Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia.

Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.

Real-world outcomes with immunosuppressive therapy for aplastic anemia in patients treated at the University of Michigan.

Aplastic anemia (AA) is a rare bone marrow failure disorder that is treated with either allogeneic stem cell transplant or immunosuppressive therapy (IST) consisting of antithymocyte globulin (ATG), cyclosporine (CSA), and eltrombopag. While outcomes are favorable in younger patients, older patients (>60) have significantly worse long-term survival. The dose of ATG is often reduced in older patients and those with multiple comorbidities given concerns for tolerability. The efficacy and safety of dose-attenuated IST in this population is largely undescribed. We performed a retrospective review of patients with AA treated with IST. Our analysis was confounded by changes in practice patterns and the introduction of eltrombopag. We identified 53 patients >60 years old, of which, 20 received dose-attenuated IST, with no statistically significant difference in overall survival between full and attenuated dose cohorts. Overall response rates in both cohorts were similar at 6 months at 71% and 68%. There were more documented infectious complications in the full dose cohort (13 vs. 3). This supports the consideration of dose-attenuated IST in older patients with concerns about tolerance of IST. Lastly, our data confirmed favorable outcomes of younger patients receiving IST, especially in combination with eltrombopag.

Evaluating the efficacy and toxicity of dose adjusted pegylated L-asparaginase in combination with therapeutic drug monitoring.

The incorporation of pediatric-inspired regimens in the adolescent-young-adult (AYA) and adult populations have resulted improved survival outcomes (Stock et al. Blood 133(14):1548-1559 2019; Dunsmore et al. J Clin Oncol 38(28):3282-3293 2020; DeAngelo et al. Leukemia 29(3):526-534 2015). Nonetheless incorporation of such regimens is limited by increased toxicity to asparaginase. Dosing strategies that reduce the weight-based dose of pegylated-L-asparaginase (PEG-asparaginase) utilizing activity monitoring have been shown to result in better tolerability of these regimens. The purpose of this study was to analyze the efficacy and safety of treating adults with Philadelphia chromosome negative (Ph-) ALL with pediatric-inspired regimens that incorporate PEG-asparaginase dose adjustments and asparaginase activity level monitoring. Patients aged 18-65 years initiated on pediatric-inspired regimens utilizing dose-reduced PEG-asparaginase with therapeutic drug monitoring-guided adjustments were included. The screening of 122 patients treated between 2015 and 2021 resulted in the inclusion of 54 patients. The median age of the cohort was 35 years (16-65 years), and median body mass index (BMI) was 30 kg/m2 (18.3-53.4 kg/m2). The 36-month survival estimate was 62.1% (95% CI 48.1-77.7%), and the median overall survival (OS) was 62.2 months (95% CI 35.1-89.3 months). In the AYA cohort, the 36-month survival was 71.2% (95% CI 55.8-91%) and the median overall survival was not reached. Survival was not significantly affected by immunophenotype or BMI. Discontinuation due to toxicity or hypersensitivity reactions was low at 11% and 9% respectively. The encouraging survival outcomes and favorable tolerability of this older population in the real-world setting support the use of individualized PEG-asparaginase dosing with PharmD-guided therapeutic drug monitoring.

ERG amplification is a secondary recurrent driver event in myeloid malignancy with complex karyotype and TP53 mutations.

ERG is a transcription factor encoded on chromosome 21q22.2 with important roles in hematopoiesis and oncogenesis of prostate cancer. ERG amplification has been identified as one of the most common recurrent events in acute myeloid leukemia with complex karyotype (AML-CK). In this study, we uncover three different modes of ERG amplification in AML-CK. Importantly, we present evidence to show that ERG amplification is distinct from intrachromosomal amplification of chromosome 21 (iAMP21), a hallmark segmental amplification frequently encompassing RUNX1 and ERG in a subset of high-risk B-lymphoblastic leukemia. We also characterize the association with TP53 aberrations and other chromosomal aberrations, including chromothripsis. Lastly, we show that ERG amplification can initially emerge as subclonal events in low-grade myeloid neoplasms. These findings demonstrate that ERG amplification is a recurrent secondary driver event in AML and raise the tantalizing possibility of ERG as a therapeutic target.

Oncology stewardship in acute myeloid leukemia.

In recent years, an explosion of novel agents has shifted the treatment paradigm for patients with acute myeloid leukemia. The optimal place in therapy for many of these novel agents remains unknown due to limited guidance from national guidelines and the way these agents were studied prior to entering the market. A critical evaluation of the literature and incorporation of oncology stewardship principles can be helpful in determining an optimal place for these agents while being mindful of the overall cost that is associated with therapies. The purpose of this review is to critically evaluate the efficacy and safety data for five controversial agents and provide examples of the use of stewardship practices in determining their place in the treatment of acute myeloid leukemia.

Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors.

Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

Utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening in patients with acute myeloid leukemia (AML).

BACKGROUND: Current literature has demonstrated the utility of the MRSA nasal screen as a de-escalation tool to decrease unnecessary anti-MRSA antibiotic therapy. However, data on the applicability of this test in patients with hematologic malignancy is lacking. METHODS: This is a single-center, retrospective cohort study of patients with acute myeloid leukemia (AML) with or without a history of hematopoietic cell transplant (HCT), with pneumonia and MRSA nasal screening with respiratory cultures obtained. The primary outcome was to determine the negative predictive value (NPV) of the MRSA nasal screen for MRSA pneumonia. Secondary outcomes included sensitivity, specificity, positive predictive value (PPV) of the MRSA nasal screen and prevalence of MRSA pneumonia. RESULTS: Of 98 patients with AML and pneumonia, the prevalence of MRSA pneumonia was 4.1% with confirmed positive MRSA respiratory cultures observed in 4 patient cases. In patients with confirmed MRSA pneumonia, 3 had positive MRSA nasal screens while 1 had a false negative result, possibly due to a long lag time (21 days) between MRSA nasal screen and pneumonia diagnosis. Overall, the MRSA nasal screen demonstrated 75% sensitivity and 100% specificity, with a PPV of 100% and a NPV of 98.9%. CONCLUSIONS: Given the low prevalence, empiric use of anti-MRSA therapy in those AML and HCT patients with pneumonia may not be warranted in clinically stable patients. For patients in whom empiric anti-MRSA antibiotics are initiated, nasal screening for MRSA may be utilized to de-escalate anti-MRSA antibiotics in patients with AML with or without HCT.

Cytogenomic array detects a subset of myelodysplastic syndrome with increased risk that is invisible to conventional karyotype.

Conventional karyotyping is essential standard practice in the initial evaluation of myelodysplastic syndrome (MDS) and is the most impactful single component of the Revised International Prognostic Scoring System (IPSS-R). While single nucleotide polymorphism array (SNP-A) has demonstrated the ability to detect chromosomal defects with greater sensitivity than conventional karyotype, widespread adoption is limited by the unknown additional prognostic impact of SNP-A analysis. Here, we investigate the significance of additional SNP-A abnormalities in the setting of MDS and demonstrate differences in survival of patients with additional abnormalities, even those initially characterized as relatively lower risk either by cytogenetic score or IPSS-R. Our findings identify specific abnormalities, particularly KMT2A partial tandem duplication, that are invisible to conventional karyotype and potentially contribute to the poor prognosis of MDS patients. Furthermore, these results demonstrate the added value of SNP-A analysis in identifying patients who may benefit from more aggressive therapy, particularly those who would otherwise be classified into lower risk categories.

The leukemia strikes back: a review of pathogenesis and treatment of secondary AML.

Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.

Outcomes of previously untreated elderly patients with AML: a propensity score-matched comparison of clofarabine vs. FLAG.

The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.

Risk factors and impact of Clostridium difficile recurrence on haematology patients.

Objectives: The incidence of Clostridium difficile infection (CDI) in adults with malignancy is 7%-14% compared with 1%-2% in the general hospitalized population. Despite the increased incidence of CDI in this population, a major concern is the propensity of CDI to recur, leading to delays in therapy impacting outcomes. We conducted a retrospective case-control study to identify risk factors for recurrent CDI (rCDI) and to determine the impact of rCDI on adult patients with a haematological malignancy. Methods: Adult haematology patients with CDI from June 2010 to December 2014 were divided into two groups: rCDI and non-rCDI. Multivariable models using logistic regression were constructed to identify risk factors for rCDI. Results: A total of 100 patients in our study yielded a 41% recurrence rate. CDI impacted chemotherapy significantly more in the rCDI group (53.7% versus 11.9%, P <0.001), primarily due to interruptions in established treatment plans (46.3% versus 10.3%, P <0.001). Risk factors for rCDI identified at index included salvage lymphoma chemotherapy (OR 9.64, 95% CI 1.02-91.15, P = 0.048) and severe CDI (OR 4.82, 95% CI 1.31-17.66, P = 0.018). Longitudinal risk factors included exposure to fluoroquinolones (OR 3.96, 95% CI 1.04-15.15, P = 0.044), ceftriaxone (OR 18.93, 95% CI 1.27-281.95, P = 0.033) and piperacillin/tazobactam (OR 10.4, 95% CI 1.81-59.64, P = 0.009). Conclusions: Haematology patients exhibit a higher rate of rCDI than general hospitalized patients. Utilization of this multivariable model to guide index CDI therapy at index may help to decrease the rCDI and prevent delays or interruptions in chemotherapy.

Shared clonal cytogenetic abnormalities in aberrant mast cells and leukemic myeloid blasts detected by single nucleotide polymorphism microarray-based whole-genome scanning.

Systemic mastocytosis (SM) is characterized by a clonal proliferation of aberrant mast cells within extracutaneous sites. In a subset of SM cases, a second associated hematologic non-mast cell disease (AHNMD) is also present, usually of myeloid origin. Polymerase chain reaction and targeted fluorescence in situ hybridization studies have provided evidence that, in at least some cases, the aberrant mast cells are related clonally to the neoplastic cells of the AHNMD. In this work, a single nucleotide polymorphism microarray (SNP-A) was used to characterize the cytogenetics of the aberrant mast cells from a patient with acute myeloid leukemia and concomitant mast cell leukemia associated with a KIT D816A mutation. The results demonstrate the presence of shared cytogenetic abnormalities between the mast cells and myeloid blasts, as well as additional abnormalities within mast cells (copy-neutral loss of heterozygosity) not detectable by routine karyotypic analysis. To our knowledge, this work represents the first application of SNP-A whole-genome scanning to the detection of shared cytogenetic abnormalities between the two components of a case of SM-AHNMD. The findings provide additional evidence of a frequent clonal link between aberrant mast cells and cells of myeloid AHNMDs, and also highlight the importance of direct sequencing for identifying uncommon activating KIT mutations.

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

Tumor lysis syndrome in patients with acute myeloid leukemia treated with venetoclax and hypomethylating agents with or without dose ramp-up.

Venetoclax with hypomethylating agents (HMAs) is an important treatment for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. However, there is limited data on the safety of venetoclax without a dose ramp-up in patients with AML. A retrospective cohort analysis of patients with AML treated with HMA/venetoclax (HMA/Ven) with or without a dose ramp-up, or HMA alone from 6/30/2014-8/22/2022 was conducted. The primary endpoint was the incidence of laboratory and/or clinical tumor lysis syndrome (TLS) by day 10. Of 225 patients, 111 patients received HMA alone or HMA/Ven with a dose ramp-up and 114 received HMA/Ven with no dose ramp-up. The incidence of TLS was similar between the control and no dose ramp-up groups, with rates of 5.4% and 5.3% respectively (p = 0.962). TLS incidence was comparable in patients with and without a dose ramp-up, suggesting that a dose ramp-up may not be mandatory in patients with AML.

Impact of number of lumens in central-venous catheters on central-line bloodstream infection (CLABSI) and venous thromboembolism (VTE) risk in patients with acute leukemia.

This retrospective study was conducted to determine whether the number of peripherally inserted central-catheter lumens affected the rate of central-line associated bloodstream infections (CLABSIs) in adult patients with acute leukemia. The results show that CLABSI rates were not significantly different between patients with triple-lumen or double-lumen PICCs (22.1% vs 23.4%; P = .827).

Aspacytarabine for the treatment of patients with AML unfit for intensive chemotherapy: a phase 2 study.

High-dose cytarabine is associated with gastrointestinal and cerebellar toxicity, precluding its use for older or unfit patients with acute myeloid leukemia (AML). Aspacytarabine, an inactive prodrug of cytarabine, was evaluated as monotherapy in a phase 2b study of patients unfit for intensive chemotherapy (NCT03435848). Sixty-five patients with AML were treated with aspacytarabine 4.5 g/m2 per day (equimolar to 3 g/m2 per day cytarabine) for 6 doses per treatment. The median age was 75 years; 60.6% of patients had de novo AML, 28.8% had AML secondary to myelodysplastic syndrome, and 10.6% had therapy-related AML. Overall, 36.9% achieved complete remission (CR) with full count recovery. CR rates in patients with secondary AML, patients with prior treatment with hypomethylating agents, and patients with TP53 mutation were 26.7%, 25%, and 36%, respectively. Median overall survival was 9 months (range, 6-15.9) and was not reached among responders. Hematologic recovery was observed in all responding patients by day 26 without prolonged cytopenias. Adverse events typically precluding the use of high-dose cytarabine in older or unfit patients were not observed. These data suggest that aspacytarabine may be an effective regimen with a reduction in the attendant toxicities associated with high-dose cytarabine, an important consideration when treating AML and other hematologic disorders that use high-dose cytarabine. This trial was registered at www.clinicaltrials.gov as #NCT03435848.

Real world outcomes in patients with Philadelphia chromosome positive acute lymphoblastic leukemia undergoing allogeneic stem cell transplantation-A single institution experience.

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with a worse prognosis compared to Ph negative ALL. Tyrosine kinase inhibitor (TKI) therapy has led to an improvement in response rates and survival, thus becoming a critical component of therapy. We performed a retrospective cohort study of Ph+ ALL patients treated at the University of Michigan who received TKI therapy pre- and post-allogeneic hematopoietic stem cell transplant (HSCT) from April 2007 to November 2019. The study included 40 patients with Ph+ ALL (47.5% female) with a median age of 54 (24-69) years. Median event-free survival (EFS) was not reached, with a 5-year EFS of 61%. Median overall survival (OS) was not reached, with a 5-year OS of 71%. There was no difference in 2-year EFS or OS for patients on pre-transplant imatinib or dasatinib (p = 0.16, 0.09, respectively), though definitive conclusions are challenging as post-transplant TKI therapy was variable. The incidence of any grade acute graft-versus-host disease (GVHD) was 62.5% (25/40) and any grade chronic GVHD was 77.5% (31/40). Complete molecular remission (CMR) was achieved in 57.5% of patients pre-transplant with no significant difference when stratified by induction TKI (p = 1). Achievement of CMR pre-HSCT showed a trend towards improved 2-year EFS (p=0.0198) but did not significantly change 2-year OS (p = 1). Patients receiving 1st and 2nd generation TKIs pre- and post-HSCT seem to have favorable outcomes, although type of TKI (pre-HSCT) did not significantly impact EFS or OS. In addition, attaining a CMR pre-transplant improved EFS, but did not change OS.

Solving coagulation conundrums: comparing prophylaxis strategies in adult patients receiving PEG-asparaginase.

PEG-asparaginase is a key component in treatment regimens for acute lymphoblastic leukemia (ALL). Major side effects include thrombosis and bleeding; however, there is currently no consensus on methods to prevent these complications. In this multi-center retrospective cohort study of 101 adults, we compared two prophylaxis strategies: cryoprecipitate and fresh frozen plasma (Cryo/FFP) versus cryoprecipitate and antithrombin (ATIII). The overall incidence of venous thromboembolism (VTE) was not significantly different between the two groups (19.7% for Cryo/FFP and 8.6% in Cryo/ATIII, p = 0.17), and neither was grade ≥3 bleeding (3% for Cryo/FFP and 11.4% for Cryo/ATIII, p = 0.18). Given the significant cost associated with ATIII without a clear benefit, a careful benefit and risk analysis should be considered before utilizing ATIII as a prophylaxis strategy to prevent thrombosis or bleeding following asparaginase administration.

Multicenter comparison of first salvage chemotherapy versus novel therapy regimens in adult relapsed/refractory acute lymphoblastic leukemia.

Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) represent a heterogeneous population and therefore there is no standard of care first salvage regimen. We conducted a multicenter, retrospective analysis to compare chemotherapy (e.g. HyperCVAD, MOAD, Larson/CALGB-9511, etc.) to novel agents (blinatumomab or inotuzumab) in first salvage. The primary endpoint, overall survival (OS), was not significantly different among treatment arms, with a median OS of 10.6 months with chemotherapy and 10.1 months with novel therapy (p = .799). Similarly, there was no difference in the CR/CRi rate, with a CR/CRi in 18 patients (41.9%) versus 16 patients (47.1%) treated with salvage chemotherapy and novel therapy, respectively (p = .817). Age significantly impacted the probability of achieving CR/CRi with novel therapy versus chemotherapy. This analysis suggests the use of chemotherapy in first salvage still represents an appropriate treatment option, particularly for young fit patients, as the median OS was roughly 10 months regardless of whether patients received novel therapy or chemotherapy in first salvage. For the reported outcomes, 100% of patients in the novel therapy arm received a novel therapy (per design), whereas only 60.5% of patients in the chemotherapy arm required a novel therapy. Thus, 40% of patients did not require a novel therapy for similar OS. This analysis demonstrates that first-line chemotherapy can achieve similar results to novel therapies, especially now that novel therapies are available for subsequent relapses. However, this study has several limitations including younger age, increased CNS involvement, and higher blast percentage in the chemotherapy arm and potential confounders, including selection of treatment sequence as 43 patients (55.8%) ultimately received both chemotherapy and novel therapy. Therefore, a larger, prospective, randomized study with adequate chemotherapy comparators and availability of novel agents upon relapse is warranted to confirm these results.