The latest insights into rare blood disorders: Diagnosis and treatment strategies.

Please visit https://bit.ly/AJHpodcast to complete the accredited learning activity and receive CME credit or NCPD contact hours. Because immune-mediated rare blood disorders are uncommon, healthcare providers often lack the knowledge and experience necessary to identify, diagnose, and treat them in accordance with best practices. As a result, there are significant gaps in care, including delays in diagnosis and suboptimal treatment. To ensure that more patients with these rare disorders are offered quality, evidence-based care, it is essential that healthcare providers possess up-to-date information about best practices and new developments in this area of medicine. In this activity, composed of three podcasts, an expert moderator will interview three expert faculty members about evidence-based guidelines for the diagnosis and treatment of acquired thrombotic thrombocytopenic purpura; developments in the diagnosis and treatment of cold agglutinin disease; and the challenges of achieving enduring remission in patients with immune thrombocytopenia.

Hypertension treatment for patients receiving ibrutinib: a multicenter retrospective study.

ABSTRACT: Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took ß blockers (BBs) with hydrochlorothiazide (HCTZ), (-5.05 mmHg; 95% confidence interval [CI], 10.0 to -0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (-5.47 mmHg; 95% CI, 10.9 to -0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

COVID-19 vaccine safety and immunogenicity in patients with cold agglutinin disease receiving concomitant sutimlimab.

Patients with cold agglutinin disease (CAD) are more vulnerable to infectious agents, thus the COVID-19 pandemic has posed a particular risk to this population. Sutimlimab Phase 3 studies CARDINAL and CADENZA spanned the period before and during the pandemic; investigators were advised to vaccinate enrolled patients without stopping treatment. Of 61 completers from both studies, 47 received ≥1 dose of a COVID-19 vaccine. In the immunogenicity analysis (n = 27) all patients developed an immune response post-COVID-19 vaccination, with detectable immunoglobulin G anti-spike antibodies. Analysis of six patients with booster vaccinations demonstrated increased immune responses pre- to post-booster. COVID-19 vaccines were well tolerated in patients with CAD receiving sutimlimab treatment, and no signs of hemolytic exacerbations were observed post-vaccination.

Efficacy and safety of the neonatal Fc receptor inhibitor efgartigimod in adults with primary immune thrombocytopenia (ADVANCE IV): a multicentre, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Primary immune thrombocytopenia is an autoimmune disorder mediated partly by platelet autoantibodies, resulting in thrombocytopenia, bleeding, and constitutional symptoms. Efgartigimod, a first-in-class novel human IgG1 Fc fragment, binds the neonatal Fc receptor with high affinity and thus reduces serum IgG concentrations, including autoantibodies. The objective of this study was to evaluate the efficacy and safety of efgartigimod in adults with persistent and chronic primary immune thrombocytopenia. METHODS: This phase 3, multicentre, randomised, double-blinded, placebo-controlled, 24-week study evaluated the efficacy and safety of intravenous efgartigimod in adults aged 18 years or older with chronic or persistent primary immune thrombocytopenia who had an average platelet count of less than 30 000, had responded to at least one previous immune thrombocytopenia therapy, and were on a concurrent therapy at baseline or had received at least a second previous immune thrombocytopenia therapy. The study took place in 71 participating sites from Asia, Europe, and North America. Patients were randomly assigned 2:1 to receive either efgartigimod (10 mg/kg) or placebo intravenously for the first 4 weeks, after which the dosing schedule could be altered to once per week or every other week depending on the patients' platelet count. The primary endpoint, evaluated in the chronic population, was sustained platelet count response (≥50 × 109 for at least 4 of the last 6 weeks). This study is registered with ClinicalTrials.gov (NCT04188379) and is completed. FINDINGS: A total of 205 patients were screened from Dec 9, 2019, to Feb 3, 2022, and 131 (86 in the efgartigimod group; 45 in the placebo group) were randomly assigned. These patients represented a population with long-term disease who had a mean time since diagnosis of 10·6 years and 67% (88/131) of whom had received at least three previous immune thrombocytopenia treatments. 22% (17/78) of patients with chronic immune thrombocytopenia receiving efgartigimod reached the primary endpoint compared with 5% (2/40) of those receiving placebo (p=0·032; adjusted difference in response, 16% [95% CI 2·6-26·4]). The median number of weeks of disease control in patients with chronic immune thrombocytopenia was 2·0 (IQR 0·0-11·0) for efgartigimod versus 0·0 (0·0-1·0) for placebo (p=0·0009). Efgartigimod was well tolerated; most adverse events were mild to moderate in severity. The most common adverse events of interest in both groups were headache (16% in efgartigimod and 13% in placebo), haematuria (16% in efgartigimod and 16% in placebo), and petechiae (15% in efgartigimod and 27% in placebo). INTERPRETATION: Efgartigimod significantly increased sustained platelet count responses compared with placebo in patients with chronic immune thrombocytopenia, including those who had received multiple previous immune thrombocytopenia therapies. Upon completion of the ADVANCE IV study, patients could enroll in the ongoing open-label extension. Subcutaneous efgartigimod is currently being evaluated in patients with immune thrombocytopenia in the ADVANCE SC+ trial. FUNDING: argenx.

Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up.

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia with a substantial burden on patient's quality of life. CARDINAL was a 2-part, open-label, single-arm, multicenter phase 3 study evaluating the C1s inhibitor, sutimlimab, for treatment of CAD. Part A consisted of the pivotal study phase, with the part B extension phase assessing long-term safety and durability of response including patient-reported outcomes, which is the focus of this report. Altogether, 22 patients continued from part A to part B, majority female (68.2%) with a median age of 71.5 years (range, 55-85). Throughout treatment, score improvement on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale exceeded a predefined, group-level clinically important change of ≥5 points vs baseline, with a mean (standard error [SE]) change of 11.7 (3.7) points at week 135. The 12-Item Short Form Health Survey physical and mental component scores remained above baseline, with week 123 mean change (SE) exceeding clinically important changes of 3.9 for physical and 2.8 for mental component scores at 4.7 (2.8) and 3.8 (5.7) points, respectively. EuroQol Visual Analogue Scale, scoring patients' self-rated health, also remained above baseline with a change of 17.1 (5.6) points at week 135. Patient Global Impression of (fatigue) Severity improved vs baseline, corroborating FACIT-Fatigue scores. Patient Global Impression of Change indicated a reduction in perceived disease burden. Data from CARDINAL part B support sustained alleviation of CAD disease burden after long-term treatment with sutimlimab over 2 years, returning toward baseline upon treatment cessation. This trial was registered at www.clinicaltrials.gov as #NCT03347396.

Efgartigimod alfa for the treatment of primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia. Most patients with ITP have antiplatelet antibodies of the immunoglobulin G (IgG) subtype which through interaction with platelet and megakaryocyte glycoproteins result in increased platelet destruction and inhibition of platelet production. There are a variety of therapeutic options available for the treatment of ITP including corticosteroids, IVIgG, TPO-RA, rituximab, fostamatinib, and splenectomy. Long-term remissions with any of these therapies can vary widely and patients may require additional therapy. The neonatal Fc receptor (FcRn) plays a pivotal role in IgG and albumin physiology through recycling pathways. Efgartigimod is a human IgG1-derived fragment that has been modified by ABDEG technology to increase its affinity for FcRn at both physiologic and acidic pH. The binding of efgartigimod to FcRn blocks the interaction of IgG with FcRn facilitating increased lysosomal degradation of IgG and decreasing total IgG levels. Based on the mechanism of action and the known pathophysiology of ITP as well as the efficacy of other therapies such as intravenous immunoglobulin (IVIG), the use of efgartigimod in patients with ITP is attractive. This article will briefly discuss the pathophysiology of ITP, current treatments, and the data available on efgartigimod in ITP.

Complement-directed therapy for cold agglutinin disease: sutimlimab.

INTRODUCTION: Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia defined as a distinct, low-grade lymphoproliferative disorder and characterized by the presence of immunoglobulin M (IgM) antibodies that recognize the 'I' antigen on red blood cell membranes. Hemolysis in CAD is mediated by activation of the classical complement pathway by IgM-antigen complexes. Sutimlimab directly targets classical complement pathway activation and has been shown to be generally well tolerated with rapid and sustained effects on hemoglobin levels, hemolytic markers, and fatigue in patients with CAD. AREAS COVERED: This review will outline the drug profile of sutimlimab and summarize the key efficacy and safety data focusing on the Phase 3 studies that formed the basis of the approval of sutimlimab in patients with CAD in the US, the EU, and Japan. EXPERT OPINION: Sutimlimab provides patients with an approved therapeutic option that can be used as part of a holistic approach to CAD management. The beneficial effects of sutimlimab go beyond rapid inhibition of hemolysis and include sustained meaningful improvements in fatigue and quality-of-life measures. Further, real-world evidence of the effectiveness and safety of sutimlimab in CAD and cold agglutinin syndrome will be assessed via the CADENCE registry.

Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare, autoimmune, classical complement pathway (CP)-mediated hemolytic anemia. Sutimlimab selectively inhibits C1s of the C1 complex, preventing CP activation while leaving the alternative and lectin pathways intact. In Part A (26 weeks) of the open-label, single-arm, Phase 3 CARDINAL study in patients with CAD and a recent history of transfusion, sutimlimab demonstrated rapid effects on hemolysis and anemia. Results of the CARDINAL study Part B (2-year extension) study, described herein, demonstrated that sutimlimab sustains improvements in hemolysis, anemia, and quality of life over a median of 144 weeks of treatment. Mean last-available on-treatment values in Part B were improved from baseline for hemoglobin (12.2 g/dL on-treatment versus 8.6 g/dL at baseline), bilirubin (16.5 µmol/L on-treatment versus 52.1 µmol/L at baseline), and FACIT-Fatigue scores (40.5 on-treatment versus 32.4 at baseline). In the 9-week follow-up period after sutimlimab cessation, CP inhibition was reversed, and hemolytic markers and fatigue scores approached pre-sutimlimab values. Overall, sutimlimab was generally well tolerated in Part B. All 22 patients experienced ≥1 treatment-emergent adverse event (TEAE); 12 (54.5%) patients experienced ≥1 serious TEAE, including seven (31.8%) with ≥1 serious infection. Three patients discontinued due to a TEAE. No patients developed systemic lupus erythematosus or meningococcal infections. After cessation of sutimlimab, most patients reported adverse events consistent with recurrence of CAD. In conclusion, the CARDINAL 2-year results provide evidence of sustained sutimlimab effects for CAD management, but that disease activity reoccurs after treatment cessation. NCT03347396. Registered November 20, 2017.

Sutimlimab provides clinically meaningful improvements in patient-reported outcomes in patients with cold agglutinin disease: Results from the randomised, placebo-controlled, Phase 3 CADENZA study.

Cold agglutinin disease (CAD) is a rare chronic autoimmune haemolytic anaemia, driven mainly by classical complement pathway activation, leading to profound fatigue and poor quality of life. In the Phase 3 CADENZA trial, sutimlimab-a C1s complement inhibitor-rapidly halted haemolysis, increased haemoglobin levels and improved fatigue versus placebo in patients with CAD without a recent history of transfusion. Patient-reported outcomes (PROs) 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 (PGIC) and Patient Global Impression of (fatigue) Severity (PGIS). Sutimlimab resulted in significant rapid and meaningful improvements versus placebo in PROs. From Week 1, the FACIT-Fatigue mean score increased >5 points above baseline (considered a clinically important change [CIC]). Least-squares (LS) mean change in FACIT-Fatigue score from baseline to treatment assessment timepoint was 10.8 vs. 1.9 points (sutimlimab vs. placebo; p < 0.001). Improvements in physical (PCS) and mental (MCS) component scores of the SF-12 were also considered CICs (LS mean changes from baseline to Week 26: PCS 5.54 vs. 1.57 [p = 0.064]; MCS 5.65 vs. -0.48 [p = 0.065]). These findings demonstrate that in addition to improving haematologic parameters, sutimlimab treatment demonstrates significant patient-reported benefits. Study registered at www.clinicaltrials.gov: NCT03347422.

Diminished humoral and cellular responses to SARS-CoV-2 vaccines in patients with chronic lymphocytic leukemia.

Previous studies have demonstrated low rates of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients with chronic lymphocytic leukemia (CLL). In this national collaboration of 11 cancer centers in the United States, we aimed to further characterize and understand vaccine-induced immune responses, including T-cell responses, and the impact of CLL therapeutics (#NCT04852822). Eligible patients were enrolled in 2 cohorts (1) at the time of initial vaccination and (2) at the time of booster vaccination. The serologic response rates (anti-S) from 210 patients in the initial vaccination cohort and 117 in the booster vaccination cohort were 56% (95% confidence interval [CI], 50-63) and 68% (95% CI, 60-77), respectively. Compared with patients not on therapy, those receiving B-cell-directed therapy were less likely to seroconvert (odds ratio [OR], 0.27; 95% CI, 0.15-0.49). Persistence of response was observed at 6 months; anti-S titers increased with the administration of booster vaccinations. In the initial vaccination cohort, positive correlations were observed between the quantitative serologic response and CD4 T-cell response for the Wuhan variant and, to a lesser degree, for the Omicron variant (Spearman P = 0.45 Wuhan; P = 0.25 Omicron). In the booster vaccination cohort, positive correlations were observed between serologic responses and CD4 T-cell responses for both variants (P = 0.58 Wuhan; P = 0.57 Omicron) and to a lesser degree for CD8 T-cell responses (P = 0.33 Wuhan; P = 0.22 Omicron). Although no deaths from coronavirus disease 2019 (COVID-19) have been reported after booster vaccinations, patients should use caution as newer variants emerge and escape vaccine-induced immunity. This trial was registered at www.clinicaltrials.gov as #NCT04852822.

Safety and efficacy of classical complement pathway inhibition with sutimlimab in chronic immune thrombocytopenia.

Chronic/refractory immune thrombocytopenia (ITP) is a rare and pathophysiologically heterogeneous disorder with variable responsiveness to available treatments. Sutimlimab, a first-in-class humanized monoclonal anti-C1s IgG4 antibody, selectively inhibits the classical pathway. This phase 1 study (NCT03275454) assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of biweekly sutimlimab in patients with chronic/refractory ITP with an inadequate response to ≥2 therapies (platelet count ≤ 30 × 109/L). Twelve patients (median age 42 years) received sutimlimab for a median of 20.5 weeks followed by a median 2-week washout period (part A). In part B, 7 of the 12 eligible patients received sutimlimab retreatment for a median of 113 weeks. In part A, the mean (standard deviation) platelet count increased from 25 × 109/L (17) to 54 × 109/L (60) 24 hours after starting sutimlimab, maintaining ≥50 × 109/L throughout part A. Five patients (42%) achieved durable platelet count responses (≥50 × 109/L in ≥50% of follow-up visits) and 4 achieved complete response (platelet count ≥100 × 109/L). The mean platelet count returned to baseline during washout and increased upon retreatment in part B. The mean platelet count improvements accompanied the rapid inhibition of the classical pathway. There were 74 treatment-emergent adverse events in part A (n = 10) and 70 in part B (n = 6). Five serious adverse events were observed; 1 event (migraine) was assessed by the investigator as related to sutimlimab. These results demonstrated that in some patients with ITP, autoantibodies activate the classical complement pathway, accelerating platelet destruction or impairing platelet production and contributing to treatment failure. Thus, C1s inhibition may be a safe and beneficial therapeutic approach for patients with chronic/refractory ITP.

Medically-attended anxiety and depression is increased among newly diagnosed patients with cold agglutinin disease: Analysis of an integrated claim-clinical cohort in the United States.

BACKGROUND: Cold agglutinin disease (CAD) is a rare, chronic form of autoimmune hemolytic anemia. Clinical manifestations can include classical complement pathway-mediated chronic hemolysis, anemia, and profound fatigue. Research has shown that patients with other anemias may develop anxiety and depression, but this has not been studied previously in patients with CAD. METHODS: CAD patients were identified in the Optum Claims-Clinical dataset (between January 1, 2006-June 30, 2016) and matched to comparison patients without CAD by patient factors. Adjusted Cox regression models estimated time to anxiety and depression, defined by three different outcomes: medication use, hospitalization, and therapy related to anxiety and depression. Subset analyses were performed for primary CAD. Patients were followed until they had anxiety and depression, they left the Optum system, death, or the study period ended (June 30, 2016). RESULTS: Patients with CAD (n = 384) were more likely to have medically attended anxiety and depression (adjusted hazard ratio [aHR]: 1.6; 95% confidence interval [CI]: 1.3-2.1), to be prescribed antidepressants or psychotherapy after their CAD diagnosis (aHR: 1.8; 95% CI: 1.2-2.9), or to be hospitalized for an anxiety and depression-related event along with medication or psychotherapy (aHR: 2.0; 95% CI: 1.4-2.9) relative to matched comparisons (n = 2789), during the follow-up period. Patients with primary CAD were at increased risk for medically attended anxiety and depression (aHR: 1.8; 95% CI: 1.4-2.4), with the highest risk for prescription medication or therapy (aHR: 2.7; 95% CI: 1.6-4.6). CONCLUSIONS: Our study indicates that medically attended anxiety and depression manifest at a higher rate in CAD patients than in a matched non-CAD cohort. Study findings suggest that CAD patients may experience a greater burden on mental health that may negatively contribute to their overall quality of life. Further investigation on this topic is warranted.

Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial.

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.

Fostamatinib for the treatment of warm antibody autoimmune hemolytic anemia: Phase 2, multicenter, open-label study.

Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) <10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B-cell lymphoma, COVID-19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double-blind, phase 3 study is nearing completion.

Complement-mediated hemolysis persists year round in patients with cold agglutinin disease.

BACKGROUND: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia mediated by immunoglobulin M autoantibodies that bind to the "I" antigen on erythrocytes. IgM binding results in either agglutination at ≤37°C, activation of the classical complement pathway, or both. Patients with CAD can have transient agglutination-mediated circulatory symptoms triggered by exposure to cold conditions. Separately, patients with CAD can experience complement-mediated symptoms such as anemia, hemolysis, and fatigue, but the effect of the season on these complement-mediated manifestations of CAD and clinical outcomes is not well understood. METHODS: Using data from the Optum® de-identified Electronic Health Record dataset, we compared hemoglobin, markers of hemolysis (bilirubin and lactate dehydrogenase [LDH]), and healthcare resource utilization (HRU) between seasons for 594 patients (62% female; 66% aged ≥65 years) with CAD (defined as having CAD-related terms in their clinical notes on ≥3 separate occasions between December 2008 and May 2016). Laboratory parameters and HRU were compared between seasons using multivariate regression models. RESULTS: Estimated median hemoglobin (9.87 g/dL in summer and 9.86 g/dL in winter; P = 0.944) and bilirubin (1.04 mg/dL in summer and 1.09 mg/dL in winter; P = 0.257) were similar in winter versus summer. While LDH was statistically significantly higher in winter compared with summer (P < 0.001), the estimated median value was above normal for both seasons (309 U/L in summer and 367 U/L in winter). HRU measures and transfusion and thromboembolism rates were similar across seasons. CONCLUSIONS: Patients with CAD had evidence of persistent chronic hemolysis, HRU, and thromboembolism risk year round.

Freeze-dried platelets are a promising alternative in bleeding thrombocytopenic patients with hematological malignancies.

Thrombosomes are trehalose-stabilized, freeze-dried group O platelets with a 3-year shelf life. They can be stockpiled, rapidly reconstituted, and infused regardless of the recipient's blood type. Thrombosomes thus represent a potential alternative platelet transfusion strategy. The present study assessed the safety and potential early signals of efficacy of Thrombosomes in bleeding thrombocytopenic patients. We performed an open-label, phase 1 study of single doses of allogeneic Thrombosomes at three dose levels in three cohorts, each consisting of eight patients who had hematologic malignancies, thrombocytopenia, and bleeding. Adverse events, dose-limiting toxicities (DLTs), World Health Organization (WHO) bleeding scores, and hematology values were assessed. No DLTs were reported. The median age was 59 years (24-71). Most patients had AML (58%) or ALL (29%), followed by MDS (8%) and myeloproliferative neoplasm (4%). The WHO scores of 22 patients who were actively bleeding at a total of 27 sites at baseline either improved (n = 17 [63%]) or stabilized (n = 10 [37%]) through day 6. Twenty-four hours after infusion, 12 patients (50%) had a clinically significant platelet count increase. Of eight patients who received no platelet transfusions for 6 days after Thrombosomes infusion, 5 had a clinically significant increase in platelet count of ≥5000 platelets/µL and 2 had platelet count normalization. Thrombosomes doses up to 3.78 × 108 particles/kg demonstrated safety in 24 bleeding, thrombocytopenic patients with hematological malignancies. Thrombosomes may represent an alternative to conventional platelets to treat bleeding. A phase 2 clinical trial in a similar patient population is underway.

Making the Correct Diagnosis in Thrombotic Microangiopathy: A Narrative Review.

PURPOSE OF REVIEW: Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli-induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment. SOURCES OF INFORMATION: Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors. METHODS: This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies. KEY FINDINGS: Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli-induced hemolytic uremic syndrome, also known as "typical" HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA. LIMITATIONS: The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach.

JUSTIFICATION: La microangiopathie thrombotique (MAT) est suspectée chez les patients présentant une thrombocytopénie et la preuve d'une anémie hémolytique microangiopathique (AHMA). Les patients atteints de MAT peuvent être gravement malades, il est donc essentiel de déterminer rapidement et précisément l'étiologie sous-jacente. Grâce à une meilleure connaissance de la physiopathologie et des causes de la MAT, nous pouvons désormais classer les MAT par catégorie: purpura thrombocytopénique thrombotique (PTT), syndrome hémolytique urémique post-infectieux (SHU) principalement induit par STEC (Escherichia coli produisant la toxine Shiga), ou MAT associée à une affection coexistante ou à un SHU atypique (SHUa). Nous avons constaté un besoin dans la communauté médicale pour guider à la fois la détection rapide et précise de la MAT, la sélection des tests pour clarifier son étiologie et la séquence des étapes menant à l'initiation du traitement. SOURCES: Des recherches documentaires sur PubMed et les connaissances antérieures des auteurs ont permis de colliger les principales études publiées portant sur la détection, la classification et le traitement de la MAT chez les enfants ou les adultes. MÉTHODOLOGIE: Cet examen est le résultat d'un processus de consultation qui reflète le consensus des experts du Canada, des États-Unis et des Émirats arabes Unis. Les membres représentent des cliniciens, des chercheurs et des enseignants en médecine pédiatrique et adulte dans les domaines de l'hématologie, de la néphrologie et de la médecine de laboratoire. Les auteurs, par le biais d'un processus d'examen itératif, ont colligé et synthétisé l'information provenant des études publiées jugées pertinentes. PRINCIPAUX RÉSULTATS: Le PTT survient lors d'une activité insuffisante de la protéase du facteur Willebrand connue sous le nom d'ADAMTS13. Le SHU-STEC, aussi appelé SHU « typique ¼, est causé par des infections gastro-intestinales dues à des bactéries produisant la toxine Shiga (initialement appelée vérocytotoxine). Plusieurs états pathologiques ou expositions à des médicaments peuvent déclencher la MAT. Quant au SHU atypique (SHUa), il survient en présence d'anomalies héréditaires ou acquises de la voie du complément alternatif qui mènent à un dérèglement de l'activation du complément, souvent à la suite d'un événement déclencheur comme une infection. On peut diviser le processus de diagnostic étiologique de la MAT en deux étapes distinctes. La première couvre la présentation initiale et le diagnostic, y compris les processus de détection de la MAT, les tests initiaux et aiguillages appropriés, ainsi que les traitements empiriques si nécessaire. La deuxième étape consiste à confirmer le diagnostic étiologique et à procéder au traitement définitif. Pour de nombreuses formes de MAT, la réponse ultime aux traitements et le résultat du patient dépendent de la détection rapide et précise de la MAT et ensuite, d'une approche standardisée pour la recherche du diagnostic étiologique. Nous présentons une approche structurée pour détecter la présence de MAT ainsi qu'une démarche pour rechercher l'étiologie, y compris des tableaux de laboratoire normalisés. Nous soulignons l'importance d'une consultation précoce avec les spécialistes appropriés en hématologie et en néphrologie, et de la détermination d'un éventuel besoin d'échange de plasma (PLEX) pour le patient. Les cliniciens devraient envisager les traitements empiriques appropriés tout en suivant la démarche que nous recommandons pour le diagnostic étiologique définitif et la gestion de la MAT. LIMITES: La base factuelle de nos recommandations est constituée de petites études cliniques, de rapports de cas et de séries de cas. Ces études ne sont généralement pas contrôlées ou randomisées et ne se prêtent pas à une méthodologie plus stricte basée sur des lignes directrices ni à une approche fondée sur le GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Sutimlimab in Cold Agglutinin Disease.

BACKGROUND: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway. METHODS: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol. RESULTS: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred. CONCLUSIONS: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.).

Increased risk of thrombotic events in cold agglutinin disease: A 10-year retrospective analysis.

BACKGROUND: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia mediated by IgM autoantibodies that trigger hemolysis via classical complement pathway. Increased incidence of thrombotic events (TEs) has been reported in patients with other forms of hemolysis. The incidence of TEs in patients with CAD is unknown. OBJECTIVE: Evaluate TE risk in patients with CAD. PATIENTS/METHODS: This is a matched cohort comparison study evaluating the risk of TEs in patients with CAD and without CAD over a 10-year period. A total of 608 patients with CAD were identified in the Optum Claims-Clinical data set by reviewing clinical notes for CAD terms and matched with up to 10 patients without CAD (N = 5873). TEs were defined as the first medical claim for a TE using International Classification of Diseases, Ninth and Tenth Revision codes. Cox regression models were used to estimate time to first TE. Sensitivity analyses were conducted to estimate TE risk among patients with primary CAD. RESULTS: At least 1 TE occurred in 29.6% of patients with CAD and 17.6% of patients without CAD. The proportion of patients experiencing venous, arterial, and cerebral TEs were each higher among CAD patients. The overall risk of having TEs was higher in patients with CAD (adjusted hazard ratio [aHR], 1.94; 95% confidence interval [CI], 1.64-2.30). Patients with presumed primary CAD also demonstrated an increased risk of TEs (aHR, 1.80; 95% CI, 1.46-2.22). Patients with CAD with the fewest comorbidities had 2.44-fold higher risk of having a TE (95% CI, 1.70-3.52). CONCLUSIONS: Patients with CAD have an increased risk of TEs when compared with a matched non-CAD population.