Ecological Considerations When Designing Mitigation Translocations: An Australian Reptile Case Study.

Translocation science has made considerable progress over the last two decades; however, reptile translocations still frequently fail around the world. Major knowledge gaps surround the basic ecology of reptile species, including basic factors such as habitat preference, which have a critical influence on translocation success. The western spiny-tailed skink (Egernia stokesii badia) is used here as a case study to exemplify how empirical research can directly inform on-ground management and future translocation planning. A combination of studies, including LiDAR scanning of microhabitat structures, camera trapping, plasticine replica model experiments and unbounded point count surveys to assess predation risk, and visual and DNA analysis of dietary requirements, were all used to better understand the ecological requirements of E. s. badia. We found that the skinks have specific log pile requirements, both native and non-native predator management requirements, and a largely herbivorous, broad diet, which all influence translocation site selection and management planning. The use of E. s. badia as an Australian case study provides a clear strategic framework for the targeted research of meaningful ecological factors that influence translocation decision-making. Similar approaches applied to other reptile species are likely to fundamentally increase the capacity for effective management, and the likelihood of future successful translocations.

Chemotherapeutic Activity of Pitavastatin in Vincristine Resistant B-Cell Acute Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells. Based on the use of pitavastatin in acute myeloid leukemia (AML), we evaluated its efficacy in an REH ALL cell line derived to be resistant to vincristine. We found that pitavastatin inhibited the proliferation of both parental and vincristine-resistant REH tumor cells at an IC50 of 449 nM and 217 nM, respectively. Mitochondrial bioenergetic assays demonstrated that neither vincristine resistance nor pitavastatin treatment affected cellular oxidative phosphorylation, beta-oxidation, or glycolytic metabolism in ALL cells. In a co-culture model of ALL cells with bone marrow stromal cells, pitavastatin significantly decreased cell viability more robustly in the vincristine-resistant ALL cells compared with their parental controls. Subsequently, NSG mice were used to develop an in vivo model of B-cell ALL using both parental and vincristine-resistant ALL cells. Pitavastatin (10 mg/kg i.p.) significantly reduced the number of human CD45+ REH ALL cells in the bone marrow of mice after 4 weeks of treatment. Mechanistic studies showed that pitavastatin treatment in the vincristine-resistant cells led to apoptosis, with increased levels of cleaved PARP and protein-signaling changes for AMP-activated protein kinase/FoxO3a/Puma. Our data suggest the possible repurposing of pitavastatin as a chemotherapeutic agent in a model of vincristine-resistant B-cell ALL.

Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia.

The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown to be active in acute myeloid leukemia, prompting us to evaluate it in our in vitro co-culture model, which supports a chemo-resistant ALL population. We used phospho-protein profiling to evaluate the use of lipid metabolic active compounds in these chemo-resistant cells, due to the up-regulation of multiple active survival signals. In a co-culture with stromal cells, a shift towards anabolic processes occurred, which was further confirmed by assays showing increased lipid content. The treatment of REH leukemia cells with pitavastatin in the co-culture model resulted in significantly higher leukemic cell death than exposure to the standard-of-care chemotherapeutic agent, cytarabine (Ara-C). Our data demonstrates the use of pitavastatin as a possible alternative treatment strategy to improve patient outcomes in chemo-resistant, relapsed ALL.

Revealing microhabitat requirements of an endangered specialist lizard with LiDAR.

A central principle of threatened species management is the requirement for detailed understanding of species habitat requirements. Difficult terrain or cryptic behaviour can, however, make the study of habitat or microhabitat requirements difficult, calling for innovative data collection techniques. We used high-resolution terrestrial LiDAR imaging to develop three-dimensional models of log piles, quantifying the structural characteristics linked with occupancy of an endangered cryptic reptile, the western spiny-tailed skink (Egernia stokesii badia). Inhabited log piles were generally taller with smaller entrance hollows and a wider main log, had more high-hanging branches, fewer low-hanging branches, more mid- and understorey cover, and lower maximum canopy height. Significant characteristics linked with occupancy were longer log piles, an average of three logs, less canopy cover, and the presence of overhanging vegetation, likely relating to colony segregation, thermoregulatory requirements, and foraging opportunities. In addition to optimising translocation site selection, understanding microhabitat specificity of E. s. badia will help inform a range of management objectives, such as targeted monitoring and invasive predator control. There are also diverse opportunities for the application of this technology to a wide variety of future ecological studies and wildlife management initiatives pertaining to a range of cryptic, understudied taxa.

Mitigation translocation as a management tool.

Mitigation translocation is a subgroup of conservation translocation, categorized by a crisis-responsive time frame and the immediate goal of relocating individuals threatened with death. However, the relative successes of conservation translocations with longer time frames and broader metapopulation- and ecosystem-level considerations have been used to justify the continued implementation of mitigation translocations without adequate post hoc monitoring to confirm their effectiveness as a conservation tool. Mitigation translocations now outnumber other conservation translocations, and understanding the effectiveness of mitigation translocations is critical given limited global conservation funding especially if the mitigation translocations undermine biodiversity conservation by failing to save individuals. We assessed the effectiveness of mitigation translocations by conducting a quantitative review of the global literature. A total of 59 mitigation translocations were reviewed for their adherence to the adaptive scientific approach expected of other conservation translocations and for the testing of management options to continue improving techniques for the future. We found that mitigation translocations have not achieved their potential as an effective applied science. Most translocations focused predominantly on population establishment- and persistence-level questions, as is often seen in translocations more broadly, and less on metapopulation and ecosystem outcomes. Questions regarding the long-term impacts to the recipient ecosystem (12% of articles) and the carrying capacity of translocation sites (24% of articles) were addressed least often, despite these factors being more likely to influence ultimate success. Less than half (47%) of studies included comparison of different management techniques to facilitate practitioners selecting the most effective management actions for the future. To align mitigation translocations with the relative success of other conservation translocations, it is critical that future mitigation translocations conform to an established experimental approach to improve their effectiveness. Effective mitigation translocations will require significantly greater investment of time, expertise, and resources in the future.

La Translocación para Mitigación como una Herramienta de Gestión Resumen La translocación para mitigación es un subgrupo de la translocación para la conservación, caracterizada por un marco de tiempo que responda a la crisis y la meta inmediata de reubicar a individuos amenazados de muerte. Sin embargo, el éxito relativo de las traslocaciones para conservación con marcos de tiempo mayores y consideraciones a nivel metapoblación y ecosistema más amplias han sido utilizadas para justificar la implementación de translocaciones para mitigación sin monitoreo post hoc adecuado para confirmar su efectividad como herramienta de conservación. Las translocaciones para mitigación ahora son más numerosas que otras translocaciones, por lo que es fundamental entender la efectividad de las translocaciones para mitigación debido a las limitaciones en el financiamiento para la conservación global - especialmente si las translocaciones para mitigación socavan la conservación de la biodiversidad al fallar en salvar individuos. Evaluamos la efectividad de translocaciones para mitigación mediante una revisión cuantitativa de la literatura global. Revisamos un total de 59 translocaciones para mitigación para analizar su adhesión al método científico adaptativo esperado de otras translocaciones de conservación y para probar las opciones de gestión para mejorar las técnicas en el futuro. Encontramos que las mitigaciones para translocación no han alcanzado su potencial como una ciencia aplicada efectiva. La mayoría de las translocaciones se centraron predominantemente en preguntas relacionadas con el establecimiento y nivel de persistencia de la población, como se observa en translocaciones más generales, y menos en resultados a nivel metapoblación y ecosistema. Aspectos relacionados con los impactos a largo plazo sobre el ecosistema recipiente (12% de los artículos) y la capacidad de carga de los sitios de translocación (24% de los artículos) fueron poco abordados, no obstante que es más probable que estos factores influyan en el éxito final. Menos de la mitad (47%) de los estudios incluyó la comparación de métodos de gestión diferentes para facilitar que los practicantes selecciones las acciones de gestión más efectivas para el futuro. Para alinear las translocaciones para mitigación con el éxito relativo de otras translocaciones para conservación, es crítico que las futuras translocaciones para mitigación se apeguen a un método experimental establecido para incrementar su efectividad. Para ser efectivas, las translocaciones para mitigación requerirán una inversión de tiempo, conocimientos técnicos y recursos significativamente mayores.

Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial.

PURPOSE: Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a complete remission. A phase 3 randomized ECOG-ACRIN-led intergroup study was conducted to determine whether post-remission therapy with the farnesyl transferase inhibitor, tipifarnib (R115777), improved the disease-free survival (DFS) of adult patients with AML in complete remission (CR), at high risk for relapse. PATIENTS AND METHODS: Adult patients with AML in remission after salvage therapy and/or over age 60 in first remission were enrolled in this study. They were randomly assigned to treatment with tipifarnib or observation (control). The primary objective was to compare the disease-free survival (DFS) between the two arms based on intention to treat, which includes all randomized patients. RESULTS: One hundred and forty-four patients were enrolled on the study. Median DFS was 8.9 vs 5.3 months, for tipifarnib vs observation (one-sided p = 0.026) and did not cross the pre-specified boundary to call the study positive. For the 134 eligible patients, median DFS was 10.8 vs 5.3 months for those randomized to tipifarnib vs observation (one-sided p = 0.008). Moreover in an ad hoc evaluation of all women (n = 71) median DFS was 12.1 vs 3.9 months for tipifarnib vs observation (one-sided p = 0.0004) while median OS was 26.5 vs 8.4 months respectively (one-sided p = 0.001). CONCLUSION: This study was not able to demonstrate a benefit to tipifarnib as maintenance therapy in patients with AML in remission. While subsets of patients may indeed benefit, additional studies would be needed to elucidate that benefit which is unlikely given that other seemingly better options have since become available.

Global meta-analysis of tree decline impacts on fauna.

Significant portions of the world's forests have been impacted by severe and large-scale tree declines characterised by gradual but widespread loss of vigour and subsequent death of either single or several tree species. Tree deaths represent a threat for fauna that are dependent on forest habitats for their survival. Although tree declines have received considerable scientific attention, surprisingly, little is known about their impacts on fauna. In total, we calculated 631 effect sizes across 59 studies that quantified the impact of tree declines on animal abundance. Data representing 186 bird species indicated an overall increase in bird abundance in response to tree declines (meta-analysis mean ± estimation g = 0.172 ± 0.053 [CI 0.069 to 0.275], P = 0.001); however, there was substantial variability in responses (significant heterogeneity P < 0.001) with a strong influence of diet as well as nesting guild on bird responses. Granivores (especially ground-foraging species, e.g. Passerellidae species), bark-foraging insectivores (e.g. woodpeckers), as well as ground- and cavity-nesting species apparently benefitted from tree declines, while nectarivorous birds [and, although not significant, aerially foraging insectivores (e.g. flycatchers) and leaf-gleaning insectivores (canopy-feeding)] were less common in the presence of tree declines. Data representing 33 mammal species indicate a tendency for detrimental effects of tree declines on mammals that use trees as refuges, while aerial foragers (i.e. bats) may benefit from opening up the canopy. Overall the average effect for mammals was neutral (meta-analysis mean estimation g = -0.150 ± 0.145 [-0.433 to 0.134], P = 0.302). Data representing 20 reptile species showed an insufficient range of responses to determine any diet or foraging effect on their responses. Data for 28 arthropod taxa should be considered with caution, as we could not adequately separate taxa according to their specialisations and reliance on key habitat. The data broadly suggest a detrimental effect of tree declines (meta-analysis mean estimation g = -0.171 ± 0.072 [-0.311 to -0.031], P = 0.017) with ground-foraging arthropods (e.g. detritivores and predators such as spiders and centipedes) more likely to be detrimentally impacted by tree declines. The range of responses to tree declines signifies substantially altered animal communities. In many instances, altered ecosystem function due to loss of key animal services will represent a significant threat to forest health.

Does aerial baiting for controlling feral cats in a heterogeneous landscape confer benefits to a threatened native meso-predator?

Introduced mammalian predators can have devastating impacts on recipient ecosystems and disrupt native predator-prey relationships. Feral cats (Felis catus) have been implicated in the decline and extinction of many Australian native species and developing effective and affordable methods to control them is a national priority. While there has been considerable progress in the lethal control of feral cats, effective management at landscape scales has proved challenging. Justification of the allocation of resources to feral cat control programs requires demonstration of the conservation benefit baiting provides to native species susceptible to cat predation. Here, we examined the effectiveness of a landscape-scale Eradicat® baiting program to protect threatened northern quolls (Dasyurus hallucatus) from feral cat predation in a heterogeneous rocky landscape in the Pilbara region of Western Australia. We used camera traps and GPS collars fitted to feral cats to monitor changes in activity patterns of feral cats and northern quolls at a baited treatment site and unbaited reference site over four years. Feral cat populations appeared to be naturally sparse in our study area, and camera trap monitoring showed no significant effect of baiting on cat detections. However, mortality rates of collared feral cats ranged from 18-33% after baiting, indicating that the program was reducing cat numbers. Our study demonstrated that feral cat baiting had a positive effect on northern quoll populations, with evidence of range expansion at the treatment site. We suggest that the rugged rocky habitat preferred by northern quolls in the Pilbara buffered them to some extent from feral cat predation, and baiting was sufficient to demonstrate a positive effect in this relatively short-term project. A more strategic approach to feral cat management is likely to be required in the longer-term to maximise the efficacy of control programs and thereby improve the conservation outlook for susceptible threatened fauna.

Quantifying and addressing the prevalence and bias of study designs in the environmental and social sciences.

Building trust in science and evidence-based decision-making depends heavily on the credibility of studies and their findings. Researchers employ many different study designs that vary in their risk of bias to evaluate the true effect of interventions or impacts. Here, we empirically quantify, on a large scale, the prevalence of different study designs and the magnitude of bias in their estimates. Randomised designs and controlled observational designs with pre-intervention sampling were used by just 23% of intervention studies in biodiversity conservation, and 36% of intervention studies in social science. We demonstrate, through pairwise within-study comparisons across 49 environmental datasets, that these types of designs usually give less biased estimates than simpler observational designs. We propose a model-based approach to combine study estimates that may suffer from different levels of study design bias, discuss the implications for evidence synthesis, and how to facilitate the use of more credible study designs.

A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia.

BACKGROUND: Midostaurin, a multikinase inhibitor, is approved for treatment of FLT3-mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML. PATIENTS AND METHODS: Primary objectives were to further describe the toxicity profile and determine the response rate in untreated patients with AML. Patients received midostaurin 75 mg orally twice daily on days 8 to 21 in combination with intravenous azacitidine at 75 mg/m2 on days 1 to 7. Plasma inhibitory activity assay for FLT3 was performed pretreatment and on day 8 and day 15 of each cycle. RESULTS: Twenty-six patients (median age, 74 years; range, 59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range, 1-10 cycles). Seven (29%) of 24 evaluable patients achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). The median overall survival was 244 days (95% confidence interval, 203-467 days). Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3 wild-type phosphorylation declined to 8% to 55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles (< 10% baseline) in 2 patients who were analyzed after cycle 3. CONCLUSION: Multiple cycles of azacitidine and midostaurin were not well-tolerated, but persistent inhibition of FLT3 wild-type phosphorylation suggest intermittent dosing of midostaurin should be considered in future low-intensity regimens for FLT3-mutant AML.

Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry.

BACKGROUND: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data. OBJECTIVES: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease. METHODS: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days. RESULTS: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months. CONCLUSIONS: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.

Fire-mediated habitat change regulates woodland bird species and functional group occurrence.

In an era characterized by recurrent large wildfires in many parts of the globe, there is a critical need to understand how animal species respond to fires, the rates at which populations can recover, and the functional changes fires may cause. Using quantified changes in habitat parameters over a ~400-yr post-fire chronosequence in an obligate-seeding Australian eucalypt woodland, we build and test predictions of how birds, as individual species and aggregated into functional groups according to their use of specific habitat resources, respond to time since fire. Individual bird species exhibited four generalized response types to time since fire: incline, decline, delayed, and bell. All significant relationships between bird functional group richness or abundance and time since fire were consistent with predictions based on known time-since-fire-associated changes in habitat features putatively important for these bird groups. Consequently, we argue that the bird community is responding to post-fire successional changes in habitat as per the habitat accommodation model, rather than to time since fire per se, and that our functional framework will be of value in predicting bird responses to future disturbances in this and other obligate-seeder forest and woodland ecosystems. Most bird species and functional groups that were affected by time since fire were associated with long-unburned woodlands. In the context of recent large, stand-replacement wildfires that have affected a substantial proportion of obligate-seeder eucalypt woodlands, and the multi-century timescales over which post-fire succession occurs, it would appear preferable from a bird conservation perspective if fires initiating loss of currently long-unburned woodlands were minimized. Once long-unburned woodlands are transformed by fire into recently burned woodlands, there is limited scope for alternative management interventions to accelerate the rate of habitat development after fire, or supplement the resources formerly provided to birds by long-unburned woodlands, with the limited exception of augmenting hollow availability for key hollow-nesting species.

The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study.

BACKGROUND: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1. METHODS: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis. RESULTS: Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89). CONCLUSIONS: This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.

Patterns of Relapse After Salvage Autologous Stem Cell Transplant for Hodgkin's Lymphoma: Should Sites of Relapse Relative to Initially Involved Sites Be Used to Guide Indications for Peri-Transplant Radiation Therapy.

PURPOSE: We aimed to assess patterns of relapse in patients undergoing salvage autologous stem cell transplant (ASCT) for relapsed Hodgkin lymphoma in the modern era with the hypothesis that patients who suffer a relapse at initially involved sites are at increased risks of relapse post-ASCT that may help guide the application of peri-transplant radiation therapy. METHODS AND MATERIALS: A retrospective review was conducted of 38 patients undergoing ASCT between 2002 and 2017 for relapsed or refractory Hodgkin lymphoma. The site of relapse at the time of ASCT and subsequent relapses were compared with sites of the initial involvement at the time of diagnosis using follow-up imaging (most commonly positron emission computed tomography). Relapse and overall survival rates were calculated from the date of ASCT using the Kaplan-Meier method with a multivariate analysis, completed using a Cox multivariate analysis. RESULTS: The median follow-up time was 38 months (interquartile range, 18-66 months). Twenty-two patients (58%) suffered a relapse after ASCT at a median time to relapse of 9.1 months (interquartile range, 2.9-12.3 months) with a 5-year risk of relapse of 58% (95% confidence interval [CI], 41%-75%). On univariate analysis, relapse at an initially involved site was significant for higher rates of relapse at 71% at 5-years (95% CI, 52%-90%) compared with relapse at initially uninvolved sites at 30% (95% CI, 2%-58%; P = .05). The relapse rate was also significantly higher in patients age <30 years at the time of diagnosis at 80% (95% CI, 59%-100%) compared with 40% (95% CI, 18%-62%) at 5 years in patients aged >30 years (P < .01). On multivariate analysis, relapse at initially involved sites was significant for higher rates of relapse (hazard ratio: 8.3; 95% CI, 1.2-57.4; P = .03). CONCLUSIONS: Relapses at initially involved sites may potentially increase the risk of relapse after ASCT. Additional studies are needed to clarify whether this should be used as an additional factor to guide recommendations for peri-transplant radiation therapy.

A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma.

This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by single-agent ixazomib maintenance, in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma. Primary phase I objectives were to determine the safety and recommended phase II dose of ixazomib-melphalan-prednisone. The primary phase II objective was to determine the complete plus very good partial response rate. In phase I, patients were enrolled to 4 arms investigating weekly or twice-weekly ixazomib (13 28-day cycles or nine 42-day cycles) plus melphalan-prednisone. In phase II, an expansion cohort was enrolled at the recommended phase II ixazomib dose. Of the 61 patients enrolled, 26 received the recommended phase II dose (ixazomib 4.0 mg [days 1, 8, 15] plus melphalan-prednisone 60 mg/m2 [days 1-4], 28-day cycles). Of the 61 enrolled patients, 36 (13 of 26 in the recommended phase II dose cohort) received single-agent ixazomib maintenance (days 1, 8, 15; 28-day cycles). In phase I, 10/38 patients reported dose-limiting toxicities in cycle 1, including grade 3 and/or 4 neutropenia (n=6) and thrombocytopenia (n=4). Complete plus very good partial response rate was 48% (48% at recommended phase II dose), including 28% (22%) complete response or better; responses deepened during maintenance in 34% (33%) of evaluable patients. After median follow up of 43.6 months, median progression-free survival was 22.1 months. Adverse events were mainly hematologic events, gastrointestinal events, and peripheral neuropathy. This study demonstrates the feasibility, tolerability, and activity of ixazomib-melphalan-prednisone induction and single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma patients. clinicaltrials.gov identifier 01335685.

Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. METHODS: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34). FINDINGS: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001). INTERPRETATION: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. FUNDING: Merck & Co., Inc.

Survival of Lymphoma Patients Experiencing Relapse or Progression after an Allogeneic Hematopoietic Cell Transplantation.

Outcome and management of patients who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has evolved in the recent decade. Using a multi-institutional retrospective database we report the predictive factors and survival of lymphoma patients who relapse after allo-HCT. We evaluated 495 allo-HCT recipients transplanted between 2000 and 2015 at 3 academic US medical centers. Landmark analysis evaluating predictive factors was performed at 1 month after allo-HCT relapse with a primary endpoint of postrelapse overall survival (PR-OS). A total of 175 lymphoma patients (35%) experienced relapse after allo-HCT. Of these, 126 patients, median age 46 years (range, 19 to 71), were assessable. Most patients (86%) received subsequent therapy; 80 patients received targeted agents and 19 donor lymphocyte infusion. On univariate analysis median PR-OS for patients with Hodgkin lymphoma was 47.9 months compared with 11.3 months in patients with indolent and 10.1 months in aggressive non-Hodgkin lymphoma (P = .04). On multivariate analysis postrelapse therapy administration (no therapy versus targeted therapy: hazard ratio, .21 [95% confidence interval, .10 to .45]; no therapy versus nontargeted therapy: hazard ratio, .26 [95% confidence interval, .11 to .57]), late relapse 130 days after allo-HCT (relative to early relapse: hazard ratio, .25; P < .001), and Eastern Cooperative Oncology Group performance status of 0 to 1 (versus Eastern Cooperative Oncology Group performance status ≥ 2: hazard ratio, .49; P = .003) were associated with a significantly reduced risk of mortality. Patients relapsing ≥ 130 days from the time of allo-HCT yielded PR-OS of 48.8 months compared with 6.5 months in patients with early relapse (P < .001). Our data suggest that in the modern era, therapies used for patients experiencing lymphoma relapse after allo-HCT can extend survival.

Analysis of Peripheral T-cell Lymphoma Diagnostic Workup in the United States.

BACKGROUND: With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. PATIENTS AND METHODS: We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States. RESULTS: A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P = .01). CONCLUSION: The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organization classification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL.