BACKGROUND: Defects in the lymphoid system have been linked to immune dysregulation, which might explain why lymphoid neoplasms and immunological disorders tend to occur concurrently. Chronic Lymphocytic Leukemia (CLL), characterised by the accumulation of dysfunctional lymphocytes, is associated with autoimmune cytopenias such as autoimmune haemolytic anaemia (AIHA). Detection of underlying alloantibody in warm AIHA, is challenging for any transfusion medicine specialist. This report highlights the significance of overflow phenomenon in detection of alloantibody in a case of warm AIHA secondary to CLL and myasthenia gravis.
METHODS: A 56-year-old male with a history of myasthenia gravis and thymoma progressed to B-cell CLL presented with severe anaemia and thrombocytopenia leading to multiple red blood cell (RBC) transfusions in the last two months. Clinical profile and laboratory workup suggested features of AIHA, and subsequent immunohaematological workup hinted towards an impending overflow phenomenon due to differential reactivity pattern observed between serum and eluate with antibody screen/identification panel. The eluate was pan-reactive with an antibody screen/ identification panel, while the serum showed a discrete anti-C alloantibody pattern. A compatible and antigen-negative RBC unit was successfully transfused, followed by medical management.
CONCLUSIONS: The overflow phenomenon in AIHA depends on antibody titre and its affinity for RBC antigens. In the index case, the impending \'overflow or spillover\' of autoantibodies into the patient\'s serum allowed us to detect underlying alloantibody without performing allogeneic adsorption and transfuse antigen-negative and crossmatch compatible PRBC unit.
CONCLUSIONS: This case emphasises the significance of understanding the overflow phenomenon in AIHA as it can guide a transfusion medicine specialist in the early detection and identification of underlying alloantibodies, which is crucial for appropriate transfusion management in AIHA. However, early presentation and timely workup, along with a high level of suspicion, is crucial to identify this phenomenon.

About 50% of immune thrombocytopenia (ITP) patients respond to rituximab induction, but most relapse. The effectiveness of rituximab maintenance remains untested. This study included autoimmune cytopenia patients who had previously responded to rituximab induction but subsequently relapsed. After re-induction, patients received rituximab maintenance regimen consisting of a single 375 mg/m2 dose administered at 4 month intervals, with a maximum of 6 doses. Primary endpoints were duration of response and safety. Sixteen patients: ITP (9), autoimmune haemolytic anaemia (2), and Evans syndrome (5) received rituximab maintenance. 15/16 achieved complete response (CR); 8/15 CR + 1 partial reponse remain in remission. Median response: 43 months; estimated 5-year relapse-free >50%. Three developed hypogammaglobulinemia. Rituximab maintenance led to prolonged remissions in patients with autoimmune cytopenias who had previously responded to rituximab induction.

Autoimmune haemolytic anaemia (AIHA) is a rare clinical condition with immunoglobulin fixation on the surface of erythrocytes, with or without complement activation. The pathophysiology of AIHA is complex and multifactorial, presenting functional abnormalities of T and B lymphocytes that generate an imbalance between lymphocyte activation, immunotolerance and cytokine production that culminates in autoimmune haemolysis. In AIHA, further laboratory data are needed to predict relapse and refractoriness of therapy, and thus, prevent adverse side-effects and treatment-induced toxicity. The metabolomic profile of AIHA has not yet been described. Our group developed a cross-sectional study with follow-up to assess the metabolomic profile in these patients, as well as to compare the metabolites found depending on the activity and intensity of haemolysis. We analysed the plasma of 26 patients with primary warm AIHA compared to 150 healthy individuals by mass spectrometry. Of the 95 metabolites found in the patients with AIHA, four acylcarnitines, two phosphatidylcholines (PC), asymmetric dimethylarginine (ADMA) and three sphingomyelins were significantly increased. There was an increase in PC, spermine and spermidine in the AIHA group with haemolytic activity. The PC ae 34:3/PC ae 40:2 ratio, seen only in the 12-month relapse group, was a predictor of relapse with 81% specificity and 100% sensitivity. Increased sphingomyelin, ADMA, PC and polyamines in patients with warm AIHA can interfere in autoantigen and autoimmune recognition mechanisms in a number of ways (deficient action of regulatory T lymphocytes on erythrocyte recognition as self, negative regulation of macrophage nuclear factor kappa beta activity, perpetuation of effector T lymphocyte and antibody production against erythrocyte antigens). The presence of PC ae 34:3/PC ae 40:2 ratio as a relapse predictor can help in identifying cases that require more frequent follow-up or early second-line therapies.

Evans syndrome (ES) is a rare disorder classically defined as the simultaneous or sequential presence of autoimmune haemolytic anaemia and immune thrombocytopenia, but it has also been described as the presence of at least two autoimmune cytopenias. Recent reports have shown that ES is often a manifestation of an underlying inborn error of immunity (IEI) that can benefit from specific treatments.
The aim of this study is to investigate the clinical and immunological characteristics and the underlying genetic background of a single-centre cohort of patients with ES.
Data were obtained from a retrospective chart review of patients with a diagnosis of ES followed in our centre. Genetic studies were performed with NGS analysis of 315 genes related to both haematological and immunological disorders, in particular IEI.
Between 1985 and 2020, 40 patients (23 men, 17 women) with a median age at onset of 6 years (range 0-16) were studied. ES was concomitant and sequential in 18 (45%) and 22 (55%) patients, respectively. Nine of the 40 (8%) patients had a positive family history of autoimmunity. Other abnormal immunological features and signs of lymphoproliferation were present in 24/40 (60%) and 27/40 (67%) of cases, respectively. Seventeen out of 40 (42%) children fit the ALPS diagnostic criteria. The remaining 21 (42%) and 2 (5%) were classified as having an ALPS-like and an idiopathic disease, respectively. Eighteen patients (45%) were found to have an underlying genetic defect on genes FAS, CASP10, TNFSF13B, LRBA, CTLA4, STAT3, IKBGK, CARD11, ADA2, and LIG4. No significant differences were noted between patients with or without variant and between subjects with classical ES and the ones with other forms of multilineage cytopenias.
This study shows that nearly half of patients with ES have a genetic background being in most cases secondary to IEI, and therefore, a molecular evaluation should be offered to all patients.

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This retrospective report focuses on the diagnosis of the Paxillus syndrome, based on two fatal cases of haemolysis following the consumption of Paxillus involutus. These mushrooms are still consumed regularly, despite earlier reports of life-threatening autoimmune haemolytic anaemia. Such cases are nevertheless rare, and thus far no toxin could be identified that causes this unusual form of mushroom poisoning. All these factors contribute to the difficulty in diagnosing the Paxillus syndrome. The following aspects support the diagnosis in the two cases presented here: Both patients consumed the mushroom oftentimes before, yet allegedly without ill effects. Symptoms occurred 2-3 h after the last consumption, exacerbating into circulatory collapse, multiorgan failure, and death. Disseminated intravascular coagulation was identified as cause of death by autopsy of patient 1. Patient 2 died of multiorgan failure, mainly hepatic. Our mycological analyses could identify the consumed mushroom in both cases as Paxillus involutus. Furthermore, we could exclude anticoagulants and several other drugs as trigger for the haemolysis by post-mortem toxicological analysis. However, findings in each of the two cases may have led to the haemolysis, independent of the consumption of Paxillus involutus. Patient 1 carried the anti-erythrocytic antibody, auto-anti-e. Patient 2 contracted chronic hepatitis C years prior to the current incident. Considering the rarity of the Paxillus syndrome, our findings suggest that these patients were particularly susceptible for haemolysis after consuming this mushroom over a prolonged period. Occurrence of the Paxillus syndrome may thus be restricted to regular consumers of Paxillus involutus mushrooms with an existing predisposition for haemolysis.

The effects of ibrutinib on the natural history of autoimmune cytopenias (AIC) among chronic lymphocytic leukaemia (CLL) patients treated in routine clinical practice require further investigation. Using the Mayo Clinical CLL Database, 193 CLL patients treated with ibrutinib between November 2013 and January 2017 outside the context of a clinical trial were identified; complete review of their medical records was performed for details of past history of AIC and treatment-emergent AIC. We identified 29/193 (15%) patients with history of AIC prior to ibrutinib start. Of 12 patients requiring AIC therapy at ibrutinib start, 8 (67%) were able to discontinue or de-escalate AIC treatment, and no patient had worsening of their AIC after initiating ibrutinib. Eleven (6%) patients developed treatment-emergent AIC after a median of 59 (range, 6-319) days following the initiation of ibrutinib, 7 of whom (64%) were able to continue ibrutinib. Overall and event-free survival from time of ibrutinib start were not significantly different between patients with history of AIC and those with no history of AIC. Treatment-emergent AIC were seen exclusively in patients with unmutated IGHV and were associated with a shorter EFS. These results suggest a low rate of treatment-emergent AIC and improvement in patients with existing AIC.

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PCH is one of the most common causes of acute AIHA in young children, although it affects patients of all ages. In children it is commonly seen following a viral illness or after immunization. Donath Landsteiner test is the diagnostic test. This is a case report of a child who presented with features of haemolysis and was diagnosed as PCH.