 1·14, 0·53 and 0·04 for mortality, and 0·66, 0·36 and 0·14 for treatment failure. RIT-based conditioning appears to improve outcome following ASCT for MCL patients unable to achieve CR after controlling for imbalances in important risk factors. These data support the further study of RIT and radiation-based strategies in a risk-adapted approach to ASCT for persistent MCL., (© 2015 John Wiley & Sons Ltd.)

Background: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined., Patients and Methods: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation., Results: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed., Conclusions: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)