Dyspnea is a prominent symptom in patients with warm autoimmune hemolytic anemia (wAIHA), yet its lived experience remain under-researched. Although clinically relevant, dyspnea is not routinely assessed in wAIHA trials, and no validated patient-reported outcome (PRO) measures exist for this population. This study explored patients’ experience of wAIHA-related dyspnea, identified its most bothersome impacts on daily life, and evaluated the content validity of the FACIT-Dyspnea 10-item Short Form (SF) in wAIHA. Hybrid concept elicitation and cognitive debriefing interviews were conducted with 15 adults diagnosed with wAIHA in the US. Patients were recruited via recruitment vendors and a patient advocacy group. Interviews were conducted online, transcribed verbatim, and analyzed using inductive and deductive coding. All fifteen patients (aged 35–74; 80

Introduction Recent advances in treatment and care have improved survival rates for children and young adults with severe blood disorders such as sickle cell disease (SCD), transfusion-dependent beta-thalassaemia (TDT) and acute leukaemia. However, their quality of life and reproductive and psychosocial outcomes are not yet well studied. For SCD and TDT, robust survival data are mainly limited to North America. Thus, there is a need to fill these knowledge gaps to guide improvements in care, address unmet clinical needs and rigorously assess the efficacy of emerging novel therapies.Methods and analysis This is an observational population-based mixed-methods study of individuals diagnosed with SCD, TDT or acute leukaemia when under the age of 18 in England, involving a data linkage component and a patient-reported outcomes measures survey. Data linkage-eligible participants will be identified from national and regional databases, including the Hospital Episode Statistics, Yorkshire Specialist Register of Cancer in Children & Young People and the National Congenital Anomaly and Rare Diseases Registration Service. Data linkage will be processed within the NHS England and the University of Leeds’ secure, trusted research environments. Data will be accessed without consent under section 251 and approval by the confidentiality advisory group. It will assess survival rates for SCD and TDT as well as clinical, educational and mental health outcomes for SCD, TDT and acute leukaemia diagnosed in childhood.Survey-eligible participants for SCD, TDT and acute leukaemia cohorts will be checked for their suitability to participate by the North of England clinical care teams. An NHS-approved survey provider will facilitate data checks with the NHS National Data Opt-Out Service. Consent is required for participation in the survey and for subsequent data linkage to existing databases. Surveys are conducted in various formats (online, paper and phone), with reminders sent after 21 days. The survey will assess quality of life and psychosocial and reproductive outcomes. Participants can withdraw at any time, and support is available via telephone helplines.Ethics and dissemination The study has received ethical and information governance approval from the Health Research Authority (Reference 24/YH/0186) and the Confidentiality Advisory Group (CAG 24/CAG/0138) to process identifiable data without consent. Study results will be available to patients, physicians, researchers, stakeholders and others through open-access publishing, results sharing via media platforms and presentations at conferences and meetings.

PurposeTo validate the use of Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire in cold agglutinin disease (CAD) patients using qualitative and quantitative methods and to estimate meaningful within-patient change (MWPC).MethodsQualitative assessment used outcomes from a survey among CAD patients and their caregivers in US. Quantitative assessment used outcomes from two Phase-3 trials in CAD wherein fatigue was evaluated as a key secondary endpoint using the FACIT-Fatigue questionnaire. The reliability, validity, and responsiveness of the FACIT-Fatigue questionnaire were assessed. MWPC was estimated using anchor-based (mean change, receiver operating characteristic [ROC] curves, and logistic regression) and distribution-based methods.ResultsQualitative analyses (n=16) showed that fatigue was the most common and bothersome symptom. All patients reported that FACIT-Fatigue questionnaire captured their experiences of CAD-related fatigue. Quantitative analysis included 55 patients from both studies. Items of FACIT-Fatigue scale were internally consistent (Cronbach’s alpha coefficient: 0.94 at baseline; 0.96 at Week 26). Generally, correlations showed good convergent validity (>0.40). The MWPC estimates ranged from 2.0 to 15.7. Based on more robust ROC and regression-based methods, IQR of MWPC estimates was 4.1–7.3, and individual responder definitions were in range of 5–8 points, where “5” is the lowest recommended MWPC threshold for FACIT-Fatigue in CAD.ConclusionFACIT-Fatigue is a reliable, valid, responsive scale in CAD. The MWPC estimates for FACIT-Fatigue in patients with CAD were consistent with other disease estimates published previously, and “5” can be considered as the lowest recommended threshold for meaningful clinical response in patients with CAD.

Introduction: wAIHA is a rare form of anemia caused by premature destruction of red blood cells (RBC) mostly due to warm agglutinins (mainly IgG) binding to RBC antigens. Key wAIHA mechanisms are extravascular hemolysis (due to FcγR-mediated RBC phagocytosis, spleen ADCC, liver CDC), intravascular hemolysis (complement cascade activation), and lack of bone marrow (BM) compensation. The clinical picture ranges from BM-compensated to life-threatening anemia and high thromboembolism risk (venous>arterial). Although most patients significantly respond to corticosteroids (CS), CS-dependence, resistance, or intolerance results in extra therapy. The reversible covalent BTKi rilzabrutinib may increase hemoglobin (Hb) levels in wAIHA through multiple mechanisms: decreasing macrophage (FcγR)-mediated RBC destruction in spleen and inhibiting pathogenic autoantibody production. Reported here are final part A results of the open-label multicenter phase 2b study of rilzabrutinib in wAIHA patients (NCT05002777). Methods: Adults ≥18 y with primary wAIHA or SLE-associated wAIHA who were relapsed/refractory to or dependent on CS were enrolled. Patients had Hb level <10 g/dL, ≥1 abnormal hemolytic marker, positive DAT, ECOG PS 0-2, and unsustained response to CS. In this two-part study, part A patients received oral rilzabrutinib 400 mg bid for 24 wks; responding patients completing part A could continue rilzabrutinib in the long-term extension (LTE, part B) until the last patient in completes 52 wks. Stable doses of concomitant CS and rescue therapy were allowed. The primary efficacy endpoint was overall Hb response (including response or complete response) by wk 24. Response was defined as increased Hb by ≥2 g/dL from baseline. Complete response was defined as Hb ≥11 g/dL (women) or ≥12 (men) with no evidence of hemolysis. Responses had to be in the absence of blood transfusion in the last 7 d and no rescue medication during the last 4 wks. Part A secondary endpoints were time to Hb response and durable response (Hb ≥10 g/dL with increase from baseline ≥2 g/dL on 3 consecutive scheduled visits during 24 wks). Fatigue was measured by FACIT-Fatigue scale. Results: 22 patients were enrolled, including 21 with primary wAIHA and 1 erroneously enrolled with cold agglutinin disease. 21 patients completed part A, 1 withdrew due to the patient decision within the first 12 wks, and 15 have entered part B LTE. At baseline, median age was 65 y (range, 33-87; 23% ≥75 y) and 59% were female. For 21 wAIHA patients, median time since diagnosis was 4.9 y (maximum 47 y; 55% ≥3 y). 11 (50%) patients had ≥3 prior medications. Rilzabrutinib monotherapy was given in 9 (41%) patients, and with concomitant CS in 13 (59%) patients. Overall Hb response was achieved in 14 (64%) patients (13 [59%] patients met criteria for response and 3 [14%] for complete response), and 9 (41%) wAIHA patients achieved durable response. Median time to Hb response in 14 responders was 50 d (range, 28-169). Increased Hb levels were associated with reduced hemolysis markers. In all patients at wks 12 and 24 relative to baseline, median LDH levels were reduced by 33% for both, and median reticulocytes reduced by 32% and 51% respectively. Overall mean (SD) baseline FACIT-fatigue scale score of 30.0 (11.1) improved with clinically meaningful increases to 36.4 (10.5) at wk 12 and 37.0 (11.5) at wk 24. Rescue medication was used in 1 patient from wks 1-12 and 3 patients from wks >12-24. 5 (23%) patients (3 responders, 2 non-responders) received blood transfusions during the first 12 wks of treatment. 1 responder, who received more frequent blood transfusions (weekly) pre-study vs others, received them 6x in wks 1-12, and 2x in wks >12-24. Rilzabrutinib was given for a median duration of 24 wks (range, 9-25). 19 (86%) patients had on-treatment adverse events (AEs) due to any cause; 10 (45.5%) patients had treatment-related AEs. The most common any-cause AEs were nausea (32%), diarrhea (23%), and upper abdominal pain (18%), all mild grade. Four (18%) patients had serious AEs; none were treatment related. Part A had no thromboembolic events, AEs leading to discontinuation, or deaths. Conclusion: Rilzabrutinib in previously treated patients with primary wAIHA resulted in robust efficacy based on overall and durable Hb response, decreased hemolysis, and clinically meaningful improvement in fatigue. Rilzabrutinib was well-tolerated with a favorable safety profile in patients with wAIHA.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Introduction The CADENCE Registry (NCT05791708) is a large international database of patients (pts) with cold agglutinin disease (CAD) or cold agglutinin syndrome (CAS, a cold antibody-driven hemolytic anemia associated with an underlying condition). CADENCE is aimed at understanding the patient demographics, clinical characteristics, treatment patterns, healthcare resource utilization, natural history of disease, long-term clinical outcomes, and impact on patient quality of life. Sutimlimab (SUT) is a humanized monoclonal antibody that selectively inhibits the classical complement pathway by inactivating C1s and is the first approved treatment for CAD. CADENCE includes a SUT cohort with an objective to assess the safety and the effectiveness of SUT in pts with CAD in a real-world setting. Here we report the data from the first interim analysis on the CAD subgroups based on treatment status. Methods Adults ≥18 years of age, diagnosed with CAD or CAS were included. Of 140 pts enrolled at time of analysis (data cutoff: October 6, 2023) 133 pts (7 pts excluded: eligibility criteria unmet) were included in the analysis (CAD, n=112; CAS, n=21). Results The treatment status among CAD pts (based on investigator-reported medications used to treat CAD) at enrollment was treatment-naive (n=50), CAD-SUT ongoing (n=15), other CAD treatment ongoing (n=33), previously on CAD therapy (n=14). The mean (SD) age of pts in the total CAD group and CAD-SUT subgroup at enrollment was 72.0 (10.29) and 74.1 (8.14) years, respectively. The mean (SD) time (months) from diagnosis to first treatment was 32.08 (48.49) in the CAD group and 55.59 (58.26) in the CAD-SUT subgroup. At diagnosis, mean (SD) hemoglobin (Hb) levels were 9.61 (2.22) g/dL and 9.40 (1.88) g/dL, mean (SD) bilirubin levels were 1.95 (0.83) mg/dL and 1.65 (0.37) mg/dL in the CAD group and CAD-SUT subgroup, respectively. At enrollment, Hb was well controlled with mean (SD) levels of 11.25 (1.86) g/dL in the total CAD group and 11.55 (2.02) g/dL in the CAD-SUT subgroup. At enrollment, hemolysis was better controlled in the CAD-SUT subgroup as indicated by the normalization of mean (SD) bilirubin levels (mg/dL) [1.15 (0.94) mg/dL]; compared to 1.64 (0.98) mg/dL in the CAD group. Demographics and clinical characteristics similar to the CAD group were observed in pts with CAS. At enrollment, the FACIT-Fatigue [CAD, 34.93 (12.77); CAD-SUT, 41.83 (11.06)], SF-36 PCS [CAD, 42.89 (10.50); CAD-SUT, 47.86 (8.15)], and SF-36 MCS [ CAD, 48.03 (11.07); CAD-SUT, 50.46 (12.64)] scores were higher in the CAD-SUT subgroup, compared to the CAD group. At enrollment, the proportion of physicians assessing patient response to current treatment as “excellent” or “good” was higher in the CAD-SUT subgroup (91.7%) than the total CAD group (68.5%). Prior to or at enrollment, 55 (49.1%) and 7 (33.3%) pts received any transfusion in the total CAD and total CAS group. The number of pts that received any transfusion in subgroups were: 14 (28.0%) treatment-naive, 9(60.0%) CAD-SUT ongoing, 26 (78.8%) other CAD treatment ongoing, 6 (42.9%) previously on CAD therapy. At enrollment, among the pts receiving ongoing CAD treatment other than SUT (n=33), the most common treatments were rituximab (15.2%), folic acid derivatives (57.6%), direct factor Xa inhibitors (12.1%) and erythropoietin (12.1%). Among all pts with CAD, the most common treatment prior to enrollment was rituximab either as a monotherapy (33%), or in combination with an antineoplastic agent (1.8%). In the subgroup of pts previously on CAD therapy (n=14), 100% had a history of rituximab treatment; about 50% of pts in the CAD-SUT subgroup and the ongoing CAD treatment subgroup and 33.4% of CAS pts had a history of rituximab use. Rituximab monotherapy was the most prescribed treatment as first or second-line therapy in all subgroups. Conclusion In this first interim analysis from the ongoing CADENCE registry, about 50% of enrolled pts with CAD were treatment-naive; among pts with ongoing or history of CAD treatment, the most common treatment prior to enrollment was rituximab, more commonly used as a monotherapy. This initial real-world data on SUT-treated pts is consistent with results from clinical trials, demonstrating the benefit of SUT in managing anemia and hemolysis, and in addressing PROs. Further analyses will provide more insights about the natural history of CAD and CAS and long-term clinical outcomes of SUT.

Autoimmune hemolytic anemia (AIHA) is a rare autoantibody-mediated disease. For steroid and/or rituximab-refractory AIHA, there is no consensus on optimal treatment. Daratumumab, a monoclonal antibody targeting CD38, could be beneficial by suppression of CD38+ plasma cells and thus autoantibody secretion. In addition, because CD38 is also expressed by activated T cells, daratumumab may also act via immunomodulatory effects. We evaluated the efficacy and safety of daratumumab monotherapy in an international retrospective study including 19 adult patients with heavily pretreated refractory AIHA. In warm AIHA (wAIHA, n = 12), overall response was 50% with a median response duration of 5.5 months (range, 2-12), including ongoing response in 2 patients after 6 and 12 months. Of 6 nonresponders, 4 had Evans syndrome. In cold AIHA (cAIHA, n = 7) overall hemoglobin (Hb) response was 57%, with ongoing response in 3 of 7 patients. One additional patient with nonanemic cAIHA was treated for severe acrocyanosis and reached a clinical acrocyanosis response as well as a Hb increase. Of 6 patients with cAIHA with acrocyanosis, 4 had improved symptoms after daratumumab treatment. In 2 patients with wAIHA treated with daratumumab, in whom we prospectively collected blood samples, we found complete CD38+ T-cell depletion after daratumumab, as well as altered T-cell subset differentiation and a severely diminished capacity for cell activation and proliferation. Reappearance of CD38+ T cells coincided with disease relapse in 1 patient. In conclusion, our data show that daratumumab therapy may be a treatment option for refractory AIHA. The observed immunomodulatory effects that may contribute to the clinical response deserve further exploration.

Background Cold agglutinin disease (CAD) is a rare subtype of autoimmune haemolytic anaemia characterised by classical complement pathway-mediated haemolysis, fatigue, and poor quality of life (QoL). Sutimlimab, a C1s inhibitor, rapidly halted haemolysis, and improved patient-reported outcomes (PROs) in patients with CAD in two phase 3 trials (CARDINAL and CADENZA). Here we report PROs from the CADENZA open-label extension (Part B). Methods The first patient was enrolled in CADENZA (NCT03347422) in March 2018 (Part A) and the last patient completed the study in December 2021 (Part B). All patients who completed the 26-week Part A were eligible to receive biweekly doses of sutimlimab in Part B for up to 1 year after the last patient completed Part A. PROs were assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout. Findings In total, 32/39 patients completed Part B; median Part B treatment duration: 99 weeks. Patients switching from placebo to sutimlimab in Part B experienced rapid improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and other PROs. Sustained, clinically important improvements in FACIT-Fatigue were observed throughout Part B in patients who switched to sutimlimab and those continuing sutimlimab treatment (combined-group mean [SE] change from baseline at LV: 8.8 [2.1]). Similarly, the combined-group mean [SE] change for 12-Item Short Form Health Survey physical (4.9 [1.7]) and mental (4.0 [1.8]) component scores exceeded clinically important changes from baseline at LV. EuroQol visual analogue scale showed consistent and sustained increases from baseline with sutimlimab treatment. Following a 9-week washout, all PROs approached baseline values. Interpretation Continued inhibition of the classical complement pathway with sutimlimab results in meaningful long-term improvements in PROs (fatigue and QoL) in patients with CAD. Funding Sanofi.

Objectives: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. This study aimed to identify disease-related symptoms and impacts important to patients with CAD, and to develop a novel CAD-specific patient-reported outcome measure. Methods: Adults with CAD were randomly selected from a United States patient panel to participate in concept elicitation (CE) interviews to identify important symptoms and impacts or cognitive debriefing (CD) interviews to assess the comprehension and relevance of the draft item set. Results: Overall, 37 adults were included (mean [range] age 67.2 [35-87] years). In CE interviews (n = 16), the most frequently reported CAD-related symptoms were reactions to cold environments and fatigue (both 93.8%). CAD had negative impacts on enjoyable activities (81.3%) and daily activities (75.0%). Following CE, standard survey methodological principles were used to develop a draft item pool of 14 concepts. Items were refined through three iterative rounds of CD interviews (n = 21), yielding 11 final items: fatigue; cold sensitivity; dyspnea; wearing extra clothing; limited physical, social, and enjoyable activities; difficulty with usual activities; mood; frustration; and anxiety/stress. Conclusions: The novel 11-item CAD-Symptoms and Impact Questionnaire provides a measure of the symptoms and impacts of CAD that are important to patients.

Topic: 35. Quality of life and palliative care Background: Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia that is mediated by the classical complement pathway, leading to chronic hemolysis, fatigue, and poor quality of life (QoL). Treatment with sutimlimab – a C1s complement inhibitor – rapidly halted hemolysis, increased hemoglobin levels, and improved fatigue in patients with CAD with no recent history of transfusion (≤1 during the previous 12 months; 0 during the last 6 months) in the randomized, double-blind, placebo-controlled Part A of the Phase 3 CADENZA trial (NCT03347422). Rapid improvements compared with placebo were also observed for patient-reported outcomes (PROs) up to 26 weeks. Aims: To report the long-term effect of sutimlimab treatment on PROs in patients with CAD from Part B, the open-label extension of CADENZA. Methods: All patients who completed Part A were eligible to receive biweekly doses of sutimlimab in Part B (6.5 g if <75 kg or 7.5 g if ≥75 kg body weight), continuing up to 1 year after the last patient finished Part A. PRO endpoints included: incidence of solicited symptomatic anemia (presence/absence of fatigue, weakness, shortness of breath, palpitations, light-headedness, and/or chest pain) and change in these symptoms by visit (improvement, unchanged, or worsened); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score; 12-Item Short Form Health Survey (SF-12) physical and mental component score (PCS, MCS); EuroQol visual analog scale (EQ-VAS); Patient Global Impression of Change (PGIC), and Patient Global Impression of [fatigue] Severity (PGIS). Results: In total, 39 patients entered Part B, and 32 (82.1%) completed. At Part A baseline (BL), 31/39 (79.5%) patients reported at least one solicited symptom of anemia, which decreased to 10/28 (35.7%) in all patients at Week 87 (Figure 1A). The most reported symptoms of anemia were fatigue, weakness, and shortness of breath at both time points. Improvement in at least one solicited symptom of anemia versus BL was observed in 22/28 (78.6%) at Week 87. Improvements in FACIT-Fatigue from BL were seen throughout Part B, with the mean change exceeding the clinically important change (CIC) of 5 points at all Part B visits up to Week 87 (Figure 1B). Improvements in PCS and MCS component scores of the SF-12 versus BL were observed in Part B, with a mean (SE) change from BL at Week 87 of 7.20 (2.06) and 3.93 (1.92) points respectively (n=27 for both). For the PCS, improvements were sustained above the CIC of 3.9 points through 87 weeks. EQ-VAS showed a consistent increase from BL, with mean (SE) change from BL at Week 87 of 15.57 (4.01, n=28) points. PGIC remained positive throughout the treatment period, with 20/28 (71.4%) of patients still reporting improvement from BL at Week 87. PGIS improved from 14/30 (46.7%) patients reporting “none” or “mild” fatigue at BL to 22/28 (78.5%) at Week 87. Summary/Conclusion: Sustained benefits from sutimlimab treatment in CADENZA Part B were observed across several PRO measures for 1 year or more after initiation of sutimlimab. These findings demonstrate that continued inhibition of the classical complement pathway via treatment with sutimlimab results in meaningful long-term benefits to fatigue and patient-reported QoL, in addition to improving symptomatic anemia in patients with CAD. Figure:Keywords: Autoimmune hemolytic anemia (AIHA), Quality of life, Patient reported outcomes

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. Although there is consensus on an increased risk of thromboembolic events (TEs) in patients with CAD than those without CAD, the evidence on mortality is mixed and the association of both risks with the time since disease diagnosis and biomarker levels has been rarely assessed. Aims: This study evaluated whether patients with CAD have higher risk of mortality and TEs compared with a matched non-CAD population at various time periods since diagnosis. The association between biomarker levels (hemoglobin [Hb], bilirubin, and lactate dehydrogenase [LDH]) and the risk of mortality and TEs in CAD patients was also assessed. Methods: This was a retrospective, cohort study of CAD patients and exact-matched non-CAD patients in the US, identified using the OPTUM® de-identified Electronic Health Record dataset (2007-2021). Mortality and TEs were assessed over the full follow-up period (till the end of medical activity, study period, or death) and at pre-defined time periods (100 days, 1 year, 2 years, 3 years, 5 years, and 10 years) from CAD diagnosis. Biomarker levels were assessed during follow-up, and categorized as follows: bilirubin: severe, >2.4 mg/dL; moderate, >1.2─≤2.4 mg/dL; normal, ≤1.2 mg/dL, LDH: severe, >500 U/L; moderate, >250─≤500 U/L; normal, ≤250 U/L, Hb: no anemia, Hb ≥12 g/dL; mild, Hb ≥10─<12 g/dL; moderate, Hb ≥8─<10 g/dL; and severe, Hb <8 g/dL. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) were obtained for the pre-defined time periods using multivariate cox proportional hazards regression analyses. Time-varying cox regressions were used in the CAD cohort to analyze the association between biomarkers (all observations until event) and risk of mortality or TE. Results: Overall, 457 patients with CAD and 2285 exact-matched non-CAD patients were included. The mortality and TE risks in CAD compared with non-CAD cohorts were significantly higher, particularly in the early periods after diagnosis (e.g., 100 day aHR [95% CI], mortality: 16.36 [6.83─39.19]; TE: 4.92 [3.22─7.45]; both P<0.001) compared with longer periods (e.g., 10 year aHR [95% CI], mortality: 2.26 [1.84─2.77]; TE: 2.08 [1.71─2.53]; both P<0.001) (Table 1). In the CAD cohort, patients with mild, moderate, or severe anemia had significantly higher risk of mortality than those without anemia (mild: aHR [95% CI]: 2.55 [1.40─4.65]; P=0.002; moderate: 7.00 [4.00─12.23]; and severe: 16.70 [9.14─30.34]; both P=0.001). Moderate and severe anemia were also correlated with higher risk of TEs compared with no anemia (aHR [95% CI]: 2.16 [1.28─3.64]; P=0.004 and 3.37 [1.81─6.26]; P=0.001, respectively). Severe bilirubin (aHR [95% CI]: 3.03 [1.98─4.64]; P=0.001) and severe LDH levels (aHR [95% CI]: 2.31 [1.29─4.13]; P=0.005) were associated with increased risk of mortality compared with normal levels. Summary/Conclusion: The clinical burden associated with CAD is significant and extends beyond anemia. Patients with CAD were twice more likely to die or experience TEs than those without CAD. These risks were particularly high in the early periods after diagnosis with mortality risk 16 times and TE risk 5 times higher in the first 100 days. Within the CAD cohort, severely deranged markers of hemolysis (LDH, bilirubin) and anemia were associated with increased mortality risk. Moderate and severe anemia were also associated with increased TE risk. Early and chronic control of complement activation and the resulting hemolysis in CAD may therefore help manage the risk of mortality and TEs.Keywords: Thromboembolic events, AIHA (see autoimmune hemolytic anemia), Hemoglobin, Mortality

The last 15 years have shown great progress in the management of immune thrombocytopenia (ITP), ranging from the introduction and licensing of two thrombopoietin receptor agonists (TPORA), eltrombopag and romiplostim, to more recently, a Syk tyrosine kinase inhibitor (fostamatinib) and two other TPORA (avatrombopag and hetrombopag). Novel therapies are being evaluated in phase 3 studies (inhibitors of BTK, FcRn and BAFF) while others have also been evaluated in clinical trials (e.g. Mycophenolate Mofetil, ATRA and oseltamivir).1 These advances have dramatically altered ITP management. Splenectomy, previously standard secondline therapy, is now rarely performed.2 In many parts of the world, patients are being treated with TPORA which are as effective as splenectomy but often require continuous administration. With the growing number of medical options, substantially fewer patients are becoming “refractory.” These advances mandate reassessment of the following conceptual definitions and goals in the treatment of ITP: disease phases, treatment response, remission, refractory, treatment goals and acceptable target platelet levels. The International Consensus Report3 and the American Society of Hematology (ASH) guidelines,4 together with an international working group (IWG) document on standardisation of terminology, definitions and outcome criteria5 define the management of ITP in much of the world. While developing recommendations can be prolonged and resourceintensive, they can also become quickly outdated. Current classification is into three phases: newly diagnosed (0– 3 m), persistent (>3– 12 m) and chronic (>12 m). The stated aim was guiding clinicians to defer splenectomy until the potential for spontaneous remission is over.5 However, patients in newly diagnosed or persistent phases have been excluded from some trials of novel treatments. Authorities licence successful therapies accordingly, thus introducing timedependent limits on access to treatment because reimbursement by health care systems is likely to be rejected outside the phases examined in trials. Phase boundaries are arbitrary cutoffs and are not based on pathophysiology. The use of these phases, which are discouraged for autoimmune haemolytic anaemia terminology,6 may no longer serve our patients. In contrast, the clinically pragmatic IWG definition of response: platelets >30 × 109/L, double baseline and absence of bleeding, has not been widely adopted in trials.7 Instead, studies designed for regulatory approval often require sustained platelets >50 × 109/L, potentially underestimating the clinical value of lower platelet targets. But even the IWG “response” may be inadequate when treatment is personalised. For example, other clinical variables affecting bleeding risk (age, prior bleeding events, anticoagulant use) may require a different “haemostatic” response, say >50 × 109/L for patients on dual antiplatelet therapy. Finally, the IWG threshold of complete response (platelets >100 × 109/L) may not be useful or predictive of bleeding risk. Also infrequently reported but of equal relevance for clinical outcome is the “durability” of treatment response. IWG proposed “proportion of cumulative time spent with response” for maintenance treatment. If this was measured as the percentage of weeks with a response, this is clinically relevant in comparing treatments. An acceptable definition of “remission” has not been created but is variably reported in studies. In many diseases, this term reflects the absence of disease activity, and the absence of concurrent therapy may not be critical. In this quest for clarity, whether “response”, “durability” or “remission” is the result of ongoing maintenance treatment is relevant given that many ITP therapies such as the TPORA may be ongoing. The likelihood of successfully discontinuing a maintenance treatment is of great interest to patients and providers of health care resources. Further confounding the concept of “maintenancefree” is that some treatment effects persist after the treatment ends; Bcell depletion may last for months or years after rituximab and splenectomy creates a lifelong disorder of asplenia. Does an ITP patient with a normal platelet count after splenectomy have an unmaintained remission? The exact meaning of a “line” of treatment, has not yet been addressed by the IWG. If the patient initially receives prednisolone and IVIg together, is that one line of combination treatment, one line and one rescue or two lines? If they then receive romiplostim and then rituximab, have they received second and third line, or two “second line” treatments? The International Consensus eschewed the concept of “lines” and simply referred to “initial” then “subsequent therapy”. As use of splenectomy declines, the definition of “refractory” ITP, which currently requires patients to be nonresponders or losing splenectomy response, needs updating. The standardisation of terminology within a field should be the domain of a single IWG, seeking broad Received: 4 March 2023 | Accepted: 23 March 2023

Disease relapse is recognized as a risk in immune-mediated thrombotic thrombocytopenic purpura (iTTP) after treatment of the acute presenting episode. Identification of patients at risk of relapse and its patterns are yet to be clearly established. We reviewed patients with iTTP having had >3 years of follow-up over 10 years in the United Kingdom to identify patient characteristics for relapse, assess relapse rates and patterns, and response to anti-CD20 therapy in those with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) relapses (ADAMTS13 activity of <20% without thrombocytopenia). We identified 443 patients demonstrating relapse rates of 40% at 5-year follow-up. At 10-year follow-up, no difference in relapse was observed irrespective of whether rituximab was used at acute presentation (P = .39). Black Caribbean ethnicity increased the risk of disease relapse in the British population. There was a distinct population of patients (6%) that relapsed early with subsequent frequent relapses occurring on average within 2 years (average time to relapse in subgroup, 1.7 years). Overall, nearly 60% of relapses described were ADAMTS13 relapses, with subsequent treatment reducing the risk of progression to clinical relapses. We demonstrate that iTTP diagnosed in the latter part of the study period had lower rates of clinical relapses (22.6% vs 11.1%, P = .0004) with the advent of regular monitoring and preemptive rituximab. In ADAMTS13 relapses, 96% responded to anti-CD20 therapy, achieving ADAMTS13 activity of >20%. Anti-CD20 therapy was demonstrated to be an effective long-term treatment regardless of relapse pattern and there was no loss of this treatment response after subsequent treatment episodes.

Background: Cold agglutinin disease (CAD) is a rare chronic autoimmune hemolytic anemia that is mediated by classical complement pathway activation, leading to fatigue and poor quality of life (QoL). In the randomized, double-blind, placebo-controlled Part A of the Phase 3 CADENZA trial (NCT03347422), treatment with sutimlimab - a C1s complement inhibitor - rapidly halted hemolysis, increased hemoglobin levels and improved fatigue in CAD patients with no recent history of transfusion. Rapid improvements compared to placebo were also observed for patient-reported outcomes (PROs) up to 26 weeks. Aim: To report the long-term effect of sutimlimab treatment on patient-reported outcomes in patients with CAD from the open-label Part B extension of CADENZA. Methods: In the open-label extension Part B, all patients who had completed Part A were eligible to receive biweekly doses of sutimlimab at 6.5 g (if <75 kg) or 7.5 g (if ≥75 kg), continuing until 1 year after the last patient completed Part A. PRO endpoints included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 12-Item Short Form Health Survey (SF-12), EuroQol visual analogue scale (EQ-VAS), Patient Global Impression of Change from baseline (PGIC), and Patient Global Impression of fatigue Severity (PGIS). Results: Of the 42 patients enrolled in Part A of the study, 39 completed Part A and entered Part B, with 32 (82.1%) patients completing Part B. Patients randomized to sutimlimab in Part A showed a clinically meaningful improvement in FACIT-Fatigue mean score over baseline that exceeded the clinically important change (CIC) of 5 points by Week 1, and this was sustained at Week 87 (n=13), beyond one year after completing Part A (Figure Panel A). Patients who were randomized to placebo in Part A (ex-placebo) demonstrated rapid improvement in FACIT-Fatigue scores upon initiating sutimlimab treatment in Part B. In this group, mean (SE) change from baseline in FACIT-Fatigue score was 7.96 points (2.83, n=18) by their first assessment after switch to open-label treatment in Part B (13 weeks after sutimilimab initiation), and mean improvements were sustained above CIC for over one year from completion of Part A. Improvements in the physical (PCS) and mental (MCS) component scores of the SF-12 in patients receiving sutimlimab in Part A were also considered to be above the CICs, determined as changes above 3.9 and 2.8 points respectively. Improvements from baseline above CIC were sustained in the PCS through 87 weeks in all patients in Part B. In Part B, the MCS remained above CIC for all patients treated with sutimlimab in Part A; improvements to MCS among patients from the ex-placebo group were consistently improved from baseline and exceeded CIC at Week 75. The mean (SE) changes from baseline for all patients at 87 weeks for PCS and MCS were 7.2 (2.06, n=27) and 3.93 (1.92, n=27), respectively. EQ VAS showed a consistent increase from baseline in all patients with mean (SE) change from baseline at Week 87 of 15.57 (4.01, n=13) points. PGIC remained positive throughout the treatment period, with 93.3% of patients still reporting improvement from baseline at Week 87. PGIS improved from 46.7% reporting no or mild fatigue at baseline to 78.6% at Week 87 (Figure Panel B). Conclusion: The PRO data in Part B demonstrated sustained benefits from sutimlimab for patient QoL beyond 26 weeks, and one year or more after initiation of sutimlimab. These findings demonstrate that continued inhibition of the classical complement pathway via treatment with sutimlimab results in meaningful long-term benefits to fatigue and patient-reported QoL, in addition to improving hematologic parameters in patients with CAD. This study was registered at www.clinicaltrials.gov: NCT03347422. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BACKGROUND:Adult primary immune thrombocytopenia (ITP) is a rare bleeding disorder of unknown cause. Recent estimates of its incidence and trend over time were acquired for England. METHOD:The primary ITP population (using ICD 10 code D693 and excluding secondary ITP cases; positive predictive value: 82.6%) was sourced from NHS Digital inpatient and outpatient. Incidence rate (IR) for England and by age groups, sex, and regions were calculated and trends were assessed using average annual percent change (AAPC). RESULTS:A total of 25 805 patients (mean age 59 years; females 57.8%) diagnosed between 2003 and 2014 was identified. IRs increased from 4.2/100 000 to 6.4/100 000 over this period (AAPC:4.3%). For all sex-specific age groups, the IRs significantly increased over time, except 18-29 years males. The greatest increase was among females aged 30-39 (AAPC:8.7%). In contrast, among ≥70 years, ITP was more common in males (highest IR among ≥80 years males: 23.9/100 000). England's average annual IR was 6.1/100 000 for 2010-14. An estimated 2.5/100 000 (based on UKITP Registry data) was estimated to require 1st line treatment whereas 2.4/100 000 would have 1st and 2nd line treatments within 6 months from diagnosis. IRs for London and East Midlands were the highest (6.5/100 000). CONCLUSIONS:This study found a rising incidence of primary ITP, with sharp increases among young women and elderly men. These findings put in context the impact of ITP on patients' lives and the healthcare services in England, especially with 17%-50% who may develop chronic ITP and require long-term care.

A single 1 g/kg dose of intravenous immunoglobulin is a safe and effective treatment for immune thrombocytopenia; results of the first HaemSTAR 'Flash-Mob' retrospective study incorporating 961 patients Key Messages 1 A one off 1 g/kg infusion of intravenous immunoglobulin (IVIg) may be as effective as two consecutive 1 g/kg doses. 2 This is the largest ever study of the efficacy of IVIg for immune thrombocytopenia (ITP).3 There is poor adherence to the 2016 NHS England guidelines on IVIg dosing.

Background: Cold agglutinin disease (CAD) is a rare hemolytic anemia. Sutimlimab, a humanized monoclonal anti-C1s antibody, received approval in the United States following results of the Phase 3 CARDINAL (NCT03347396) trial. Aims: This post-hoc analysis aimed to describe the characteristics of patients with CAD who received prior off-label rituximab treatment versus rituximab-naïve patients and present the efficacy of sutimlimab in these subgroups, using pooled data from the Phase 3 CARDINAL and CADENZA (NCT03347422) trials. Methods: CARDINAL was an open-label, single-arm, multicenter study for patients with a recent blood transfusion. CADENZA was a randomized, double-blind, placebo-controlled, multicenter study in patients without a recent blood transfusion. Included patients had a hemoglobin (Hb) level of ≤10 g/dL and were excluded if they received rituximab monotherapy <3 months, or combination therapy <6 months, prior to enrollment. For this analysis, composite efficacy endpoint was response rate; responders received no blood transfusions or prohibited medications from Week 5 to 26, and had an improvement in Hb from baseline of ≥2.0 g/dL (level chosen for post-hoc analysis) or a Hb level of ≥12 g/dL, at an average of Weeks 23, 25, and 26 (treatment assessment timepoint [TAT]). Secondary endpoints included mean change from baseline to TAT in Hb, bilirubin, lactate dehydrogenase (LDH), and FACIT-Fatigue score. Endpoints were analyzed descriptively according to prior rituximab use (previous monotherapy and/or combination therapy). Results: Overall, 46 patients receiving sutimlimab were included in this analysis (CARDINAL, n=24; CADENZA, n=22) and mean (SD) time between last rituximab intake and sutimlimab treatment start date was 26.4 (24.0) months. At baseline, 54% (n=25) of patients had prior rituximab use; mean number of rituximab courses received prior to trial enrollment was 1.92. Mean (SD) age was 67.8 (9.7) for patients with prior rituximab use and 69.2 (10.4) years for rituximab-naïve patients. Baseline clinical and laboratory characteristics were similar between subgroups, including Hb, bilirubin, LDH, and FACIT-Fatigue score; however, in CADENZA, immunoglobulin M level and cold hemagglutinin titer were greater in the rituximab-naïve subgroup versus the prior rituximab group (Table). Accounting for differences in blood transfusion inclusion criteria between CARDINAL and CADENZA, in both trials at baseline there were a greater number of blood transfusions in patients with versus without prior rituximab use (Table). CAD disease duration was longer and corticosteroid use was greater in patients with prior rituximab versus those without. In CARDINAL, CAD-related hospitalizations were greater in prior rituximab users (84.6%) versus those with no prior use (45.5%). The response rate was 60% in patients with prior rituximab use (n=15/25) and 67% in rituximab-naïve patients (n=14/21). Mean (SD) change from baseline to TAT in Hb level was 2.6 (1.8) and 2.7 (1.8) g/dL for patients with versus without prior rituximab use, respectively. Corresponding values for bilirubin were -28.5 (18.9) versus -25.6 (11.9) µmol/L, and for LDH were -183.8 (267.8) versus -58.9 (178.2) U/L. Mean (SD) change in FACIT-Fatigue score was similar in both subgroups (9.9 [13.0] and 9.8 [11.4], respectively). Image:Summary/Conclusion: In this post-hoc analysis, response rates were similar between subgroups of patients with prior off-label rituximab treatment versus rituximab-naïve patients. These results suggest that sutimlimab is effective in patients with CAD, irrespective of prior off-label rituximab use.

Key Content The haemoglobinopathies encompass a complex collection of red blood cell disorders that are responsible for considerable morbidity and mortality in women and their unborn children. Sickle cell disease and the thalassaemias are the commonest haemoglobinopathies encountered in UK clinical practice. A consistent standard of care will enable women with haemoglobinopathies to have a pregnancy that is as safe as possible, with good outcomes and minimal long‐term effects on their health and the health of their babies. The most effective way to deliver a consistent standard of care for these women is via the multidisciplinary team (MDT). The MDT should include a haematologist, cardiologist, maternal medicine obstetrician, specialist midwife, reproductive medicine specialist and a nurse specialist. The care of these women, within the MDT, should start with pre‐conception advice and continue through their antenatal care, intrapartum support and finally, provide postnatal considerations including contraception advice. Learning Objectives To understand the inheritance, incidence, detection and pathophysiology of the commonest haemoglobinopathies. To appreciate the role of pre‐conception advice and prenatal diagnosis in the management of women with a haemoglobinopathy. To appreciate the multidisciplinary team approach in managing women with these conditions. Ethical Issues Prenatal diagnostic techniques can be used to diagnose an affected pregnancy; however, diagnosis after conception means families must address the option of terminating the pregnancy. This requires expert counselling to minimise long‐term sequelae. The definitive prenatal tests – chorionic villus sampling and amniocentesis – are both associated with a small risk of miscarriage. Non‐invasive free fetal DNA (ffDNA) tests that will minimise the risk of testing to the developing fetus are being developed, but use of these tests will still require expert counselling both before and after a test is taken.