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

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

Blood ◽

10.1182/blood-2021-144594 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3087-3087

Author(s):

Alessia Pepe ◽

Antonella Meloni ◽

Elena Facchini ◽

Antonella Quarta ◽

Vincenzo Spadola ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Myocardial Fibrosis ◽

Reference Values ◽

Healthy Subjects ◽

Myocardial Iron ◽

Advisory Committees ◽

Age And Gender ◽

Advisory Boards ◽

And Gender

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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Quality of Life after Diagnosis in Survivors of Aggressive Lymphomas

Blood ◽

10.1182/blood-2020-134897 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Robert M. Kraft ◽

Melissa C. Larson ◽

Kathleen J. Yost ◽

Thomas M. Habermann ◽

Matthew J. Maurer ◽

...

Keyword(s):

United States ◽

General Population ◽

B Cell ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Advisory Committees ◽

Aggressive Lymphomas ◽

The Us

Background: Aggressive lymphomas are potentially curable; however, long-term effects of treatment and the disease may adversely affect patients' quality of life (QoL). We investigated QoL at baseline, and up to nine years after diagnosis in survivors of aggressive lymphomas. Methods: Patients newly diagnosed with lymphoma were prospectively enrolled within nine months of diagnosis in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) and systematically followed. Patients were enrolled from September 1, 2002 until June 30, 2015. Eligibility criteria included being a United States resident, English-speaking, no history of HIV, and aged 18 years and older. All pathology was reviewed by a lymphoma hematopathologist. Aggressive lymphoma subtypes included in this analysis were diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma grade III, Hodgkin lymphoma, T-cell lymphoma, other non-Hodgkin lymphoma not otherwise specified (NOS), other B-cell lymphoma NOS, and composite lymphomas. We assessed QoL using the Functional Assessment of Cancer Therapy-General (FACT-G) scale at baseline enrollment, and 1, 2, 3, 6, and 9 years post-diagnosis. FACT-G measures well-being (WB) in four domains-physical (PWB), social/family (SFWB), emotional (EWB), and functional (FWB), which are added to create a total (TOT) score. Those who completed <80% of FACT-G questions at any given time point were excluded. "Survivor" was defined as alive at 1, 2, 3, 6, and 9 year follow-up with no active disease or treatment within six months of a given time point. Because patients could be enrolled at any time within the first 9 months from diagnosis, the timing of initial QoL assessment was variable with respect to the start of lymphoma treatment. We estimated longitudinal change in QoL using mixed models incorporating scores from all available time points. The minimally important difference (MID) of 5 points for TOT and 2 points for each of the domains was used to determine clinical significance. Scores were compared to United States (US) general population normative data. All statistical analyses were performed using SAS (v 9.4). Results: From September 1, 2002 to June 30, 2015, 3,028 patients with aggressive lymphomas were prospectively enrolled in the MER, of which 2,018 completed the FACT-G baseline assessment (47% prior to therapy initiation). Of these patients, 1,144 at 1 year, 1,002 at 2 years, 943 at 3 years, 562 at 6 years, and 289 at 9 years post-diagnosis completed the FACT-G at both baseline and each of the respective time points after diagnosis, and met the definition of survivor. The median age at diagnosis of patients analyzed was 59 years (range 18-93). The cohort included 844 female patients (42%). DLBCL comprised 44% of cases, Hodgkin lymphoma 19%, T-cell lymphoma 11%, composite lymphomas 8%, other B-cell NOS 6%, other non-Hodgkin lymphoma NOS 7%, and Follicular lymphoma grade III 5%. QoL increased from baseline enrollment; the largest increase was seen from baseline to 1 year after diagnosis with a statistically and clinically significant mean TOT score difference of 6.7 points. This mean increase in TOT scores sustained over time with an increase of 7.8 points above baseline at 9 years after diagnosis. At baseline, PWB, EWB, and FWB scores were significantly lower in patients with aggressive lymphomas compared to the US general population, and SFWB scores were significantly higher (all p <0.01); however, only SFWB and EWB score differences were clinically significant as defined by MID. SFWB showed only a mild decline from baseline over the course of 9 years. Despite this, all SFWB scores were statistically and clinically significantly higher than the US general population at 1, 2, 3, 6, and 9 years after diagnosis (all p <0.01 and MID >2). Patients with aggressive lymphomas TOT scores at baseline did not differ from the US general population, while TOT scores at 1, 2, 3, 6, and 9 years post-diagnosis were statistically and clinically significantly higher. Overall, the results in the pre-treatment QoL subset were consistent with the cohort as a whole. Conclusions: In survivors of aggressive lymphomas, QoL improved primarily in the first year after diagnosis, and sustained over the course of nine years. QoL in survivors of aggressive lymphomas is higher than the United States general population at 1, 2, 3, 6, and 9 years after diagnosis. Figure Disclosures Maurer: Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Farooq:Kite, a Gilead Company: Honoraria. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding.

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Comparison of the Myleloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) Across Nine Linguistic Translations Among an International Sample of 1,851 Myeloproliferative Neoplasm (MPN) Patients.

Blood ◽

10.1182/blood.v120.21.2852.2852 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2852-2852

Author(s):

Amylou Constance Dueck ◽

Robyn M. Emanuel ◽

Holly Lynn Geyer ◽

Jean-Jacques Kiladjian ◽

Stephanie Slot ◽

...

Keyword(s):

Board Of Directors ◽

Factor Structure ◽

Internal Consistency ◽

Research Funding ◽

Disease Type ◽

Cronbach’S Alpha ◽

Advisory Committees ◽

Cronbach's Alpha ◽

Language Groups ◽

And Gender

Abstract Abstract 2852 Background: The 18-item Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF, Scherber et al Blood 2011) given in conjunction with the 9-item Brief Fatigue Inventory (BFI, Mendoza et al Cancer 1999) is a patient-completed questionnaire for assessing symptoms in persons with MPNs. The MPN-SAF has been translated and validated in 9 languages to date. The Total Symptom Score (TSS) is computed from 10 of the most pertinent MPN-SAF items to assess symptom burden in MPN patients and to evaluate response to therapy. Psychometric properties of the TSS have been previously reported (Emanuel et al Blood 2012). The purpose of this analysis is to compare MPN-SAF symptoms and psychometric properties of the TSS across 9 languages in an international sample. Methods: Data were collected in an international cohort of subjects with MPNs. Surveyed symptoms included fatigue, early satiety, abdominal pain and discomfort, inactivity, headaches, concentration, dizziness, extremity tingling, insomnia, sexual problems, mood changes, cough, night sweats, pruritus, bone pain and fever on a 0 (absent) to 10 (worst imaginable) scale. TSS was computed using the published scoring algorithm on a 0 (all symptoms absent) to 100 (all symptoms worst imaginable) scale. Demographic and disease-related data including disease type, gender, and age had to be present to be included in analysis. Demographics were compared across languages groups using ANOVA and chi-squared tests. Symptoms and TSS were compared across language groups using a general linear model adjusting for disease type, age, and gender with post-hoc Tukey pairwise comparisons. Internal consistency and factor structure of the TSS were investigated overall and within language groups using Cronbach's alpha and principal-axis factoring analysis. Results: Subject Demographics and Disease Type: 1,851 subjects with polycythemia vera (PV N=655), essential thrombocythemia (ET N=769) and myelofibrosis (MF N=427; 286 primary MF, 61 PV-MF, 80 ET-MF) were prospectively enrolled and administered the MPN-SAF and BFI in 1 of 9 languages: English [UK] 55, English [US] 102, Italian 186, Swedish 114, German 112, French 457, Spanish 192, Dutch 236, and Chinese 397. Age (median 61, range, 15–94) and gender (55% F) were typical. Disease type and age varied across language groups (both p <0.001). MPN-SAF Symptoms and TSS: Symptom frequencies ranged from 19% (fever) to 88% (fatigue) overall with mean severities ranging from 0.4 (SD=1.3, fever) to 4.3 (SD=2.3, fatigue). Fatigue had the highest mean severity among all symptoms within each language group. Overall, mean TSS was 21.5 (SD=16.7) with the Swedish (mean=18.1, SD=15.2) and Dutch (mean=27.6, SD=17.1) cohorts reporting the lowest and highest unadjusted TSS means, respectively. When comparing symptom items across languages (adjusting for disease type, age, and gender), concentration and sexual problems had the most statistically significant pairwise differences (11 and 10, respectively, out of a possible 36) followed by dizziness and overall quality of life (9 each, out of a possible 36). No statistically significant pairwise differences were observed for abdominal discomfort, headache, extremity tingling, or insomnia. For the TSS, the Dutch cohort appeared to statistically significantly differ (all p <0.05) with all other languages except the English cohorts. All other TSS pairwise comparisons were not statistically significant. TSS Internal Consistency and Factor Structure: The TSS had excellent internal consistency overall (Cronbach's alpha 0.83) as well as within language groups (Cronbach's alpha 0.81–0.86). Overall factor analysis identified a single underlying construct among the 10 TSS items. Factor loadings ranged from 0.41 for fever to 0.73 for inactivity. A single factor solution was appropriate for each language group with factor loadings ranging from 0.18 to 0.85. Conclusion: This analysis suggests that the available translations of the MPN-SAF are generally acceptable for use in a broad context. The TSS demonstrated acceptable internal consistency and similar factor structure across all language groups. Most symptom and TSS comparisons between languages were not statistically significant, but for the few which differed, further studies are needed to evaluate whether these variances are due to disease-related factors or due to linguistic or cultural influences present in the cohorts. Disclosures: Kiladjian: Novartis: Honoraria, Research Funding; Celgene: Research Funding; Shire: Honoraria. Griesshammer:Shire: Honoraria. Roy:Novartis, BMS: Speakers Bureau. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

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CML Patients In Clinical Trials Represent Fairly Well The General Population Of CML Patients: A Comparative Analysis Of 5803 Patients From The EUTOS Registry

Blood ◽

10.1182/blood.v122.21.2735.2735 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2735-2735 ◽

Cited By ~ 1

Author(s):

Verena S Hoffmann ◽

Doris Lindoerfer ◽

Markus Pfirrmann ◽

Susanne Saussele ◽

Andreas Hochhaus ◽

...

Keyword(s):

General Population ◽

Board Of Directors ◽

Risk Score ◽

Peripheral Blood ◽

Research Funding ◽

Chronic Phase ◽

Newly Diagnosed ◽

Advisory Committees ◽

Study Section ◽

Oncology Research

Abstract Introduction The centerpiece of the European Treatment and Outcome Study (EUTOS) for Chronic Myeloid Leukemia (CML) is a registry collecting representative samples of CML patients in Europe. The In-Study section of the registry combines data of patients enrolled in investigator-sponsored prospective studies of treatment with imatinib-based regimens. The population-based (PB) section includes data of all newly diagnosed CML patients in specified regions of 27 European countries in an attempt to represent the general population of CML patients. Aims There is a common assumption that patients enrolled in prospective trials are highly selected, do not represent the ‘typical’ patient and that thus the results of such trials may not be easily generalized to all patients. Thus we analyzed possible differences in the baseline characteristics of the two patient groups. Available were age, sex, EUTOS score, phase of disease, spleen enlargement, platelets, leukocytes, and percentages of blasts, eosinophils, and basophils in peripheral blood. Methods For all analyzed factors we calculated distribution parameters or percentages depending on the scale of the factor. To identify significant differences we used χ2-tests and Mann-Whitney U-tests. Level of significance was 0.05. Results The In-Study section included 2346 patients from study groups in Germany, Italy, France, Spain, the Nordic study group, the Netherlands, and the United Kingdom, newly diagnosed from 2002 to 2006. The PB section of the registry included 3457 patients newly diagnosed with CML from 2008 to 2012 in 27 European countries. The median age at diagnosis of In-Study patients (51 years (18-88)) was significantly lower than the age of the general population newly diagnosed with CML (56 years (18-99), p<0.0001). Also, while in the PB section the percentage of male patients was 54%, in the In-Study section the percentage was significantly higher (60%, p<0.0001). The median spleen size enlargement (cm below costal margin) did not differ significantly between the two groups (In-Study (1 cm (0-38), PB section 0 cm (0-40)). While 7% of patients in the PB section were not in chronic phase, this was only true for less than 1% of patients included into the In-Study section. Accordingly, there were significant differences (both p<0.0001) regarding percentages of blast cells in peripheral blood (In-Study: 1% (0-14), PB 1% (0-92)) and leukocytes (In-Study: 74 x109/L (20-650), PB 85 x109/L (3-932)). There were no differences in percentage of basophils, eosinophils and in platelet count. The EUTOS risk score was developed to predict the treatment success of patients in chronic phase and thus is calculated for patients in chronic phase only. In the In-Study section 10.5% of patients had a high EUTOS risk score while the percentage in the general population was 11.4%. The resulting difference was not significant (p=0.3374). Conclusions With a total of 5803 patients included in the two sections of the EUTOS registry analyzed for this work, the combined data allow a unique insight into the characteristics of CML patients in Europe. The comparison between the In-Study and the PB sections shows some important differences between the two populations, such as age and sex distribution. However, several other clinical and hematological factors which are known to be predictive for treatment outcome did not differ substantially. We conclude that patients enrolled in investigator-sponsored studies represent fairly well the general population of CML patients in Europe, with the exception of sex and age distribution, which may limit the value of the calculations of overall survival because those are affected by both age and gender. Disclosures: Hoffmann: Novartis Oncology: Research Funding. Lindoerfer:Novartis Oncology: Research Funding. Pfirrmann:Novartis: Consultancy. Saussele:Novartis Oncology: Honoraria, Research Funding. Hochhaus:Novartis: Research Funding; Bristol Myers Squibb: Research Funding. Rosti:Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Castagnetti:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Turkina:Bristol Myers Suibb: Consultancy; Novartis Pharma: Consultancy. Zaritskey:University of Heidelberg: Research Funding. Steegmann:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Cervantes:Bristol Myers Squibb: Speakers Bureau; Teva Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Novartis: Speakers Bureau. Porkka:BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Griskevicius:Novartis: Consultancy, Research Funding. Panagiotidis:GSK: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Hehlmann:Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Baccarani:Novartis: Research Funding.

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Expected Survival in Patients with Smoldering Multiple Myeloma and Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-118084 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4497-4497

Author(s):

Moritz Binder ◽

S. Vincent Rajkumar ◽

Arjun Lakshman ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

General Population ◽

Board Of Directors ◽

Research Funding ◽

Excess Mortality ◽

Advisory Committees ◽

Smoldering Multiple Myeloma ◽

Similar Survival

Abstract Background: The introduction of novel therapeutics has led to improved outcomes in patients with multiple myeloma (MM). MM and its precursor lesion smoldering multiple myeloma (SMM) have traditionally been associated with increased mortality despite treatment. We aimed to assess the impact of a diagnosis of SMM and MM compared to the general population in the context of established prognostic factors. Methods: We studied the overall survival of 1697 patients with smoldering multiple myeloma (SMM, n = 582) and multiple myeloma (MM, n = 1115) diagnosed at Mayo Clinic between 01/2005 and 12/2015. Expected survival accounting for age and sex was calculated using the United States general population (US) as the reference group. Observed and expected overall survival was expressed as the standardized mortality ratio (SMR) of observed to expected deaths. Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in subgroups. The subgroups of interest were based on the International Staging System (ISS) and the presence of fluorescence in situ hybridization (FISH) high-risk cytogenetics: t(4;14), t(14;16), t(14;20), and del(17p). Proportional hazards regression models were used to assess the associations between the aforementioned prognostic factors and overall survival. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in patients with SMM and MM was 65 (32 - 92) and 63 years (24 - 90), respectively. Two hundred forty-nine patients (57%) and 663 (60%) were male. The median follow-up in patients with SMM and MM was 4.7 (0.1 - 11.0) and 2.6 years (0.2 - 9.5). The median overall survival for patients with SMM and MM was 9.0 (95% CI 8.4 - 9.7) and 7.9 years (6.4 - 8.7). With age- and sex-matched population controls as the reference, the SMRs in patients with SMM and MM were 2.6 (95% CI 2.2 - 3.0) and 4.6 (4.1 - 5.2). Among those MM patients with available data on ISS staging and FISH cytogenetics, 30% (236/780) had ISS III and 21% (188/878) had high-risk cytogenetics. Patients with MM (compared to SMM) experienced worse overall survival (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001, n = 1697). Patients with ISS I/II MM (compared to SMM) experienced similar survival (HR 1.0, 95% CI 0.8 - 1.3, p = 0.698, n = 1131). Patients with ISS III MM (compared to MM with high-risk cytogenetics) experienced similar survival (HR 1.3, 95% CI 0.9 - 2.0, p = 0.128, n = 329). Conclusions: Patients with SMM and MM in this cohort experienced excess mortality compared to the general population. In the absence of universal screening the true morbidity and mortality of patients with SMM and MM remains unknown and is likely overestimated in hospital-based cohorts. Overall survival in patients diagnosed with SMM and patients with ISS I/II MM receiving contemporary anti-myeloma therapy was clinically indistinguishable. Patients treated for ISS III MM experienced overall survival similar to patients with cytogenetic high-risk disease. MM remains associated with excess mortality, the magnitude of which varies considerably based on the presence of additional tumor and host factors. The outcomes with modern therapy among the ISS I/II patients highlight the potential for improving outcomes of SMM by early intervention, especially for the higher risk patients. Figure. Figure. Disclosures Lacy: Celgene: Research Funding. Gertz:Medscape: Consultancy; Alnylam: Honoraria; janssen: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; annexon: Consultancy; celgene: Consultancy; Teva: Consultancy; Prothena: Honoraria; Apellis: Consultancy; Abbvie: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; Research to Practice: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Acquired Hemophilia a Relapse Is Related to Th2 Response, and Increased Expression of B-Cell Activating Factor (BAFF)

Blood ◽

10.1182/blood-2021-152589 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 497-497

Author(s):

Jessica O Frade-Guanaes ◽

Ana P Racanelli ◽

Lucia H Siqueira ◽

Carolina Costa-Lima ◽

Samuel S Medina ◽

...

Keyword(s):

B Cells ◽

Autoimmune Diseases ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Healthy Individuals ◽

Th2 Response ◽

Advisory Committees ◽

Th17 Response

Abstract Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by the development of autoantibodies against the factor (F)VIII of coagulation with higher incidence in elderly individuals. The treatment includes immunosuppressive alternatives, and the majority of patients reach complete remission of symptoms. Although the role of immune T and B cells in the physiopathology of several autoimmune diseases is widely established, few studies have explored the T and B cells immune response pathway in AHA. This study aimed to determine the role of T cells through their cytokines expression and B cells through their expression of proteins that activate the B cell receptor (BCR), such as B-cell activating factor (BAFF) and A-proliferation inducing ligand (APRIL), in a longitudinal evaluation of patients with AHA. We included in this study 11 patients, 4 (36%) male, with the diagnosis of AHA, based on the occurrence of low FVIII levels (median FVIII level at the diagnosis was 0.10 IU/dL; range 0-18.8) and anti-FVIII inhibitor titer positive (≥0.6 Bethesda units (BU)/mL) (median inhibitor titer at the diagnosis was 60BU/mL; range 7.6-1000.2). The median age at the diagnosis was 59 years (range 9-75). Idiopathic AHA was evident in 72.7% of cases, while autoimmune diseases (18.2%), and pregnancy (9.1%) were the other underlying etiologies. All patients received immunosuppressive therapy (IST). Eight (72.7%) patients used corticosteroid (CS) plus cyclophosphamide (CP), one (9.1%) received only CP, one (9.1%) used CS plus rituximab and one (9.1%) received CS, CP and three cycles of rituximab. The response to IST was defined as complete remission (CR) with anti-FVIII < 0.6BU/mL and FVIII >50IU/dL, without further IST. Relapse was defined when anti-FVIII titer became >0.6BU/mL after previous remission. In this cohort, we observed 64% of sustained CR and 4(36%) AHA patients had at least one relapse, including two AHA patients considered idiopathic and two with other autoimmune diseases associated. Peripheral blood mononuclear cells (PBMC) were collected from all AHA patients at the diagnosis previously IST (baseline), when patient achieved CR, and at the occurrence of relapse. PBMCs were maintaining frozen in liquid nitrogen. Cells were taw and cultivated with RMPI-1640 medium in 7.5x10 5 cells/well in a 48-well plate. After 24h, cells were stimulated with a 1IU/well of a full-length recombinant FVIII concentrate (rFVIII) or phorbol myristate acetate (PMA) (1µM) with ionomycin (1µM). After 24h incubation, cells were analyzed by flow cytometry at BD FACSCalibur™. To determine T CD4 + cells' cytokine production profile, we stained T cells with anti-CD4, anti-interleukins (IL)-17a, IL-4, and IL-21, anti-TGF-b, and anti-TNF-a. We observed a significant increase of IL-17a production in the rFVIII-stimulated cells isolated at baseline from all patients compared to cells isolated from healthy individuals (P=0.01). However, IL-17a expression at baseline was not different between cells from patients who sustained CR to those who relapsed. Interestingly, when we compared cells isolated at baseline from patients that relapsed after different immunosuppressive attempts, we observed a significant difference for IL-4 (P=0.009), IL-21 (P=0.02), and TGF-b (P=0.01) expression in comparison to cells from healthy individuals. However, this difference was not observed in cells from sustained CR vs. cells from healthy individuals (figure 1). Thus, suggesting that all patients present Th17 response, while only patients that relapsed also showed Th2 response at the diagnosis. We also evaluated B cells' expression of BAFF and APRIL. The cells were stained with anti-CD19, BAFF, and APRIL. Only cells isolated at baseline from AHA relapsed patients after rFVIII stimulation or without any stimuli presented increased expression of BAFF (P=0.01 with rFVIII-stimulated and P=0.007 for unstimulated cells) when compared to PBMCs isolated from healthy individuals (figure 1). BAFF is responsible for controlling B-cell maturation and is associated with autoantibody production of different autoimmune conditions. Our finds reveal an increase in the Th17 response in patients with AHA at the diagnosis. However, the presence of Th2 response and increase of BAFF expression was observed only at the diagnosis of patients with recurrence of autoimmune response to FVIII, which suggests a potential biomarker for AHA evaluation. Figure 1 Figure 1. Disclosures Ozelo: BioMarin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Other: Grant review.

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Impaired Sars-Cov-2 Specific Antibody Responses in Patients Treated with Anti-CD20 Antibodies

Blood ◽

10.1182/blood-2020-141234 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 47-48

Author(s):

Alessandra Sottini ◽

Luisa Imberti ◽

Simone Paghera ◽

Vanessa Previcini ◽

Chiara Cattaneo ◽

...

Keyword(s):

Autoimmune Diseases ◽

B Cell ◽

Board Of Directors ◽

Specific Antibody ◽

Research Funding ◽

Advisory Board ◽

Clinical Indication ◽

Advisory Committees ◽

Hematological Disorders ◽

Anti Cd20

It has been proposed that patients with hematologic malignancy and autoimmune diseases receiving anti-CD20 monoclonal antibody (mAb) therapy are particularly at risk of severe Coronavirus disease (COVID-19) because the profound and long-lasting B-cell depletion induced by anti-CD20 mAb may impair virus clearance and may also contribute to reactivation of latent viruses, especially hepatitis B and JC viruses. As of July 20, 2020, the total number of COVID-19 cases reported by the Italian authorities reached 245,000. The north of the country was mostly hit, and Milan and Brescia were among the Italian provinces that registered the highest number of COVID-19 cases. Consistent with this, a high number of COVID-19 patients affected with multiple types of hematological disorders (n. 137) and with multiple sclerosis (MS, n. 114) were referred to ASST Spedali Civili di Brescia. Antibodies to SARS-CoV-2 were analyzed in 70 patients with hematological disease, and in few patients with MS. Among these, 10 patients (7 with hematologic disease and 3 with MS) had received treatment with rituximab or ocrelizumab, two anti-CD20 mAbs, within 3 months prior to COVID-19 onset. Clinical indication to CD20-depleting treatment for patients with hematological disorders included Diffuse Large B Cell Lymphoma (DLBCL) or Follicular Non Hodgkin Lymphoma (NHL). Anti-spike protein (anti-S) and anti-nucleocapsid (anti-N) antibodies to SARS-CoV-2 were analyzed during the acute phase of infection and up to 3 months since the onset of symptoms by quantitative measurements of plasma or serum antibodies with luciferase immune precipitation assay systems (LIPS). With this technique, production of anti-S and anti-N antibodies has been demonstrated between day 8 and day 14 after onset of symptoms in immunocompetent individuals, whereas specific antibody production was delayed by few days in immunocompromised patients (Burbelo PD et al, medRxiv. 2020 Apr 24:2020.04.20.20071423). All 10 patients remained seronegative to SARS-CoV-2 for the first 20 days since onset of symptoms. One patient with DLBCL secondary to Follicular NHL had detectable anti-S and anti-N antibodies at day +25, and one patient with MS developed anti-N antibodies by day +23. Two patients, one with DLBCL secondary to Follicular NHL and one with Follicular NHL were still seronegative for both anti-S and anti-N antibodies at 133 and 74 days since onset of symptoms. Two MS patients were seronegative at the last examination, and one other MS patient was anti-S seronegative at day +74. Three of the 10 patients have died; all three were SARS-CoV-2 RT-qPCR+ and seronegative at the time of death. While it has been reported that SARS-CoV-2 is cleared without significant problems by the majority of people with MS or other autoimmune diseases on immunotherapy, these data indicate that treatment with anti-CD20 mAb may significantly alter humoral responses to the virus. Until a vaccine to SARS-CoV-2 is available, the risk-benefit ratio of anti-CD20 mAb therapy in areas with high rates of SARS-CoV-2 infection should be carefully weighed. Moreover, for patients with B-cell malignancies or autoimmune diseases, transient discontinuation of this therapy, or use of alternative therapeutic approaches, should be considered once an efficacious vaccine becomes available. This study was performed according to protocol NP-4000 (Comitato Etico Provinciale), and supported by Regione Lombardia and by the Division of Intramural Research, NIAID. Figure 1 Disclosures Imberti: Biogen: Honoraria; Genzyme-Sanofi: Honoraria; Meck-Serono: Honoraria; Novartis: Honoraria; Biogen: Other: Advisory board; FISM (Fondazione Italiana Sclerosi Multipla): Research Funding; Regione Lombardia: Research Funding. Capra:Biogen: Other: travel grants, Speakers Bureau; Roche: Other: travel grants, Speakers Bureau; Celgene: Other: travel grants, Speakers Bureau; Merck: Other: travel grants, Speakers Bureau; Novartis: Other: travel grants, Speakers Bureau. Rossi:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Notarangelo:NIAID, NIH: Research Funding. Cohen:NIAID, NIH: Research Funding.

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COVID-19 Infection in Patients with Paroxysmal Nocturnal Hemoglobinuria in Italy

Blood ◽

10.1182/blood-2020-138721 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Wilma Barcellini ◽

Bruno Fattizzo ◽

Luisa Quattrocchi ◽

Juri Alessandro Giannotta ◽

Semra Aydin ◽

...

Keyword(s):

General Population ◽

Aplastic Anemia ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Young Male ◽

Clinical Severity ◽

Advisory Committees ◽

Clone Size ◽

Complement Inhibition

COVID-19 pandemic has raised several concerns regarding patients with hematologic and immune-mediated diseases. It can be assumed that Paroxysmal nocturnal hemoglobinuria (PNH), both classic hemolytic and associated with aplastic anemia, particularly on treatment with complement inhibitors, may be more susceptible and have higher morbidity and mortality rates from COVID-19 than the general population. Italy has been heavily affected from the COVID-19 outbreak with the peak of contagions at the end of March 2020. As of July, 23 2020 the cumulative incidence of COVID-19 in Italy was 0.4% (1 case every 246 residents) (ranging from 0.06% - 1/1621- in Calabria to 0.9% - 1/106 - in Lombardy). We conducted a survey on 126 patients with PNH (77 females/49 males, median age 48 years, range 19-86) among 7 reference Italian centers in order to evaluate the occurrence and clinical characteristics of COVID-19 infection from the outbreak until the time of writing. According to International PNH Interest Group (IPIG) classification, 95 patients suffered from classic hemolytic PNH, 24 had associated bone marrow failures (aplastic anemia or myelodysplastic syndrome), and 7 had subclinical PNH (clone size <10%). Sixty-nine cases were on complement fraction 5 (C5) inhibition (72 eculizumab and 19 ravulizumab). Comorbidities were present in 33 patients, including arterial hypertension (N=14), ischemic cardiomyopathy (N=3), atrial fibrillation (N=2), diabetes mellitus (N=2), breast cancer (N=3), colon cancer (N=1), prostate cancer (N=1), Crohn disease (N=1), and Hashimoto thyroiditis (N=1). During the observation period, only one patient (55 years female), from Milan, Lombardy, not on C5-inhibitor was diagnosed with COVID-19 infection (positive swab, ageusia, and mild fever for few days). No hemolytic flare occurred, nor hospital admission was required. She received azithromycin and low molecular heparin. Other 6 patients, all on C5-inhibitors, experienced fever (N=5) and cough (N=2), and/or dysgeusia (N=1), of whom 2 experienced breakthrough hemolysis (BTH), but swabs and CT scans (N=2) were negative. At variance, 6 patients (4 on eculizumab and 2 on ravulizumab) experienced BTH without COVID-19 symptoms. Interestingly, a young male patient on eculizumab, working as medical doctor in a COVID-19 ward, did not contract the infection. In conclusion, this survey suggests that PNH subjects, either on complement inhibition or not, are not at significantly higher risk of COVID-19 infection as compared with the general population. As a matter of fact, the basic protective measures against COVID-19 have always been advised to PNH patients particularly during treatment and were presumably carefully followed during the pandemic. On the other hand, immune activation and inflammation are thought to play an important role in the clinical severity of COVID-19 pneumonia. Complement inhibition, which is under investigation in COVID-19 disease, seems at least not disadvantageous in PNH. Disclosures Barcellini: Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding; Novartis: Honoraria, Other: invited speaker , Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor. Notaro:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria.

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