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  • American Society of Hematology  (6)
  • 1
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1045-1045
    Abstract: Mutations in genes encoding isocitrate dehydrogenase 1/2 (IDH 1/2) enzymes result in increased 2-hydroxyguterate (2-HG) levels, which may provide a non-invasive marker of disease in IDH-mutant AML. The purpose of this study was to characterize patients with IDH-mutant AML by assessing presenting features, concurrent mutations, and 2-HG levels. From 7-2011 through 6-2014, we identified 170 consecutive patients with newly diagnosed AML and measured 2-HG by liquid chromatography-tandem mass spectrometry in serum, urine, marrow aspirate, and marrow pellet samples. All patients had IDH1 R132, IDH2 R140 and R172 testing; 169/170 had hotspot mutational profiling for AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, KIT, KRAS, MAP2K1,NOTCH1, NRAS, PIK3CA, P53, and PTEN. We assessed FLT3 (168/170), NPM1 (168/170), CEBPA (100/170) mutational status as routine clinical care; 2 patients had BCR/ABL alterations, and 6 were JAK2 positive (of 36 tested). IDH1/2-mutant were compared to wildtype (WT) patients using a Wilcoxon rank sum test, Fisher's exact test, or Kruskal Wallis test, as appropriate. The group was 54% male; 83% white, 2.4% black, 2.4% Asian, and 6.5% Hispanic. 12 patients had APL. IDH mutations included IDH1 R132C (n=10), IDH2 R172 (n=7), and IDH2 140Q (n=22). Other mutations included NPM1 (20.8%), FLT3-ITD (17.3%), FLT3-TKD (6.6%), NRAS (18.4%), TP53 (3%), KRAS (6.5%), and KIT (1.2%). CEBPA mutations occurred in 13 of 100 patients. IDH mutations (n=39) more frequently co-occurred with normal cytogenetics and NPM1 mutations, vs IDH-WT, consistent with prior reports (Table 1). No patients with favorable cytogenetics harbored an IDH1/2 mutation. Significantly higher 2-HG levels were detected among those with IDH1/2 mutations compared to IDH WT, in the serum (p 〈 0.0001), urine (p 〈 0.0001), marrow aspirate (p 〈 0.0001) and marrow pellet (p 〈 0.0001). Overall, elevated 2-HG levels were present regardless of type of IDH mutation. Serum and marrow pellet 2-HG levels were elevated ( 〉 1000 ng/mL in serum and 〉 1000ng/2x10^6 cells in marrow pellet) in 30/38 and 24/29 IDH-mutant patients, respectively, compared to 1/129 and 5/117 IDH WT patients. All but 2 IDH-mutant patients displayed either or both an elevated marrow pellet or serum 2-HG. Patients with IDH2 R172 mutations had lower marrow 2HG levels compared to those with R140Q mutations (Figure 1, p=0.0434). The WBC and blast count was lower among IDH2 R172-mutant compared to R140Q- or IDH1 R132C-mutant patients (p= 0.0134 and p=0.0039, respectively); there was no significant difference in serum 2HG levels. All three canonical IDH1/2 mutations have higher 2HG levels compared to IDH WT. IDH2 R172 mutated AML may present with lower WBC counts and peripheral blast percentage compared to IDH1 R132C and IDH2 R140Q mutant AML. Urine and serum 2HG levels effectively identify patients with mutant IDH1/2, of particular relevance given targeted therapies for these mutations. Table 1. Characteristics of IDH1/2-mutant and WT AML patients. IDH1/2 Mutated IDH1/2 WT p-value Age, y (median, range) 67 (41-86) 65 (20-87) 0.4718 AML History (n, %) De Novo 28 (72%) 82 (63%) 0.6336 Therapy-related 4 (10%) 15 (11%) MDS 2 (5%) 17 (13%) Cytogenetic Risk (n, %) Favorable 0 23 (18%) 0.0006 Intermediate 30 (81%) 71 (55%) Normal 25 (68%) 44 (34%) Poor 7 (19%) 34 (27%) Concurrent Mutations (n, %) NPM1 15 (38%) 20 (16%) 0.0033 FLT3-ITD 3 (8%) 26 (20%) 0.0907 FLT3-TKD 2 (5%) 9 (7%) 1.000 CEBPA Heterozygous Homozygous 3 (14%) 0 8 (10%) 2 (3%) 0.8118 NRAS 9 (23%) 22 (17%) 0.4788 KRAS 0 11 (8%) 0.0700 KIT 1 (3%) 1 (1%) 0.4093 P53 1 (3%) 4 (3%) 1.000 Table 2. WBC and 2-HG levels by IDH mutation (median, range). BQL, below quantitative limit. IDH1 R132C N= 10 IDH2 R172 N=7 IDH2 R140Q N=22 IDH WT N=131 WBC count 10.1 [1.8-333.2] 1.6 [0.7-3.2] 5.9 [0.9-122.8] 6.3 [0.4-315.4] Peripheral blast % 33.0 [0-98] 1.0 [0-9.8] 18.2 [2-91] 15 [0-94] Marrow aspirate 2-HG (ng/mL) 20,900 [1330-93500] (n=7) 4300 [2230-26000] (n=6) 30800 [BQL-311000] (n=19) BQL [BQL-22000] (n=116) Serum 2-HG (ng/mL) 1807 [101-66207] (n=9) 1102 [287-2908] (n=7) 1464 [365.1-11696] (n=22) 86.9 [BQL-1224] (n=128) Urine 2-HG (ng/mL) 33850 [7260-282000] (n=10) 7430 [2460-63700] (n=7) 11300 [2070-177000] (n=20) 3140 [BQL-53200] (n=125) Marrow pellet 2-HG (ng/2*10^6 cells) 13680 [193-172,800] (n=7) 7480 [1056-79600] (n=5) 5560 [564-96400] (n=17) 65 [BQL-4040] (n=116) Figure 1 Figure 1. Disclosures Brunner: NIH T32 CA 71345-18: Research Funding. Attar:Agios: Employment. Yen:Agios: Employment. Yang:Agios Pharmaceuticals: Employment, Stockholder Other. Straley:Agios: Employment. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other. Stone:Agios: Consultancy. Fathi:Millennium: Research Funding; Seattle Genetics: Advisory Board, Advisory Board Other; Agios: Advisory Board, Advisory Board Other.
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    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 2
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1984-1984
    Abstract: Introduction: Geriatric assessment (GA) is a multidimensional evaluation of patient health and function that may detect impairments not identified as part of routine care, predict treatment-related morbidity and mortality, and inform treatment plans. Given evidence of these benefits, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend GA for older candidates of hematopoietic stem cell transplantation (HCT). However, both older and younger HCT candidates will often receive multiple rounds of chemotherapy before HCT, leading to functional impairments in all age groups. Furthermore, HCT patients often experience a significant gap between when they are first evaluated and actually proceed to transplant (e.g., while a donor search is conducted), creating an opportunity to identify impairments and optimize function prior to transplant. Methods: To address this opportunity, we created a clinical pre-HCT optimization program (C-POP) to evaluate physical function, cognitive function, nutritional status, and mental health in all adults who were deemed potential candidates for allogeneic HCT by a HCT physician. We applied this standard of care program to all adult candidates for HCT, regardless of age, with the goal of identifying functional impairments and then referring patients to services to optimize those impairments prior to HCT. We defined impairments using validated measures and compared results to established norms or scoring, controlling for age and gender where appropriate (e.g., the cut-off for six-minute walk distance was adjusted for age, gender, height, and weight, while the cut-off for falls was any fall regardless of characteristics). Patients with impairments were referred to the appropriate supportive care (e.g., physical function impairment - 〉 referral to physical therapy). Results were prospectively analyzed at new patient evaluation (NPE), which was the first time the patient met a HCT physician and sign-off, which occurred within a week before starting transplant. While the program is ongoing, we present here the results of patients evaluated between October 16th, 2017 and July 1st, 2019. Patients are divided into three pre-specified age groups: 〈 40 years old, 40-59 years old, and 〉 =60 years old, with results compared using a chi-squared test. Results: We evaluated 115 patients: 21 (18%) 〈 40 years, 40 (35%) 40-59 years, and 54 (47%) 〉 =60 years). There were no differences between the age groups in other demographics (gender, race, and ethnicity). At NPE, 93 (81%) met criteria for at least 1 impairment in physical function, cognitive function, nutritional status, or mental health; 62 (54%) met criteria for impairments in 2 or more areas. Surprisingly, patients 〈 40 years were more likely to screen positive for physical function (20/21, 95%) than patients 40-59 years (26/40, 65%) and patients 〉 =60 years (36/54, 67%) (p=0.03). Of those 115 patients, 52 (45%) proceeded to HCT, including 12 (57%) 〈 40 years, 18 (45%) 40-59 years, and 22 (41%) 〉 =60 years (p=0.75); of those patients who have not proceeded to HCT, 40 (35%) will never proceed to HCT (e.g., deemed not a candidate after functional evaluation or died of disease prior to HCT) while 23 (20%) are still awaiting HCT (e.g., donor search ongoing). Patients who proceeded to HCT were less likely to have mental health impairments (2/52, 4% vs. 9/40, 23%, p=0.006). Of the 52 who were seen at new patient evaluation and proceeded to transplant, 40 (77%) were seen at sign off. Of those who had impairments at NPE, 12/23 (52%) improved their physical function to normal limits, 4/9 (44%) improved their cognitive function, and 9/13 (69%) improved their nutritional status by the time of sign-off (of those who were seen at sign-off, none had mental health impairments at NPE). Discussion: These results demonstrate that younger as well as older candidates for HCT exhibit a high degree of functional impairment. However, this impairment could be amenable to improvement prior to HCT. These findings support application of GA to all HCT candidates regardless of age. We will investigate the effect of referred interventions (e.g., physical therapy, seeing a dietician) in improving functional impairments in future studies, as well as look at the effect of these findings on HCT outcomes. Disclosures Wiggins: Incyte, Inc.: Speakers Bureau. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Rizzieri:Millennium: Speakers Bureau; Novartis: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy, Speakers Bureau; TEVA: Consultancy; Spectrum: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Horwitz:Abbvie Inc: Membership on an entity's Board of Directors or advisory committees. Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding.
    Type of Medium: Online Resource
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    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 3
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2597-2597
    Abstract: Mutations in genes encoding the isocitrate dehydrogenase 1/2 (IDH 1/2) enzymes increase production of the oncometabolite 2-hydroxyglutarate (2HG), resulting in elevated 2HG in patients with IDH-mutant AML. This may allow for non-invasive diagnostic and predictive markers of disease; however, the optimal threshold of 2HG levels to predict IDH mutation status, or whether 2-HG measurements in different compartments are equally predictive, is unknown. We measured 2-HG levels in serum, urine, bone marrow aspirate, and bone marrow cell pellet to determine the optimal predictive value of 2HG levels for IDH mutations at AML diagnosis. Patients with newly diagnosed AML had prospective measurements of 2HG levels at diagnosis by liquid chromatography-tandem mass spectrometry in serum, urine, marrow aspirate, and marrow pellet samples. Patients analyzed had IDH1 R132 and IDH2 R140 and R172 testing. Hotspot mutational profiling was performed for AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, P53, and PTEN; patients were also tested for FLT3, NPM1, and CEBPA mutations. IDH1/2 mutant patients were compared to wildtype (WT) patients using a Wilcoxon rank sum, Fisher's exact, or Kruskal Wallis test, as appropriate. Performance characteristics of 2HG to predict the presence of IDH1/2 mutations were done using a recursive partitioning algorithm in R version 3.2.1, with the rpart package. 228 patients with newly diagnosed AML had 2HG levels in serum, urine, marrow aspirate, and marrow pellet samples. All patients had testing for IDH1 R132 and IDH2 R140 and R172 mutations. The patients were 56% male; 13 patients had APL, none with IDH mutations. IDH mutations were identified in 23% (n=52) of the cohort: IDH1 R132C (n=12), IDH2 R172 (n=9), and IDH2 R140Q (n=29), and 2 additional patients had mutations in both IDH1 R132 and IDH2 R140 (Table 1). The optimal test cut-off of 2HG to predict IDH status was 534.5 ng/mL in the serum (n=221), 16650 ng/mL in the urine (n=213), 2210 ng/mL in the marrow aspirate (n=190), and 1146 ng/2*10^6 cells in the pellet (n=159). Serum and pellet values had the greatest specificity for the presence of an IDH1/2 mutation (0.9882 and 1.000, respectively; Table 2). The positive predictive value of an elevated serum or pellet 2HG level at these cut-offs was 95.4% and 100%, given a 23% IDH mutation prevalence in this study population. The marrow aspirate had the greatest sensitivity (0.8837) and negative predictive value (96.6%). Urine 2HG levels were less sensitive than serum 2HG levels, although above the urine cut-off the specificity for IDH mutations was similar (Figure 1). 2HG levels in the serum, urine, and marrow can be used to identify IDH mutations in AML. Serum 2HG testing is an effective non-invasive mechanism to predict IDH1/2 mutation status. A serum cut-off of 534.5 ng/mL has a specificity of 0.9882 and, with an IDH mutation prevalence of 23%, was associated with a PPV of 0.9535.Table 1.Patient CharacteristicsNo IDH mutationIDH mutationTotalp-valueMale sex101 (57%)26 (50%)127 (56%)0.43Cytogenetics0.0002Favorable26 (15%)026 (12%)Intermediate95 (54%)41 (82%)136 (61%)Adverse52 (30%)9 (18%)61 (27%)Age (median, range)66 (20, 87)66.5 (41, 86)66 (20, 87)0.27WBC (median, range)5.35 (0.60, 315.4)3.65 (0.20, 333.2)5.25 (0.20, 333.2)0.33No IDH mutationIDH mutationNumber assessedp-valueNRAS27 (17%)9 (19%)2100.83KRAS16 (10%)0 (0%)2100.03TP5315 (9%)1 (2%)2100.13KIT2 (1%)1 (2%)2100.54FLT3ITD34 (20%)4 (8%)2180.06FLT3TKD10 (6%)2(4%)2180.74NPM129 (17%)15 (30%)2190.07CEBPA13 (13%)3 (10%)1021.002HG MeasurementsNo IDH mutationIDH mutationTotalSerum (ng/mL)79.5 [52,123] n=1701420 [675,2735] n=51101 [58,101] n=221Urine (ng/mL)3590 [2230,6220] n=16318300 [7260,59500] n=504330 [2450,8580] n=213Marrow aspirate (ng/mL)BQL [BQL,BQL] n=14718400 [4270,43100] n=43BQL [BQL,1430] n=190Pellet (1000 ng/2*10^6 cells)64 [BQL,169] n=1271420 [675,2735] N=32107 [BQL,500] n=159 Table 2. Test characteristics based on optimal 2HG cut-off, by compartment. Compartment 2HG cut-off Sensitivity Specificity 23% prevalence PPV NPV Serum 534.5 ng/mL 0.8039 0.9882 0.9535 0.9438 Urine 16650 ng/mL 0.5600 0.9877 0.9333 0.8798 Marrow Aspirate 2210 ng/mL 0.8837 0.9660 0.8837 0.9660 Marrow Pellet 1146 ng/2*10^6 cells 0.7813 1.000 1.000 0.9478 Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 2. Figure 2. Disclosures Chen: Bayer: Consultancy, Research Funding. Stone:Agios: Consultancy; Celator: Consultancy; Pfizer: Consultancy; Merck: Consultancy; AROG: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Roche/Genetech: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Juno: Consultancy; Novartis: Research Funding. Fathi:Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding.
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    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 4
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2896-2896
    Abstract: Background: Current treatment of advanced stage Mycosis fungoides (MF) and Sézary syndrome (SS) remains unsatisfactory. Complete responses (CR) are typically 〈 10% and partial responses (PR) tend to be short-lived. Antibodies targeting PD1 expressed by healthy tumor-infiltrating T cells can induce long-lasting and deep remissions in cancer patients by activating the host immune response. However, the malignant T-cells of MF/SS also express PD-1. Additionally, genomic alterations involving PD-1, PD-L1, and PD-L2 have been reported in MF/SS, suggesting an important role for the PD-1/PD-L1 axis. We hypothesized that PD-1 checkpoint blockade would be an effective treatment in targeting a T cell malignancy that itself expresses PD-1. Here, we report the efficacy of pembrolizumab in relapsed/refractory MF/SS and correlative biomarker studies. Methods: This single-arm, multicenter study by the Cancer Immunotherapy Trials Network (CITN) enrolled 24 patients with MF/SS stages IB-IV, with at least one prior systemic therapy. Pembrolizumab was administered at 2 mg/kg every 3 weeks for up to two years. The primary endpoint was overall response rate (ORR) using global response criteria according to the ISCL/EORTC consensus guidelines. Skin responses were measured by mSWAT. Secondary endpoints were safety/tolerability, time to response (TTR), duration of response (DOR) and progression-free survival (PFS). Correlative studies included immunohistochemistry (IHC), mass cytometry, whole exome sequencing, gene expression profiling, and serum cytokine analysis. Results: Patients had advanced stage disease (23/24 with stage IIB-IV MF/SS), and were heavily pretreated (median of 4 prior systemic therapies). The ORR was 38% with 2 CR and 7 PR. Of the 9 responding patients, 6 had ≥90% improvement in skin disease by mSWAT. The median TTR was 11 weeks. Responses were durable, with 8 of 9 responses ongoing at last follow up (median DOR 64 weeks, range 32-153 weeks). One responding patient progressed 2 months after discontinuing treatment due to an adverse event (AE). The median PFS was not reached. Overall, the toxicity profile was similar to prior studies of pembrolizumab. Four patients discontinued treatment due to treatment related serious AEs of duodenitis, pneumonitis, hepatitis, and corneal ulcer. Skin flare reactions were observed early in the treatment course in 40% of patients with SS, but none with MF. The skin flare reactions did not result in any treatment discontinuation, and did not correlate with subsequent response to treatment. There was no significant association between response and clinical characteristics including stage, disease type (MF vs. SS), or number of prior therapies. IHC assessment of PD-1, PD-L1, and PD-L2 did not predict response. Treatment resulted in an increase of PD-L1 expression by both IHC and nanoString analysis. A nanoString18 gene signature of tumor inflammation that is predictive of response to pembrolizumab in other tumor types was not predictive in this cohort. High dimensional mass cytometry enabled precise identification and phenotyping of malignant T cells. There was a positive correlation between PD-1 expression on the malignant T cells and development of the skin flare reaction. Whole exome sequencing revealed genomic disruptions of PD-1 signaling including copy loss of PD-1. No associations were found between outcomes and genomic events involving the PD1/PD-L1 axis, total mutation number, or neoantigen numbers. Conclusions: The 38% ORR rate in this heavily pretreated population was 38% with a highly encouraging DOR of 64 weeks. No predictive biomarkers have emerged thus far, but additional studies are ongoing. Additional combination studies with pembrolizumab are warranted to improve response rates. Figure. Figure. Disclosures Khodadoust: Innate Pharma: Research Funding. Porcu:Innate Pharma: Consultancy. Foss:Miragen: Consultancy, Speakers Bureau; Seattle genetics: Consultancy; Spectrum: Consultancy; Mallinkrodt: Consultancy. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding. Shustov:Seattle Genetics: Research Funding. Sokol:Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. Yearley:Merck: Employment. Horwitz:Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Trillium: Consultancy; Innate Pharma: Consultancy; Spectrum: Research Funding; Corvus: Consultancy. Kim:miRagen: Research Funding; Horizon Pharma: Consultancy, Research Funding; Neumedicine: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding.
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    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 5
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1009-1009
    Abstract: Abstract 1009 Background: Leg ulcerations are a serious and debilitating complication of sickle cell disease (SCD) and other hemolytic anemias, whose etiology is not completely understood. Wound healing involves an ordered progression of vasoconstriction (hemostatic phase), followed by vasodilatation (inflammatory and proliferative phase) and epithelialization. Little is known about the changes in the microcirculation of chronic wounds in patients with sickle cell disease. Endothelial function affects microcirculation and regulates blood flow. Endothelial dysfunction is a recognized pathway to end organ dysfunction in SCD. Laser speckle contrast imaging (LSCI) and Infrared Thermography (IR) are non-invasive technique used to assess dynamic changes in blood flow in response to vaso-reactive and other insults in both health and disease, while peripheral arterial tonometry is utilized for early detection of cardiovascular disease. The aim of this study was to evaluate skin's microvasculature response and endothelial function in adults with HbSS and chronic leg ulceration. Methods: Twelve adults with HbSS and chronic leg ulcers ( 〉 1 month duration) were evaluated at steady state with a detailed medical and ulcer history, physical examination, and clinical labs. Clinical and laboratory data were compared to 269 adults with Hb SS, without active leg ulcers, enrolled in a Pulmonary Hypertension screening protocol (Clin trial no. NCT00011648). Blood flow (LCSI) and IR measurements of the ulcer bed, the peri-ulcer area and of a distant, unaffected area (baseline) were obtained and compared. Peripheral arterial tonometry (PAT) was obtained to calculate the ratio of post-occlusion dilatation to baseline reactive hyperemia index: RHI. An RHI 〉 1.67 is indication of normal endothelial function. Results: Mean age for the 12 subjects with chronic active leg ulcer: 31 years ± 11yrs, 5 male, 5 had a history of trauma. When compared to SS patients without active leg ulcers: mean MAP 82 vs 103 mmHg (p 〈 0.0001), Hb 7.6 vs 9.0 g/dL (p=0.001), and LDH 533 vs. 375 (p=0.023). CRP was higher, 9.4 vs 0.81(p 〈 0.0001), Arginine/ornithine ratio was lower (0.66 vs. 1.06) in patients with active leg ulcers (p=0.005). Thrombophila w/u was negative in 11, but half of patients were on anticoagulation for previous PE/DVT's. A third of the patients had been admitted for VOC in the previous 12 months and 11/12 were taking daily opioids. Blood flow was highest in the ulcer center: 731+421, with progressively lesser flow measurements in the periwound: 370+157 and in the distal region(or baseline) 165+89. Temperature, as measured by IR, was higher (34.9 C°) in the periwound area than in the distant, or baseline area (34.5 C°) (p 〈 0.03). Blunted RHI on PAT was seen in 5/12 subjects, with values 〈 1.67. Conclusions: With this study we confirm that patients with HbSS and leg ulcers represent a subgroup with severe disease, as demonstrated by the high use of HU and/or transfusion, and number of complications at a relatively young age. We report high blood flow in the ulcer bed and immediate surrounding regions, compared to unaffected areas, never prior demonstrated. It is probable that the increase in blood flow observed in the wound and peri-wound regions reflect s a high vasodilated state, resulting from severe anemia, relative hypotension, and chronic inflammation. Laboratory and clinical data supports the presence of a persistent inflammatory and hemolytic state, as well as low arginine bioavailabitlity. Laser Speckle Contrast Imaging, Infrared Thermography and Peripheral Arterial Tonometry are effective, non invasive novel techniques useful for studying microvascular and endothelial function in patients with SCD and leg ulcers. Disclosures: No relevant conflicts of interest to declare.
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    Publication Date: 2012
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  • 6
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 86-86
    Abstract: Abstract 86 Background: Leg ulcers are a common and debilitating complication of sickle cell anemia and other hemolytic disorders. Despite many advances in the care of SCD, there is still a clinical need for a well-tolerated, safe and effective therapy. Sodium nitrite may function as a reservoir for local delivery of nitric oxide, whose vasodilating, angiogenic, and antimicrobicidal activities make it an attractive novel therapy for chronic wounds. We describe the safety data and preliminary efficacy data of topical sodium nitrite in adults with sickle cell anemia. Design and Methods: This is a phase 1 dose-escalation, single institution, study of topical sodium nitrite (ClinicalTrials.gov NCT01316796). Eligibility criteria: 〉 18 years old, have a leg ulcer of 〉 4 weeks duration, between 2.5 and 100 cm2 in size, and not acutely infected. Patients were screened with medical history, physical exam and laboratory tests. Sodium nitrite cream was applied twice a week for 4 weeks on one leg ulcer (“study ulcer”) in four cohorts of three subjects each with escalating concentrations in each cohort of 0.5., 1, 1.5 and 2%. Safety, tolerability and pharmacokinetic data of plasma nitrite and nitrate were obtained during the first 48 hours of drug exposure and then weekly for four weeks. Leg ulcer healing was a secondary endpoint and was assessed by calculating the change in surface area from visible light photographs of the study leg ulcer obtained at week 1, 3, and end of study, using a digital camera at a distance of 0.25 – 0.5 m from the ulcer. Borders were traced using ENVI software and ulcer size was calculated by converting the pixel area of the ulcer to cm2 using a calibrated square for reference. Pain at the ulcer site was assessed both with a Brief Pain Inventory and Visual Analog Pain Scale at predetermined time points. Results: Sixteen subjects were screened and 12 enrolled. There were no serious adverse events associated with the drug. Possibly related, grade 1; adverse events occurred in 10 of the subjects, more frequently in the cohorts with the highest concentration, which included non-clinically significant decrease in diastolic blood pressure in two subjects of cohort 4. Adverse events resolved without clinical intervention. Methemoglobin levels did not exceed pre-established safety thresholds (max of 4.1 % in one subject in cohort 3). Tolerability was excellent, with short-lived stinging at the site of application reported by two subjects. Pharmacokinetics of plasma nitrite and nitrate indicated minimal systemic absorption of topically applied sodium nitrite (median plasma nitrite AUC: 0.311 (0.169–0.659) umol*h/L/umol nitrite dose), with high interpatient variability. There was no evidence of plasma nitrite and nitrate and methemoglobin accumulation during the 4- week study trial. All but one subject experienced a decrease in leg ulcer surface area, fig 1, (pretreatment 4.65 vs. post-treatment 2.78 cm2, p 〈 .001) and improvement in pain scores (pretreatment 4.87 vs. 2.91, p=.024 ), which often preceded the decrease in size. Healing was most marked in cohort 4, the one treated with the highest strength of sodium nitrite cream, with 2 of 3 subjects experiencing complete closure of the ulcer. Conclusions: On the basis of these safety, pharmacokinetic and tolerability data, and promising efficacy results, topical sodium nitrite warrants further clinical evaluation in patients with sickle cell disease or other hemolytic disorders and leg ulcers. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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