Autoimmune Hemolytic Anemia Research Articles

Evans Syndrome in a Patient with Auto Immune Thyroiditis – A Rare Association

A 46-year-old woman, diagnosed with hypothyroidism, was on treatment with synthetic thyroxine 100 micrograms per day for one year. She complained of recent-onset exertional dyspnoea, and had malaise, lethargy, and pica. Investigations revealed significant anaemia and severe thrombocytopenia, necessitating blood transfusion. She had Coombs-positive autoimmune haemolytic anaemia and immune thrombocytopenic purpura, confirming a diagnosis of Evans syndrome. She also had a positive antinuclear antibody test but had no other notable findings of autoimmune disease, suggesting a diagnosis of primary Evans syndrome. The patient was treated with intravenous dexamethasone for four days, followed by oral prednisolone at 1mg/kg/ day, with supplemental calcium and vitamin D. Thyroperoxidase antibody was positive and there was reduced uptake in thyroid scintigraphy, confirming a diagnosis of autoimmune thyroiditis. Hashimoto’s thyroiditis frequently coexists with non-endocrine autoimmune disorders. Presence of antithyroid antibodies is sometimes observed in Evans syndrome, a condition where there is simultaneous occurrence of autoimmune Haemolytic Anaemia, Cytopoenia and immune thrombocytopenic purpura. However, the development of Evans syndrome in patients with overt hypothyroidism and Hashimoto’s thyroiditis is rare. This case implies the potential existence of a shared immunogenetic pathway among three distinct autoimmune diseases, namely autoimmune haemolytic anemia, immune thrombocytopenic purpura, and Hashimoto’s thyroiditis, in the pathogenesis.

A rare cause of Acquired Hemolytic Anemia in a child; Donath-Landsteiner antibody

Abstract Introduction/Objective INTRODUCTION: The Donath-Landsteiner (DL) antibody is known to cause paroxysmal cold hemoglobinuria (PCH), a rare form of intravascular hemolytic anemia which is precipitated by an IgG biphasic hemolysin with specificity to the P blood group antigen and most commonly reported in children. The DL test is a serologic test specifically examines, the biphasic nature of the antibody activity. Methods/Case Report CASE PRESENTATION: A 4-year-old previously healthy boy presented at an academic medical center with rhinorrhea and nasal congestion. His family reported that his urine became darker almost coke colored after his symptoms started. His initial vitals; temperature of 37.1 C, heart rate of 140, blood pressure of 122/87 and O2 saturation of 96% on room air. Laboratory investigations showed a hemoglobin level of 4.2 g/dL, hematocrit level of 12.5%, platelets count of 229 K/uL, indirect bilirubin of 6.2mg/dL, haptoglobin <30 mg/dL, LDH >1800 U/L. Direct antiglobulin test was positive with complement only. Thermal Amplitude and indirect Donath-Landsteiner tests were both positive. Respiratory viral panel was positive for Rhinovirus. The antibody screen was negative, and the patient was provided supportive care including as needed RBC transfusion, warming of fluids and body. By day day 9 patient Hgb stabilized, LDH, bilirubin and haptoglobin normalized and his urine turned yellow color and was discharged in stable condition. Results (if a Case Study enter NA) NA Conclusion CONCLUSIONS PCH is classified as a cold autoimmune hemolytic anemia caused by an IgG antibody that sensitizes RBCs at cold temperatures by attaching complement to the RBCs, causing intravascular hemolysis upon rewarming. The DL test for PCH involves in vitro testing for hemolysis with the patient's serum, washed group-O cells expressing the P antigen, and fresh normal serum. To prevent autoadsorption of the antibody and hemolysis, blood should be collected in prewarmed tubes that do not contain anticoagulants and kept at 37°C during the collection procedure. A high index of suspicion especially in pediatric population should be maintained after a viral infection. The treatment is usually supportive.

Exploration of B and T Cell Receptor Repertoires Reveals Distinct Mechanisms in Pure Red Cell Aplasia, Autoimmune Hemolytic Anemia, and Aplastic Anemia

Background: Pure red cell aplasia (PRCA), autoimmune hemolytic anemia (AIHA) and aplastic anemia (AA) are immune-mediated diseases that mainly attack erythrocyte or erythroid progenitor cells. This study aimed to investigate changes related to autoimmunity in the B cell receptor (BCR) and T cell receptor (TCR) repertoires in these diseases. Methods: Patients with newly diagnosed primary PRCA, AIHA, and AA and healthy individuals with matched age and sex (normal controls, NC) were recruited. Peripheral blood was collected, and BCR and TCR repertoires were sequenced by next-generation immunosequencing. The diversity and clonal expansion of the repertoires, gene and gene combination usage, somatic hypermutation (SHM) of BCR, and the sequence length, hydrophobicity, motifs of the most diverse epitope encoded (complementary-determining region 3, CDR3), T cell clustering, and BCR light chain and TCRα chain were analyzed. Results: 10 PRCA, 10 AIHA, 10 AA, and 7 NC were finally enrolled. For the broad repertoire metrics analysis, only the TCR repertoire of the AA group was more diverse compared with NC (p＜0.05). For BCR and TCR repertoires, PRCA, AIHA, and AA showed uniform characteristics in gene usage. The preferential gene usage of PRCA immunoglobulin heavy (IGH) chains such as IGHV3-23, IGHV3-74 were correlated with memory cells and red blood cell antigen recognition; the higher usage of IGHV4-31 in the AIHA group was associated with secretion of auto-antibodies; whereas AA patients had more gene usage of neutralizing antibodies (p＜0.05). In the gene usage in T cell receptor β (TRB) chains, PRCA patients had skewed usage of genes associated with T cell dysregulation and hyperinflammation such as TRBV1 and TRBV11-2; the increased gene usage in AIHA and AA were also found in other autoimmune diseases, which correlated with abnormal antigen recognition. PRCA and AA also had specific TRBV-J gene combination usage. Only PRCA had higher BCR SHM compared with NC (p＜0.05). The length of CDR3 was similar but the hydrophobicity was different among different disease groups. 12, 28, and 22 motifs were found respectively in BCR of PRCA, AIHA, and AA; and 13, 6, and 6 motifs were found in TCR. Compared with NC, PRCA, AIHA, and AA showed a considerable lack of physiology T cell clusters, and 147, 98, and 141 disease-specific T cell clusters in each disease was found, respectively. For light chain of BCR, PRCA and AIHA had the tendency of more usage of κ chains, whereas AA had more usage of λ chains. For TCRα chains, the three diseases used more genes related to hypersensitivity reactions (p＜0.05). Conclusion: PRCA, AIHA, and AA had different BCR and TCR repertoire characteristics in gene and gene combination usage, hydrophobicity and motifs of CDR3, and T cell clustering, which might contribute to autoimmune antigen recognition. The abnormalities were mainly T cell-related for PRCA, B cell-related for AIHA and both for AA. Keywords: pure red cell aplasia; autoimmune hemolytic anemia; aplastic anemia; BCR; TCR

Infectious Complications in Autoimmune Hemolytic Anemia: A Multi-Center Italian Experience

Introduction: Infections may play an important role in the development or relapse of autoimmune hemolytic anemia (AIHA) as well as possible complications of long-term immunosuppression secondary to its management. The prevalence and severity of infection in AIHA are still under-investigated. Methods: Hereby we studied retrospectively 324 patients older than 18 years old, diagnosed with AIHA and followed at 10 Italian centers between 1981 and 2022, focusing on infectious complications and their predictors. Results: At diagnosis, median age was 60 years (range 18-94), with 27% of patients older than 70 years and with a slight male predominance (65%) and classified as warm AIHA in 53% (Table 1). Median Hb was 7.3 g/dL (2-14), median WBC of 7,5x10 9/L (1,4-94) and median platelets of 260x10 9/L (4-695). Sixty-two (60%) out of 103 patients presented lymphopenia. Among 111 evaluable patients, reduced serum IgG/IgA/IgM levels were detected in 37%, 27%, and 23%, respectively. Twenty-nine (9%) patients had Evans Syndrome. During a median follow-up of 35 months (1-553 months), patients received a median of 1 line of therapy (1-7), including steroids, rituximab, chemotherapy, and immunosuppressive (IS) drugs in 90%, 45%, 10% and 12% of cases, respectively. Twenty (6%) patients underwent splenectomy and 43 (13%) received intravenous Ig supplementation. Sixty-five (20%) patients presented at least one infection episodes, with 17 experiencing recurrences. Pneumonia was the most frequent (44 cases), followed by 11 sepsis and 4 urinary tract infections, requiring hospitalization in 37 (71%) of cases. Pathogens were isolated in 23 patients (62% viral and 38% bacterial agents). Overall, 17 (16%) suffered from SARS-CoV-2 infection, of whom 8 requiring specific therapy. Eleven (18%) patients were receiving prophylaxis at the time of infection, including acyclovir (18%), cotrimoxazole (18%), both (55%) or anti-HBV prophylaxis (18%). Forty-seven (77%) patients were on active treatment for AIHA at the time of infection (32 steroids, 8 rituximab, 1 IS and 11 not specified), and 16 (25%) also experienced a thrombotic event. Patients receiving more than one therapy lines had 2-fold higher probability of developing infections (RR 2.03, 1.27-3.25, p=0,0017), particularly for those treated with IS (RR 1.77, 1.04-3.01, p=0,041) and with rituximab (RR 1.96, 1.20-3.20, p=0,0048). Among patients with infections, median time from the last dose of rituximab was 15 months (range 1-147 months). Moreover, patients with thrombotic events were more likely to experience infection episodes (RR 2.41, 1.52-3.83, p=0,001). During observation, 55 patients (23%) died, among them 10 for AIHA complications, including 6 infections. Conclusions: In conclusion, infections complicate about 20% of AIHA. Most episodes occurred during active AIHA-therapy and were more common in patients with prior exposure to rituximab or IS, suggesting an iatrogenic effect. The association with thrombotic events may indicate a relationship with more severe AIHA. Strategies to reduce the burden of IS in AIHA should be pursued.

Comparison of Time to Relapse between Low-Fixed Dose Versus Standard-Dose Rituximab in the Treatment of ITP, TTP, and AIHA

Background: The optimal Rituximab dosing regimen for the treatment of immune thrombocytopenia purpura (ITP), autoimmune hemolytic anemia (AIHA), or thrombotic thrombocytopenia purpura (TTP) has not been well established. To our knowledge, there has not been a randomized trial examining the time to relapse with the different Rituximab dosing regimens (low-fixed dose of 100 mg x 4 weekly doses versus standard dose of 375 mg/m2 x 4 weekly doses) in the treatment of ITP, TTP, and AIHA. Previous comparative studies have shown that the weekly low-fixed Rituximab dosing regimen has been shown to be just as effective in treating these diseases as demonstrated by similar response and duration of response. Therefore, we conducted a comparative analysis to evaluate the time to first recurrence after being treated with Rituximab. Methods: We collected clinical data from a single center of patients with diagnosis of ITP, TTP, or AIHA and were treated with 4 weekly low-fixed or standard dose Rituximab. Time to first recurrence was measured to compare if there was a significant difference between the two Rituximab dosing regimens. Kaplan-Meier time to recurrence estimates were used to generate time to recurrence curves. Results: Of the 30 patients analyzed, 10 patients were diagnosed with AIHA, 12 patients with ITP, and 8 with TTP. All patients had a complete response (CR) per the specific disease CR definition prior to first disease recurrence. 17 patients were treated with standard dose Rituximab and 13 patients were treated with low-fixed dose Rituximab. 17 patients did not have a recurrence in the selected time frame of the study. Recurrence was observed in 40% of the AIHA patients, 50% of the TTP patients, and 37.5% of TTP (P=0.8297). 47% females had a recurrence compared to 36% males (P=0.7084). Recurrence was observed in 61% patients who received the low-fixed dose Rituximab and 29% of patients who received the standard dose Rituximab (P=0.1376). The median time of recurrence was 16 and 27 months among patients who received low-fixed dose vs standard dose Rituximab, respectively (P=0.1914). Conclusions: The use of low-fixed dose Rituximab versus standard dose Rituximab for treatment of ITP, TTP, and AIHA appears to have a higher recurrence rate but did not meet statistical significance. The median time difference in recurrence was 9 months. This could potentially be significant in a larger study population. Further investigation through large, randomized controlled trials is needed to assess if there is a significant difference in recurrence rate and time to recurrence between the two Rituximab dosing regimens.

The ‘Weekend Effect’ on Immune Cytopenia: Insights from the National Inpatient Sample Database

Introduction: Outcomes for weekend versus weekday admissions for immune cytopenias including immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), and autoimmune hemolytic anemia (AIHA)/Evan's Syndrome are explored in this abstract. Methods: A query of the 2012-2019 National Inpatient Sample was performed for primary hospitalizations with immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), and autoimmune hemolytic anemia (AIHA)/Evan's Syndrome using ICD-9/10 codes. Demographics, comorbidities, and outcomes were identified. Univariate analysis with t-tests or chi-square performed as appropriate. A 1:1 nearest neighbor propensity score matched cohorts was generated for each of the ITP, TTP and AIHA/Evan's hospitalization dataset. Variables with standardized mean differences >0.1 used in multivariate regression to generate adjusted odds ratios (AOR)/β-coefficients for weekend admission status on outcomes. Significance was set at an alpha level of <0.05. All analysis performed in SPSS versions 26. Results: 24,325, 2992,and 7,609 hospitalizations were included with 4592, 656, and 1468 weekend admissions in ITP, TTP, and AIHA/Evan's respectively. Propensity matched cohorts were generated adjusting for age, sex, race, median household income and co-morbidities including DM, CHF, CKD/ESRD, and liver disease. The results showed significantly higher, almost two-fold, in-hospital mortality in AIHA for weekend admissions (Odds ratio (OR): 1.85, CI 1.20-2.85, p-value=0.005). In addition, there was significantly higher risk of circulatory shock and mechanical ventilation requirement for weekend admissions in AIHA along with significantly increased length of hospital stay and total hospital charges. TTP patients also showed similar trend towards higher mortality with significantly higher incidence of AKI and increased length of stay for weekend admissions. There was no significant difference seen in ITP. The results are summarized in table 1. These results are partly in agreement with findings of Manadan et al study, which showed lower rate of procedures and higher adjusted mortality for general inpatient admissions in weekends. Conclusion: Weekend admissions showed poorer outcomes especially in AIHA and TTP. Although the exact reasons are unknown, decreased staffing and procedural availability may be responsible for such findings. Further studies are needed to clarify the steps needed to decrease adverse outcomes for weekend admissions.

Risk and Outcomes of Hospitalizations in Patients with Anti-Phospholipid Syndrome Admitted with Autoimmune Hemolytic Anemia: A Nation-Wide Analysis

Introduction: Autoimmune hemolytic anemia (AIHA) can occur as a primary disorder or as a secondary manifestation of an underlying autoimmune condition. The coexistence of anti-phospholipid syndrome (APS) and AIHA can be very complex and challenging to manage given the intertwining of the prothrombotic and hemolytic states. In this study, we explored the outcomes of underlying antiphospholipid syndrome in autoimmune hemolytic anemia hospitalizations. Method: The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases (ICD) codes to identify hospitalizations for AIHA and then the data was subclassified into hospitalizations with and without APS. Demographics, comorbidities, and outcomes were identified using appropriate ICD 9/10 codes. Propensity score matched cohorts were generated for APS status and adjusted for age, race, sex, smoking, obesity, DM, CHF, CKD/ESRD, and liver disease. Results: A total of 7,609 AIHA hospitalizations were included, with 76 patients having underlying APS and 7,533 did not have APS. Mean age was younger in the APS cohort and there were also more females, blacks and Hispanics compared to the non-APS cohort. Propensity score matching was used to generate two cohorts, adjusting for age, race, sex, and for co-morbidities including obesity, smoking, DM, CHF, CKD/ESRD and liver disease. The adjusted analysis showed an 8.59 times higher risk of developing venous thromboembolic events (VTE) in AIHA with APS as compared to those hospitalizations without APS (Odds ratio (OR): 8.59, CI: 1.05-70.5; p=0.03). There was also a statistically significant increase in mean hospitalization cost in the APS group (p=0.001). A trend towards more arterial athero-embolic events (AAE), major bleeding events, and AKI as well as longer length of stay was seen in hospitalizations with APS, but it did not reach statistical significance. No significant difference in in-hospital mortality was seen between the two groups. The results are summarized in the Figure 1. Conclusion: APS confers additional risk to AIHA hospitalizations with significantly higher VTE events and added costs. Further studies should address the complex management of anticoagulation and prothrombotic risk in APS in the setting of active hemolytic anemia.

Autoimmune cytopenias in patients with malignant lymphoma: A multicenter report by the Polish Lymphoma Research Group.

Autoimmune cytopenias (ACs), including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA) and autoimmune granulocytopenia, are rare complications observed in lymphoma patients. They may appear before, during or after lymphoma diagnosis, whether the patients had disease progression or not. This study aims to correlate ACs with lymphoma type, disease course and prognosis. We performed a multicenter retrospective analysis of adult patients with malignant lymphoma and ACs coexistence diagnosed and treated in centers aligned with the Polish Lymphoma Research Group (PLRG). The analysis covers the years 2016-2022 and included 51 patients comprised of 23 women and 28 men. Of these, 35 patients were diagnosed with AIHA, 15 patients with ITP and 1 patient with both AIHA and ITP. The most common type of lymphoma was Hodgkin lymphoma (HL) (12 patients) and diffuse large B-cell lymphoma (DLBCL) (14 patients). At the time of diagnosis, 31 (61%) of patients had stage 4 of HL or DLBCL, according to Ann Arbor classification. In total, the response to treatment was evaluated in 50 patients, with 25 being in complete remission and 6 in partial remission. We observed that B cell symptoms (p = 0.036), bone marrow involvement (p = 0.073), splenomegaly (p = 0.025), and more than 2 lines of treatment were more common in AIHA compared to ITP patients. Conversely, eucopenia (p = 0.056) and ACs without lymphoma progression (p = 0.002) were more often diagnosed in ITP patients. In the study group, relapsed and refractory disease was observed more often, and shorter overall survival (OS) was noted in patients with DLBCL. We found that AC is associated with a worse prognosis in comparison to the general population of lymphoma patients. There were no differences in response to AC therapy. To have more accurate data, a larger group, as part of a multicenter study, should be evaluated.

Hematological Manifestations of Antiphospholipid Antibodies: A Case Series from South India

Introduction: Antiphospholipid syndrome (APS) is known for its association with unexplained vascular thrombosis and pregnancy-related complications. However, APS can also present with various hematological abnormalities, including thrombocytopenia, autoimmune hemolytic anemia, Evan's syndrome, and thrombotic microangiopathy. While APS is often considered in patients with these manifestations, its laboratory testing yield and patterns in hematology clinics remain underexplored. In this study, we aimed to investigate the prevalence of laboratory positivity for APS in patients attending hematology clinics, even in the absence of meeting the clinical criteria for APS. Methodology: This retrospective study was conducted at two tertiary care centers in southern India from January 2018 to June 2023. Patients who visited hematology clinics and underwent APS workup were included. The APS workup involved evaluating Anti Cardiolipin IGG and IGM, Anti Beta2 Glycoprotein IGG and IGM, Lupus Anticoagulant, and ANA. The laboratory criteria for APS were based on the ACR/EULAR APS Criteria. Patients with transiently positive results were excluded from the study. Chi Square test was used for statistical analysis. Results: Among the 624 patients who underwent APS workup, 100 patients (16.03%) tested positive for at least one of the laboratory criteria for APS. Remarkably, a significant proportion (56%)of these patients did not fulfill the clinical criteria for APS. The most common hematological manifestations prompting APS testing in these 100 patients were thrombocytopenia (38%) and unprovoked thrombosis (35%). Additional hematological abnormalities included autoimmune hemolytic anemia (13%), prolonged activated partial thromboplastin time (APTT) (5%), Evan's syndrome (4%), pancytopenia (4%), and thrombotic thrombocytopenic purpura (TTP) (1%). Baseline characterstics of our study subjects are shown in Table 1 Anti-beta2 glycoprotein IGG or IGM antibodies were detected in 74% of APS-positive patients, and Anti-cardiolipin IGG or IGM antibodies were found in 57%. Lupus Anticoagulant (LA) was present in 59%. Additionally, 28% of the patients showed positivity for all three antibodies, indicating a significant overlap in laboratory findings. No statistically significant difference in antibody positivity patterns was observed between patients satisfying the clinical criteria for APS and those without, as shown in Table 2 Conclusion: Our study sheds light on the hematological presentations of APS in patients attending hematology clinics in southern India. Importantly, a substantial number(56%)of patients with APS lab test positivity did not meet the clinical criteria for APS. These findings emphasize the importance of considering APS as a potential diagnosis in patients presenting with hematological manifestations, especially thrombocytopenia and autoimmune hemolytic anemia. Identifying APS in such cases can guide appropriate therapeutic interventions and may help prevent pregnancy-related complications in affected females. Raising awareness among healthcare professionals about the diverse hematological presentations of APS is vital for improving patient outcomes and ensuring timely and accurate diagnoses

Hematological Activity in Primary Antiphospholipid Syndrome: A Common Manifestation Outside the Classification Criteria

Introduction: Thrombocytopenia and autoimmune hemolytic anemia (AIHA) are extra-criteria manifestations of antiphospholipid syndrome (APS). They have a higher incidence in secondary cases, and there is little information on primary antiphospholipid syndrome (pAPS). Aim: To evaluate the clinical characteristics and profile of antibodies in pAPS with hematological activity. Material and methods: A retrospective study included patients with pAPS, diagnosed according to the Sapporo criteria with follow-up at third level of care in Mexico City from 1990 to 2021. Descriptive statistics were used, and chi-squared test, Mann-Whitney U test, and logistic regression were performed. Results: A total of 97 patients with pAPS were included; 73.2% (71) were women with a mean age of 33.9 + 11.5 years and a mean follow-up of 132 months (24-360). We found that 77% (75) presented thrombotic and 37% (36) obstetric manifestations. In 68% (66) of patients, hematological manifestations (non-exclusive groups) were found. Further, 63.9% had thrombocytopenia, the most common kind being severe, and a minority had AIHA in 13.4%. Table 1 describes the clinical manifestations. Patients with thrombocytopenia were younger, with 32 + 10.3 years vs 37 + 13 years ( p = 0.046). A total of 59.7% (37) had a triple marker. In comparison with patients without thrombocytopenia, 69.4% (43) presented positive lupus anticoagulant vs 48.6% ( p = 0.043) and OR 2.5 (CI 95% 1.06-6.1). An 83.9% (52) had positive IgG anticardiolipin vs 62.9% ( p = 0.019), OR 3.21 (CI 95% 1.19-8.63) with a higher titer of 19.4 vs 6.1 ( p = 0.017) and OR 1.01 (CI 95% 0.99-1.04). They had higher titers of antiβ2 glycoprotein-I IgM of 6.8 vs 5.2 ( p = 0.019) with OR 1.03 (CI 95% 0.99-1.06) and of antiphosphatidyl serine/prothrombin IgM of 52.8 vs 16.8 ( p = 0.004), OR 1.01 (CI 95% 1- 1.02). In patients with AHAI, anti-β2 glycoprotein-I IgM antibody titers of 7.1 vs 5.9 were identified, which were higher compared with those who did not present it ( p = 0.026). Those without hematological activity had more thrombosis ( p < 0.001). When comparing the groups with and without thrombosis, we observed that those with thrombosis had lower titers of antiβ2 glycoprotein-I IgM in 5.8 vs. 7.4, p = 0.036, OR 0.97 (CI 95% 0.94-1) and higher anti-phosphatidyl serine/prothrombin titers in 61.2 vs 12.1, p = 0.021 with OR 1.02 (CI 95% 1-1.04). A total of 76.3% (74) received anticoagulant and 24.7% (24) received antiplatelet. Immunosuppression was prescribed in 38.1% (37). Those with severe thrombocytopenia received: prednisone in 54.5% (18) of cases, methylprednisolone in 36.4% (12), rituximab in 3% (1), and splenectomy in 36.4% (12). In patients with AHAI, 84.6% (11) received immunosuppressants and 46.2% (6) underwent splenectomy. Conclusion: A higher incidence of hematological activity was identified in pAPS, mostly in young women. The most common kind was severe thrombocytopenia, as opposed to what was described in literature as mild to moderate. Differences were found regarding the titer and positivity of antibodies. With thrombocytopenia, there was a higher frequency of positive lupus anticoagulant, anticardiolipin IgG and antiβ2 glycoprotein-I IgM with higher titers. Patients had anti-phosphatidyl serine/prothrombin antibodies as an extended panel and a correlation with hematological activity was identified. Knowing the serology of pAPS is useful to identify in good time patients who may present severe hematological manifestations. No patient died of a hematologic complication; however splenectomy was required in some cases. To our knowledge this is one of the few studies that evaluate hematological manifestations in pAPS.

A Single Center Experience for Clinical Evaluation of Paroxysmal Cold Hemoglobinuria and Donath-Landsteiner Testing

Introduction: Paroxysmal cold hemoglobinuria (PCH) is a rare form of autoimmune hemolytic anemia (AIHA), mainly affecting children. The diagnosis and management is challenging due to similarities to other causes for AIHA and limited availability to Donath-Landsteiner (DL) testing. Methods: In this single-center retrospective study, we aimed to characterize the clinical presentation and outcomes of PCH patients, defined as having positive Donath-Landsteiner antibodies, compared to a cohort of AIHA patients. Results: DL-positive patients were observed to have higher lactose dehydrogenase levels and lower reticulocyte counts compared to DL-negative patients, although this was not statistically significant. We also observed that using steroids in DL-positive patients did not significantly impact their recovery. Conclusions: Our findings support the limited published data on PCH patients and further prompt prompting larger multicenter studies to further characterize these patients so that they are more readily identified, especially in centers where DL antibody testing is not readily available.

Mutations in Histone Lysine Methyltransferase Genes Are Associated with Autoimmune Cytopenias

Introduction Epigenetic mechanisms are important in regulation of gene expression by modifying chromatin structure to facilitate DNA accessibility (Lau et al Nat Immunol. 2018). DNA methylation and histone modifications are critical for the pathogenesis of hematologic malignancies and autoimmune diseases (Surace et al Front Immunol. 2019) Alterations in enzymes involved in histone modification are associated with immunodeficiencies, including Kabuki syndrome (KS), a rare genetic disorder associated with autoimmune cytopenias, such as immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) (Margot et al J Am Coll Med Genet 2020) caused by loss-of-function KMT2D and KDM6A mutations. Somatic mutations in the KMT2D gene have also been observed in patients with Cold Agglutinin Disease. (Małecka et al Br J Haematol. 2018). Aims: The aims of this study are: 1) to identify the frequency of mutations in histone methyltransferase genes (MT) KMT2D, KMT2A, KMT2C and KDM6A in patients with autoimmune cytopenias, and 2) to compare clinical, laboratory and immunological characteristics, and response to therapy in patients with or without mutation in MT and autoimmune cytopenias (AIC). Methods Data mining software from the electronic medical record was used to identify patients ≥ 18 years with a diagnosis of AIC, including ITP, warm and cold AIHA, autoimmune neutropenia, and Evans Syndrome (ES), who had Next Generation Sequencing (NGS) performed. Cytopenias due to malignancy, nutritional deficiency, medications, pregnancy, or infection were excluded. Patients were categorized into two groups based on the presence or absence of mutation in the MT genes (MT+, MT-) with variant allelic frequency (VAF) > 2%. Demographic, laboratory, and clinical characteristics, treatment outcomes, and NGS sequencing data were collected and compared between groups. Next, KMT2 mutations seen in patients with AIC were cross-referenced against the 1000 Genome Project (1000GP) population database to evaluate the frequency of polymorphisms in the general population (Auton et al Nature 2015). CADD in silico prediction algorithm was used to score the potential deleterious effect of MT mutations (Kirchner Nat Genet. 2014). Chi-Square test was used for categorical variables. Statistical analysis was completed in R software. Results Among 495 patients who underwent NGS, 79 (16%) had a mutation in MT genes. These mutations were present in 36% of patients with AIC as compared to 13% in those without AIC (p=0.0005). Among 55 patients with AIC, mutations in the MT genes were present in 20 patients (MT+), 35 patients did not have these mutations (MT-). KMT2C mutations were seen in 10 (50%) patients, KMT2D mutations in 9 patients (45%, one patient had two KMT2D mutations), 1 patient (5%) had both KMT2C & KMT2D variants (Figure 1). The median VAF was 39.5% (IQR, 15.45 - 49.80). The MT+ group had a significantly higher proportion of Hispanic (60% vs 31%) and non-Hispanic White patients (25% vs 14%), p=0.038, Table 1. The median age at diagnosis for the MT+ cohort was younger compared to MT- (45.5 vs 58 years old, respectively), though not statistically significant. AIC diagnoses in both groups were ITP (44%) wAIHA (22%) cAIHA (9%) Autoimmune Neutropenia (2%), and ES (24%). Compared to the MT- group, the MT+ group had lower IgG levels (p=0.0041) and absolute lymphocyte count (p=0.041). MT+ patients with AIHA were more likely to have positive Direct Coombs and complement involvement. No significant differences were found in median nadir hemoglobin and platelet counts, need for therapy, or median number of lines of therapy. Best overall response to therapy was similar in the two groups (93%), with more complete responses in MT- group (55% vs 33%) though not statistically significant. Next, we assessed KMT2 polymorphisms in the general population. Most of the polymorphisms were not present in the 1000GP database and none had a frequency > 0.001. The average Phred score was 19.8; 12/20 patients had Phred score > 20, suggesting that most mutations are in the top 1% of the deleterious variants. Conclusion We report for the first time that patients with autoimmune cytopenias have a high frequency of variants in MT genes. Median allelic frequency close to 50% suggests potential germline predisposition to immune dysregulation and autoimmunity however further studies are needed to better understand the impact of these observations.

Determinants of Relapse and Treatment-Free Survival Following Splenectomy in Patients with Immune Cytopenias

Background: Splenectomy has historically been a treatment option for patients with immune cytopenia not responding to standard treatment. Despite being a highly effective treatment option, current guidelines recommend this strategy as a third-line treatment. There is a need for more evidence regarding predictive response factors that could help adequately select the ideal candidate for splenectomy, its effectiveness, and related complications. The study aims to identify factors associated with relapse in patients diagnosed with immune cytopenia who have undergone splenectomy. Methods: Retrospective cohort study including patients with immune cytopenia, including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome (ES), who underwent splenectomy between January 1990 and March 2023 in a tertiary referral center in Mexico City. Response criteria were based on the 2019 American Society of Hematology guidelines for ITP and the 2020 First International Consensus Meeting for AIHA. We defined early surgical complications as those occurring in the first 30 days from splenectomy; a durable response after splenectomy was described as lasting one year or more. Results: With a median follow-up of 100 months (interquartile range [IQR] 55.6 - 141.7 months), 173 patients were analyzed: 70% were female, 83% had primary ITP, 10% AIHA, and 7% ES. Only 15% had secondary autoimmune cytopenia: 4% systemic lupus erythematosus, 4% antiphospholipid antibody syndrome (APS), and 4% both; 3% had other autoimmune diseases; one (0.5%) patient had common variable immunodeficiency (CVI). Before splenectomy, all the patients received corticosteroids as first-line treatment, 13% rituximab, and 10% thrombopoietin receptor analogs (TPO-RA). Splenectomy was performed as the second-line treatment (2L) in 43% of the cases and as a third or later line of therapy (>2L) in 57%. When analyzing periods, there is a decline in the frequency of splenectomy as 2L: 62% from 1990-2010, 48% from 2011-2015, and 33% from 2016-2023. The median time from diagnosis to splenectomy was 6.3 months (IQR 2.6 - 19.9 months), 10.9 months (IQR 3.7 - 30.9 months), and 16.5 months (IQR 3.5 - 49.5 months) in the respective periods. The global response rate after splenectomy was 97.7%: complete response in 91.9%, partial response in 5.8%, and durable responses in 77.5%. The relapse rate after splenectomy was 32.0%, significantly lower in patients undergoing splenectomy as 2L vs. >2L: 20.0% vs. 40.8% (p<0.001). The relapse rate after splenectomy was the same in the different periods (p = 0.244). The number of patients free of a new line treatment after splenectomy at 100 months was significantly higher in patients undergoing splenectomy as 2L vs. >2L: 82.7% vs. 65.3% (p=0.014). When analyzing factors associated with relapse requiring a new line of treatment, splenectomy as the 2L (HR 0.403; 95% CI 0.206-0.788, p = 0.008) and post-splenectomy thrombocytosis (HR 0.301; 95% CI 0.144-0.6, p = 0.001) were associated with higher treatment-free survival in the multivariate analysis (See Table 1 and Figure 1). The rate of early surgical complications was 14%: severe infections (8.7%), bleeding (5.2%), and thrombosis (3.5%). Late surgical complications occurred in 8%: thrombosis (5.8%), infections (2.9%), and bleeding (2.3%). Five patients (3%) died during the follow-up period: 3 related to thrombocytopenia, one to splenectomy (abdominal sepsis in a patient with CVI), and one due to prostate adenocarcinoma. The use of TPO-RA before splenectomy and the diagnosis of APS were associated with post-surgical thrombosis in the multivariate analysis: OR 6.8 (95% CI 1.9 - 23.5, p = 0.002) and OR 4.3 (95% CI 1 - 17.8, p = 0.044), respectively. Conclusions: At our center, splenectomy is frequently employed as a very early 2L treatment. However, this tendency has diminished due to improved access to new drugs. Interestingly, splenectomy as 2L vs. >2L is associated with better outcomes which contrast with current recommendations. In a center where splenectomy is frequently performed, the procedure is associated with a reasonable rate of complications. In patients with immune cytopenia, splenectomy as a second-line treatment is a valid, effective, relatively safe, and cost-effective option, particularly in low-income areas with limited access to new therapies.

Immunotherapy-Related Hematological Adverse Events: Incidence and Outcomes

Introduction: Immunotherapy (IO) is frequently used in the treatment of several malignancies and has been associated with various off-target manifestations of autoimmunity. Hematological immune-related adverse events (heme irAEs) are relatively uncommon, but potentially life-threatening complications that can be challenging to diagnose as both cancer and cancer-directed therapies may cause cytopenias. We sought to determine the incidence, treatment patterns and outcomes associated with heme irAEs in individuals with cancer treated with IO from a large database. Methods: We used a de-identified national health research network, TriNetX, with data sourced from 76 health care organizations (HCOs) located in the United States with over 107 million patients. We identified all adults (≥ 18 years) with a diagnosis of neoplasm (ICD-10: C00-D49), and documented use of IO including pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab and ipilimumab, between 2015-2023. Heme irAEs were defined as immune thrombocytopenia (ITP; ICD-10: D69.3), autoimmune hemolytic anemia (AIHA; ICD-10: D59.0, D59.8, D59.10, D59.19, D59.11, D59.12, or D59.13), and pure red cell aplasia (PRCA; ICD-10: D60, or D61.01) occurring after IO initiation. We collected demographic, clinical and treatment characteristics from our baseline cohort. We further compared all-cause mortality and all-cause hospitalization outcomes between individuals with heme irAEs vs. without heme irAEs. To account for potential confounders and sample size differences between cohorts, we performed 1:1 greedy nearest neighbor propensity score matching, based on patient demographics, cancer type, radiation therapy and bone metastasis. For continuous data, we performed independent t-tests or one-way ANOVA. For categorical data, we performed chi-square tests. To evaluate survival probabilities, we used a Kaplan-Meier analysis and compared hazards ratios. All tests were two-tailed with an alpha level of .05. Results: We identified a total of 83,693 individuals with neoplasms who used IO since 2015. Of those 435 (0.52%) had a diagnosis of heme irAEs: 253 (58.2%) ITP, 167 (38.4%) AIHA, 29 (6.7%) PRCA. Individuals who developed heme irAEs had a median age of 64 years old (21-87), were predominantly male (51.7%), white (77.9%) and had a history of cancer of the respiratory system (40.9%) (Table). Also, 52.9% of them received radiation therapy and 36.1% had associated bone metastasis. Most frequently used IO were PD-1 inhibitors, pembrolizumab (52.6%) and nivolumab (39.1%). Overall, the majority (97.2%) of individuals with heme irAEs were treated with glucocorticoids. Additionally, patients with ITP were treated with IVIG (15.4%), Romiplostim (11.1%), Rituximab (9.1%), and Eltrombopag (8.3%), less commonly with MMF and cyclosporine. Patients with AIHA received in addition to steroids, IVIG and Rituximab. Only a small number of patients with a diagnosis of PRCA required cyclosporine. Altogether, individuals who developed heme irAEs had a higher mortality rate than individuals without heme irAEs (57.4% vs 46.5% HR 1.57 95% CI 1.30-1.89, p value <0.001) (Figure). There was no statistical difference in the number of all-cause hospitalizations between groups (4.13 vs 4.55, t -0.417 p value 0.67). Conclusions: In this large national cohort, the real world incidence of heme irAEs was low. However, despite its rarity, development of heme irAEs was associated with increased mortality in individuals with cancer who received IO. Early recognition and prompt intervention are crucial to optimize its management.

Using a Quality Improvement Activity to Enhance the Knowledge, Competence and Confidence of Clinicians Managing Patients with Cold Agglutinin Disease

Introduction Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia that is rare and poorly understood. This means that clinicians can find understanding the immunopathogenesis of CAD and individualizing therapy challenging, and may struggle to maintain their knowledge of current and emerging therapies, so patients may not receive optimal care. Therefore, we designed an easily accessible, online, continuing medical education activity for hematologists and hematologist-oncologists, using quality improvement principles together with other change approaches, to improve the care clinicians provide to patients with CAD. Methods The online activity included 3 short videos presented by faculty who shared their expertise in managing patients with CAD. We set learning objectives based on key topics we identified as being challenging for clinicians. This allowed us to measure the impact of the education on knowledge, competence (based on Moore's outcomes framework Levels 3 and 4), intention to change practice and clinical confidence. We also measured participation and satisfaction (Moore's Levels 1 and 2), and changes by region (EU5, Latin America and USA) and clinician experience. Questionnaires were fielded by an independent third party (Nuaxia Limited [Richmond, UK]) at baseline (n=100) and within 3 months (n=100) and 6 months (n=50) after participation in the activity to assess knowledge, competence, satisfaction, intention to change practice and confidence. Additionally, these assessments allowed us to identify the need for further educational activities and the topics they should cover. Participation was measured using Google Analytics. Questionnaire responses were analyzed by touchIME statisticians and data from 3 and 6 months were pooled for combined analysis. The margin of error was calculated as ~3% based on a standard confidence interval of 95%. Results At 6 months, the combined analysis showed an increase from baseline in declarative and procedural knowledge, and competence of 12%, 25% and 20%, respectively (Figure 1). These improvements did not show any significant variation by geography (p=0.432) or by years in practice (p=0.923). Analysis by question topic showed that the significant improvements were achieved consistently (p=0.003) for immunopathogenesis, p<0.001 for current and emerging therapies, and p<0.001 for individualizing treatments; Figure 2). The total number of questions answered correctly also increased significantly (p<0.001) from baseline (64.3%; SD 1.808) at the 6-month combined follow-up (82.0%; SD 1.808). The combined analysis showed clinician confidence in managing CAD improved from 44%, being moderately or extremely confident at baseline, to 72% at 6 months; a median of 57% of learners said they would make a change in their clinical practice. At 6 months post-launch, 6,754 participants had engaged with the education and the overall satisfaction was 88%. Conclusion This educational activity led to significant improvements in the knowledge and competence of hematologists and hematologist-oncologists in the understanding and management of CAD. Further, the majority of participants stated they were more confident and would change their clinical practice, which may improve the quality and effectiveness of patient care. The short, accessible format of this activity meant clinicians could participate whenever convenient and the use of expert-led videos made it engaging and applicable, which may have contributed to the success of the activity. Feedback from learners and our analysis indicate that further quality improvement initiatives on this topic would be beneficial and should cover integrating novel therapies into the clinic, as well as improving diagnostic accuracy in the non-speciality clinic.

Autoimmune Cytopenia Associated with Indolent B-Cell Clones: A Large Multicentric Cohort Study

Introduction Autoimmune cytopenias (AIC) are a group of rare diseases sharing immune-induced accelerated destruction and/or impaired production of blood cells. AIC can be associated with overt B-cell lymphoid neoplasia. In that case, the management is based on the treatment of the hematological malignancy. However, AIC can be associated with indolent B-cell clones (IBC). In that case, the treatment of the AIC is not consensual. We aimed to describe the treatments used in France for IBC-associated AIC, and to compare their effectiveness, safety, and impact on IBC progression. Methods We conducted a multicenter, retrospective observational study including adults treated between 2000 and 2022 for a definite AIC (immune thrombocytopenia, ITP; autoimmune hemolytic anemia, AIHA; or Evans syndrome, ES) associated with an IBC, namely: chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma, monoclonal B lymphocytosis, and mantle cell lymphoma. Patients who required a specific treatment of the underlying IBC for one or several of the following reason(s) were excluded: extensive marrow infiltration leading to impaired megacaryopoiesis and/or erythropoiesis, massive organ infiltration and/or compressive lymphadenopathies, lymphocytosis doubling within 6 months (with a lymphocytes count >30 x 10 9/L), doubling of lymphadenopathy size within 2 months, hyperviscosity, and any other IBC-related condition requiring treatment (amyloidosis, neuropathy...). Patients were classified according first-line treatment for AIC: group 1 for those treated without chemotherapy (corticosteroids, intravenous immunoglobulin, rituximab...); group 2 for those treated with chemotherapy (cyclophosphamide, ibrutinib...). Only the first-line treatment was assessed. Response to treatment was defined according to standard international criteria. An infection was defined as serious if graded >2, according to the Common Terminology Criteria for Adverse Events. The progression was defined as the need to urge lymphoma-specific therapy. Subgroup analyses were performed by type of AIC (ITP, warm/mixed AIHA, cold agglutinin disease, and ES). Overall survival was estimated using the Kaplan-Meier method and comparison was performed using Log-rank test. Results In total, 187 patients were included throughout 30 French university and general hospitals using the French reference center network for immune cytopenias in adults. The median age at diagnosis of AIC was 75 years (range 43 to 97 years) with a male/female ratio of 1.47 (Table 1). We observed 105 (56.1%) patients with AIHA, 80 (42.8%) with CLL and 44 (23.5%) with MZL. In most cases (58.8%), the time elapsed between IBC and AIC diagnosis was £6 months. We included 132 (72.2%) patients in group 1. Among them, 75 (55.6%) patients were treated with only corticosteroids +/- intravenous immunoglobulin, 52 (38.5%) with rituximab, 2 with splenectomy, and 1 with dapsone. We included 52 (27.8%) patients in group 2. Among them, 46 (88.5%) patients were treated as first-line with a rituximab-cyclophosphamide-dexamethasone combined regimen, 2 with rituximab-bendamustine, 2 with chloraminophen, 1 with fludarabine-cyclophosphamide-dexamethasone, and 1 with ibrutinib. Both overall response and relapse rates were similar between groups: 86.6% versus 86.5% and 45.5% versus 41.5%, respectively. We did not find any difference in subgroup analyses by type of AIC. Serious infections were observed in 17.6% patients: 17.8% in group 1, 17.3% in group 2. With a median of follow-up of 39.8 months (95% IC 30.0 to 51.3), the overall survival did not differ between group 1 (84.0% at 4 years, 95% IC 73.7 to 90.5) and group 2 (81.8% at 4 years, 95% IC 66.1 to 90.7), nor the progression rate of IBC was similar in both groups (9.6% and 7.7%, respectively). Conclusion We report the largest cohort of AIC associated with IBC. So far, very few patients with lymphomas such as MZL have been described in this situation. We observed that treatments were heterogeneous. Whatever the strategy used (treating AIC only or also using chemotherapy for the IBC), the effectiveness and safety profiles of first-line treatments were not different. Additional analyses are ongoing to better clarify the impact of rituximab alone versus rituximab and chemotherapy, and IBC' characteristics on the overall progression-free survival.

Hospitalization for Infection in Patients with Primary Autoimmune Hemolytic Anemia Treated with Rituximab. a Prospective, Nationwide Cohort Study in France

Introduction Autoimmune hemolytic anemia (AIHA) is a rare disease caused by the production of autoantibodies directed against red blood cells. Infections are frequent and severe in patients with primary AIHA. Rituximab is the reference second-line treatment for warm AIHA and the basis of the treatment of symptomatic cold agglutinin disease. However, the risk of infection after rituximab is not known in these patients with primary AIHA the real-world. Opportunistic infections had been described and the use of specific prophylaxis is debated. Consequently, this cohort study aimed to: (i) measure the incidence of hospitalization for infection after the exposure to rituximab in adult patients with primary AIHA; (ii) describe the types of these infections; (iii) measure the 30-day overall mortality after the first hospitalization for infection; (iv) determine the factors associated with hospitalization for infection; and (v) assess the effectiveness of pneumocystis prophylaxis. Methods Patients were selected from the AHEAD cohort (Autoimmune HEmolytic Anemia: a population-baseD study) between January 2012 and July 2018. This cohort consists in all adult patients with incident AIHA, selected in the French National Health Database. This database covers virtually the entire French population (67 million individuals). It links socio-demographic, outpatient, and hospitalization data. Patients with AIHA were identified using the International Classification of Diseases, tenth version (ICD-10) D59.1 code as hospital discharge or long-term disease diagnosis (the latter being coded by general practitioners). Incident cases were selected using a prior observation period of at least 2 years without the D59.1 diagnosis code. This code yielded a positive predictive value of 90.0% (95% CI: 79.5 to 96.2) in a previous validation study. We restricted the study population to adult patients exposed to rituximab. The first infusion of rituximab defined the index date. Patients with causes of secondary AIHA before the index date were excluded. We assessed the cumulative incidence of hospitalizations with a discharge diagnosis of infection during the six months after the index date (median duration of B-cell depletion). The overall mortality was measured during the 30 days after hospitalization for infection. We assessed the association of age, sex, comorbidities, red blood cell transfusions before the index date (as indicator of AIHA severity), exposure to corticosteroids, to other immunosuppressive drugs, splenectomy (time-varying exposures) as well as pneumococcal and influenza vaccinations before the index date on the occurrence of hospitalization for infection using Cox regression models. A sensitivity analysis was performed using Fine and Gray's models with death as competitive risk. Pneumocystis pneumonia was identified using the B48.5 and B59 discharge diagnosis codes. The association with specific prophylaxis was assessed. Results Between 2012 and 2018, we identified 959 adult patients with incident primary AIHA who received rituximab. The mean age was 67 years and 61% of the patients were women. The 6-month cumulative incidence of hospitalization with a discharge diagnosis of infection was 18.3% (95% CI: 15.9 to 20.9). The most frequently characterized infections were pulmonary, urogenital, and gastrointestinal. Opportunistic infections were observed in 28 (16.6%) patients. The 30-day overall mortality after the first hospitalization for infection was 12.5% (95% CI: 8.0 to 18.0). The risk factors associated with hospitalization for infection in multivariable analysis were an age ≥70 years (HR: 2.7; 95% CI: 1.6-4.6) and current exposure to corticosteroids (HR: 1.6; IC 95%: 1.2-2.2). The results of the sensitivity analysis were concordant. In total, 189 (19.7%) patients were exposed to pneumocystis prophylaxis and 14 pneumocystis pneumonia occurred. All cases occurred during the exposure to corticosteroids and in patients with no specific prophylaxis. All but 2 were aged ≥70 years. Conclusion The incidence of hospitalizations for infection and mortality after hospitalization for infection were high in adult patients with primary AIHA treated with rituximab. Opportunistic infections were not uncommon. Concomitant exposure to corticosteroids and an older age are the main risk factors for infection. Pneumocystis prophylaxis should be discussed for these patients.

Sars-Cov-2 and Chronic Myeloid Leukemia: A Systematic Review

Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus causing the coronavirus disease of 2019. Numerous mutations had developed in SARS-CoV-2 virus that resulted in strains (Alfa Beta Delta Omicron) with varying degrees of virulence disease severity. In coronavirus disease of 2019 (COVID-19) patients with chronic myeloid leukemia (CML), there is a controversy regarding the effect of tyrosine kinase inhibitors (TKI) on SARS-CoV-2 infection and patients' outcomes. Some studies showed that CML patients with COVID-19 had better outcomes; other reports showed no significant difference. Method Following the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines, PubMed, Scopus, and Google Scholar databases were searched for published articles through 20 April 2023 for qualified studies. The search included retrospective, prospective studies, reviews, case series, and case reports. The inclusion criteria were English literature with CML patients above 18 years who had SARS-CoV-2 infection. Articles in languages other than English and articles with non-sufficient information were excluded, and patients with bone marrow transplants were excluded. Search terms were (chronic myeloid leukemia) OR (chronic myelogenous leukemia) AND (SARS-CoV-2) OR (COVID-19). Two eligibility checks were done on the included studies. Title and abstract screening was completed first, and the full text of articles that met the requirements for inclusion was subsequently obtained. The search included all articles published up to 20 April 2023. The review is registered in PROSPERO (registration number is: CRD42022326674). Results We reviewed 36 articles of published literature up to April 2023 and collected data for a total of 686 CML patients with COVID-19. The vast majority of patients were in the chronic phase; seven patients were in the accelerated phase, and eight patients were in the blast phase. Disease severity was classified according to WHO criteria. Twenty-seven patients were managed at home, and 21 patients were in ICU (intensive care unit) during the hospital course. Twenty-six patients required oxygen therapy; among them, seven patients required intubation and mechanical ventilation, and six patients required non-invasive ventilation. Mortality was seen in 47 patients, and there were no reports of thrombotic events, but some patients developed AKI, autoimmune hemolytic anemia, rhabdomyolysis, and DKA during COVID-19. Limitations The major limitation is the lack of details about the use or hold of TKIs during SARS-CoV-2 infection in the majority of the reports. Also, the specific or predominant strain of SARS-CoV-2 was not mentioned. Few studies mentioned the variant of the virus, which make it difficult to compare the outcome of the different variant of the SARS-CoV-2 virus in patients with CML. Discussion/Conclusions Hematological cancers are associated with an increased risk of thrombosis. Thrombosis risk is expected to increase in patients with COVID-19; interestingly, patients with CML have not been reported to have a significant increase in the risk of thrombosis during COVID-19. The crucial point is, does TKI continuation during COVID-19 beneficial or harmful? Few patients continued TKIs during Covid-19 without serious adverse events. For patients who had the TKI continued, there were no mortality or serious adverse events. In vitro, TKIs were found to have a significant effect on inhibiting viral replication, which might be the reason behind the better outcome in CML patients infected with SARS-CoV-2 virus. On the other hand, there is a theoretical risk of increased severe infection in CML patients taking TKI due to targeted inhibition of kinases involved in immune cell function. This might result in suppressed cellular immune response that facilitates viral replication. Despite that, CML patients with COVID-19 have no significant increase in mortality or ICU admission compared to other hematological malignancies. in fact, our review showed that the mortality of CML patients with COVID-19 has significantly improved from 0.12% in the pre-vaccination period to 0.04% in the post-vaccination era. The available data indicates that, COVID-19's effect on patients with chronic myeloid leukemia (CML) still needs to be better understood due to the limited data.

Omission of Anti-CD20 Antibody in Chronic Lymphocytic Leukemia during COVID-19 Pandemic: Twelve Month Course of Venetoclax Is a Safe and Effective Alternative Regimen

Introduction The current treatment for patients with advanced stages of Chronic Lymphocytic Leukemia (CLL) is the combination of the Rituximab - an Anti-CD 20 Antibody and Venetoclax - a BCL-2 inhibitor. However, during COVID-19 Pandemic, we were concerned that the immunodeficiency state induced by anti-CD20 antibody infusions would increase the risk of COVID-19 complications. Also, we were concerned about exposing cancer patients to long term anti-neoplastic treatments when there were so many unknowns about the new Sar-CoV-2 virus. Thus, in order to minimize these deleterious effects, and long exposure to cancer treatment, the CLL treatment was modified through omitting Rituximab, and using a 12-month course of Venetoclax as a single agent, with the goal of preventing COVID complications, but still achieving durable remissions. Methods Between February 2020 and September 2022, 13 patients with advanced stage CLL who met the treatment criteria, were treated with single agent Venetoclax with the mean age of 77 ranging from ages 56-99 and a Male to Female ratio of 10:3. Indications of treatment were as follows: bulky lymphadenopathy (8), markedly elevated lymphocyte count (3), and bone marrow failure (2). Among these 13 patients, there were 7 treatment naive patients and 6 had previously received between 1 to 3 treatments. These treatments included: Chlorambucil-Obinutuzumab, Ibrutinib, Fludarabine-Cyclophosphamide-Rituximab, and Bendamustine-Rituximab. Following are the FISH analysis results of these patients: 13Q14, 12+, TP53- , 11Q22-. Single agent venetoclax was administered to patients as a 5 week ramp up schedule per standard dosing guidelines, with the goal being to achieve 400 mg by week 5 of the treatment. The 400 mg dosage was continued for another 11 months and patients were monitored monthly for treatment response and toxicity. After the conclusion of 12 months of treatment, patients were followed up clinically at regular intervals to monitor durability of treatment response. Patients were informed that if there was progression noted during Venetoclax treatment, a new regimen that included Anti-CD20 Antibody will be started. Results Eleven out of 13 patients achieved full dosage escalation to 400 mg by week 5. Of the 2 patients that did not escalate the full dose, one patient - age 99- only achieved dosage up to 100 mg due to physician discretion, and the other patient achieved dosage up to 200 mg due to extreme fatigue. Common side effects amongst the patients were fatigue and mild cytopenia whilst the toxicity overall was manageable. One patient required treatment interruption for Autoimmune Hemolytic Anemia (AIHA) and only one patient contracted COVID-19. This patient recovered, however, quickly with no complications and treatment of Venetoclax was resumed at full dosage. Temporary increase in absolute lymphocyte count was noted in 8 patients. Mild persistent anemia was shown in 2 patients at the completion of treatment and mild thrombocytopenia was present in 7 patients. Neutropenia was not observed in any patients. Overall, treatment response was noted in 12 out of 13 patients with 11 complete remission (CR) and 1 partial remission (PR). Time to response was 3 months from the start of treatment for all responding patients. All patients who achieved CR and PR remain in remission during follow up with a median remission duration of 15 months. One patient had stable disease while on treatment but progressed immediately after discontinuation of Venetoclax. This patient then received the combination of Obinutuzumab-Acalabrutinib and achieved complete remission. Conclusion Thus, we can conclude that a 12-month course of Venetoclax administered without anti-CD 20 antibody, is an effective treatment regimen in advanced stage CLL. The avoidance of the anti-CD 20 antibody resulted in preservation of the immunity as noted in the one patient who contracted COVID-19 during treatment but recovered quickly from infection without any COVID-19 associated complication. We believe that although Rituximab with Venetoclax remains the standard of care in advanced stage CLL, but in unusual circumstances such as during the COVID-19 pandemic, short, limited course of single agent Venetoclax is a viable option of treatment to achieve durable remission.

Steroid-Refractory Paroxysmal Cold Hemoglobinuria in a 6-Year-Old Male

Background Paroxysmal Cold Hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia (AIHA) that is often seen as a sequela of viral upper respiratory tract infections and immunizations in children. It is characterized by a positive Coombs test with a biphasic auto anti-P IgG known as the “Donath-Landsteiner antibody,” which sensitizes red cells and fixes complement at 0-4°C, and hemolyzes red cells near body temperature. The mainstay treatment of PCH includes cold avoidance, intravenous hydration, and supportive blood transfusions. Glucocorticoids may be used in the setting of significant hemolysis, with debated efficacy. We present a case of steroid-refractory PCH in a 6-year-old boy secondary to human rhinovirus/enterovirus. Methods Patient clinical data was abstracted from the electronic medical record. Blood bank testing was performed through the in-house blood bank. Donath-Landsteiner testing was performed at a reference laboratory. Findings A 6-year-old male with a history of mild upper respiratory tract infection 1 week prior presented to the emergency department with abdominal pain, dark urine, and jaundice. Initial laboratory evaluation uncovered anemia with hemoglobinuria, hyperbilirubinemia, elevated LDH, and decreased haptoglobin, raising concerns for acute hemolytic anemia (Table 1). Follow-up blood bank testing revealed a cold autoantibody. Viral PCR was positive for human rhinoenterovirus. Despite supportive therapy through intravenous fluids and warming, the patient's anemia worsened significantly (Hgb 5.1g/dL) and packed red blood cell (pRBC) transfusion was required. Methylprednisolone 0.8 mg/kg IV twice daily was initiated as empiric therapy for autoimmune hemolysis without significant improvement. Blood was sent for Donath-Landsteiner antibody testing at a reference laboratory and revealed a bi-phasic hemolysin consistent with paroxysmal cold hemoglobinuria. The patient required an additional pRBC transfusion and was discharged after 4 days inpatient. Conclusion Our case supports a growing body of evidence that finds steroid therapy inefficacious in the treatment of hemolysis in the setting of PCH.