Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.

Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.

Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study.

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.

Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial.

BACKGROUND: Voriconazole has been recommended as primary treatment for patients with invasive aspergillosis. Intravenous and tablet formulations of posaconazole that have improved systemic absorption could be an effective alternative to voriconazole. We aimed to assess non-inferiority of posaconazole to voriconazole for the primary treatment of invasive aspergillosis. METHODS: We did a randomised, prospective, double-blind, double-dummy, controlled trial comparing posaconazole (intravenous or oral posaconazole 300 mg twice on day 1, followed by 300 mg once a day for days 2-84) with voriconazole (6 mg/kg intravenous or 300 mg oral twice on day 1 followed by 4 mg/kg intravenously or 200 mg orally twice a day for days 2-84) for 12 weeks or less in the primary treatment of invasive aspergillosis. Participants were from 91 study sites in 26 countries, were aged 13 years or older, weighed at least 40 kg, and met criteria for proven, probable, or possible fungal disease. Participants were randomly assigned (1:1) via a computer-generated randomisation schedule with stratification by risk status. The primary endpoint was cumulative all-cause mortality up until day 42 in the intention-to-treat (ITT) population (defined as randomly assigned participants who received ≥1 dose of study drug), with a 10% non-inferiority margin. The ITT population was also evaluated for safety. This study is registered with ClinicalTrials.gov, NCT01782131, and EudraCT, 2011-003938-14. FINDINGS: Between Oct 25, 2013, and Sept 10, 2019, of 653 individuals assessed for eligibility, 575 ITT participants were randomly assigned and received one or more doses of study drug (n=288 [50%] posaconazole, n=287 [50%] voriconazole). Mortality up until day 42 was 15% (44 of 288) in the posaconazole group and 21% (59 of 287) in the voriconazole group (treatment difference -5·3% [95% CI -11·6 to 1·0]; p<0·0001). Mortality up until day 42 in the full-analysis-set subpopulation (ITT participants with proven or probable invasive aspergillosis) supported this conclusion: 31 (19%) of 163 participants in the posaconazole group and 32 (19%) of 171 participants in the voriconazole group (treatment difference 0·3% [95% CI -8·2 to 8·8]). The most frequently reported treatment-related adverse events (incidence >3%) were increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT), nausea, hypokalaemia, and vomiting in the posaconazole group and increased ALT, AST, or alkaline phosphatase, hallucination, increased γ-glutamyltransferase peptidase, nausea, and blurred vision in the voriconazole group. The overall incidence of treatment-related adverse event rates in the ITT population was 30% for posaconazole and 40% for voriconazole (treatment difference -10·2% [95% CI -17·9 to -2·4]). INTERPRETATION: Posaconazole was non-inferior to voriconazole for all-cause mortality up until day 42 in participants with invasive aspergillosis. Posaconazole was well tolerated, and participants had fewer treatment-related adverse events than in the voriconazole group. This study supports the use of posaconazole as a first-line treatment for the condition. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.

Phase I study of expanded natural killer cells in combination with cetuximab for recurrent/metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) cells express high levels of epidermal growth factor receptor (EGFR). Cetuximab is an anti-EGFR monoclonal antibody that promotes natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) via engagement of CD16. We studied safety and efficacy of combining cetuximab with autologous expanded NK cells in patients with recurrent and/or metastatic NPC who had failed at least two prior lines of chemotherapy. METHODS: Seven subjects (six patients) received cetuximab every 3 weeks (six doses maximum) in the pre-trial phase. Autologous NK cells, expanded by co-culture with irradiated K562-mb15-41BBL cells, were then infused on the day after administration of cetuximab. Primary and secondary objectives were to determine safety of this combination therapy and to assess tumor responses, respectively. RESULTS: Median NK cell expansion from peripheral blood mononucleated cells after 10 days of culture with K562-mb15-41BBL was 274-fold (range, 36-534, n = 10), and the median expression of CD16 was 98.4% (range, 67.8-99.7%). Skin rash, the commonest side effect of cetuximab in the pre-trial phase, was not exacerbated by NK cell infusion. No intolerable side effects were observed. Stable disease was observed in four subjects and progressive disease in three subjects. Three patients who received NK cells twice had time to disease progression of 12, 13, and 19 months. CONCLUSION: NK cells with high ADCC potential can be expanded from patients with heavily pre-treated NPC. The safety profile and encouraging clinical responses observed after combining these cells with cetuximab warrant further studies of this approach. (clinicalTrials.gov NCT02507154, 23/07/2015). PRECIS: Engaging NK cell-mediated ADCC using cetuximab plus autologous NK cells in EGFR-positive NPC was well tolerated among heavily pre-treated recurrent NPC. Promising results were observed with 3 out of 7 subjects demonstrating durable stable disease.

Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit.

INTRODUCTION: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. METHODS: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). RESULTS: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2-3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. CONCLUSION: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. PRECIS: The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.

Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis.

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400-mg daily was based on results of an updated analysis of the pivotal phase III, placebo-controlled JAKARTA trial in patients with JAK-inhibitor-naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first-line fedratinib in patients with myelofibrosis.

Phase 2 Study of Anti-Human Cytomegalovirus Monoclonal Antibodies for Prophylaxis in Hematopoietic Cell Transplantation.

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.).

Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies.

BACKGROUND: Pracinostat is a potent histone deacetylase inhibitor with antitumor activity in both solid tumor and acute myeloid leukemia (AML) cell lines. Pracinostat is reported to have modest clinical activity in patients with advanced solid tumors. Given the higher preclinical sensitivity of hematologic malignancies to pracinostat, the authors conducted a phase 1 study to assess the safety, maximum tolerated dose, recommended phase 2 dose, efficacy, pharmacokinetics, and pharmacodynamics of pracinostat in patients with advanced hematological malignancies. METHODS: Pracinostat was administered orally 3 times a week for 3 weeks on a 28-day cycle. Patients were assigned to 7 dose levels using a 3 + 3 dose escalation design. RESULTS: A total of 44 patients were enrolled, 25 of whom had AML and 14 of whom had myelodysplastic syndrome. The maximum tolerated dose was 120 mg and the recommended phase 2 dose was 60 mg. Two patients with AML achieved a response: 1 complete remission (CR) and 1 complete cytogenetic response. Despite a dose-dependent increase in the plasma concentration of pracinostat, a similar increase in histone acetylation was not observed. As an extension, 10 additional patients with myelodysplastic syndrome were enrolled to assess the safety and efficacy of pracinostat in combination with azacitidine. Six patients achieved a CR and 3 achieved a CR without platelet recovery with no added toxicity. CONCLUSIONS: The results of the current study demonstrate that pracinostat is safe, with modest single-agent activity in patients with hematological malignancies. Cancer 2017;123:4851-9. © 2017 American Cancer Society.

Long-term renal outcome after allogeneic hemopoietic stem cell transplant: A comprehensive analysis of risk factors in an Asian patient population.

Allogeneic hemopoietic stem cell transplantation (allo-HSCT) poses a significant challenge to renal function due to multiple drug- and complication-related renal toxicity. In this single-center series of 216 adult Asian patients with a long and complete follow-up, 41 developed chronic kidney disease (CKD) giving a cumulative incidence of 19.0% at 25 years (median follow-up duration 7.84 years, range 2.0-27.7 years), but only two of the 41 patients reached stage 4 CKD and another two required dialysis. In contrast, acute kidney injury occurred in most patients, where glomerular filtration rate (GFR) suffered a mean fall of 50 mL/min/1.73 m2 at 6 months post-transplant compared with baseline. Suppression of renal function may last beyond 6 months but is potentially reversible, although not to baseline level in most patients. Analysis of a comprehensive range of 18 risk factors showed that older age, lower GFR at transplant, unrelated donor, diagnosis of AML, presence of diabetes mellitus at transplant, and duration of foscarnet use were significantly associated with CKD development, with the first three remaining as independent risks for CKD in multivariate analysis. Long-term survival is not affected by renal function, being 78.6% as compared to 85.5% for patients with low vs normal GFR at 2 years, respectively.

Combination antifungal therapy for invasive aspergillosis: a randomized trial.

BACKGROUND: Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy. OBJECTIVE: To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA. DESIGN: Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479). SETTING: 93 international sites. PATIENTS: 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed. MEASUREMENTS: The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures. RESULTS: Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P  = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different. LIMITATIONS: Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability. CONCLUSION: Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority. PRIMARY FUNDING SOURCE: Pfizer.

Expansion and homing of umbilical cord blood hematopoietic stem and progenitor cells for clinical transplantation.

The successful expansion of hematopoietic stem and progenitor cells (HSPCs) from umbilical cord blood (UCB) for transplantation could revolutionize clinical practice by improving transplantation-related outcomes and making available UCB units that have suboptimal cell doses for transplantation. New cytokine combinations appear able to promote HSPC growth with minimal differentiation into mature precursors and new agents, such as insulin-like growth factor-binding protein 2, are being used in clinical trials. Molecules that simulate the HSPC niche, such as Notch ligand, have also shown promise. Further improvements have been made with the use of mesenchymal stromal cells, which have made possible UCB expansion without a potentially deleterious prior CD34/CD133 cell selection step. Chemical molecules, such as copper chelators, nicotinamide, and aryl hydrocarbon antagonists, have shown excellent outcomes in clinical studies. The use of bioreactors could further add to HSPC studies in future. Drugs that could improve HSPC homing also appear to have potential in improving engraftment times in UCB transplantation. Technologies to expand HSPC from UCB and to enhance the homing of these cells appear to have attained the goal of accelerating hematopoietic recovery. Further discoveries and clinical studies are likely to make the goal of true HSPC expansion a reality for many applications in future.

WPSS is a strong prognostic indicator for clinical outcome of allogeneic transplant for myelodysplastic syndrome in Southeast Asian patients.

To better understand the predictive factors and improve clinical outcome of allogeneic transplant for patients with myelodysplastic syndrome (MDS), we retrospectively analyzed the post-transplant outcome of 60 Southeast Asian patients with MDS. Multivariate analysis showed that WHO classification-based Prognostic Scoring System (WPSS) significantly affect overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR), and cumulative incidence of non-relapse mortality (CINRM). Stratified by WPSS into very low/low, intermediate, high, and very high-risk categories, 3-year OS was 100, 61, 37, and 18% (p = 0.02); PFS was 100, 55, 32, and 18% (p = 0.014); CIR was 12, 24, 38, and 59% (p = 0.024); CINRM was 0, 6, 12, and 26% (p = 0.037), respectively. WHO classification, Revised International Prognostic Scoring System (IPSS-R), IPSS-R-defined cytogenetic risk groups, donor gender, and acute and chronic graft vs host disease (GVHD) also influenced different aspects of transplant outcome. We found that WPSS is a powerful predictor of post-transplant outcome. WPSS provides an important model not only for prognostication but also for exploration of further post-transplant measures such as immunological maneuvers or novel therapy to improve the poor outcome of high-risk patients.

Direct costs associated with febrile neutropenia in inpatients with hematological diseases in Singapore.

PURPOSE: This prospective cohort study aims to investigate the direct hospitalization costs incurred during febrile neutropenia (FN) in inpatients with underlying hematological conditions and also to elucidate the factors associated with a high cost of managing febrile neutropenia. METHODS: Patients with underlying hematological conditions and documented FN were recruited between October 2008 and February 2011. FN-related costs included all costs incurred from the first day of FN until the last day of antibiotics prescribed. Relevant clinical factors were analyzed using generalized estimating equation models to elucidate the factors that were associated with higher costs of FN. RESULTS: A total of 175 patients were recruited with 303 documented episodes of FN. In non-transplant patients, 75.6 % of the FN episodes occurred. The median and mean cost incurred for each FN episode was USD9,060 (interquartile range = USD5,047-16,631) and USD15,298 (standard deviation ± USD17,459), respectively, accounting for approximately 38 % of the median total hospitalization cost and 37 % of the mean total hospitalization cost. The ward charges (44.1 %) constituted the largest component of the cost, followed by the laboratory charges (27.3 %) and medications (18.7 %), of which antimicrobials constituted 9.6 % of the cost of FN. The factors associated with higher costs of FN include cytomegalovirus reactivation (p < 0.001), longer duration of antibiotics (p < 0.001), lower absolute neutrophil count nadir (p < 0.001), allogeneic stem cell transplantation (p < 0.01), and diagnosis of invasive fungal infection (p < 0.05). CONCLUSION: The economic cost of management of FN in hematology inpatients is considerable and in addition to the overall risk of mortality for this condition. Strategies to reduce FN or ameliorate its costs are essential for this group of patients.

Health-Related Quality of Life Following Allogeneic Hematopoietic Cell Transplantation with Omidubicel versus Umbilical Cord Blood.

Omidubicel is an advanced cell therapy derived from umbilical cord blood (UCB) for use in allogeneic hematopoietic cell transplantation (HCT). A recent randomized phase 3 clinical trial demonstrated faster engraftment, shorter length of hospital stays, and lower rates of infection with omidubicel compared with standard UCB transplantation in patients with high-risk hematologic malignancies. Despite the proven clinical benefits of omidubicel, its impact on health-related quality of life (HRQL) from the patient's perspective has not been described. This study analyzed patient-reported HRQL measures collected prospectively in the randomized phase 3 trial comparing omidubicel to standard UCB transplantation. A total of 108 patients at 33 international stem cell transplantation centers underwent myeloablative allogeneic HCT with either omidubicel or standard UCB. Patients completed serial HRQL questionnaires at screening and on days 42, 100, 180, and 365 post-transplantation. The HRQL surveys included the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), a 50-item cancer-specific questionnaire assessing physical, functional, emotional, social/family, and HCT-specific well-being, and the EuroQol 5-Dimension 3-Level, a 5-item generic HRQL survey. A mixed model with repeated measures was used to compare changes in HRQL from baseline in the 2 treatment arms. The average change in HRQL scores over time was compared by estimating the difference in the area under the curve (AUC) in each treatment group. Seventy-five patients (omidubicel arm, n = 37; standard UCB arm, n = 38) who completed the FACT-BMT at baseline and on 1 or more follow-up visits were included in this study. Baseline characteristics were similar in the 2 treatment arms. Over the first year post-transplantation, the AUCs of mean changes in physical, functional, and total FACT-BMT scores indicated significantly better HRQL with omidubicel (P < .05), with mean differences across time points ranging from 1.4 to 3.1 points, 1.6 to 3.2 points, and 7.2 to 11.0 points, respectively. The minimal clinically important difference was exceeded at 1 or more time points for each of these measures. The HRQL improvements with omidubicel were observed as early as 42 days post-transplantation and persisted at 1 year, indicating the potential long-term benefits of omidubicel on HRQL. Across all patients, adverse clinical outcomes, such as grade 3 viral infections and lower rates of neutrophil engraftment, were associated with worse HRQL scores. The observed improvements in HRQL measures may reflect the known clinical benefits of omidubicel. Compared with standard UCB, allogeneic HCT with omidubicel resulted in significant and clinically meaningful improvements in patient-reported HRQL measures.

Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials.

Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3+, CD4+, CD8+, CD19+, CD116+CD56+, and CD123+ immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up.

Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition.

In up to one-third of patients with acute myeloid leukemia, a C-terminal frame-shift mutation results in abnormal and abundant cytoplasmic accumulation of the usually nucleoli-bound protein nucleophosmin (NPM), and this is thought to function in cancer pathogenesis. Here, we demonstrate a gain-of-function role for cytoplasmic NPM in the inhibition of caspase signaling. The NPM mutant specifically inhibits the activities of the cell-death proteases, caspase-6 and -8, through direct interaction with their cleaved, active forms, but not the immature procaspases. The cytoplasmic NPM mutant not only affords protection from death ligand-induced cell death but also suppresses caspase-6/-8-mediated myeloid differentiation. Our data hence provide a potential explanation for the myeloid-specific involvement of cytoplasmic NPM in the leukemogenesis of a large subset of acute myeloid leukemia.

Elevated Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor Binding Protein-7 Predict Drug-Induced Acute Kidney Injury.

BACKGROUND: Urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding protein-7 (IGFBP7) predict severe acute kidney injury (AKI) in critical illness. Earlier but subtle elevation of either biomarker from nephrotoxicity may predict drug-induced AKI. METHODS: A prospective study involving serial urine collection in patients treated with vancomycin, aminoglycosides, amphotericin, foscarnet, or calcineurin inhibitors was performed. Urinary TIMP2 and IGFBP7, both absolute levels and those normalized with urine creatinine, were examined in days leading to AKI onset by KDIGO criteria in cases or at final day of nephrotoxic therapy in non-AKI controls, who were matched for age, baseline kidney function, and nephrotoxic exposure. RESULTS: Urinary biomarker analyses were performed in 21 AKI patients and 28 non-AKI matched-controls; both groups had comparable baseline kidney function and duration of nephrotoxic drug therapy. Significantly higher absolute, normalized, and composite levels of TIMP2 and IGFBP7 were observed in AKI cases versus controls as early as 2-3 days before AKI onset (all P<0.05); >70% of patients with corresponding levels above 75th percentile developed AKI. Normalized TIMP2 at 2-3 days pre-AKI predicted AKI with the highest average AUROC of 0.81, followed by that of composite [TIMP2]x[IGFBP7] (0.78) after cross-validation. [TIMP2]x[IGFBP7] >0.01 (ng/mL)2/1000 predicted AKI with a sensitivity of 79% and specificity of 60%. CONCLUSION: Elevated urinary TIMP2 or IGFBP7 predicts drug-induced AKI with a lead-time of 2-3 days; an opportune time for interventions to reduce nephrotoxicity.

An ex vivo platform to guide drug combination treatment in relapsed/refractory lymphoma.

Although combination therapy is the standard of care for relapsed/refractory non-Hodgkin's lymphoma (RR-NHL), combination treatment chosen for an individual patient is empirical, and response rates remain poor in individuals with chemotherapy-resistant disease. Here, we evaluate an experimental-analytic method, quadratic phenotypic optimization platform (QPOP), for prediction of patient-specific drug combination efficacy from a limited quantity of biopsied tumor samples. In this prospective study, we enrolled 71 patients with RR-NHL (39 B cell NHL and 32 NK/T cell NHL) with a median of two prior lines of treatment, at two academic hospitals in Singapore from November 2017 to August 2021. Fresh biopsies underwent ex vivo testing using a panel of 12 drugs with known efficacy against NHL to identify effective single and combination treatments. Individualized QPOP reports were generated for 67 of 75 patient samples, with a median turnaround time of 6 days from sample collection to report generation. Doublet drug combinations containing copanlisib or romidepsin were most effective against B cell NHL and NK/T cell NHL samples, respectively. Off-label QPOP-guided therapy offered at physician discretion in the absence of standard options (n = 17) resulted in five complete responses. Among patients with more than two prior lines of therapy, the rates of progressive disease were lower with QPOP-guided treatments than with conventional chemotherapy. Overall, this study shows that the identification of patient-specific drug combinations through ex vivo analysis was achievable for RR-NHL in a clinically applicable time frame. These data provide the basis for a prospective clinical trial evaluating ex vivo-guided combination therapy in RR-NHL.