Normal CMR Bi-Atrial and Biventricular Reference Values in Sickle Cell Disease Patients without Heart Damage

Abstract Background. Cardiac function indices in patients with hemoglobinopathies are different from those in healthy population, mainly due to chronic anemia. Normal reference values specific for SCD patients are not available by CMR. Aim. We aimed to define the normal cut-off value in SCD patients for bi-atrial and biventricular cardiac magnetic resonance (CMR) parameters. Methods. We considered forty-eight adult SCD patients with no known risk factors or cardiac disease, normal electrocardiogram, no macroscopic myocardial fibrosis, and all cardiac segments with T2*≥20 ms, consecutively enrolled in the MIOT network (Myocardial iron overload in thalassemia). SCD patients were compared with ninety-six healthy controls and 96 thalassemia major (TM) patients without cardiac damage, both matched for age and gender. Nine pediatric SCD patients were also analysed in comparison with 9 TM patients and 9 healthy subjects matched for age and gender. Cine images were acquired to quantify biventricular function parameters: LV and RV end-diastolic volume (EDV), end-systolic volume (ESV) and stroke volume (SV) were normalized for body surface area (EDVI, ESVI, SVI), as well as biventricular mass and atrial areas. Myocardial iron overload was assessed by segmental T2* technique. Late gadolinium enhancement (LGE) images were acquired for evaluation of macroscopic myocardial fibrosis. Results. In all three groups males showed higher biventricular volumes and mass indexes than females. SCD male patients had significantly higher LVEDVI (p<0.0001), LVESVI (p=0.010), LVSVI (p=0.003), cardiac index (p=0.002), LV and RV mass index (p=0.008 and p=0.001, respectively) and left and right atrial areas (p<0.001 and p=0.011) than healthy subjects. No significant differences were found in RVEDVI, EVESVI and biventricular EF. Compared to healthy volunteers, females with SCD showed a larger LVEDVI (p=0.020), LVSVI (p=0.039), RV mass index (p=0.002) and left atrial area (p=0.008). SCD and TM patients showed comparable values of bi-atrial and biventricular volumes and function. When compared to TM, SCD patients showed a larger LV (p<0.001) and RV mass index (p=0.001) in male group and a larger RV mass index (p=0.001) in female group. Table 1 shows the cut-offs for bi-atrial and biventricular MR parameters for adult SCD patients by gender. No significant differences in MR parameters were found among the pediatric groups. Conclusions. Normal reference ranges of bi-atrial and biventricular MR parameters for adult males and females SCD patients were established. The use of these reference values will prevent possible misdiagnosis of cardiomyopathy in patients with SCD. Figure 1 Figure 1. Disclosures Pepe: Chiesi Farmaceutici S.p.A: Other: no profit support; Bayer S.p.A.: Other: no profit support. Quarta: Sanofi - Genzyme: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Blue Bird Bio: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Celgene: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Takeda: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; speaker at conferences; Bristol Meyer Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Speaker at conferences. Maggio: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Normal CMR bi-atrial and biventricular reference values in sickle cell disease patients without heart damage

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeab090.038 ◽

2021 ◽

Vol 22 (Supplement_2) ◽

Author(s):

A Pepe ◽

A Meloni ◽

R Righi ◽

V Vinci ◽

F Pezzullo ◽

...

Keyword(s):

Iron Overload ◽

Myocardial Fibrosis ◽

Reference Values ◽

Healthy Subjects ◽

Right Atrial ◽

Reference Ranges ◽

Myocardial Iron ◽

Age And Gender ◽

Normal Reference ◽

And Gender

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The MIOT project receives “no-profit support” from industrial sponsorships (Chiesi Farmaceutici S.p.A., ApoPharma Inc.). Background. Cardiac function indices in patients with hemoglobinopathies are different from those in healthy population, mainly due to chronic anemia. Normal reference values specific for SCD patients are not available by CMR. Aim. We aimed to define the normal cut-off value in SCD patients for bi-atrial and biventricular cardiac magnetic resonance (CMR) parameters. Methods. We considered forty-eight adult SCD patients with no known risk factors or cardiac disease, normal electrocardiogram, no macroscopic myocardial fibrosis, and all cardiac segments with T2*≥20 ms, consecutively enrolled in the MIOT network (Myocardial iron overload in thalassemia). SCD patients were compared with ninety-six healthy controls and 96 thalassemia major (TM) patients without cardiac damage, both matched for age and gender. Nine pediatric SCD patients were also analysed in comparison with 9 TM patients and 9 healthy subjects matched for age and gender. Cine images were acquired to quantify biventricular function parameters: LV and RV end-diastolic volume (EDV), end-systolic volume (ESV) and stroke volume (SV) were normalized for body surface area (EDVI, ESVI, SVI), as well as biventricular mass and atrial areas. Myocardial iron overload was assessed by segmental T2* technique. Late gadolinium enhancement (LGE) images were acquired for evaluation of macroscopic myocardial fibrosis. Results. In all three groups males showed higher biventricular volumes and mass indexes than females. SCD male patients had significantly higher LVEDVI (p < 0.0001), LVESVI (p = 0.010), LVSVI (p = 0.003), cardiac index (p = 0.002), LV and RV mass index (p = 0.008 and p = 0.001, respectively) and left and right atrial areas (p < 0.001 and p = 0.011) than healthy subjects. No significant differences were found in RVEDVI, EVESVI and biventricular EF. Compared to healthy volunteers, females with SCD showed a larger LVEDVI (p = 0.020), LVSVI (p = 0.039), RV mass index (p = 0.002) and left atrial area (p = 0.008). SCD and TM patients showed comparable values of bi-atrial and biventricular volumes and function. When compared to TM, SCD patients showed a larger LV (p < 0.001) and RV mass index (p = 0.001) in male group and a larger RV mass index (p = 0.001) in female group. Table 1 shows the cut-offs for bi-atrial and biventricular MR parameters for adult SCD patients by gender. No significant differences in MR parameters were found among the pediatric groups. Conclusions. Normal reference ranges of bi-atrial and biventricular MR parameters for adult males and females SCD patients were established. The use of these reference values will prevent possible misdiagnosis of cardiomyopathy in patients with SCD.

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Changes in CMR Parameters and Prediction of Cardiac Complications in Thalassemia Major: Fibrosis Tells Us More Than Iron

Blood ◽

10.1182/blood-2021-144584 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2014-2014

Author(s):

Alessia Pepe ◽

Laura Pistoia ◽

Pietro Giuliano ◽

Nicola Giunta ◽

Rosamaria Rosso ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Myocardial Fibrosis ◽

Thalassemia Major ◽

Cardiac Complications ◽

Myocardial Iron ◽

Advisory Committees ◽

Risk Class ◽

Cox Regression Analysis

Abstract Introduction. Cardiovascular magnetic Resonance (CMR) has dramatically changed the clinical practice and improved the prognosis in thalassemia major (TM). This is the first study evaluating the predictive value of changes in CMR parameters (myocardial iron, function, and fibrosis) for cardiac complications in TM. Methods. We followed prospectively 709 TM patients (374 females; 29.77±8.53 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network who performed a baseline and a 1 st follow up CMR scan after 18 months. Myocardial iron overload (MIO) was measured by multislice multiecho T2* technique and atrial dimensions and biventricular function by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. Risk classes were defined based on the 4 patterns of MIO from worst to normal. For patients with baseline MIO (at least one segmental T2*<20 ms), improvement was defined as a transition to a better risk class, stabilization as no change in risk class, and worsening as a transition to a worse risk class. For patients without baseline MIO, the worsening was the transition to a worse risk class. The percentage change was used for continuous variables. For biventricular ejection fractions, improvement was a %change>10%, stabilization a %change between -10% and 10%, and worsening a %change<-10%. For biventricular volumes, LV mass index, and atrial areas, improvement was a % change<-10%, stabilization a % change between -10% and 10%, and worsening a % change>10%. Myocardial fibrosis was considered absent if not detected in any of the two CMRs and present if detected in at least one examination . Results. During a mean follow-up of 89.4±33.3 months, cardiac events were recorded in 50 (7.1%) patients: 24 (48%) episodes of heart failure, 24 (48%) arrhythmias (23 supraventricular and 1 hypokinetic), and 2 (4.0%) pulmonary hypertension. Mean time from the 1 st follow up CMR to the development of a cardiac complication was 75.31±35.35 months. In the univariate Cox regression analysis, cardiac iron cleareance and myocardial fibrosis were identified as univariate prognosticators (Table 1). In the multivariate analysis only myocardial fibrosis remained an independent predictor factor. Conclusion. The presence of myocardial fibrosis at the baseline CMR or developed within 18 months emerges as the strongest long-term predictor for cardiac complications in TM. Our data demonstrate the importance in using the contrast medium for CMR scans in thalassemia patients. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.

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Combined Chelation Therapy with Deferasirox and Deferoxamine In Transfusion-Dependent Thalassemia

Blood ◽

10.1182/blood.v116.21.4269.4269 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4269-4269 ◽

Cited By ~ 1

Author(s):

Ashutosh Lal ◽

Nancy Sweeters ◽

Vivian Ng ◽

Drucilla Foote ◽

Patricia Evans ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Liver Weight ◽

Myocardial Iron ◽

Advisory Committees ◽

Single Drug ◽

Median Plasma ◽

Group B

Abstract Abstract 4269 Therapeutic regimens that combine two iron chelators may enhance chelation efficiency by improving access to different tissue iron stores and control of the toxic labile iron pool. The combination of two chelators can reduce toxicity through averting the need for high doses of a single drug, but it is essential to establish the safety such regimens. We therefore explored the combined use of deferasirox (DSX) and deferoxamine (DFO) in patients with transfusion-dependent thalassemia who had failed standard chelation therapy with single drug. Patients were eligible if the liver iron concentration (LIC) >15 mg/g dry liver-weight or if iron-induced end organ injury was present. Subjects were monitored for hepatic and renal toxicity, visual or auditory changes, and the development of new complications from iron overload. The ability of the combined therapy to control systemic iron burden (serum ferritin and LIC) and myocardial iron overload (MRI T2*) was evaluated. We also measured changes in plasma levels of non-transferrin bound iron (NTBI) and labile plasma iron (LPI). Fifteen subjects were enrolled in 3 groups: adults with LIC <15 mg/g dry liver-weight (group A), adults with LIC >15 mg/g (group B), and children 8–18 years with LIC >5 mg/g (group C). The duration of therapy was 52 weeks. DSX (20-30 mg/Kg) was administered daily and DFO (35-50 mg/Kg/infusion) was infused on 3–7 days/week (as 8–12 hour infusion) based upon the degree of iron overload present at baseline. At the initiation of the study, the mean daily dose of DFO was 16, 33, and 17 mg/Kg/day and mean DSX dose was 21, 25 and 22 mg/Kg/day for groups A, B and C, respectively. At the conclusion of the trial, the median LIC declined by 48% from 10.8 mg/g (3.9-34.8 mg/g) to 5.7 mg/g (1.0-24.0 mg/g, p=0.003). The median ferritin fell by 43% from 2030 ng/mL (1000-5230 ng/mL) to 1150 ng/mL (421-5260 ng/mL, p=0.008). Myocardial iron in the 3 subjects who had T2* <20 msec at study entry (range 6.5–19.5 msec at week 0) showed an average improvement of +2.43 msec following treatment (range 8.8–21.3 msec at week 52, p=0.027). All 3 subjects with left ventricular ejection fraction below 60% at baseline (47.5-58.1%) showed improvement at end of study (60.6-64.4%). There was progressive decline in median plasma NTBI level during the study from 3.26 μM (1.79-5.79 μM) at baseline to 2.38 μM (1.59-3.08 μM) at 12 months (p=0.008). DSX produced immediate and significant decline in plasma NTBI when administered during infusion of DFO. The median plasma NTBI measured on DFO alone was 2.46 μM (0.92-5.90 μM), which decreased to 1.96 μM (0-3.50 μM) following administration of the dose of DSX (p<0.001). A sustained control of the LPI fraction was also demonstrated throughout the study period. At baseline the median LPI was 0.87 μM (0-2.43 μM) which decreased to 0.05 μM (0-1.20 μM) during the study period (p=0.004). No significant toxicity or unusual adverse events were observed with combined chelation therapy in this group of high-risk patients with thalassemia. Elevation of serum creatinine or ALT was not observed in any subject. One subject from group B died at 9 weeks from start of trial from sepsis. One subject interrupted DSX therapy because of abdominal pain. In all other cases the treatment was well tolerated and no dose adjustment or suspension of therapy was required on account of toxicity. Protocol-mandated modification of treatment (temporary cessation of DSX or DFO) occurred in three subjects owing to a marked fall in serum ferritin and LIC. These results suggest that simultaneous administration DSX and DFO is well tolerated and has low potential for toxicity. Combined chelation therapy appears to be effective in rapidly reducing systemic iron burden, lowering myocardial iron, and controlling plasma NTBI and LPI in patients at risk of developing end-organ damage. Disclosures: Harmatz: Ferrokin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vichinsky:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Comorbidities and Complications in Adults with Pyruvate Kinase Deficiency

Blood ◽

10.1182/blood-2019-123069 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2175-2175

Author(s):

Audra N. Boscoe ◽

Yan Yan ◽

Elizabeth Hedgeman ◽

Eduard J. van Beers ◽

Hanny Al-Samkari ◽

...

Keyword(s):

Clinical Trial ◽

General Population ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees ◽

Age And Gender ◽

Look Back ◽

And Gender ◽

Transfusion History

Introduction: Pyruvate kinase (PK) deficiency causes a defect in the glycolytic pathway, leading to a hereditary hemolytic anemia. Management is supportive and consists of splenectomy, transfusions, and chelation therapy. Aim: To better understand the comorbidity and complication profile of adults with PK deficiency, and the extent to which transfusion frequency contributes, the objectives of this study were to (1) quantify the prevalence of comorbidities and complications according to transfusion history and (2) compare the types and rates of select comorbidities and complications with the general population. Methods: Data were obtained from the enrollment survey of the PK Deficiency Natural History Study (NHS), a longitudinal, retrospective and prospective cohort study in which clinical, laboratory, transfusion, and radiologic data were collected; all participants were confirmed to have 2 mutations in the PKLR gene. Patients (n=122) were eligible for this analysis if they were ≥18 years of age and had sufficient data on transfusion history to enable classification into 1 of 3 cohorts: "Ever Regularly Transfused" (ERT, defined as ≥6 transfusions in any 12-month period), "Never Regularly Transfused" (NRT, defined as having ≥1 lifetime transfusion but never having >4 transfusions in any 12-month period), or "Never Transfused" (NT). To contextualize the findings, the frequencies of select conditions were compared with an age- and gender-matched cohort of individuals from the insured, general US population who did not have any hemolytic anemia diagnoses and had ≥5 years of continuous enrollment in the Truven MarketScan administrative claims database. The NHS reported lifetime prevalence rates, whereas rates obtained from the MarketScan data were based on diagnosis and procedure codes over varying look-back periods; therefore, to minimize bias, we limited PK deficiency vs. general population comparisons to (1) chronic conditions that require lifetime management and would thus still be recorded in claims data years after initial diagnosis, and/or (2) conditions for which a diagnosis/procedure date was available in the NHS and could be matched in time to the average 8-year look-back period for the general population. Frequencies were compared across mutually exclusive cohorts using Fisher's exact 2-tailed tests of significance. Results: ERT (n=65), NRT (n=30), and NT patients (n=27) had a mean age of 34.2, 39.5, and 37.2 years at enrollment, respectively (not significant [ns]), with 46.2%, 56.7%, and 59.3%, respectively, being male (ns). ERT patients trended toward being more likely than NT patients to be Amish and have the homozygous R479H splice variant (30.8% vs 11.1% [p=0.064]) but were significantly less likely to have a missense/missense PKLR genotype (32.3% vs 70.4% [p=0.001]). Compared with the general population, patients with PK deficiency had significantly higher rates of splenectomy, cholecystectomy, osteoporosis, liver cirrhosis, pulmonary hypertension, and current prophylactic antibiotic and anticoagulant use (Table). Rates of splenectomy, cholecystectomy, and osteoporosis were significantly higher in patients with PK deficiency, regardless of transfusion cohort, and both ERT and NRT patients had significantly higher rates of liver cirrhosis than individuals from the general population. A gradient was seen across transfusion cohorts for other conditions. Notably, 83.1% of ERT patients, 50.0% of NRT patients, and 25.9% of NT patients had a history of liver iron overload. ERT patients were also significantly more likely than NRT and NT patients to have had a splenectomy, cholecystectomy, and/or thrombosis, and to currently use prophylactic antibiotics. Findings were consistent when the analysis was restricted to non-Amish patients with PK deficiency. Conclusions: Patients with PK deficiency have higher rates of select comorbidities and complications than age- and gender-matched individuals who do not have PK deficiency. Even patients with PK deficiency who have never been transfused are at increased risk of complications of the disease and its treatment. Disclosures Boscoe: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Agios Pharmaceuticals, Inc.: Consultancy. Hedgeman:IBM Watson Health: Employment. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Al-Samkari:Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Moderna: Consultancy. Barcellini:Incyte: Consultancy; Alexion: Consultancy, Speakers Bureau; Agios Pharmaceuticals, Inc.: Consultancy; Novartis: Speakers Bureau; Apellis: Consultancy; bioverativ: Consultancy. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Rothman:Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Kwiatkowski:Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Terumo: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored). Holzhauer:Agios Pharmaceuticals, Inc.: Consultancy. Verhovsek:Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy; CRSPR/Vertex: Other: Clinical Trial Steering committee. Despotovic:Novartis: Research Funding; Dova: Honoraria. Grace:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

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Left Ventricular Volumes, Mass and Function normalized to the body surface area, age and gender from CMR in a large cohort of well-treated Thalassemia Major patients without myocardial iron overload

Journal of Cardiovascular Magnetic Resonance ◽

10.1186/1532-429x-13-s1-p305 ◽

2011 ◽

Vol 13 (S1) ◽

Cited By ~ 7

Author(s):

Antonella Meloni ◽

Maria Chiara Dell'Amico ◽

Brunella Favilli ◽

Giovanni D Aquaro ◽

Pierluigi Festa ◽

...

Keyword(s):

Iron Overload ◽

Body Surface ◽

Thalassemia Major ◽

Left Ventricular ◽

The Body ◽

Left Ventricular Volumes ◽

Myocardial Iron ◽

Age And Gender ◽

And Gender ◽

And Function

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Risk Factors for Early Sudden Cardiac Death in Patients with Systemic Light-Chain Amyloidosis on Treatment

Blood ◽

10.1182/blood-2021-150760 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3756-3756

Author(s):

Cherng-Horng Wu ◽

Philip Tracy ◽

Denis Toskic ◽

Raymond Comenzo

Keyword(s):

Clin Oncol ◽

Board Of Directors ◽

Autonomic Dysfunction ◽

Research Funding ◽

Troponin I ◽

Nyha Class ◽

Al Amyloidosis ◽

Advisory Committees ◽

Age And Gender ◽

And Gender

Abstract Introduction: Despite advances in therapy for patients with light-chain (AL) amyloidosis, mortality remains high in the first 6 months after diagnosis in those on treatment (Blood 2017;129:2111). The early deaths are usually sudden cardiac deaths (SCD); a prior study showed that troponin I level and lack of response to therapy influenced survival (Br J Haematol 2008;143:369). In January 2021 at the approval of daratumumab with cyclophosphamide, bortezomib and dexamethasone for AL (Dara/CyBorD), the FDA label warned that patients with higher cardiac staging may be at risk for fatal cardiac events. We sought to analyze risk factors for SCD in patients on treatment, defining SCD as a sudden unexpected death caused by loss of cardiovascular function (Arrhythm Electrophysiol Rev 2016;5:177). Methods: From a database of 398 patients with AL amyloidosis collected from 2005-2019, we identified patients who suffered out-patient SCD on treatment within 180 days of diagnosis. We recorded baseline age, gender, systolic BP, presence of syncope, LVEF, FLC, cardiac biomarkers, NYHA class, cycles of treatment with bortezomib, and data on SCD. For comparison we identified an age and gender matched group who achieved complete or very good partial responses (CR or VGPR) based on standard criteria and recorded that group's data (J Clin Oncol 2012;30:4541). We compared these datasets by two-tailed Mann-Whitney and where appropriate by contingency table analysis. We computed the medians of the involved FLC, BNP and troponin for all the cases to determine the frequency with which patients in either group had baseline values above or below those medians. Results: Comparative results are shown in Table 1. We identified 13 SCD and 74 age and gender matched CR/VGPR patients. Compared with the CR/VGPR group, both hypotension and exertional syncope were significantly more common in the SCD group, indicating the presence of autonomic dysfunction. NYHA class 3 or 4 status was also more common in the SCD group (40% and 13% vs 26% and 13% in the CR/VGPR group). In addition, more SCD patients were Mayo cardiac stage III (80% vs 46% in the CR/VGPR group) (Blood 2004;104:1881; J Clin Oncol 2004;22:3751). The SCD patients had significantly lower LVEF and higher iFLC and were significantly more likely to have iFLC values above the median. Similarly they had significantly higher BNP and troponin-I levels and were more likely to have values above the medians. The causes of death were unclear in 9 cases but were described by witnesses as due to syncopal events associated with micturition, climbing stairs, or light exertion. In 4 cases seen in emergency rooms, PEA was documented in 3 and septic shock in 1. The SCD patients had a median of 1 cycle of subcutaneous bortezomib-based therapy (CyBorD) (range, 1-5). Three patients received daratumumab subcutaneously with CyBorD. The median starting dose of bortezomib was 1.3mg/m2 (0.7-1.5) usually on a weekly schedule; 2 patients initiated therapy at 1.5mg/m2 weekly, one of whom had had progression of disease (POD) after 2 cycles of oral melphalan and dexamethasone and then had further progression despite completing 3 cycles of CyBorD (POD=1). Eight patients were inevaluable for hematologic response (NR=8), 2 achieved PR after 2 and 4 cycles of CyBorD (PR=2), and of the 3 who got Dara/CyBorD, 1 was inevaluable, 1 achieved VGPR after C1 and 1 CR in C2 (CR/VGPR=2), before having SCD. Conclusion: These findings indicate the contribution that the presence of autonomic dysfunction makes in this population of AL patients with advanced cardiac disease and high levels of iFLC, key variables in the revised Mayo staging system (J Clin Oncol 2012;30:989). The potential pre-morbid significance of exertional syncope has been identified previously (Am J Cardiol 1997;80:1242). In conclusion, this case series suggests that compared with AL amyloid patients who achieve CR or VGPR with treatment, patients who suffer early SCD on treatment have symptoms indicative of autonomic dysfunction and may benefit from in-patient initiation of treatment and from obtaining insurance approval for Dara/CyBorD but starting therapy with weekly subcutaneous daratumumab and dexamethasone, adding cyclophosphamide and bortezomib at a later timepoint based on hematologic response. Moreover, weekly assessment of FLC response is reasonable in these patients in order to guide therapy and adjust supportive care. Figure 1 Figure 1. Disclosures Comenzo: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Prothena Biosciences: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Multiparametric cardiac magnetic resonance assessmenti in sickle-beta-thalassemia

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeab090.037 ◽

2021 ◽

Vol 22 (Supplement_2) ◽

Author(s):

A Pepe ◽

A Meloni ◽

G Peritore ◽

M Zerbini ◽

N Vallone ◽

...

Keyword(s):

Magnetic Resonance ◽

Iron Overload ◽

Myocardial Fibrosis ◽

Sickle Cell ◽

Healthy Subjects ◽

Beta Thalassemia ◽

Myocardial Iron ◽

Private Company ◽

Funding Sources ◽

Biventricular Function

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Relative Trends in Myocardial T2* Versus Myocardial Iron Concentration As Representations of Myocardial Iron Chelation Efficacy in Patients with β Thalassemia Major Treated with Deferasirox for up to 3 Years

Blood ◽

10.1182/blood.v124.21.4040.4040 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4040-4040

Author(s):

John B Porter ◽

Ali T Taher ◽

Yesim Aydinok ◽

Amal El-Beshlawy ◽

Mohsen Elalfy ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Myocardial Iron ◽

Advisory Committees ◽

Post Hoc

Abstract Background: Heart failure due to iron-induced cardiomyopathy is rare yet remains one of the leading causes of death in patients with β thalassemia. Using myocardial T2* (mT2*) cardiovascular magnetic resonance (CMR) to estimate myocardial iron burden has improved the management of cardiac siderosis. Myocardial T2* >20 ms is considered normal and as iron accumulates, mT2* reduces, with values <10 ms associated with an increased risk of heart failure. As reported by Carpenter et al (2011), a calibration for CMR R2* against atomic emission spectroscopy-measured myocardial iron concentration (MIC), showing a curvilinear relationship between R2* and MIC, actual MIC can now also be assessed and affords an additional efficacy measure for patients undergoing iron chelation therapy. In a previous post-hoc analysis of the 3-year EPIC (Evaluation of Patients’ Iron Chelation with Exjade®) cardiac substudy, the long-term effects of deferasirox on mT2* and MIC were reported. Here, we report relative trends between mT2* and MIC as a representation of myocardial chelation efficacy by determining how far the patient has progressed from baseline toward reaching normal levels, in order to further understand the interpretation of these two parameters. Methods: Patients aged ≥10 years with mT2* >5 to <20 ms by CMR, left ventricular ejection fraction ≥56%, serum ferritin >2500 ng/mL, MR (R2) liver iron concentration >10 mg Fe/g dry weight (dw) and ≥50 lifetime transfused blood units were included in the study. Cardiac iron removal was analyzed over 3 years in patients with mT2* at baseline and each considered time point. Post-hoc calculation of MIC from mT2* values was conducted using the formula described by Carpenter et al as follows: [Fe] = 45.0 x (mT2*)−1.22 where [Fe] is measured in milligrams per gram dw and mT2* is measured in milliseconds. Data are presented descriptively as the percentage of the progression of the patients toward achieving normalization of mT2* (>20 ms) or MIC (>1.16 mg Fe/g dw as derived from the formula based on normal mT2*) by mT2* at baseline: >5 to <10 ms, 10 to <15 ms and 15 to <20 ms. Results: Data were analyzed at Month 12 (n=67: baseline mT2* >5 to <10 ms, n=24; 10 to <15 ms, n=19; 15 to <20 ms, n=24), Month 24 (n=66: baseline mT2* >5 to <10 ms, n=24; 10 to <15 ms, n=18; 15 to <20 ms, n=24) and Month 36 (n=63: baseline mT2* >5 to <10 ms, n=22; 10 to <15 ms, n=18; 15 to <20 ms, n=23). As previously reported (Pennell et al. 2012), geometric mean mT2* in the overall population significantly increased from 12.0 ms at baseline to 13.9 ms at Month 12, 15.6 ms at Month 24 and 17.1 ms at Month 36. In parallel, mean MIC significantly decreased from 2.43 mg Fe/g dw at baseline to 2.10 mg Fe/g dw at Month 12, 1.94 mg Fe/g dw at Month 24 and 1.80 mg Fe/g dw at Month 36. The median percentage progression of patients towards normalizing mT2* and MIC by baseline mT2* category are presented in the Figure. In patients with severe myocardial iron overload at baseline, the percentage toward normalization in mT2* in the first, second and third year was less than the percentage towards normalization in MIC. This difference was less pronounced, but still evident, in patients with mild-to-moderate myocardial iron overload. Figure 1 Figure 1. Discussion: The calibration of the relationship between CMR measurements and MIC by Carpenter et al allows an additional assessment to mT2* to determine chelator efficacy in terms of the actual concentration of iron in the myocardium. Here we show that, particularly in patients with severe myocardial iron overload, when analyzing the progression towards normalization, improvement in MIC is proportionally greater than that seen with mT2*. It could be interpreted that a small improvement (ie 1 ms) in mT2* when baseline values are >5 to <10 ms is not equivalent in terms of myocardial iron removal to a small improvement in patients with less severe myocardial iron overload at baseline; a consequence of the reciprocal relationship between mT2* and MIC. Therefore, analysis of mT2* only may underestimate the efficacy of iron chelation with respect to the myocardium in patients with severe myocardial iron loading (mT2* <10 ms) and thus MIC may better reflect response to chelation therapy. It would therefore be valuable if MIC were calculated and reported in parallel with mT2* when assessing and monitoring patients on iron chelation therapy across a range of baseline mT2* values. Disclosures Porter: Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy; Cerus: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Taher:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Barbier:Novartis: Employment. Cappellini:Novartis: Honoraria, Speakers Bureau; Genzyme: Honoraria.

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Development of Autoimmune Diseases in Women with HPA-1a Alloimmunization and Fetal-Neonatal Alloimmune Thrombocytopenia (FNAIT)

Blood ◽

10.1182/blood.v128.22.2556.2556 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2556-2556

Author(s):

Ramanjot S. Kang ◽

Peter J. Keefe ◽

James B. Bussel

Keyword(s):

Autoimmune Disease ◽

General Population ◽

Autoimmune Diseases ◽

Board Of Directors ◽

Research Funding ◽

Immune Response Gene ◽

Advisory Committees ◽

Age And Gender ◽

And Gender ◽

Hla Dr3

Abstract Introduction: Fetal-NeonatalAlloimmune Thrombocytopenia (FNAIT) is the result of an incompatibility between maternal and fetal human platelet alloantigens (HPA). Affecting 1 in 1000 births, it is one of the most common causes of thrombocytopenia in the neonate. Prospective studies reveal that only 5-10% of pregnancies with HPA-1a incompatibilities result in maternalalloimmunization. The association of HPA-1a incompatibility andalloimmunization is largely based on an immune response gene: the Human Leukocyte Antigen (HLA) class II DRB3*0101 haplotype. Clinical studies have shown that >90% of women that produce HPA-1a antibodies express HLA-DRB3*0101. The HLA-DRB3*0101 haplotype is found on the HLA-DR3 locus of HLA-A1-B8-DR3 - amultigene haplotype which has been implicated in the development of a number of autoimmune diseases. The presence of HLA-A1-B8-DR3 has been shown to impact susceptibility to, the age of onset, and severity of autoimmune diseases. In this study we seek to investigate whether the HPA-1aalloimmunization that results in FNAIT, which is linked to the autoimmune haplotype, is also associated with an increased incidence of maternal autoimmune diseases following pregnancy. Methods: A retrospective review was conducted to identify patients with HPA-1a cases of FNAIT associated pregnancies. Patients with serologically confirmed anti-HPA-1a FNAIT completed a general health status survey developed by our laboratory in 2013 (n = 51; mean age = 30.6 years). In addition to questions about their health, patients described the course of their pregnancy, complications, and any health problems that followed their pregnancy. A follow-up survey was conducted in 2015 (n = 49, mean age = 33.4 years) with additional questions focusing on the development of autoimmune diseases. The incidence of autoimmune disease in our sample population was compared with that in the general population controlled for age and gender (Centers for Disease Control; Table 1). Results: Analysis revealed that of the 49 patients contacted in 2015, 25 patients (51%) had a confirmed diagnosis of an autoimmune disease. Patients reported Rheumatoid Arthritis (RA) (34.6%), Systemic LupusErythematosus (SLE)(10.2%),Sjogren's Syndrome (SS) (4%), and Type 2 Diabetes Mellitus (T2DM) (2%). When compared with the general population, controlled for age and gender, there was an increased incidence of both RA and SLE in the study population. Conclusions: Our results reveal that patients with HPA-1aalloimmunization have indeed developed autoimmune diseases or symptoms that may suggest an autoimmune disease since initial contact in 2013. Specifically, of the 49 patients that were contacted in 2015 and completed the autoimmune disease questionnaire, 25 had confirmed diagnoses of an autoimmune disease. Given the role of the HLA-DR3*0101 haplotype in HLA-1aalloimmunization and that of HLA-A1-B8-DR3 in the development of autoimmune disease, this data suggests that women who do not encode for HPA-1a (i.e., those that express HPA-1b1b) and develop HPA-1aalloimmunization may be susceptible to the development of autoimmune disease(s) later in life. These findings will be compared with women who do not encode for HPA-1a (i.e., those that express HPA-1b1b) but do not make anti-HPA-1a antibodies.Future studies can be aimed at investigating not only the frequency with which autoimmune diseases occur followingalloimmunization but also if they can be prevented. Disclosures Bussel: Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; BiologicTx: Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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