An Ongoing Global, Longitudinal, Observational Study of Patients with Pyruvate Kinase Deficiency: The PEAK Registry

Pyruvate kinase (PK) deficiency is an autosomal recessive disease caused by mutations in the PKLR gene that lead to reduced red blood cell PK (PK-R) enzyme activity. This rare hereditary glycolytic enzymopathy, with over 300 causative PKLR mutations identified to date, results in defective red blood cell glycolysis and hemolytic anemia. While the clinical presentation is variable, patients with PK deficiency may experience symptoms of hemolytic anemia, most commonly fatigue (sometimes extreme), jaundice, and dyspnea. No disease-specific therapy currently exists and treatment is limited to supportive care, including red blood cell transfusions, splenectomy/cholecystectomy, and iron chelation. Affected neonates may need phototherapy or exchange transfusions for severe hyperbilirubinemia. Allogeneic stem cell transplantation may cure the disease but experience is limited and the outcome is variable. Due the rarity of PK deficiency, its prevalence, clinical burden, and long-term clinical course are not well defined. To address this gap, Boston Children's Hospital is nearing completion of the observational PK deficiency Natural History Study (ClinicalTrials.gov NCT02053480; N=254) to better understand the natural history and clinical burden of the disease. This longitudinal analysis (2-year follow-up) will report on PK deficiency-related signs, symptoms, and treatment outcomes. In order to continue and expand upon the collection of longitudinal data for PK deficiency, the Pyruvate Kinase Deficiency Global Longitudinal Registry (the PEAK Registry; NCT03481738) was developed. This registry study is a global, longitudinal, observational study for adult and pediatric patients with PK deficiency. Its primary objective is to record the natural history, treatment, outcomes, variability in clinical manifestations, and disease burden of patients with PK deficiency. Secondary objectives include data collection to assess the prevalence, incidence, and complications associated with PK deficiency; evaluate pregnancy outcomes; and investigate possible phenotype-genotype correlations. The study also aims to provide longitudinal data to assist physicians with the clinical management of individual patients. In order to maximize the amount of longitudinal data available, a novel data management system is being employed to harmonize Natural History Study and PEAK Registry data. Approximately 500 patients will be enrolled over 7 years at an estimated 60 study centers in up to 20 countries in the 9-year study. All enrolled patients will be followed prospectively for at least 2 years and up to 9 years. Site and patient recruitment began in 2018. As of July 2019, 43 sites in 11 countries are active (Figure) and site recruitment has begun in Thailand, South Korea, and Australia. An update on patient enrollment will be provided. Disclosures Grace: Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Bianchi:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Glenthøj:Celgene: Consultancy; Novo Nordisk: Honoraria; Alexion: Research Funding; Novartis: Consultancy; Agios Pharmaceuticals, Inc.: Consultancy. Jones:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kanno:Agios Pharmaceuticals, Inc.: Honoraria. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Bluebird Bio: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees. van Beers:Pfizer: Research Funding; RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding. Xu:Agios: Employment, Equity Ownership.

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Hemoglobin Utilization in Asplenic and Non-Splenectomized Transfusion Dependent Thalassemia Patients Supported with Pathogen Reduced Red Blood Cell Concentrates in a Phase 3 Study (SPARC)

Blood ◽

10.1182/blood-2018-99-112685 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3812-3812

Author(s):

Yesim Aydinok ◽

Antonio Piga ◽

Raffaella Origa ◽

Nina Mufti ◽

Anna Erikson ◽

...

Keyword(s):

Blood Cell ◽

Board Of Directors ◽

Red Blood Cell ◽

Research Funding ◽

Treatment Sequence ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

La Jolla ◽

And Control

Abstract Introduction: Transfusion dependent thalassemia (TDT) requires regular transfusion of red cell concentrates (RBCC) to prevent the complications of anemia and excessive erythroid expansion. Despite donor testing, long-term transfusion has a substantial cumulative risk of transfusion-transmitted infection (TTI) due to undetected viruses, bacteria, and protozoa. Splenectomized (-S) TDT patients may have greater TTI morbidity than patients with spleens (+S); but may benefit from reduced use of red blood cell concentrates (RBCC) and reduced transfusion iron (Fe) loading. Pathogen reduction (PR) of RBCC with amustaline-glutathione (A-GSH) offers potential to reduce the risk of TTI. Objectives: To determine, the impact of PR-RBCC on hemoglobin (Hb) use, transfused Fe burden, incidence of RBC antibodies, and safety in -S and +S TDT patients. Methods: TDT patients at 3 sites, not stratified by spleen status, were prospectively enrolled in a two- period cross-over study randomized by sequence for RBCC preparation. Leukocyte reduced PR-RBCC (Test) were treated with 0.2mM amustaline and 20 mM GSH, re-suspended in saline-adenine-glucose mannitol (SAGM), and stored up to 35 days at 4°C. Leukocyte reduced conventional RBCC (Control) were suspended in SAGM and stored for up to 35 days at 4°C. Patients received 6 transfusions in each treatment sequence of Test or Control RBCC over ~ 5 months. Clinicians, blinded to RBCC Hb content and treatment sequence, ordered RBCC to maintain targeted pre-transfusion Hb thresholds of ~ 9-10 g/dL. Transfusion intervals or number of RBCC transfused were adjusted for clinical management. The primary efficacy outcome was assessed by non-inferiority (NI) analysis for Hb use (expressed as g/kg body weight/ day) using a pre-specified NI margin (≤ 15% of the observed Control mean). Results : Overall, mean (SD) Hb content (g) of 1024 Test RBCC = 54.6±5.9 (range: 39-73) and of 1008 Control RBCC = 55.6 ± 5.9 (range: 35-74) and varied widely. By intent-to-treat (ITT), 80 patients (40 +S and 40 -S) were transfused. For ITT patients (Table), the baseline Hb level (BL-Hb, g/dL) at first transfusion of Control periods was significantly lower than at Test periods; but the mean number of RBCC transfused, RBCC storage days, total Hb dose (g), and transfusion intervals were not significantly different for Test and Control. ITT analysis for all transfusion episodes showed Hb use for Test RBCC (0.110 g/kg/d) was not different from Control RBCC (0.112 g/kg/day). Non-inferiority was demonstrated (T-C = - 0.002 g/kg/d: 95% CI: -0.005, 0.001). ITT Test patients received a slightly lower mean total Hb dose (- 14g), and mean pre-transfusion Hb levels declined after 6 transfusions (9.4 to 8.8 g/dL). -S patients had lower BL-Hb levels (g/dL) than S+ patients in Test (9.2 vs 9.7) and Control (8.8 vs 9.2) periods (Table). -S patients received a lower mean total Hb dose of Test than Control RBCC (p=0.019); and had a decline in mean pre-transfusion Hb levels during Test periods (from 9.2 to 8.7 g/dL). Transfusion intervals were significantly longer for -S patients than +S patients with both Test and Control RBCC (p< 0.001 by 2-sample t test, respectively); and -S patients had lower Hb use than +S patients. However, Hb use of Test and Control RBCC was comparable within -S and + S cohorts (Table). Transfused Fe was less for -S patients for Test and Control RBCC. During 6 Test and 3 Control treatment periods, 8 patients (6 -S, 2 +S) had worsening anemia with pre-transfusion Hb levels (6.0-7.8 g/dL) substantially below the targeted transfusion threshold, but without evidence of hemolysis. Each of these patients received one or more Hb doses below the average RBCC transfusion episode dose (Test: 114.5 g) or (Control: 116.7 g); and 3 patients had concurrent infections. None of 80 patients had evidence of increased RBC clearance, developed antibodies to PR-RBCC, or had treatment emergent RBC alloantibodies in either treatment period. There were no differences in the overall safety profiles for Test and Control RBCC. Conclusions: Amustaline-GSH PR treatment of RBCCs offers the potential to reduce TTI risk without impacting Hb use or Fe burden in TDT. However, Hb content of Test and Control RBCC varies widely and may contribute to unexpected changes in pre-transfusion Hb levels. Spleen status affected Hb use comparably for PR-RBCC and Control RBCC, and remains an important factor in assessing transfusion requirements and Fe loading. Table. Table. Disclosures Aydinok: TERUMO: Research Funding; Cerus: Honoraria, Research Funding; CRISPR Tech: Other: DMC; Protagonist: Other: SSC; La Jolla Pharmaceuticals: Research Funding; Celgene: Research Funding; Novartis: Research Funding, Speakers Bureau. Piga:Apopharma: Honoraria, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Honoraria; Acceleron: Research Funding; Novartis: Research Funding. Origa:Novartis: Honoraria; Bluebird Bio: Consultancy; Cerus Corporation: Research Funding; Apopharma: Honoraria. Mufti:Cerus Corporation: Employment, Equity Ownership. Erikson:Cerus Corporation: Employment, Equity Ownership. North:Cerus Corporation: Employment, Equity Ownership. Waldhaus:Cerus Corporation: Employment, Equity Ownership. Ernst:Cerus Corporation: Employment, Equity Ownership. Lin:Cerus Corporation: Employment, Equity Ownership. Huang:Cerus Corporation: Employment, Equity Ownership. Benjamin:Cerus Corporation: Employment, Equity Ownership. Corash:Cerus Corporation: Employment, Equity Ownership.

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Utilization and Costs of Red Blood Cell Transfusions Pre- and Post-Azacitidine in Higher-Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v120.21.4261.4261 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4261-4261

Author(s):

Eric Tseng ◽

Soojin Seung ◽

Nicole Mittmann ◽

Jeannie Callum ◽

Richard A. Wells ◽

...

Keyword(s):

Blood Cell ◽

Board Of Directors ◽

Median Time ◽

Red Blood Cell ◽

Research Funding ◽

Care Center ◽

Tertiary Care ◽

Advisory Committees ◽

Transfusion Requirements ◽

The Cost

Abstract Abstract 4261 Objectives: To determine the healthcare resources utilized and cost of red blood cell (RBC) transfusions pre- and post-azacitidine (AZA) treatment in patients with higher-risk myelodysplastic syndrome (MDS). Methods: A retrospective review of 51 MDS patients (3 low-risk, 9 Int-1, 26 Int-2, 13 high-risk) treated with AZA at our center was performed. Patients were followed from 6 months prior to and up to 18 months after initiation of AZA. We audited the clinical response rates and changes in transfusion requirements in higher-risk MDS patients treated with AZA at our tertiary care center. Clinical management information was obtained from our local institution and peripheral hospitals to document transfusion requirements pre- and post-AZA initiation. Health services utilized included transfusions (blood products), hospitalizations and medications. Canadian costs (2012 Canadian $) were applied to resources. The cost of RBC ($1273 per unit) transfusions is presented here. Results: 58.8% of MDS patients were male; 80.4% were ≥65 years. Patients received on average 11 cycles of AZA (IQR 7–17), with 54.9% of individuals receiving 9 or more cycles. Seven (14%) patients stopped AZA prematurely due to progressive disease (5), disease transformation (1), and toxicity (1). Median time to first response with AZA was 3 months; median time to best response was 6 months; and median time to progression was 10 months. Before AZA treatment, 62.7% were considered transfusion dependent (TD); 56% of the TD patients became transfusion independent within 12 months after starting AZA. 32 (62.7%) patients received RBCs six months prior to AZA initiation (mean 11.1 units/6 months; IQR 0–18). At 6 months post-AZA initiation, 41 (80.4%) of patients received RBCs (mean 10.8 units; IQR 1–17.5); between 6–12 months after AZA initiation, 26 (55.3%) patients (mean 7.8 units; IQR 0–11.5; 4 patients excluded for deaths/progression/lack of follow-up); and between 12–18 months, 14 (45.2%) patients (mean 6.7 units, IQR 0–11.5; 20 patients excluded). The cost per patient for RBC transfusions was $14,336 over the six months prior to AZA start, and $14,082, $10,533, $8,912 (1.8%; 35.3%; 62.7% reduction) at 6, 12 and 18 months after AZA initiation, respectively. Conclusions: At 6 months post-AZA initiation, more MDS patients received transfusions but fewer RBCs were transfused when compared to 6 months prior to AZA. At 12 and 18 months, fewer MDS patients received transfusions and fewer RBCs were used compared to both 6 months pre- and post-AZA administration. At 18 months, there was a 63% reduction in RBC costs from pre-AZA initiation. Disclosures: Seung: Celgene: Research Funding. Mittmann:Celgene: Research Funding. Wells:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kim:Celgene: Employment. Buckstein:Celgene: Honoraria, Research Funding.

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The Effect of Ruxolitinib on White Blood Cell Counts in Patients with Polycythemia Vera: Results from the RESPONSE Trial

Blood ◽

10.1182/blood.v126.23.4070.4070 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4070-4070 ◽

Cited By ~ 1

Author(s):

Carole B. Miller ◽

Jean-Jacques Kiladjian ◽

Martin Griesshammer ◽

Ahmad B. Naim ◽

William Sun ◽

...

Keyword(s):

Blood Cell ◽

Board Of Directors ◽

Research Funding ◽

Thromboembolic Events ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

The Impact ◽

Over Time ◽

Response Trial

Abstract Background: Age, prior thrombotic events, and an elevated hematocrit are established risk factors for increased risk of thrombosis in patients with polycythemia vera (PV). Evidence also suggests that elevated white blood cell (WBC) counts ≥ 11×109/L are a significant independent risk factor for thrombosis in patients with PV (P =0.02; Barbui T, et al. Blood. 2015; 126:560-561). Therefore, this analysis was conducted to evaluate the impact of ruxolitinib (Rux) and best available therapy (BAT) treatment on WBC counts among patients with Baseline WBC counts ≥ 11×109/L in the RESPONSE trial. RESPONSE is a global, multicenter, open-label phase 3 trial investigating Rux and BAT in patients with PV who are resistant to or intolerant of hydroxyurea (HU). In the RESPONSE trial, Rux was associated with durable improvements in hematocrit control without phlebotomy compared with BAT as well as reductions in WBC counts. Methods: Changes from Baseline in WBC counts in the Rux arm (n=110), BAT arm (n=112), and HU subgroup of the BAT arm (n=66) were evaluated as part of an exploratory analysis using the RESPONSE 80-Week analysis dataset. Patient subgroups with Baseline WBC counts ≥ 11×109/L and < 11×109/L were analyzed for changes in WBC counts at Weeks 12, 32, and 80. For patients with Baseline WBC counts ≥ 11×109/L, the proportion of patients who achieved a decrease in WBC counts to ≤ 10×109/L or a ≥50% reduction at Week 12 and Week 32, respectively, was summarized; time to achieve the decrease was analyzed by Kaplan-Meier method. Results: Baseline mean WBC counts were generally similar among patients in the Rux arm, BAT arm, and HU subgroup (17.6×109/L, 19.0×109/L, and 17.4×109/L, respectively). The proportion of patients with Baseline WBC counts ≥ 11×109/L was also similar among the Rux arm, BAT arm, and HU subgroup (75%, 71%, and 70%, respectively). In patients with Baseline WBC counts ≥ 11×109/L, patients treated with Rux had greater mean reductions in WBC counts compared with the BAT arm and HU subgroups, and these reductions were maintained over time; mean changes from Baseline in WBC values at Week 12/Week 32 (×109/L) were -7.7/-7.2 for Rux, -3.2/-4.2 for BAT, and -1.2/-2.2 for HU. In patients with lower Baseline WBC counts, mean values remained stable over time. The change from Baseline to Week 12 for individual patients with Baseline WBC counts ≥ 11×109/L is shown in Figure 1. In patients with Baseline WBC counts ≥ 11×109/L, worsening WBC counts were observed in 10.8% of patients in the Rux arm vs 35.4% in the BAT arm (P =0.0002) and 47.8% in the HU subgroup (P <0.0001). In this same subgroup with elevated WBC counts, a greater proportion of patients in the Rux arm achieved WBC counts ≤ 10×109/L or a ≥50% reduction compared with the BAT arm or HU subgroup (Week 12: Rux, 41% vs BAT, 19% vs HU, 13%; Week 32: Rux, 45% vs BAT, 22% vs HU, 9%); median time to this reduction was 8 weeks in the Rux arm and was not reached in the BAT arm or HU subgroup. Conclusion: Rux treatment resulted in better control of WBC counts compared to BAT in patients with PV. These changes in the Rux arm occurred early after study initiation (within a median of 8 weeks) and were durable over time. Although RESPONSE was not powered to assess the impact of Rux on thromboembolic events, the lower rate of thromboembolic events observed in the Rux arm vs the BAT arm (1.8 vs 8.2 per 100 patient-years of exposure) is consistent with the observed effects of Rux on hematocrit, WBC counts, and C-reactive protein levels, which are all associated with thromboembolic risk. Disclosures Miller: Incyte Corporation: Honoraria, Research Funding. Kiladjian:Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Incyte Corporation: Consultancy; Novartis: Consultancy. Naim:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Gadbaw:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Vannucchi:Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Speakers Bureau.

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Symptom Burden Profile in Myelofibrosis Patients with Thrombocytopenia: Lessons and Unmet Needs

Blood ◽

10.1182/blood.v126.23.4080.4080 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4080-4080 ◽

Cited By ~ 2

Author(s):

Holly Geyer ◽

Robyn M Scherber ◽

Heidi Kosiorek ◽

Amylou C. Dueck ◽

Jean-Jacques Kiladjian ◽

...

Keyword(s):

Blood Cell ◽

Board Of Directors ◽

Red Blood Cell ◽

Research Funding ◽

Myeloproliferative Neoplasm ◽

Symptom Burden ◽

Severe Thrombocytopenia ◽

Advisory Committees ◽

Symptom Scores ◽

Red Blood Cell Transfusions

Abstract Background Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) associated with a high degree of symptomatology, progressive cytopenias and potential to transform into acute myelogenous leukemia (AML). Thrombocytopenia amongst MF patients is a proven negative prognostic indicator and predictor of transformation to AML. Ruxolitinib is an effective JAK inhibitor for MF symptoms and splenomegaly, but is not indicated in patients with severe thrombocytopenia. Phase III trials of pacritinib have shown alleviation of the MF symptom burden amongst patients with thrombocytopenia (ASCO 2015 Mesa et. al.). In this study, we assessed the symptom burden of MF patients with significant thrombocytopenia who were naïve to pacritinib. Methods Data was assessed from a prospectively collected international database of MF patients in which demographics, disease features, and MF symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. MF risk scores were calculated using the DIPSS criteria (Gangat, 2011). Thrombocytopenia was defined as a platelet count <100 x 10(9)/L, anemia was defined as hemoglobin<10 g/dL and leukopenia was defined as a white blood cell count <4.0 x 10(9)/L. Associations between the MPN-SAF individual symptoms were investigated using Pearson correlations. Results Demographic and Disease Features: A total of 418 patients with (n=89) and without (n=329) thrombocytopenia completed the MPN-SAF. Patients with thrombocytopenia were slightly younger (57.4 vs. 61.0, p=0.01) with longer disease durations (11.9 years vs. 8.8 years, p=0.0489) and had a higher prevalence of primary myelofibrosis (PMF; 82% vs. 66%, p=0.01). The presence of thrombocytopenia was associated with other laboratory abnormalities including anemia (60.7% vs. 25.3%, p<0.001) and leukopenia (34.8% vs. 52.3%, p<0.001), along with the need for red blood cell transfusions (34.8% vs. 14.6%, p<0.001). Patient cohorts did not differ by gender, DIPSS risk score, history of prior thrombosis or hemorrhage. In comparing patients with severe thrombocytopenia (<50 x 10(9)/L, n=43) to those with moderate thrombocytopenia (51-100 x 10(9)/L, n=46), severe thrombocytopenia patients were more likely to have anemia (74.4% vs. 47.8%, p=0.01) and require red blood cell transfusions (51.2% vs. 19.6%, p=0.002). Symptoms Scores for individual MPN-SAF items were assessed for each subgroup. Patients with thrombocytopenia had markedly higher total symptom scores than patients without thrombocytopenia (32.8 vs. 24.1, p<0.001). Individual scores were also higher for most items (fatigue, early satiety, inactivity, dizziness, sad mood, sexuality, cough, night sweats, itching, fever, weight loss, overall QOL)[Figure 1]. No significant differences in MPN SAF TSS or individual symptom scores were observed in comparing severe vs. moderate thrombocytopenia patients. Discussion MF patients with thrombocytopenia have distinctive clinical characteristics and face a significantly more severe symptom burden. Importantly, despite thrombocytopenia being a recognized risk factor for disease advancement, no correlations are noted between patient symptomatology and risk category. In addition, patients with severe thrombocytopenia do not differ symptomatically from patients with moderate thrombocytopenia despite having more severe anemia, leukopenia and transfusion requirements. This implies that the degree of symptomatology expressed by thrombocytopenic MF patients occurs independent from the exact platelet value. Conclusion The results of this study suggest that patients with thrombocytopenia will benefit from aggressive symptomatic control, potentially from targeted agents. Figure 1. MF Symptoms in Patients With and Without Thrombocytopenia Figure 1. MF Symptoms in Patients With and Without Thrombocytopenia Disclosures Kiladjian: Novartis: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Incyte Corporation: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Shire: Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Vannucchi:Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

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Reduced Packed Red Blood Cell Utilization Via Implementation of Transfusion Guidelines in a Large Health System Hospital

Blood ◽

10.1182/blood-2019-124193 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3451-3451

Author(s):

Reid Christian Bowers ◽

Michael A. Thompson ◽

Julie Van Dreser ◽

Federico Augusto Sanchez

Keyword(s):

Blood Cell ◽

Health System ◽

Board Of Directors ◽

Red Blood Cell ◽

Research Funding ◽

Medical Center ◽

Further Education ◽

Advisory Committees ◽

Transfusion Guidelines ◽

Individual Clinician

Background: We have previously discussed how implementation of Patient Blood Management (PBM) principles such as transfusion guidelines helped reduce packed red blood cell (PRBC) usage in cardiovascular surgery patients (Bowers et al, Reduced Blood Product Utilization via Implementation of an Anemia Clinic and Consult Service in a Large Health System Hospital https://tinyurl.com/y3ucr3sz). We now discuss the effect of implementing transfusion guidelines on PRBC transfusion practices at an institutional level at St. Luke's Medical Center, Advocate Aurora Health in Milwaukee, WI. Methods: Beginning in 2015 Aurora Health Care made 7 g/dL the standard threshold below which packed red blood cell (PRBC) transfusion is considered appropriate. Additionally, transfusing PRBCs as single units with a hemoglobin (Hgb) measurement between each unit was made standard. Education was provided to clinicians on the new standard including best practice advice in the transfusion ordering workflow. Data was gathered on institutional PRBC use and individual clinician PRBC ordering practices. Further education was provided based on the extent to which data showed conformity to the new standard. Results: PBM implementation 2015-2018 was associated with a drop in institutional PRBC usage from 11,490 to 9301 units. The percentage of transfusions ordered with Hgb < 7 g/dL rose from 41.6% to 71.8%. The percentage of single unit orders increased from 67.3% to 91.8%. See Graph/Table 1 & 2 for further analysis of individual practitioner PRBC ordering. See Table 3 for reporting period volume data. Conclusions: Implementation of PRBC transfusion guidelines was associated with a greater than 2000-unit annual reduction in PRBC usage. Reduction was associated with individual clinician transfusion practices that increasingly conformed with guidelines over time. Disclosures Thompson: Adaptive: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; UpToDate: Patents & Royalties: Myeloma reviewer; BMS: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Lynx Bio: Research Funding; VIA Oncology: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Doximity: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Patient-Reported Outcomes and Frailty Among Participants in the NHLBI MDS Natural History Study

Blood ◽

10.1182/blood-2020-136992 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Gregory A. Abel ◽

Donnie Hebert ◽

Cecilia Lee ◽

James M. Foran ◽

Steven D. Gore ◽

...

Keyword(s):

Physical Activity ◽

At Risk ◽

Natural History ◽

Board Of Directors ◽

Research Funding ◽

Patient Reported Outcomes ◽

Advisory Committees ◽

Natural History Study ◽

Diagnostic Categories ◽

Patient Reported

Introduction: Patient-reported outcomes (PROs) such as quality of life (QOL) are variably affected in patients with myelodysplastic syndromes (MDS), but the heterogeneous composition of disease states grouped together as "MDS" increases the difficulty of assessing and understanding these outcomes. Moreover, little is known about the potential relationship between QOL and frailty in this population. Methods: The NHLBI MDS Natural History Study (NCT02775383) is a prospective cohort enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenias. Untreated participants undergo bone marrow assessment with centralized histopathology review at enrollment for assignment into subcategories for longitudinal follow-up: MDS, MDS/MPN, ICUS, AML (<30% blasts), and "At-Risk" (cases with sub-threshold dysplasia or select karyotypic or genetic mutations). PRO and frailty data are collected at enrollment and every six months thereafter. PRO instruments include MDS-specific (QUALMS) and general (FACT-G, PROMIS Fatigue Short Form 7a, EQ-5D-5L) instruments, and a measure of frailty (VES-13). While no frailty instrument alone has been shown to be a substitute for comprehensive geriatric assessment, VES-13 has been successfully used in cancer-related studies for basic screening, where a score of 3 or more is considered frail (vulnerable). An analysis of variance (ANOVA) was used for the overall comparisons of mean baseline scores between diagnostic categories. Pairwise comparisons of scores between diagnostic categories and vulnerability subgroups were performed via two-sample t-tests. Results : Of 835 participants assessed for eligibility, 369 (44%) were classified as MDS, MDS/MPN, AML, ICUS or At-Risk, and further evaluated. Mean age was 72 years (standard deviation (SD)=10.7) and 68% were male. Mean baseline scores on the PRO measures are compared between diagnostic categories in the Table; scores did not differ significantly across categories. In particular, no significant differences were found between MDS and the other diagnostic categories. ICUS had similar QOL scores to MDS and MDS/MPN (e.g., means (SD) on EQ-5D-5L of 74.1 (17.8) in ICUS and 70.8 (19.4) in MDS, p=0.348) but had significantly higher scores than those for AML on EQ-5D-5L (60.7 (28.4), p=0.031). For the 216 participants with diagnostically-confirmed MDS, QOL impairment was similar to that routinely seen in other cancers; for example, the mean total FACT-G was 81.8 (SD=15.9), similar to localized breast cancer (82.4, SD=16.2), localized colorectal cancer (79.6, SD=16.1), and lung cancer with no current evidence of disease (82.6, SD=15.5; comparison means from Pearlman, Cancer, 2014). For frail/vulnerable participants with MDS or MDS/MPN (N=87), the most common reasons for vulnerability were age ≥75 years (68%), overall rating of health as poor or fair (62%), and difficulty with prolonged physical activity (90%) such as walking a quarter mile (75%) or doing heavy housework (70%). A minority also were vulnerable due to requiring help with instrumental activities of daily living (iADLS) such as shopping (28%) or managing money (16%). Mean QOL scores were compared between vulnerability subgroups (Figure). Vulnerable participants pooled over all diagnostic categories had significantly worse PROs than non-vulnerable participants for all measures (p<0.001). In particular, vulnerable MDS participants scored significantly worse on the QUALMS (mean 64.4, SD=13.4) vs. non-vulnerable MDS participants (mean 72.7, SD=13.3), p<0.001. Conclusions: Participants in our cohort with histologically-confirmed MDS-even low-grade MDS-had similar impairments in PROs as those with other cancers. Among those with histologically-confirmed MDS, vulnerable participants had significantly worse QOL on many measures compared to non-vulnerable participants, suggesting that this domain of function be specifically assessed in clinic. Moreover, while a "gestalt" of frailty may be inferred by observing how patients present and move in the office, these data suggest that other contributing domains, such as difficulty with prolonged physical activity and iADLs, should be evaluated explicitly. Disclosures Foran: H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Takeda: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Agios: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Actinium: Research Funding; Aprea: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding; Revolution Medicine: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Padron:Incyte: Research Funding; Kura: Research Funding; Novartis: Honoraria; BMS: Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Transcriptional Signaling Centers Govern Human Erythropoiesis and Harbor Genetic Variations of Red Blood Cell Traits

Blood ◽

10.1182/blood-2018-99-118637 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1277-1277

Author(s):

Avik Choudhuri ◽

Eirini Trompouki ◽

Brian J. Abraham ◽

Leandro Colli ◽

William Mallard ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Transcription Factors ◽

Blood Cell ◽

Board Of Directors ◽

Red Blood Cell ◽

Erythroid Differentiation ◽

Regulatory Elements ◽

Advisory Committees ◽

Equity Ownership

Abstract Single Nucleotide Polymorphisms (SNPs) identified through genome-wide association studies (GWAS) provide insight into the mechanism of human genetic diseases, and majority of functional GWAS mutations target genomic regulatory elements. During erythroid differentiation of human CD34+ cells, we mapped regulatory DNA elements (enhancers and open chromatin regions) by H3K27Ac ChIP-seq and ATAC-seq, and studied the SNPs that reside within these DNA regulatory elements. We followed genomic binding of lineage restricted GATA transcription factors and also chose to examine the binding of the BMP signal responsive transcription factor SMAD1 in CD34+ cells during erythropoiesis. By overlapping their genomic occupancy with stage-matched RNA-seq, we found that SMAD1, in association with GATA-factors, serves as marker of genes responsible for differentiation at every step of erythropoiesis. ChIP-seq for other crucial signaling transcription factors, such as WNT-responsive and TGFb-responsive factors (TCF7L2 and SMAD2, respectively) demonstrated a remarkable co-existence of such factors at GATA+SMAD1 co-bound regions nearby stage-specific genes. We defined such regions as "Transcriptional Signaling Centers (TSC)" where multiple signaling transcription factors converge with master transcription factors to determine optimum stage-specific gene expression in response to growth factors. Our bioinformatics-algorithms demonstrated that PU1 and FLI1 binding sites were present in progenitor-specific TSCs whereas KLF1 and NFE2 sites were enriched in TSCs of red blood cells. We performed CRISPR-CAS9 mediated perturbations of each of the PU1, GATA and SMAD1 motifs separately in a representative progenitor TSC in K562 and HUDEP2 cells. Similar to loss of PU1 and GATA motifs, loss of SMAD1 motif selectively inhibited expression of the associated gene and showed defects in erythroid differentiation, demonstrating that TSCs are important to provide optimum gene expression and proper erythroid differentiation. To determine if such TSCs are targeted by GWAS mutations, we have studied 1270 lead and additional 27,799 SNPs in linkage disequilibrium with lead SNPs that are associated with six critical red blood cell traits - hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). Surprisingly, we observed that, out of the 3831 "functional" SNPs that fall within non-exonic H3K27Ac enhancers, while only 5% (188) of RBC-SNPs target only blood-master-transcription-factor motifs, at least 48% (1821) of them reside on various signaling pathway associated transcription factor motifs including SMADs (BMP/TGFb signaling), RXR/ROR (nuclear receptor signaling), FOXO/FOXA (FOX signaling), CREBs (cAMP signaling) and TCF7L2 (WNT signaling). Additionally, these RBC-trait-SNPs are specifically enriched in GATA+SMAD1 co-bound TSCs and fall within signaling factor binding sites. We validated such SNPs that target SMAD-motifs. The SNP rs9467664 is associated with the MCV-trait near HIST1H4A, a gene that increases in expression during differentiation. Using gel-shift assay, we found that SMAD1 binding is compromised when the major allele T changes to minor allele A under MCV-trait. Remarkably, eQTL analysis using microarray gene expression profiles of peripheral blood obtained from the Framingham Heart Studies revealed that expression of HIST1H4A is significantly more in a population with T-allele than that with A-allele. This demonstrates that inhibition of SMAD1 binding by the SNP causes a loss of allele-specific HIST1H4A expression. Another MCV-associated SNP rs737092 targets a SMAD motif within an erythroid-specific TSC near RBM38 gene. T-allele, in comparison with C-allele, that retains SMAD1 binding showed more expression in luciferase-based reporter assays specifically under BMP stimulation suggesting that rs737092 compromise BMP-responsiveness. Taken together, our study provides the first evidence that naturally occurring GWAS variations directly impact gene expression from signaling centers by modulating binding of signaling transcription factors under stimulation. Such aberrant signaling events over time could lead to "signalopathies", ultimately resulting in phenotypic variations of RBC traits. Disclosures Abraham: Syros Pharmaceuticals: Equity Ownership. Young:Omega Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Camp4 Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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COVID-19 Outcomes Among Participants in the NHLBI Myelodysplastic Syndromes (MDS) Natural History Study

Blood ◽

10.1182/blood-2021-147249 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2611-2611

Author(s):

Eric Padron ◽

Donnie Hebert ◽

Steven D. Gore ◽

Nancy Gillis ◽

Rami S. Komrokji ◽

...

Keyword(s):

At Risk ◽

Cohort Study ◽

Natural History ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Cross Sectional ◽

Natural History Study ◽

Privately Held

Abstract Introduction: The NHLBI MDS Natural History Study (NCT02775383) is an ongoing prospective cohort study conducted across 144 sites in the U.S. and Israel intended to establish a data and biospecimen repository to advance the understanding of MDS. In response to the COVID-19 pandemic, the study also collected data on COVID-19 infection and management. Here, we report a summary of COVID-19 outcomes from participants in this study and the impact of the pandemic on study operations. Methods: This prospective cohort study initiated in June, 2016 is enrolling patients (pts) undergoing diagnostic work up for suspected or newly diagnosed MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenia. Study enrollment was paused from Mar. 27, 2020 to May 18, 2020 due to COVID-19. Previously untreated pts underwent a bone marrow assessment with a centralized histopathology review at enrollment for assignment to a longitudinal cohort (MDS, MDS/MPN overlap, idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with <30% blasts, or "At-Risk" (pts with sub-threshold dysplasia, select karyotype, or select genetic mutations) for follow-up every six months; or a cross-sectional cohort (other cytopenia or cancers) with no further follow-up. COVID-19 outcomes, including tests, status, hospitalizations and treatments for COVID-19, were collected for all eligible pts. Protocol deviations related to COVID-19 were also collected. Fisher's exact test was used for comparing the proportions of pts tested or positive between groups. Results : Of 758 eligible pts with available COVID-19 data, 507 (67%) were assigned to the longitudinal cohort and 251 (33%) to the cross-sectional cohort or are pending assignment. Among longitudinal pts, 74 (15%) had ICUS, 240 (47%) MDS, 47 (9%) MDS/MPN overlap, 11 (2%) AML with <30% blasts, and 135 (27%) At-Risk for MDS. The median age over all pts was 72 years (range=21-95) and 66% were male, 92% White, 4% Black, 2% Asian, and 2% other. Among 244 pts (32%) tested for COVID-19 (Table 1), 23 (9%) were positive. Twelve (>50% of the positive pts) were in Wisconsin, California (CA), and Missouri (Figure 1), with 8 identified from Sep. to Dec. 2020, which overlaps with third waves of COVID-19 reported in CA and in the Midwest. Tests from 17 (74%) of the 23 pts were based on a polymerase chain reaction (PCR) assay. The proportion of pts positive were similar between pooled disease (ICUS, MDS, MDS/MPN, AML <30%), At-Risk, and cross-sectional groups (8%, 8%, 16%, respectively; Table 2) but the proportions tested differed significantly (39%, 28%, and 25%, respectively, p=0.004). Among all positive pts, 21 (91%) are recovering or have recovered (16 with sequelae), 1 (4%) died, and 1 outcome is unknown (Table 1). The one participant who died had MDS with excess blasts-1 (MDS-EB1, 5-9% blasts). Eight pts (35% of positive pts) required hospitalization (median duration of 7 days (range=2-17)) or treatment (tx) in response to COVID-19, 7 of whom required both. In the 8 pts who required tx for COVID-19, 4 reported Remdesivir-use, 3 of whom were diagnosed with MDS or MDS/MPN overlap. The study monthly accrual rates were similar when compared pre- vs. post-study pause (23 vs. 22 pts, respectively) but the rate of missed follow-up visits increased from 5% to 11% post-pause. About half (49%) of the 144 COVID-19-related study deviations occurred during the months the study was paused. Conclusions: In this analysis of 758 pts with MDS and related conditions, the largest reported for these diagnoses, the COVID-19 mortality rate (13%) in MDS was lower than has been reported in a smaller (n=61) case study (39%, Feld et al Blood 2020) but is similar to the rates for MDS observed annually each year prior to study pause (range=11-19%) and to the rate reported in a larger (n=2186) observational study of cancer patients (16%, Rivera et al Cancer Discov 2020). Infection rates were similar across disease groups. The pandemic also resulted in substantial study-specific challenges, including increased rate of deviations, the study being paused, and difficulty sourcing material for biospecimen processing. Data on vaccine efficacy and rates of pts with long-haul symptoms post-COVID may be of interest in future work. Figure 1 Figure 1. Disclosures Padron: BMS: Research Funding; Kura: Research Funding; Taiho: Honoraria; Stemline: Honoraria; Blueprint: Honoraria; Incyte: Research Funding. Komrokji: Novartis: Honoraria; Geron: Honoraria; Acceleron: Honoraria; Agios: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Saber: Govt. COI: Other. Al Baghdadi: Bristol-Myers Squibb: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Current holder of individual stocks in a privately-held company; Epizyme: Current holder of individual stocks in a privately-held company; Heron Therapeutics: Current holder of individual stocks in a privately-held company; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Membership on an entity's Board of Directors or advisory committees. DeZern: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

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Diagnosis of Myelodysplastic Syndromes and Related Conditions: Rates of Discordance between Local and Central Review in the NHLBI MDS Natural History Study

Blood ◽

10.1182/blood-2018-99-116629 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4370-4370 ◽

Cited By ~ 2

Author(s):

Ling Zhang ◽

Donald M Stablein ◽

Pearlie Epling-Burnette ◽

Alexandra M. Harrington ◽

Lynn C. Moscinski ◽

...

Keyword(s):

Bone Marrow ◽

Natural History ◽

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Diagnostic Errors ◽

Advisory Committees ◽

Natural History Study ◽

Oncology Research ◽

Blast Count

Abstract Background Myelodysplastic syndromes (MDS) are a collection of hematopoietic disorders with widely variable prognoses and treatment options. Pathologic diagnosis can be challenging and misdiagnosis can impact patient therapy and outcome. How commonly misdiagnosis occurs, and the severity of diagnostic errors, is not known. Here, we report interim analyses of patients (pts) with cytopenia and suspected MDS from the NHLBI National MDS Natural History Study (https://thenationalmdsstudy.net ClinicalTrials.gov: NCT02775383) assessing MDS occurrence and rates of agreement on classification of MDS/MDS-related disorders by local and centralized review. Methods Pts with cytopenias and clinically suspected MDS were identified between 6/16 and 6/18 from 84 participating centers in this ongoing multi-Institutional Cooperative Group study, with a goal of recruiting 2000 MDS (WHO 2016 subcategories), MDS/MPN or low blast count acute myeloid leukemia (AML, <30% blasts without core binding factor) and 500 cases with idiopathic cytopenia of undetermined significance (ICUS) from both NCI community oncology research program (NCORP) and lead academic participating sites. Centrally submitted clinical and pathologic data and bone marrow samples were analyzed by pathologists in the central laboratory & biorepository (CL/B) blinded to the original site's diagnosis, with a third-level review for cases with disagreement between the local and CL/B assignment. Disagreements in the 5 categories detailed in Figure 1 were considered clinically meaningful. Cases were assigned to longitudinal (MDS, MDS/MPN, ICUS, low blast count AML) versus cross-sectional (other cytopenias or cancers) cohorts after central classification based on clinical, pathologic, and cytogenetic features. Interrater-agreement was evaluated with the Kappa statistic. Results Of 375 pts for whom data and samples were submitted with completed classification, 88 (23%) had MDS, 15 (4%) MDS/MPN, 12 (3%) ICUS, 23 (8%) AML, and 237 (63%) other cytopenias (Figure 1). The median age of all pts was 71 years (range, 20-92), 44% were female, and median baseline blood counts and other baseline measures are in Figure 2. MDS pts had single lineage dysplasia (SLD, 0), SLD with ring sideroblasts (RS, 9 (10%)), multi-lineage dysplasia (MLD, 17 (19%)), MLD -RS (18 (20%)), excess blasts I (EB, 14 (16%)), EBII (19 (22%)), del(5q) (6 (7%)), and MDS-U (5(6%)). IPSS-R categories were defined in 51 of 88 MDS cases (58%): Very Low (27%), Low (43%), Intermediate (27%), High (16%), and Very High (14%). Overall site/central agreement on diagnosis occurred in 225 cases (60%) with inconsistency associated with recognized site coding errors resolved in 54 cases (14%) without 3rd party review. Seventy-eight others (21%) were referred to 3rd level review; confirmation of CL/B classification occurred in 49/78 cases (63%), agreement with site in 13/78 (17%), and a different diagnosis in 16/78 (21%). Clinically meaningful changes in diagnoses between local and central review occurred 26% of the time (Figure 1, n=97/375 kappa =.53 95% CI (.45, .61)). Site assigned MDS was changed to ICUS or other cytopenia in 35% (n=34/99); and to AML in 3% (n=3/99). For cases with site assignment to other causes of cytopenias (225 of 375 cases, 60%), central assignment identified ICUS in 3, MDS/MPN overlap in 8, AML in 2 and MDS in 22, totaling a change in diagnosis in 16%. Of note, 60% (15/25) of ICUS diagnosed locally were interpreted as reactive marrow or normal according to central review. Within MDS cases diagnosed locally, the greatest discrepancy was observed in the MDS-U classification, reported 31 times (31/99 31%) but confirmed in only 2 cases (6%), with 22 (71%) found to not have MDS. Across the study when compared to local assignment, central review changed the follow-up cohort assignment for 87 pts (23%). Conclusions In this well-characterized series of pts evaluated for MDS with bone marrow biopsy and paired site/central morphologic assessment, 40% of site diagnoses were changed at central review and site coding errors were common. In 26%, the changes were clinically meaningful, potentially affecting patient treatment and prognosis. In particular, site designation of MDS-U was an unreliable classification category, which could only partially be attributed to miscoding errors at the local site. Incorporating genomics data might help refine MDS diagnoses. Disclosures Bejar: Genoptix: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Honoraria; Modus Outcomes: Consultancy; Astex/Otsuka: Consultancy, Honoraria; AbbVie/Genentech: Consultancy, Honoraria; Foundation Medicine: Consultancy. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Scott:Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy, Research Funding; Alexion: Consultancy. Gore:Celgene: Consultancy, Research Funding. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

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Trends in Iron Overload over Past Two Decades: Results from the Natural History of Iron Burden Study with the SQUID Biosusceptometer

Blood ◽

10.1182/blood-2019-129701 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 961-961

Author(s):

Ashutosh Lal ◽

Roland Fischer ◽

Elliott Vichinsky ◽

Marcela Weyhmiller

Keyword(s):

Natural History ◽

Longitudinal Data ◽

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Iron Status ◽

Advisory Committees ◽

Liver Iron ◽

Non Invasive ◽

History Of

Established in 2002, the Iron Overload Program in Oakland relies on a biosusceptometer (Ferritometer®, model 5700, Tristan Technologies, San Diego, USA) utilizing low temperature SQUID technology to quantify liver iron concentration (LIC). The procedure is non-invasive and patients as young as 2 years can be been measured without sedation. The measurement and analysis are rapid (30 - 45 min) and the results have been validated against biopsy. Over 3500 measurements have been performed on 1055 patients at risk of iron overload. Longitudinal data were acquired under the natural history of iron burden by non-invasive measurement techniques study since November 2002. Patients were referred for liver iron assessment at intervals determined by their providers. Seventy-one patients had ≥10 measurements, 34 had ≥15 measurements, and 7 had ≥20 measurements. Over the course of the study, the average age at enrollment fell from 23 +/- 17 years (range 2 - 88 years) to 18 +/- 15 years (2 - 73 years). There was an increase in the proportion of patients with non-transfusion dependent thalassemia and those with iron overload from red cell transfusions associated with chemotherapy or stem cell transplantation. In comparison to the first five years (2003 - 2008) in the most recent five years (2014 - 2018) chelation has shifted from deferoxamine to deferasirox and there has been an increase in the simultaneous use of two chelators. We observed an overall decrease in mean LIC from 2400 to 1800 micrograms Fe/g liver wet weight (14.4 to 10.8 mg/g liver dry weight). Ferritin to LIC ratios were 0.46 in non-transfused thalassemia, 0.85 in intermittently transfused (< 7 mL/Kg/month), and 1.10 in transfusion-dependent (≥7 mL/Kg/month). A subgroup analysis of longitudinal data in transfusion-dependent thalassemia with multiple measurements was conducted. The mean (±s.d.) LIC decreased by 42% from 15.8 ± 10.2 at the first measurement to 9.2 ± 9.7 mg/g at the last visit. At the same time, mean ferritin decreased from 2629 to 2115 ng/mL, a change of 20%. In this group of patients ferritin levels now overestimate LIC by a significant amount (Figure). This reflects either a change in transfusion practices or the type of chelation. These results show a positive impact of oral chelators and combined chelation regimens leading to a significant improvement in iron overload in thalassemia. The development of organ complications from iron toxicity is expected to decrease, but there is a risk of over-chelation if ferritin is the sole measure of iron status. Liver biosusceptometry has been a valuable method to assess diverse conditions associated with iron overload and to monitor chelation treatment in patients across all ages. Figure Disclosures Lal: Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Terumo Corporation: Research Funding; Insight Magnetics: Research Funding; bluebird bio: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding. Vichinsky:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Agios: Research Funding.

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