New Perspectives and Challenges Regarding Fertility, Conception and Pregnancy in Hemoglobinopathies. a Multidisciplinary Report of 66 Outcomes

Introduction Major thalassemia (TM) and sickle cell disease (SCD), two common genetic hemoglobinopathies, were often fatal 50 years ago. Novel therapeutic and diagnostic methods are increasing lifespan and quality of life. Recent advances in iron chelation for transfusion-dependent hemoglobinopathies have significant improved patient prognosis. Young adult TM and SCD patients often ask about the possibility of conception and pregnancy. The increase in the worldwide movement of carriers and subjects has lead to new cultural, ethical and psychosocial aspects that must be taken into consideration. The present study investigated the fertility rate, maternity/paternity status, need for assisted reproductive techniques (ART), abortion rate, pregnancy/newborn complications in patients with hemoglobinopathies. Methods We followed 130 female (FPs) and male (MPs) patients (F:M=93:37); 75 with TM, 32 with thalassemia intermedia (TI), 13 with SCD and 10 with microdrepanocytosis (MDC). Median age is 55 yo (15-90) for TM+TI and 45 yo (18-79) for SCD+MDC. Pregnancy was reported in 37/52 FP of childbearing age (15-49 yo), and conception in 15 MP with fertility rates of 71% and 70%, respectively. Results We reviewed 66 conceptions from 1999 to 2020. Mother age at pregnancy was between 32-39 yo. Forty-seven pregnancies were spontaneous and 19 medically assisted. There were 3 ovodonations and 2 ICSI; 64% of pregnancies were planned. Pregnancy outcomes of 22 TM, 16 TI, 8 SCD and 3 MDC patients are described. There were 7 miscarriages in the first 12 weeks: 3 in TI, 1 in SCD FP; 1 in TM and 2 in SCD MP. Abortion rate was 9%, comparable to the general population. Intrauterine death at 24w occurred in a SCD FP for placental thrombosis and eclampsia. Sixty live healthy newborns were delivered;4 twin pregnancies occurred (1 TM MP, 3 TM FP). Only 1 malformation was observed, in an infant born after ovodonation in a TM FP who had minor gastroenteric and urinary malformations that were surgically corrected. Obstetric complications were eclampsia, disseminated intravascular coagulation, cardiac failure, and acute chest syndrome in SCD patients. One ovarian hyperstimulation syndrome in the 1st month of pregnancy with ascites and admission to the ER was reported. There were 30 (94%) caesarians (CD) and 3 vaginal deliveries (VG) in FP, with 7 preterm babies (22%). In partners of MPs there were 15 CD (56%), and 11 VG with 5 preterm babies (Table I). Births from MPs occurred between 34-40w with a median birth weight of 3 kg (2.17-4) and 30-41w in FPs with a median birth weight of 2,5 kg (1,1-3,4) . FPs were able to breast fed in 56% of cases for a medium time of 66 days (20-120), while female partners of MPs breastfed for 193 days (20-540). Newborn events includes 14 jaundices; 9 babies were placed in intensive care and required incubator use due to cerebral hemorrhage or infections requiring antibiotic therapy. Discussion Spontaneous pregnancies occur in well chelated and transfused patients but a relevant part of those patients are infertile due to hypogonadism due to transfusional hemosiderosis and may need ART. These patients present a base-line pro-coagulant state which can worsen during pregnancy, needing antithrombotic prophylaxis and require regular consultations, since pregnancies are considered high risk for both mother and baby. As osteopenia-osteoporosis are the common endocrine complications in hemoglobinopathies (67% of FPs), both cesarean delivery and breast feeding are strongly suggested. Even though chelating therapy during lactation does not alter iron excretion, our patients didn't receive chelating therapy when breastfeeding. Multidisciplinary programs including transfusions, cardiac and clinical evaluations should be monthly performed. Our Institution has a team of hematologists and other dedicated specialists that work together during the planning, conception, pregnancy, delivery and immediate post-delivery processes to assure best care to mother and child. Conclusions Survival of hemoglobinopathic patients in developed countries is improving and patients aspire to reproductive aims of their healthy peers. TM and SCD patients often request fertility and pregnancy information, including screening of partners. We provide insights regarding reproductive health experience of hemoglobinopathies in both genders. Detailed results, mothers and child follow up and practical management will be presented. Figure Disclosures Abruzzese: Incyte: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;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Bms:Honoraria.

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Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽

10.1182/blood-2020-140743 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Rita V Masese ◽

Dominique Bulgin ◽

Liliana Preiss ◽

Mitchell Knisely ◽

Eleanor Stevenson ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Transfusion Requirement ◽

The United States ◽

Acute Chest Syndrome ◽

Maternal Outcomes ◽

Maternal Complications ◽

Advisory Committees ◽

Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

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Positive Maternal-Fetal Outcomes with Treatment of Lymphoma During Pregnancy: UT MD Anderson Cancer Center Prospective Experience

Blood ◽

10.1182/blood.v120.21.3670.3670 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3670-3670 ◽

Cited By ~ 1

Author(s):

Michelle A. Fanale ◽

Chao-Ming Lai ◽

Sue A Rimes ◽

Mildred M Ramirez ◽

Fredrick B Hagemeister ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Fetal Loss ◽

Outcome Data ◽

Advisory Committees ◽

Maternal Fetal Medicine ◽

Elective Abortion ◽

Relapsed Disease ◽

Median Birth Weight

Abstract Abstract 3670 Background: Diagnosis of cancer during pregnancy is emotionally stressful for the patient and her family and presents challenges for the medical team including how to best minimize risk of adverse fetal events while still ensuring the best disease outcome for the woman. Cancer is diagnosed during 0.1% of pregnancies with lymphoma being the 4th most common cancer effecting 1 in 6000 pregnancies (Brenner, B et al, The Lancet, 2012 & Pereg, D et al, Haematologica, 2007). This prevalence is anticipated to grow given the shift towards increasing average age at time of pregnancy. The overall rarity of this presentation and the variance of the histological diagnoses have prevented the conduction of large prospective clinical trials, and thus no stringent management algorithms exist. Methods: From 2005 women with a diagnosis of lymphoma during pregnancy were consented and enrolled into this IRB-approved prospective database trial. Patients received multidisciplinary care including counseling and co-management with our maternal-fetal medicine and reproductive medicine collaborators. Results: A total of 19 patients (pts) were consented with full treatment (tx) and fetal outcome data available for 16. The median age of the women was 30 (20–38) years with a slightly lower median age for the classical Hodgkin lymphoma (HL) pts of 28.5 (20–35) years. Ten pts had HL (6 early stage [ES], 2 advanced stage [AS], 2 relapsed), while the remaining 9 had NHL (3 [2 ES, 1 AS] diffuse large B-cell lymphoma [DLBCL], 1 ES anaplastic lymphoma kinase [ALK]-positive LBCL, 1 primary CNS DLBCL, 1 AS follicular lymphoma [FL] with transformation to DLBCL, 1 ES FL, 1 AS MALT, and 1 ALK+ anaplastic LCL). Fifteen pts had diagnoses made of initial or relapsed disease during pregnancy at a median of 18 (3–34) weeks (wks) gestation with 33% during 1st trimester, 54% during 2nd trimester, and 13% during 3rd trimester. Four pts with chronic oligomenorrhea with baseline negative serum pregnancy tests became pregnant while on tx (ABVD, rituximab plus gemcitabine, R-CHOP, and maintenance rituximab) with fetal loss in all 4 with spontaneous abortions from wk 8 to 26 and an elective abortion at wk 6. Four pts of the 15 pts deferred start of tx until after delivery (ES HL and ES primary mediastinal DLBCL pts, a relapsed HL pt, and a ES FL grade 3B pt diagnosed respectively at wks gestation of 31, 34, 14, and 27) and the 3 pts for whom outcome data is available have durable complete remissions (CRs) at a median of 25 (5–52) months (mos) of follow-up with babies born at a median of 35 (31–37) wks at a median birth weight of 2381 (1814–3004) grams with 75% being above the 50% weight percentile. Ten pts started tx while pregnant (80% during 2nd/3rd trimester) at a median of 18 (11–29) wks (ABVD/AVD in 5, R-CHOP/AVD in 1, R-CHOP in 2, HCVAD in 1, and DeAngelis regimen in 1) with all but 1 pt having MRIs and ultrasounds for staging. Seven of these pts delivered babies at a median of 37 (33–39) weeks with 57% delivered at term, a median birth weight of 2948 (2494–3061) grams with 50% being above the 50% weight percentile, and no fetal malformations. At a median of 20.5 (8–53) mos of follow-up 60% of the pts who received tx while pregnant are free of progression while 2 HL pts (1 ES HL pt 22 months after delivery) died from disease progression and 2 pts are on active treatment for relapsed disease (HL and ALK+ LBCL). Three pts experienced fetal loss including a AS HL pt with SVC syndrome necessitating intubation with prolonged ICU care (spontaneous abortion at 23 wks), a AS HL pt who started ABVD at 14 wks of gestation (stillbirth of twins at 26 wks), and the pt with CNS DLBCL who initiated the DeAngelis regimen with high dose methotrexate at 13 wks (elective abortion at 19 wks). Conclusions: Given the rarity of the diagnosis of lymphoma during pregnancy our series to our knowledge represents one of the largest single center prospective clinical studies. Our data highlight that ABVD, R-CHOP, and HCVAD can be given with excellent outcomes for pt and fetus at a preferred start of 2nd trimester or later, although 1 pt with symptomatic HL did start ABVD early at 11 wks of gestation with preservation of positive outcomes. These findings also emphasize the importance of co-management through all the steps of treatment with a maternal-fetal medicine colleague. Furthermore, we show the need to counsel oligomenorrheic pts on the risk of still becoming pregnant and perform assessments to rule-out pregnancy beyond the baseline pre-tx visit. Disclosures: Fanale: Millennium: Research Funding; MedImmune: Research Funding; Novartis: Honoraria, Research Funding, Travel Expenses, Travel Expenses Other; Genentech: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Expenses, Travel Expenses Other; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Expenses Other; Onyx: Research Funding; Allos: Membership on an entity's Board of Directors or advisory committees. Lai:Celgene: Membership on an entity's Board of Directors or advisory committees. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Affimed: Research Funding; Gilead: Research Funding; Johnson & Johnson: Research Funding.

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Adolescents and Young Adults with Immune Thrombocytopenia (ITP): A Project of the Carmen-France and Parc-ITP Registry

Blood ◽

10.1182/blood-2021-148488 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2079-2079

Author(s):

Alexandra Schifferli ◽

Guillaume Moulis ◽

Bertrand Godeau ◽

Thierry Leblanc ◽

Marc Michel ◽

...

Keyword(s):

Young Adults ◽

Platelet Count ◽

Chronic Disease ◽

Board Of Directors ◽

Clinical Data ◽

Research Funding ◽

Diagnostic Methods ◽

Adolescents And Young Adults ◽

Advisory Committees ◽

Platelet Counts

Abstract Introduction The prognosis of ITP is age-related. In 80% of cases, children have a self-limiting course, whereas adults recover less frequently or relapse and overall ITP has a chronic course in ~70% of the cases. The risk of chronicity increases above the age of 10 years in pediatric cohorts, but data describing adolescents and young adults (AYAS) are lacking. Based on the assumption that adults are at greater risk of bleeding, treatment protocols and practice guidelines usually advise medical intervention. This is surely the right strategy for elderly patients or those with co-morbidities with indisputable higher bleeding risks. We assume that defining ITP in only two age categories might be an inaccurate oversimplification. AYAS have other needs, such as body appearance, mental health, social and financial issues. In addition, limitation of activity, side effects of steroids and risk of chronic disease are major reasons to adapt medical care. Even if AYAS have a similar risk of chronicity like adults, they may have greater potential to restore immune tolerance -in analogy to children- but with the help of an appropriate immunomodulatory therapy. The analysis of clinical data is the first step to design new strategies. Methods Data were extracted from the PARC-ITP and the CARMEN-France registry, open since 2004 and 2013, respectively. PARC is an international multi-center registry collecting data prospectively of children and adults with newly diagnosed ITP. The CARMEN-France registry enrolls all incident ITP in adults 18 years from the French Midi-Pyrénées region, and since 2016 increasingly in other French centers. Demographics, diagnostic methods, clinical data, management are continuously documented in CARMEN and at defined timepoints in PARC (initial, at 6,12 months follow-up (FU), and then yearly). Patients 12-25 years old with initial platelet counts <100x10 9/l were included. Patients with secondary or misdiagnosed ITP (n=57), and pregnant women were excluded (n=10). Sustained remission was defined as a platelet count 100x10 9/l at 12 months (measured at 11-18 months) and without treatment for at least 6 months. For patients with borderline values (100-149 x10 9/l), later FUs were analyzed to determine the persistency of remission, and, if necessary, reassign patient's remission state. Only bleeding location, but not grade was analyzed in common. Data were analyzed with descriptive statistics. Results A total of 656 AYAS (61% female) with the initial diagnosis of primary ITP were recorded in the combined database until 2021. FU information was available for 547 (83%) and 470 (72%) patients at 6 and 12 months, respectively. Initial median platelet count was 12 x10 9/l (IQR 5). In 109 patients the diagnosis was incidental (17%), 538 patients suffered of bleeding symptoms (82%) (Table 1). At 6 months 49% of patients had platelets <100 x10 9/l. At 12 months 50% fulfilled the criteria of chronic disease, with a median platelet count of 57x10 9/l (IQR 32). Asymptomatic chronic ITP was reported in 40% (no bleeding between 6-12 months). Platelet-enhancing drugs were reported in 66%, 45% and 30% at diagnosis, until 6 months and between 6-12 months, resp. Corticosteroids were preferred at all time-points, second-line treatments were various and given to 29% of patients with treatment beside 6 months (Table1). There were no differences in initial diagnostic procedures, comorbidity, bleeding symptoms, median platelet counts, percentage of severe thrombocytopenia (<20 x10 9/l) and need of treatment and drug choice between women and men (besides gynecological bleeding). There were small differences in the subgroup of adolescents (12-18 years, 59% female) compared to young adults (18-25 years, 70% female), the later had more moderate thrombocytopenia at diagnosis, less bleeding at all FUs, but similar or even more treatments (Table 2). Conclusion This is the first prospective project describing AYAS with a diagnosis of primary ITP. Analysis exhibited a clinical pattern among children and adults, with a risk of chronicity of 50%, and prolonged need of treatment (6-12 months) in 30% of cases. At diagnosis 17% had no bleeding signs, compared to 9% of children and 31% of adults in previous analysis of the PARC. There were no gender differences. Surprisingly, young adults experienced a greater number of non-bleeding phenotype than adolescents at all FUs, with comparable need of treatment between 6-12 months FU. Figure 1 Figure 1. Disclosures Schifferli: Novartis: Honoraria, Research Funding; Sobi: Honoraria. Moulis: Argenx: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Godeau: Novartis: Consultancy; Grifols: Consultancy; Sobi: Consultancy; Amgen: Consultancy. Michel: Rigel: Honoraria; Argenx: Honoraria; UCB: Honoraria; Alexion: Honoraria; Amgen: Consultancy; Novartis: Consultancy. Grainger: Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Kuehne: Amgen: Research Funding; SOBI: Honoraria; UCB: Honoraria; Novartis: Research Funding.

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Benefits of a Disease Management Program for SCD in Germany 2011 - 2019: The Increased Use of Hydroxyurea Correlates with a Reduced Frequency of Acute Chest Syndrome

Blood ◽

10.1182/blood-2021-148550 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 973-973

Author(s):

Joachim B. Kunz ◽

Andreas Schlotmann ◽

Andrea Daubenbüchel ◽

Stephan Lobitz ◽

Andrea Jarisch ◽

...

Keyword(s):

Disease Management ◽

Board Of Directors ◽

Disease Management Program ◽

Treatment Guidelines ◽

Management Program ◽

Acute Chest Syndrome ◽

Insurance Company ◽

Advisory Committees ◽

Defined Daily Doses ◽

Number Of Patients

Abstract Background Worldwide, Sickle Cell Disease (SCD) is the most common single gene disorder affecting >250,000 newborns annually. In Germany, SCD qualifies as a rare disease and almost exclusively affects immigrants from endemic countries and their descendants. The recent surge of immigration from high-prevalence countries increased the numbers of patients with SCD in Germany and raised awareness for the need of specialized care. In 2012, the German Society for Pediatric Oncology and Hematology (GPOH) mandated a consortium of five university hospitals to develop a disease management program for patients with SCD. This consortium issued treatment guidelines for SCD that strongly favor the use of hydroxyurea, initiated patient and physician education events, prepared for a universal newborn screening program that will start 09/2021, moderated a consensus on the indication of allogeneic stem cell transplantation for patients with SCD, and established a national patient registry. Methods In order to quantify the effect of these activities, we made use of claims data that were collected by the research institute (WIdO) of the major German insurance company, the Allgemeine Ortskrankenkasse (AOK), and of publicly accessible data collected by the Federal Statistical Office (Statistisches Bundesamt, Destatis). ICD10 codes were used to identify patients with SCD and their comorbidities. Pharmacologic treatments were quantified using the German Anatomical Therapeutic Chemical (ATC)-Classification with defined daily doses. Results We estimate that the number of patients with SCD in Germany increased from approximately 2,200 in 2011 to approximately 3,200 in 2019. Analyses of administered treatments illustrate that important components of recently issued national treatment guidelines have been largely implemented. Specifically, the use of hydroxyurea has more than doubled, resulting in a proportion of approximately 45% of all patients with SCD being treated with hydroxyurea in 2019 (Figure 1A). In strong negative correlation with the use of hydroxyurea, the frequency of acute chest syndromes decreased (Figure 1B). While before the widespread use of hydroxyurea (2011-2013) 8.1% of patients with SCD were admitted at least once per year for ACS, this proportion dropped to 6.6% in the period 2017 to 2019. Similarly, the proportion of patients who required analgesics, red blood cell transfusions and hospitals admissions declined from 2011 to 2019, indicating a reduced burden of SCD with the increased use of hydroxyurea. Conclusion In sum, these data demonstrate an association between the dissemination of nationwide treatment guidelines and changes in clinical practice in particular relating to the use of hydroxyurea. These changes translate into a remarkable improvement of key measures of disease activity in a representative population based analysis. Figure 1 Figure 1. Disclosures Lobitz: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kulozik: BioMedX: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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A Pilot Study of Eptifibatide for Treatment of Acute Pain Episodes in Sickle Cell Disease.

Blood ◽

10.1182/blood.v120.21.2102.2102 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2102-2102

Author(s):

Payal C Desai ◽

Julia Brittain ◽

Susan Jones ◽

Adam McDonald ◽

Douglas R Wilson ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Acute Pain ◽

Research Funding ◽

Point Estimate ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Opioid Use ◽

Advisory Committees

Abstract Abstract 2102 Background: Despite the abundant laboratory evidence of platelet activation and inflammation in sickle cell disease (SCD), the contribution of these changes to the pathogenesis of SCD remains uncertain. Patients with SCD exhibit increased platelet activation in the non-crisis, “steady state,” and further increases with acute pain episodes. In addition, levels of the inflammatory mediator, CD40 ligand (CD40L) are increased in the plasma and significantly reduced in the platelets of SCD patients compared to healthy individuals. CD40L may contribute to the pathogenesis of acute pain episodes. Despite an improved understanding of the pathophysiology of SCD, the treatment of acute pain episodes is supportive. We performed a randomized, placebo-controlled study to evaluate the safety and efficacy of eptifibatide, a synthetic peptide inhibitor of the glycoprotein (GP) IIb/IIIa receptor, in patients with SCD during acute painful episodes. Methods: In this single site placebo-controlled trial, eligible patients admitted for acute painful episodes received eptifibatide (two 180 mg/kg boluses 10 minutes apart, followed by a continuous infusion at 2 mg/kg/min for 6 hours) or placebo at a ratio of 2:1. The Post-Treatment Phase lasted for up to 7 days or until resolution of the crisis, whichever was shorter, but no less than 24 hours after discontinuation of infusion. The Follow-up Phase included safety evaluations obtained 14 to 17 days and 28 to 35 days after discontinuation of infusion. The primary outcomes were major bleeding episodes and the largest observed decrease in platelet count during the study. We also evaluated the effect of eptifibatide on the duration of acute pain episodes, pain intensity, duration of hospitalization, total opioid use and acute chest syndrome. Results: Thirteen patients (SS - 10, Sb0 - 2, SC - 1) were randomized to receive either eptifibatide (N=9; 6 females; median age - 25 years) or placebo (N=4; 3 females; median age - 31 years). One patient in the eptifibatide arm withdrew consent following completion of study drug infusion and 1 patient in the placebo arm was withdrawn early because she did not meet eligibility criteria. In the intent-to-treat analysis, there were no major bleeding episodes in either group (point estimate of difference in eptifibatide vs. placebo proportion: 0.0, 95% CI; −0.60, 0.37).There was one minor bleeding episode in a patient on the eptifibatide arm (point estimate of difference in eptifibatide vs. placebo proportion: 0.11, 95% CI: −0.502, 0.494). There was a trend for the largest decrease in platelet count to be greater in the eptifibatide arm compared to the placebo arm, although the difference was not statistically significant (Hodges-Lehman estimate of location shift for eptifibatide vs. placebo: −82, 95% CI; −281, 54). There was no significant difference in the proportion of patients with thrombocytopenia between the treatment groups (point estimate of difference in eptifibatide vs. placebo proportion: 0.11, 95% CI: −0.587, 0.495). The median time to discharge and the median time to crisis resolution were 3.0 days for both treatment arms. The median total opioid use was 400.2 morphine equivalents (ME) for the eptifibatide group and 1471 ME for the placebo group (Hodges-Lehman estimate of location shift for eptifibatide vs. placebo: −65.8, 95% CI: −2519, 1700). There was one episode of acute chest syndrome in each treatment arm. Conclusions: In this small study of SCD patients hospitalized with acute painful episodes, eptifibatide appeared to be safe, but did not improve the times to crisis resolution or hospital discharge. Eptifibatide was associated with a reduced requirement for opioid analgesics, although the difference was not statistically significant. Clinicaltrials.gov Identifier: NCT00834899. Disclosures: Parise: BD: Consultancy; Biogen-Idec: Consultancy; NIH: Research Funding; AHA: Research Funding; SCDAC-NIH: Membership on an entity's Board of Directors or advisory committees; BRI Milwaukee: Membership on an entity's Board of Directors or advisory committees. Ataga:Pfizer: Consultancy; HemaQuest Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adventrx Pharmaceuticals: Consultancy. Off Label Use: Eptifibatide, a glycoprotein IIb/IIIa inhibitor, was evaluated as treatment for acute pain episodes in patients with sickle cell disease.

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Characterizing the Process of Urgent Referrals and Transfers to a Large Tertiary Care Apheresis Centre in Ontario

Blood ◽

10.1182/blood-2020-136784 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 28-28

Author(s):

Kristine Matusiak ◽

Kevin H.M. Kuo ◽

Andrew Binding ◽

David Barth ◽

Christopher J. Patriquin

Keyword(s):

Linear Regression ◽

Board Of Directors ◽

Personal Health Information ◽

Categorical Variables ◽

Patient Acceptance ◽

Acute Chest Syndrome ◽

Process Data ◽

Advisory Committees ◽

Term Care ◽

Male Sex

Background: Therapeutic plasma exchange (TPE) and red blood cell exchange (RBCX) are potentially life-saving treatments. Given the specialized nature of care, apheresis is only offered in 7 centres in Ontario (population: 14.5 million), and therefore effectively functions as a provincial service. Patients can be referred to any apheresis centre, regardless of home local health integration network (LHIN). Referrals are directed by CritiCall Ontario (CritiCall), a 24/7 consultation and referral service funded by the Ontario Ministry of Health and Long-Term Care (MOHLTC). CritiCall facilitates the MOHLTC Life or Limb Policy, which provides that patients with life or limb threatening conditions will receive timely consultation, and if necessary, transfer to an appropriate centre within a best effort window of 4 hours. We used CritiCall data to examine referral, acceptance, and transfer processes of urgent TPE and RBCX apheresis calls to our centre. Methods: Time and process data for all CritiCall transfers to our centre for TPE and RBCX between October 2013 and December 2018 were included. TPE cases were analyzed if transferred for codes related to thrombotic thrombocytopenic purpura (TTP) or other thrombotic microangiopathies, and RBCX cases were analyzed only for acute sickle cell indications (e.g. stroke, acute chest syndrome). As such, we assumed all transfers to be "life or limb." Continuous variables were analyzed by linear regression. Categorical variables were analyzed using nonparametric tests. Data were provided in accordance with the Personal Health Information Protection Act, 2004 (www.criticall.org/Article/Privacy). Results: A total of 69 cases (43 TPE, 26 RBCX) were included. Median patient age was 51 (IQR 37) years for TPE and 29 (IQR 16) for RBCX. Most patients (61%) were female. Total time from referral to patient arrival at our centre was 243 (IQR 168) minutes. The greatest proportion of this total was from patient acceptance to arrival (169 [IQR 108] minutes), whereas time from referral to contact with the physician, and time from contact to patient acceptance were 23 (IQR 53) and 12 (IQR 41) minutes, respectively. The life or limb benchmark was met in 74% of cases, assessing time between acceptance and arrival. Fifty-two percent of the patients were accepted by the first apheresis physician contacted, with an average of 3 physicians contacted before a patient was accepted. Distance between referring and accepting centres was 39 (IQR 39) kilometres, and ground transportation was used most often. A minority of cases (7%) transferred were within our own LHIN. Multiple linear regression examining factors that contribute to total time from referral to arrival demonstrated that distance was independently associated with total time (p<0.001). Transfers took an additional 6.7 minutes for every 10 km between the referring and accepting centres. Male sex was also independently associated with total time (p=0.041), with 55 additional minutes required per transfer of male patients compared to female. Transfer time was not significantly associated with age, procedure (TPE vs. RBCX), mode of transport, number of centres contacted, or within-LHIN referral. Conclusions: We have described the processes of urgent apheresis referrals to our centre. The 4 hour "life or limb" benchmark was met in just under 75% of transfers, with the greatest delay occurring between patient acceptance and arrival. This is important given that time to initiate treatment is associated with better outcomes. Distance between centres is an important factor and potential target for improvement. Our analysis shows that >90% of cases were from outside our LHIN, reflecting a truly provincial catchment. Quality improvement strategies should be aimed at pairing referrals with nearest apheresis centres, and creating efficiency in the interval between patient acceptance and arrival. It is unclear from these data why male sex is associated with longer transfer times, but it is a target for further analysis. There are limitations of this analysis: data were not available for cases that were not ultimately transferred, nor for transfers to other centres. Future work will include examining patterns of province-wide transfers, as well as including blood bank data to further characterize steps involved in initiating aphaeresis. Acknowledgements: We thank M. Shaikh, J. Dempsey, M. Gavel at CritiCall for their contributions. Disclosures Kuo: Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Apellis: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Bluebird Bio: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Preliminary Results of a Phase II Study to Determine the Safety of Defibrotide in Children and Adolescents with Sickle Cell Disease-Associated Acute Chest Syndrome (IND 127812)

Blood ◽

10.1182/blood-2020-139617 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Jordan Milner ◽

Deborah Friedman ◽

Marise D'Souza ◽

Krishnan Sankaran ◽

Liana Klejmont ◽

...

Keyword(s):

Chest Pain ◽

Pulmonary Function ◽

Board Of Directors ◽

Research Funding ◽

Pulmonary Infiltrate ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Advisory Committees ◽

The Us

Background: Sickle cell disease (SCD) is a vasculopathy resulting in recurrent vaso-occlusive crises leading to endothelial dysfunction, chronic end-organ damage, poor quality of life, early mortality and the major curative therapy to date is allogeneic stem cell transplantation (AlloSCT) (Talano/Cairo, EJH, 2015). Acute chest syndrome (ACS) can result in pulmonary hypertension and is the leading cause of morbidity and mortality in patients with SCD (Gladwin et al, NEJM, 2008). ACS accounts for 25% of deaths (Vichinsky et al, Blood, 1997). Clinical definition of ACS is chest pain, fever, cough, dyspnea, and new pulmonary infiltrate on chest radiography. Defibrotide was approved in the US for the treatment of severe sinusoidal obstructive syndrome (SOS) with renal or pulmonary dysfunction following HSCT (Cairo et al, BJH, 2020). Defibrotide primarily targets endothelium in microvascular beds and has anti-inflammatory and anti-coagulant activity, which can treat the underlying pathophysiology of ACS (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996 and Pescador et al, Vasc Pharm, 2013). Objective: To determine the safety and toxicity of defibrotide in children, adolescents, and young adults with SCD-associated ACS. Design/Methods: Patients with SCD aged 2 to 40 years meeting ACS criteria (at least two of the following: fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on chest imaging, decreased oxygen saturation with or without supplemental oxygen requirements) and eligibility were enrolled within 72 hours of diagnosis after consent was obtained (NCT03805581). Baseline studies comprised of chest radiograph, CT chest angiogram, echocardiography with TRJ velocity and brachial artery reactivity, pulmonary function tests, and biomarkers (IFN-a and -g, TNF-a, IL-6, 8, and 10, sCD163, TSP-1, secretory phospholipase A(2), sVCAM-1, sTNFR1, Ang2, sTei-2, PAI-1, sICAM-1, sP-and sE-selectin, sPECAM-1, VEGF-A, C, D and sVEGFR1 and 2). Defibrotide was administered at 6.25mg/kg IV q6 hours and continued for 7 days or until time of discharge, whichever occurred earlier and patients were followed until day +30 following defibrotide. Dose limiting toxicities include Grade III/IV infusion/allergic reaction or hemorrhage probably or directly related to defibrotide. Results: We have enrolled thirteen patients aged 3 to 18 years with a gender ratio (M/F) of 4/9. Patients' genotypes are as follows: hemoglobin SS disease in nine patients, hemoglobin SC disease in two patients, and hemoglobin Sb0/+ thalassemia in two patients. Presenting symptoms included fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on imaging, and hypoxia.Eight patients completed seven days of treatment, one patient received 6 days of treatment, three patients were discharged after three days of treatment, and one patient withdrew due to recurrent fevers unrelated to defibrotide. All but one patient had resolution of fevers prior to end of treatment. Patients required an average of 1.15 days of oxygen support, with one patient requiring high flow nasal cannula, and no patients required mechanical ventilation. There were no adverse events possibly, probably, or directly related to defibrotide. There was no evidence of hemorrhage in any patient despite four patients receiving concomitant ketorolac or ibuprofen. Of the eleven patients who had pulmonary infiltrates on imaging, eight were evaluated on day +30, two had complete resolution of infiltrate, five had improvements, and one had no change. Seven patients did not follow-up for echocardiography or pulmonary function testing and two of those patients were unable to be evaluated at day +30 due to COVID-19. Discussion: The preliminary data suggest defibrotide is safe and well tolerated in patients with SCD-related ACS. All patients at diagnosis have had baseline studies, which included biomarkers; however, only eight of the thirteen patients have completed all required observations due to poor compliance. After four patients were enrolled and three failed to follow-up, changes to appointment schedules were made with detailed information on all follow-ups. Efforts at improving compliance post therapy are ongoing. Further accrual is needed to determine clinical significance of improvements in cardiac and/or pulmonary function. This study was funded in part by a grant from Jazz Pharmaceuticals. Disclosures Cooke: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairo:Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Miltenyi: Research Funding. OffLabel Disclosure: Defibrotide is utilized in patients with acute chest syndrome to decrease the amount of time they are hospitalized and to assist in alleviating symptoms. Defibrotide is approved in the US for sinusoidal obstructive syndrome with renal or pulmonary dysfunction.

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The Immature Reticulocyte Fraction As an Aid in the Diagnosis and Prognosis of Parvovirus B19 Infection in Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-117152 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3678-3678

Author(s):

Robert Mitrani ◽

Kandace Gollomp ◽

Michele P. Lambert ◽

Amrom Obstfeld

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Reticulocyte Count ◽

Parvovirus B19 ◽

Acute Chest Syndrome ◽

Molecular Testing ◽

Cell Disease ◽

Advisory Committees ◽

Chronic Hemolysis

Abstract Background Sickle cell disease (SCD) is characterized by hemoglobin polymerization leading to vaso-occlusion, chronic hemolysis and vasculopathy. Parvovirus B19 (B19) infection causes an acute arrest of erythropoiesis leading to reticulocytopenia and potentially life-threatening anemia in patients with chronic hemolysis such as SCD. Diagnosis of B19 infection relies on clinical history in combination with expensive and often belated serological and molecular testing. The immature reticulocyte fraction (IRF) is a relatively new reticulocyte parameter available on automated hematology analyzers that assesses the maturity of circulating reticulocytes by quantifying the fraction that stain strongest for RNA. Aims We hypothesized that the IRF could provide diagnostic information in the evaluation and management of patients with SCD who are being evaluated for B19 infection. Specifically, given that the IRF quantifies the fraction of circulating reticulocytes that have just exited the bone marrow and are least mature, we speculated that changes in IRF would precede changes seen in the reticulocyte counts in aplastic crisis and recovery. Methods We performed a retrospective analysis of records at the Children's Hospital of Philadelphia of complete blood count (CBC) and reticulocyte indices in patients with sickle cell disease in whom B19 infection by PCR testing was assessed between January 1, 2015 and October 31, 2017. CBC testing was performed on the Sysmex XN 3000 analyzer. Medical records were reviewed to verify that the B19 testing was sent during an acute aplastic episode. Diagnostic performance of reticulocyte percent (RET%) and count (RET) compared to the IRF and the absolute IRF count (AIR) was assessed by receiver-operator characters (ROC) curves on GraphPad Prism. For recovery studies, an increasing IRF was defined as an increase of 10 per 24 hour period and a recovering reticulocyte count was defined as an increase of 50,000 cells/uL per 24 hour period. Results At baseline, patients with SCD have an average IRF of 27.2% (16.7 - 37.7%), far higher than the reference interval (9.3 - 17.4%). This parallels the elevations in reticulocyte counts in this population and relates to their chronically high RBC turnover. A total of 119 patients had B19 testing performed in the study period of which 26 were found to have acute infection. The most common diagnoses amongst the B19 negative patients were unspecified fever/viral syndrome, vaso-occlusion/pain crisis, and acute chest syndrome. ROC curve analysis demonstrates that RET%, RET, IRF, and AIR lab values are predictive of B19 infection on the day that B19 PCR testing was sent with an AUC of 0.73, 0.76, 0.76, and 0.83 (p < 0.001 for all) respectively. The AUC for each parameter increased when the respective minimum value was analyzed; RET%, RET, IRF, and AIR showed an AUC of 0.83, 0.87, 0.87, and 0.91 (p < 0.0001 for all, figure 1 and table 1). In particular, an IRF value below 2.45% demonstrated a sensitivity of 50% and a specificity of 99% for B19 infection in the study population. Finally, amongst B19 positive patients we found that an increasing IRF was strongly associated with a reticulocyte recovery within the following 48 hour period (chi-square p-value = 0.015). A rising IRF was associated with a higher mean reticulocyte increase in the following assessment (2,500/24 hour period vs. 33,000/24 hour period, p < 0.05, figure 2). Moreover, an increasing IRF had a sensitivity of 31% and a specificity of 92% for a recovery in reticulocyte count. These results were consistent amongst all aplastic patients who were tested for B19 as well (data not shown). These data suggest that a high IRF is closely associated with a rising reticulocyte count within the following 24-48 hours. Conclusions Our data confirms that amongst a cohort of complicated patients with SCD and other causes for reticulocytopenia, the IRF is highly specific for detecting the severe aplasia caused by B19 infection in this group. This additional data may be useful in better triaging patients with SCD and reticulocytopenia and potentially in improving utilization of the more expensive B19 diagnostic testing. Furthermore our study suggests that an increasing IRF predicts reticulocyte recovery in reticulocytopenic patients with SCD and could have utility in clinical decision making such as whether to transfuse packed red blood cells or whether they can be safely discharged from the hospital. Disclosures Lambert: Amgen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Educational Concepts in Medicine: Consultancy; Summus: Consultancy; Rigel: Consultancy; Shionogi: Consultancy; CSL: Consultancy.

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Rare Cases of Infusion-Related Reactions (IRRs) Presenting As Pain Events during or after Crizanlizumab Infusion in Patients (Pts) with Sickle Cell Disease (SCD): A Systematic Evaluation of Post-Marketing (PM) Reports

Blood ◽

10.1182/blood-2021-152362 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3112-3112

Author(s):

Julie Kanter ◽

Amit Shah ◽

Vikas Joshi ◽

Harshit Mehta ◽

Michael Levine ◽

...

Keyword(s):

Back Pain ◽

Chest Pain ◽

Board Of Directors ◽

Reporting Rate ◽

Systematic Evaluation ◽

Biologic Agent ◽

Acute Chest Syndrome ◽

Publicly Traded ◽

Advisory Committees ◽

Data Limitations

Abstract Background: Vaso-occlusive crises (VOCs) are the hallmark of SCD. VOCs and silent vaso-occlusion can lead to complications (eg acute chest syndrome, hepatic/renal dysfunction, chronic pain, multi-organ failure) and premature death. Crizanlizumab, an anti-P-selectin monoclonal antibody (mAb), is authorized in >40 countries to prevent/reduce VOCs in SCD pts aged ≥16 yrs. IRRs are defined as any signs/symptoms (S/S) experienced by pts during/within 24 hrs of infusion of a pharmacologic/biologic agent. IRRs are quite common with mAbs (frequency 1.6‒99%; Rombouts et al Anticancer Res 2020). S/S of IRRs vary; pain events, such as headache, back pain, myalgia, chest pain and joint pain, have been described as S/S of IRRs. Although pain events are known adverse drug reactions in the crizanlizumab label (eg arthralgia, myalgia, pain at various locations), due to data limitations and confounding manifestations of SCD, pain events occurring during/within 24 hrs of crizanlizumab infusion in SUSTAIN were not identified as potential IRRs (Ataga et al N Engl J Med 2017). For pts receiving crizanlizumab, IRR-related pain events may differ in location, severity and/or nature from a pt's usual SCD/VOC pain. Aim: To review data on IRRs presenting as pain events in SCD pts treated with crizanlizumab via reports received by Novartis since approval in Nov 2019. Methods: Data sources included PM reports from providers (spontaneous) and reports from the managed access/pt orientation program. To obtain the reports (which could include ≥1 event), a cumulative custom search of the Novartis safety database was performed up to Jun 2021, using ~111 MedDRA terms associated with potential S/S of IRRs presenting as pain events. IRRs must have occurred during/within 24 hrs of the most recent crizanlizumab infusion, and pain could differ from a pt's usual SCD/VOC, with/without other S/S. IRR incidence was measured by the reporting rate (RR). Reports were not gathered via a uniform data collection system, so there are limitations, including potential underreporting, incompletely documented cases, or bias towards reporting severe events. Results: IRRs presenting as pain events were experienced by 28 pts (Table 1); the most common S/S were back pain, pain in extremity, arthralgia, musculoskeletal chest pain and headache. RR was 1.67 cases per 100 pt-yrs (95% CI 1.11‒2.42). Most pts (n=24) initially experienced IRR at the 1st or 2nd infusion, and the majority recovered within 3 days. IRR recurred on subsequent infusion(s) in 6 pts. Of the 28 pts, 20 (71%) were hospitalized for further treatment, including analgesics, antihistamines, IV fluids and/or steroids. Nine pts (32%) reported SCD complications after IRR (Table 2). Crizanlizumab was discontinued in 23 pts (82%) after their most recent IRR occurrence, including all pts who experienced secondary SCD complications. Discussion: Comprehensive investigation identified 28 pts with reported IRRs presenting as pain events that had a potential causal relationship with crizanlizumab infusion based on temporality. All pts recovered or are recovering, except 1 who had SCD complications and refused blood transfusions for personal reasons. Most pts had initial IRR at the 1st or 2nd infusion and discontinued crizanlizumab after initial IRR; 6 experienced recurrent IRRs on subsequent infusion(s). Resolution time was prolonged for pts who reported known SCD complications following IRR. Causal association of complications following IRR was confounded by the underlying disease and use of steroids to treat IRRs. Systemic corticosteroid exposure in SCD pts has been associated with pain and other complications, from severe VOCs to hemorrhagic stroke and death. No data are available regarding whether the 28 pts had an active VOC or other SCD complications prior to receiving crizanlizumab. Conclusions: Although rare, based on review of PM data, healthcare professionals should be aware of the possibility of IRRs presenting as pain events during or after any crizanlizumab infusion. Crizanlizumab labels have been/are being updated by Novartis to provide information on monitoring for S/S of IRRs presenting as pain events, and guidance on management/prevention of subsequent IRRs, including a statement recommending caution when using corticosteroids in SCD pts. Given the limited data regarding IRRs and predictability of complications, Novartis is committed to further understanding these events. Figure 1 Figure 1. Disclosures Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Shah: Johnson & Johnson: Current equity holder in publicly-traded company; Novartis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Joshi: Novartis Healthcare Private Limited: Current Employment. Mehta: Novartis Healthcare Pvt. Ltd.: Current Employment. Levine: Biontech: Current equity holder in publicly-traded company; Novartis: Current Employment, Current equity holder in publicly-traded company. Arunagiri: Novartis Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Paulose: Novartis Pharmaceuticals Corporation: Current Employment. Donohue: Novartis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Scalera: Novartis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Manwani: Novartis: Consultancy.

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Association of Hospitalization Due to Vaso-Occlusive Crisis with Subsequent Sickle Cell Disease-Related Organ Damage Hospitalization: Retrospective Analysis of 3-Year Observational Study Data

Blood ◽

10.1182/blood-2021-144723 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2037-2037

Author(s):

Matthew M. Heeney ◽

Thirupathi Pattipaka ◽

Jilles M. Fermont

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Gallbladder Disease ◽

Organ Damage ◽

Study Data ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Advisory Committees ◽

History Of

Abstract Background: Hospitalization due to vaso-occlusive crisis (H-VOC) is common in individuals with sickle cell disease (SCD), with an increasing occurrence of SCD-related complications, including organ damage, as the disease progresses. Evidence regarding the relationship between H-VOC and SCD-related organ damage, however, is lacking. Aim: To assess whether H-VOC is associated with hospitalization due to SCD-related organ damage, through retrospective analysis of data collected prospectively during a 3-year, multicenter, observational US study (NCT01220115) that aimed to better understand disease burden and management of SCD in individuals aged ≥2 years. Methods: Of the 498 individuals with SCD who were recruited into the US study, data were analyzed from 202 (100 men and 102 women) who were aged ≥16 years and had available hospital admission data. Organ damage was defined based on hospital discharge diagnosis. 1 Variables tested at baseline, in addition to H-VOC, included demographics, blood measures, and treatment history. Age and sex were included by default in all models based on literature suggesting they are relevant factors influencing organ damage. Hazard ratios (HRs) for the time from H-VOC to the first subsequent hospitalization due to SCD-related organ damage were estimated using multivariable Cox regression. Worsening of pre-existing organ damage was not considered as an event due to potential confounding (ie worsening of organ damage related to the pre-existing condition rather than as a consequence of the VOC). Results: During median 3-year follow-up, 55 (27%) individuals experienced at least one hospitalization due to SCD-related organ damage; 2 19 (9%) had multiple visits. Within the 12 months preceding baseline, 22 (11%) individuals had a history of organ damage, there was a median of two H-VOC in the 90 (45%) individuals with history of H-VOC, and 43 (21%) individuals had received chronic transfusion (≥6). History of H-VOC (HR 2.54, 95% confidence interval [CI] 1.46 to 4.43 in past 12 months), genotype (HR 2.69, 95% CI 1.34 to 5.41 for HbSS), and sex (HR 1.90, 95% CI 1.08 to 3.34 for women) were all significantly associated with subsequent hospitalization for SCD-related organ damage. Discussion and conclusion: This analysis demonstrates that history of H-VOC within the preceding 12 months is significantly associated with a higher rate of subsequent hospitalization due to SCD-related organ damage, independent of age, sex, and genotype, and may therefore help identify individuals at high risk of developing organ damage. Despite 21% of individuals receiving chronic transfusions at baseline, this factor did not remain significantly associated with the outcome when also considering genotype and H-VOC. Age and sex were unexpectedly insignificantly associated with the outcome; this is likely due to the relatively short follow-up time. Extending the historical timeframe of organ damage to 5 years did not change our findings, except that age also became significantly associated with subsequent hospitalization for organ damage. Acute chest syndrome and pneumonia were the most common types of historical (baseline) organ damage, whilst gallbladder disease was the most common organ damage observed during the follow-up period that was not observed at baseline. Our data have limited statistical power and generalizability; additional studies are required to confirm these findings. Nevertheless, our findings support the existing evidence of the impact that VOCs may have on individuals with SCD, and highlights the importance of preventing and reducing H-VOC. 1Acute chest syndrome or pneumonia; avascular bone necrosis of hip(s), shoulder(s) or spine; cardiac failure; central nervous system disease (ie abnormal transcranial Doppler, silent infarct, stroke and transient ischemic attack); gallbladder disease; leg ulcer; liver disease (ie hepatic fibrosis/ cirrhosis, hepatic sequestration/sickle-hepatopathy/intrahepatic sickling, pulmonary fibrosis, pulmonary hypertension); priapism; renal disease (ie acute renal failure, chronic renal failure-supportive, dialysis, microalbuminuria/ proteinuria, transplant); retinopathy; and splenic sequestration. 2The top 3 reasons for hospitalization due to SCD-related organ damage were acute chest syndrome or pneumonia (n=29; 53%), renal disease (n=7; 13%) and gallbladder disease (n=6; 11%). Figure 1 Figure 1. Disclosures Heeney: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; FORMA: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vertex / Crispr Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; bluebird bio: Consultancy; Keros: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Cyclerion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pattipaka: Novartis: Current Employment, Current holder of individual stocks in a privately-held company. Fermont: Novartis Pharma AG, Basel, Switzerland: Current Employment, Current equity holder in publicly-traded company.

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