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Background: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. Objective: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. Methods: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. Results: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P

As a result of significant recent developments, the management of patients with chronic lymphocytic leukemia (CLL) is changing, and new therapeutic options will continue to emerge in the near future. The recommendations of the French Innovative Leukemia Organization (FILO-CLL) group presented here are intended to provide practical recommendations for physicians taking care of CLL patients, taking into account the availability of both biological tests and therapies in daily practice in France at the time of publication. This text details the documented information and guidelines on diagnosis, indications for treatment, infectious complications and therapeutic strategies in frontline and relapsed CLL as well as in particular conditions such as autoimmune cytopenia or Richter syndrome.

The aim of the study was to determine peculiarities of the distribution, diagnosis and development of immune cytopenias in patients with chronic lymphocytic leukemia (CLL) and to evaluate the efficacy of the different therapeutic approaches. Materials and methods Treatment response and survival of 83 patients with CLL complicated by immune cytopenia (IC) were analyzed. Treatment schedules in 58 medicated patients included corticosteroids; chemotherapy (COP, CHOP regimens), immunotherapy (rituximab alone), immunochemotherapy (rituximab-containing regimens - R-COP, R-CHOP). Twenty-five patients underwent splenectomy. Results The use of corticosteroids, as the first line of treatment, resulted in short-term remission in most patients. Chemotherapy was effective in a half of CLL patients, but duration of the remission did not exceed 32 months in CLL associated with autoimmune hemolytic anemia and immune thrombocytopenia. After rituximab monotherapy (10 patients) the stable remission was reached in 60% of the patients with median relapse-free survival of 40 months. Rituximab containing chemotherapy (22 patients) caused the long-term remission in 72% of the patients with median relapse-free survival of 76 months. Splenectomy performed in 25 patients with CLL complicated by IC was effective in 70% of the patients. The outcome of splenectomy depends on IC entity. The best response was registered in associated immune thrombocytopenia (median overall survival 118 months), the worst - in Fisher - Evans syndrome (15 months). Conclusions The treatment of patients with CLL complicated by ICs should be individualized. For CLL patients without significant enlargement of lymph nodes and spleen, low lymphocytosis, associated with autoimmune hemolytic anemia or immune thrombocytopenia, the monotherapy with rituximab is optimal. In case of occurrence of autoimmune hemolytic anemia, immune thrombocytopenia or Fisher - Evans syndrome in CLL patients with enlargement of lymph nodes, spleen, significant lymphocytosis, the use of R-COP or R-CHOP schemes, 4-6 courses, is the most effective. Splenectomy is indicated in patients with massive splenomegaly, the resistance to medication, recurrent relapses after adequate therapy.

The incidence and clinical implications of autoimmune diseases (ADs) in patients with non-Hodgkin's lymphoma(NHL) remain unclear. The aim of this study was to examine the prevalence of ADs in NHL and define the clinical characteristics and prognosis of AD-associated NHL patients. Patients diagnosed with NHL in our institute between 1995 and 2017 were retrospectively reviewed to assess the incidence of ADs. Of 4880 patients with NHL, 140 (2.9%) presented with autoimmunity, with a total of 24 ADs. The most common AD was Sjögren syndrome, followed by autoimmune cytopenia, psoriasis, rheumatoid arthritis, etc. Psoriasis and rheumatoid arthritis were significantly associated with pre-existing ADs, whereas autoimmune cytopenia was significantly associated with secondary AD. Sjögren syndrome was significantly associated with B-cell lymphoma, and systemic vasculitis was significantly associated with T-cell lymphoma. Patients with AD-associated NHL had a high frequency of extranodal involvement(87%), with significant associations between specific extranodal sites of lymphoma and subtypes of ADs. Among patients with available data on pre-treatment peripheral blood Epstein-Barr virus (EBV) DNA(n = 68), elevated EBV-DNA load was observed in a variety of NHL subtypes, including 20% of marginal zone lymphoma and 14.3% of follicular lymphoma patients. In a matched-pair analysis, survival did not differ significantly between NHL patients with and without ADs. However, for NHL patients with pre-existing ADs, a prior history of systemic corticosteroids therapy was significantly associated with worse survival (HR = 7.33, P = 0.006). Taken together, our data suggest that a broad spectrum of ADs is associated with NHL, and AD-associated NHL has distinct features with regard to clinical manifestations and prognosis.

The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia. The genetic etiology of the ALPS was described in 1995 by the discovery of the FAS gene mutations. The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic defects of this apoptosis pathway, such as FADD and CASPASE 8 deficiencies. The ALPS-FAS was the first description of a monogenic cause of autoimmunity, but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients. The recognition of these genetic diseases brought new information on the role of this apoptotic pathway in controlling the adaptive immune response in humans.

Leukocyte Adhesion Deficiency type 1 (LAD-1) is a rare primary immunodeficiency due to mutations in the gene encoding for the common β-chain of the β2 integrin family (CD18). Herein, we describe clinical manifestations and long-term complications of eight LAD-1 patients. Four LAD-1 patients were treated with hematopoietic stem cell transplantation (HSCT), while the remaining four, including two with moderate LAD-1 deficiency, received continuous antibiotic prophylaxis. Untreated patients presented numerous infections and autoimmune manifestations. In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved. Other two LAD-1 patients developed type 1 diabetes and autoimmune cytopenia after HSCT, suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications.

Previous data have suggested that B-cell-depletion therapy may induce the settlement of autoreactive long-lived plasma cells (LLPCs) in the spleen of patients with autoimmune cytopenia. To investigate this process, we used the AID-CreERT2-EYFP mouse model to follow plasma cells (PCs) engaged in an immune response. Multiplex polymerase chain reaction at the single-cell level revealed that only a small fraction of splenic PCs had a long-lived signature, whereas PCs present after anti-CD20 antibody treatment appeared more mature, similar to bone marrow PCs. This observation suggested that, in addition to a process of selection, a maturation induced on B-cell depletion drove PCs toward a long-lived program. We showed that B-cell activating factor (BAFF) and CD4+ T cells play a major role in the PC survival niche, because combining anti-CD20 with anti-BAFF or anti-CD4 antibody greatly reduce the number of splenic PCs. Similar results were obtained in the lupus-prone NZB/W model. These different contributions of soluble and cellular components of the PC niche in the spleen demonstrate that the LLPC expression profile is not cell intrinsic but largely depends on signals provided by the splenic microenvironment, implying that interfering with these components at the time of B-cell depletion might improve the response rate in autoimmune cytopenia.

Autoimmune or alloimmune cytopenia (AIC) is a known rare complication of hematopoietic stem cell transplantation (SCT). AIC after SCT is considered difficult to treat and is associated with high morbidity and mortality. In this retrospective study in pediatric patients we evaluated incidence, outcome, potential risk factors, and current treatment strategies. A nested matched case-control study was performed to search for biomarkers associated with AIC. Of 531 consecutive SCTs at our center between 2000 and 2016, 26 were complicated by the development of AIC (cumulative incidence, 5.0%) after a median of 5 months post-SCT. Autoimmune hemolytic anemia was the most common AIC with 12 patients (46%). We identified nonmalignant disease, alemtuzumab serotherapy pre-SCT, and cytomegalovirus (CMV) reactivation as independently associated risk factors. The cytokine profile of patients at the time of AIC diagnosis appeared to skew toward a more pronounced Th 2 response compared with control subjects at the corresponding time point post-SCT. Corticosteroids and intravenous immunoglobulin as first-line treatment or a wait-and-see approach led to resolution of AIC in 35% of cases. Addition of step-up therapies rituximab (n = 15), bortezomib (n = 7), or sirolimus (n = 3) was associated with AIC resolution in 40%, 57%, and 100% of cases, respectively. In summary, we identified CMV reactivation post-SCT as a new clinical risk factor for the development of AIC in children. The cytokine profile during AIC appears to favor a Th 2 response. Rituximab, bortezomib, and sirolimus are promising step-up treatment modalities.

Ibrutinib (IBR) covalently binds to the active site of Bruton’s tyrosine kinase (BTK) and is used for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). Approximately 5-10% of CLL is complicated by autoimmune cytopenia (AIC), such as autoimmune hemolytic anemia (AIHA). Several cases of AIC have reportedly demonstrated improvement during IBR treatment. However, in our case, the patient developed AIHA during oral IBR treatment. As AIHA is exacerbated by the increased number of CLL cells in the peripheral blood, it may have developed because of disease progression rather than IBR use. This phenomenon may also be attributed to the production of autoantibodies due to increased number of CD5+ B cells. In this case, withdrawal of IBR and administration of rituximab improved hemolysis. If AIHA develops during treatment, its etiology must be examined to confirm the effects of treatment.

The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia. This clinical entity was recognized in the mid 60s and its genetic etiology was described in 1995 by the discovery of the FAS gene mutations. This was the first description of a monogenic cause of autoimmunity but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients. The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic causes of ALPS such as somatic mutations of RAS or the recently described CTLA-4 insufficiency. The recognition of these genetic diseases brought new information on the regulation of the adaptive immune responses and uncovered new therapeutical targets. Finally, the deciphering the role of somatic mutations may pave the way to the understanding of more common autoimmune diseases.

Approximately 4.3–9.7% of chronic lymphocytic leukemia (CLL) patients will present with an autoimmune cytopenia (AIC) at some point during the course of their disease [1]. Autoimmune hemolytic anem...

Background LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency caused by mutation in LRBA gene. The patients have a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, autoimmunity and enteropathy. Methods A total of 17 LRBA-deficient patients were enrolled in this longitudinal study. For all patients, demographic information, clinical records, laboratory and molecular data were collected. Results Hypogammaglobulinemia were reported in 14 (82.4%), CD4+ T cell deficiency in five (29.4%), NK cell deficiency in three (21.4%) and CD19+ B cell deficiency in 11 (64.7%) patients. All patients had history of infectious complications; pneumonia was the most common (76.5%) occurring infection. A history of lymphoproliferative disorders was observed in 14 (82.3%), enteropathy in 13 (76.5%), allergic symptoms in six (35.5%), neurological problems in four (23.5) and autoimmunity (mostly autoimmune cytopenia) in 13 (76.5%) patients. Sirolimus treatment improved enteropathy of patients with remarkable success. The 20-year overall survival rate declined to 70.6%. Conclusion LRBA deficiency has a very broad and variable phenotype and should be considered, especially in children with early onset hypogammaglobulinemia, severe autoimmune manifestations, enteropathy, lymphoproliferation, and recurrent respiratory tract infections. This article is protected by copyright. All rights reserved.

This disease is characterized by the onset of primary immunodeficiency, which expresses itself as autoimmune multisystem failure, often clinically manifests during the first year of life; there are only about 150 cases in the world described by now. IPEX syndrome is caused by FOXP3 gene defect, which is a transcription factor that affects the activity of regulatory T-cells responsible for the maintenance of aytotolerance. There are around 70 pathogenic mutations in this gene described so far. Most patients with IPEX-syndrome have a clinical manifestations of the disease in the early neonatal period or during the first 3-4 months of life. For this disease the following clinical triad of manifestations is typical: Autoimmune enteropathy (100%), diabetes mellitus (70%), skin lesions (65%), as in the syndrome structure includes severe developmental delay (50%), thyroid disease (30%), recurrent infections (20%), rarer autoimmune cytopenia (Coombs-positive hemolytic anemia), pneumonia, nephritis, hepatitis, artrit, myositis, alopecia. However, some cases of later manifestations were described (in patients of more than 1 year of age) when patients did not show all clinical and laboratory symptoms typical for severe forms of the disease. Due to the severity of the disease and the high mortality in this group of patients, it is very important to diagnose it early and start therapy timely. The article describes a clinical case of permanent neonatal diabetes mellitus in the structure of IPEX syndrome.

Thrombotic thrombocytopenic purpura (TTP) has a devastating prognosis without adapted management. Sources of misdiagnosis need to be identified to avoid delayed treatment. We studied 84 patients with a final diagnosis of severe (

Sjogren’s syndrome (SS) is a chronic systemic autoimmune disease, characterized by lymphocytic infiltration of lacrimal and salivary glands. Although extra glandular manifestations are uncommon, they can occur with the musculoskeletal, renal, pulmonary and hematological disease. We report the case of a 35-year-old woman presented to us with persistent unexplained bicytopenia (anemia and thrombocytopenia). Antinuclear antibody and direct Coombs test were positive. Anti-Ro/SSA and anti-La/SSB antibodies were also positive in high titer. The final diagnosis of primary SS with autoimmune cytopenia was made. Cytopenias in SS are rarely reported. Our case illustrates that clinically significant cytopenias may present as an extraglandular manifestation of SS.

Objective To describe the clinical, biological and pathological characteristics of patients with the association of SLE and thymic epithelial tumors (TET) in a retrospective multicenter series. Methods Cases diagnosed in France between 2000 and 2015 were collected after a call for observations from the French network for thymic epithelial tumors (RYTHMIC database) and the French National Society of Internal Medicine (SNFMI). Results Fourteen patients were identified, the majority were women (93%). The median age at diagnosis of lupus was 43.5 [range: 30–66] years and 43.5 [range: 26–73] years at diagnosis of thymoma. TET required chemotherapy and/or radiotherapy complementary to surgery in >90% cases. Lupus was diagnosed before, simultaneously, or after diagnosis of thymoma in 6, 3 and 5 cases, respectively. Among the lupus manifestations, joint involvement was predominant (78.6%), followed by autoimmune cytopenia (35.7%), cutaneous affections (28.6%), serositis (28.6%) and renal involvement (21.4%). SLE was associated with one or more AID in 5/14 patients. These characteristics were compared with those from 17 patients identified in the literature. Among them, joint and skin involvement as well as pleural/pericardial effusions occurred in >50%. SLE was controlled by prednisone and hydroxychloroquine in the majority of cases, but 7 out of 31 patients had an immunosuppressant. Conclusion The association of SLE and TET is rare, and its clinical profile seems to be distinguished by the frequency of cytopenias. The management of these patients is complicated by the need to treat cancer, lupus and/or associated autoimmune diseases.

Objectives: Common variable immunodeficiency is a primary immunodeficiency disease characterized by hypogammaglobulinemia and heterogeneous clinical features. Neutropenia is a rare complication amo...

8 to 22% of patients with Common Variable Immunodeficiency (CVID) develop GLILD, associated with bad prognosis. GLILD is characterized by diffuse radiological abnormalities and/or histologic evidence of granulomatous inflammation with lymphoproliferative changes. Proper management is unknown. In this retrospective single-centre study, chest HRCT scans of 34 CVID patients were blind-reviewed by 2 radiologists. 15/34 patients presented HRCT findings consistent with GLILD. Different parameters were compared between patients with HRCT patterns consistent with GLILD and those without GLILD features. The mean percentage of circulating B lymphocytes was lower in GLILD-patients. GLILD-patients presented a reduced percentage of switched-memory B cells and a higher percentage of activated B cells. IgG, IgA and IgM levels at diagnosis were lower in GLILD patients, requiring higher levels of IgG replacement. Splenomegaly was found in 53.3% of GLILD patients and in 15% of controls. 3/15 GLILD-patients underwent splenectomy due to autoimmune cytopenias. None of the controls had autoimmune cytopenia. 14/15 GLILD-patients had FEV1 and FVC > 70%. DLCO was reduced (

Autoimmune lymphoproliferative syndrome (ALPS) is caused by germline or somatic loss of function FAS mutations resulting in impaired apoptosis and consequent expansion of T-lymphocytes causing organomegaly and autoimmune anemia, neutropenia and thrombocytopenia. Herein, we report on a case of disseminated varicella zoster infection after post-partum vaccination in a patient found to have CD4 lymphopenia and eventually diagnosed with ALPS caused by a novel germline missense mutation in FAS death-domain. A subsequent retrospective analysis of 169 patients of the NIH ALPS-FAS cohort, revealed that CD4-T-cells lymphopenia (< 300 cells/μl) may occur in 5% of ALPS-FAS patients irrespectively of the underlying genetic defect, organomegaly or immunosuppressive treatment. Although immunophenotyping did not show depletion of specific CD4-T-cells subpopulations, CD4-lymphopenic ALPS-FAS subjects had an expansion of a subset of circulating T-follicular-helper (cTfh) cells, associated with autoantibody production (CCR7lowPD-1high). Furthermore, autoantibodies binding on CD4-T-cells were detected in 50% of the CD4-lymphopenic ALPS-FAS patients and caused cytotoxicity in a natural killer (NK)-mediated antibody-dependent-cellular cytotoxicity assay. Such autoantibodies can therefore be associated with CD4-T-cell death, impaired activation induced proliferation or impaired trafficking. The expansion of autoreactive T-cells in ALPS-FAS is known to be associated with autoimmune clinical manifestations, however our study reveals that ALPS-FAS can also be associated with a paradoxical depletion of CD4-T-cells due to the presence of autoantibodies on the surface of CD4-T-cells which can in turn result in increased susceptibility to opportunistic infections. These novel findings have implications for the diagnosis, clinical monitoring, and management of patients with ALPS-FAS.

Background Signal Transducer and Activator of Transcription 3 (STAT3) gain-of-function germline mutations are associated with diverse clinical manifestations, including autoimmune cytopenia, lymphadenopathy, immunodeficiency, endocrinopathy, and enteropathy. We describe a new feature: raised intracranial pressure with papilledema. Materials and methods Report of two cases. Results The first patient had a de novo heterozygous c.2144C>T (p.Pro715Leu) mutation in the STAT3 gene. At age 1 she had papilledema with marked sheathing of the proximal vessels on the optic discs. Follow-up 8 years later showed chronic papilledema, cystoid macular edema, and vision loss. The second patient had a de novo heterozygous c.2147C>T (p.Thr716Met) mutation. At age 12 he developed papilledema, which recurred despite treatment. In both patients, repeated sampling of the cerebrospinal fluid demonstrated a lymphocytic pleocytosis. Conclusions Papilledema can occur as a manifestation of STAT3 gain-of-function mutation, sometimes accompanied by prominent vascular sheathing and cystoid macular edema. The mechanism may be chronic meningeal infiltration by white blood cells, impairing cerebrospinal fluid absorption.

International audience; PURPOSE: Immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are associated in the definition of Evans syndrome (ES). The occurrence of neurological involvement in this population is poorly described and suggests an underlying primary immunodeficiency (PID). We aimed to describe the clinical manifestations, evolution, and PID profiles of these patients.METHODS: OBS'CEREVANCE is a French, nationwide prospective cohort that includes children with chronic ITP, AIHA, and ES. Patients with a neurological involvement were described. Centralized radiological and pathological reviews and genetic analyses were performed.RESULTS: On October 2016, eight patients (7/181 ES, 1/371 AIHA, and 0/615 ITP) were identified, all male, with a median age (range) at cytopenia onset of 11.5 years (1.6-15.8). Neurological symptoms appeared with a median delay of 6 years (2.5-18) after cytopenia and were polymorphic: seizures (n = 4), cranial nerve palsy (n = 2), Brown-Sequard syndrome (n = 2), intracranial pressure (n = 2), vertigo (n = 1), and/or sensory neuropathy (n = 1). Magnetic resonance imaging (MRI) showed inflammatory lesions, confirmed by pathology for five patients with macrophagic or lymphoplasmocytic infiltrates. All patients had other relevant immunopathological manifestations: pulmonary nodules (n = 6), lymphoproliferation (n = 4), abnormal immunophenotype (n = 8), and hypogammaglobulinemia (n = 7). Treatment consisted of steroids that improved symptomatology and MRI. Five patients relapsed and three had an asymptomatic radiological progression. A PID was identified in 3/8 patients: 22q11.2 microdeletion (n = 1) and CTLA deficiency (n = 2).CONCLUSION: Neurological involvement is a rare and severe late event in the course of childhood ES, which can reveal an underlying PID. Imaging and pathology examination highlight a causative immune dysregulation that may guide targeted therapeutic strategies.

Background Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients. Objective To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA. Methods We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes. Results Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naive CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naive ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002. Conclusions Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.

This retrospective study explored the incidence of autoimmune cytopenia (AIC) in 530 paediatric and adult patients with acquired aplastic anaemia (aAA) who underwent first allogeneic HSCT between 2002 and 2012. AIC was a rare complication with a cumulative incidence of AIC at 1, 3, 5 and 10 years post HSCT of 2.5% (1.2–3.9 95% CI), 4.4% (2.6–6.2 95% CI), 4.6% (2.8–6.5 95% CI) and 5.1% (3.1–7.2 95% CI). Overall survival at 5 years after diagnosis of AIC was 85.9% (71–100 95% CI). Twenty-five patients were diagnosed with AIC at a median of 10.6 (2.6–91.5) months post HSCT. Eight (32%) patients were diagnosed with immune thrombocytopenia (ITP), seven (28%) with autoimmune haemolytic anaemia (AIHA), seven (24%) with Evans syndrome and four (16%) with autoimmune neutropenia (AIN). Treatment strategies were heterogeneous. Complete responses were seen in 12 of 25 patients, with death in three patients. In multivariable Cox analysis of a subgroup of 475 patients, peripheral blood stem cell (PBSC) transplant was associated with higher risk of AIC compared with bone marrow (BM) when conditioning regimens contained fludarabine and/or alemtuzumab (2.81 [1.06–7.49 95% CI]; p = 0.038), or anti-thymocyte globulin (ATG) (2.86 [1.11–7.37 95% CI]; p = 0.029). Myeloablative conditioning was associated with a lower risk of AIC compared with reduced intensity conditioning (RIC) in fludarabine and/or alemtuzumab (0.34 [0.12–0.98 95% CI]; p = 0.046) and ATG containing regimens (0.34 [0.12–0.95 95% CI]; p = 0.04). These findings provide clinically useful information regarding the incidence of a rare and potentially life-threatening complication of allogeneic HSCT for aAA, and further support for BM as the preferred stem cell source for transplant of patients with aAA.

The presence of anemia and/or thrombocytopenia is not infrequent in CLL and defines advanced, poor prognosis disease. Given their multiple possible causes, patients with CLL presenting cytopenia require a careful evaluation and an individualized management. The association of CLL with cytopenias of immune origin is based on experts’ consensus, and its impact on patients’ outcome remains controversial. It is widely accepted that treatment should be the same as in idiopathic immune cytopenias (i.e., corticosteroids and/or anti-CD20 monoclonal antibodies) with failure to respond to conventional treatment being an indication for anti-CLL therapy. Interestingly, analysis of retrospective series suggests that novel oral targeted therapies (i.e., ibrutinib) might be effective to treat autoimmune cytopenias complicating CLL. Prospective studies are needed to clarify the role of signal inhibitors in the management of autoimmune cytopenias in CLL.

International audience; Objective: Angioimmunoblastic T-cell lymphoma (AITL) is frequently associated with autoimmune cytopenia (AIC). Whether such patients have a particular phenotype and require particular management is unclear. Method: Angioimmunoblastic T-cell lymphoma patients from the multicentric database of the Lymphoma Study Association presenting with AIC during disease course were included and matched to AITL patients without AIC (1/5 ratio). Results: At diagnosis, AIC patients (n = 28) had more spleen and bone marrow involvement (54% vs 19% and 71% vs 34%, P < 0.001), Epstein-Barr virus replication (89% vs 39%, P < 0.001), gamma globulin titers (median 23 vs 15 g/L, P = 0.002), and proliferating B cells and plasmablasts in biopsies, as compared to control patients (n = 136). The 28 AIC patients had 41 episodes of AIC, diagnosed concomitantly with AITL in 23 (82%) cases. After a median follow-up of 24 months (range 3-155), 10 patients relapsed, all associated with AITL relapse. Conclusion: Our results provide new insight into AIC associated with AITL by highlighting the significant interplay between AITL and B-cell activation leading to subsequent autoimmunity.

BACKGROUND: Peripheral autoimmune cytopenia is defined by the immune-mediated destruction of hematological cell lines, including platelets, red blood cells, white cells (neutrophils), and multi-line destruction, called Evans syndrome. METHODS: Our retrospective study includes 59 patients admitted to the hematology service in Constantine Regional Military University Hospital during a period of 10 years (2010–2019) with the aim of specifying the epidemiological, clinical and biological characteristics as well as the characteristics therapy of adult autoimmune cytopenia in eastern Algeria region. RESULTS: Through this study, it can be noted that immunological thrombocytopenic purpura (ITP) is the most frequent of cytopenia 79.33% (47 cases) followed by autoimmune hemolytic anemia (AHAI) by 20.34% (11 cases). The average age for ITP is 52.04 ± 5.78 years with a male predominance and a gender F/M ratio of 0.81. People over the age of 60 were the most affected. The diagnosis is evoked in the presence of a hemorrhagic syndrome in 51.06% of cases. Thrombocytopenia (platelet count

In the past decade the introduction of targeted therapies has dramatically transformed the landscape of treatment for chronic lymphocytic leukemia (CLL). Whether this new therapeutic scenario will modify the current prevalence statistics and natural history of autoimmune cytopenias complicating CLL is still a matter of debate. Here we present a comprehensive review of the literature on this topic, with special emphasis on the incidence of autoimmune hemolytic anemia (AIHA). The potential to induce autoimmune cytopenia has been studied mostly with ibrutinib, a first- in-class bruton kinase (BTK) inhibitor, licensed for the treatment of relapsed/refractory high-risk CLL. Recent observations suggest that emergent AIHA occurring during therapy with ibrutinib is more an expression of CLL activity than an ibrutinib-mediated process. Since available information on AIHA occurring during and after therapy with small-molecule kinase inhibitors relies mainly on data collected from clinical trials, a close post- marketing surveillance is mandatory in order to improve our understanding of this topic.

Childhood-onset chronic and refractory cytopenias are rare and may be genetic in etiology. We report three pediatric cases of severe autoimmune thrombocytopenia or anemia associated with growth retardation and spastic diplegia with intracranial calcification. The identification of platyspondyly and metaphyseal lesions suggested a potential diagnosis of spondyloenchondrodysplasia (SPENCD), which was confirmed with the identification of biallelic ACP5 mutations. Two patients demonstrated elevated serum interferon alpha levels. Our report highlights ACP5-associated disease as a cause of childhood-onset autoimmune cytopenia, particularly combined with growth retardation and/or spasticity. Furthermore, a role for type I interferon in the pathogenesis of autoimmune cytopenias is supported.

Autoimmune cytopenias (AIC) are common in chronic lymphocytic leukemia (CLL) and include autoimmune hemolytic anemia, immune thrombocytopenia and, less frequently, pure red blood cell aplasia. It is generally accepted that treatment of CLL-associated AIC should be primarily directed against the

Introduction Thymic epithelial tumor (TET)-associated cytopenia is rare but difficult to treat. Methods We performed a multicenter, retrospective study of TET and associated forms of cytopenia in France. Cases were collected by the French National Reference Center for Autoimmune Cytopenia and the French National Thymic Malignancy Interest Group (Reseau Tumeurs Thymiques et Cancer) and through a call for cases by the French Society of Internal Medicine. Results Thirty-six cases were recorded between 2002 and 2014 and followed up for a median of 38 months (interquartile range, 23–106 months). Thirty-two patients underwent surgery for TET, and 14 of the latter were in complete remission at last follow-up. Cytopenia can occur before, simultaneously, or after diagnosis of TET. The most common types of cytopenia were pure red cell aplasia (in 30% of cases) and Good syndrome (GS) (also in 30% of cases). Eleven patients displayed two or more episodes of cytopenia. Eighteen patients received steroids as their first-line treatment, leading to a complete response in nine. Other first-line treatments (cyclosporine and rituximab) were less effective but should be considered as treatment options. Infections developed in 84% of the patients with GS; this did not appear to be related to the presence or absence of immunosuppressive treatment or chemotherapy. Eight patients died during the follow-up period (two died of cytopenia and five of infections). Conclusions The optimal treatment for TET-associated cytopenia has not been clearly defined and the outcome does not appear to be correlated with TET progression. For GS, prophylactic immunoglobulin replacement therapy and prophylactic antibiotic therapy can be recommended.

Development of autoimmune cytopenia (AIC) after allogeneic hematopoietic cell transplantation (HCT) is a serious complication requiring urgent intensification of immunosuppressive therapy. The pathophysiology and predictors of AIC are not completely understood. In this retrospective cohort analysis of 380 pediatric patients, we evaluated the incidence, outcomes, and related various variables, including immune reconstitution markers to AIC. Three hundred eighty patients (median age, 7.4 years; range, .1 to 22.7) were included, of which 30 patients (7.8%) developed AIC in 1 (n = 6), 2 (n = 6), or 3 (n = 16) cell lineages at a median of 133 days (range, 46 to 445) after HCT. Using multivariate analysis we found that chemo-naivety before HCT, acute graft-versus-host disease (aGVHD) grades II to IV, and serotherapy were associated with the development of AIC. Development of AIC was preceded by increased levels of IgM, IgA, and IgG. Immune profiles of total absolute lymphocytes were very similar between AIC patients and control subjects. However, CD3-CD16+CD56+ natural killer cells, CD3+ T cells, CD3+CD4+ T cell subset, and CD3+CD8+ T cell subset were lower in AIC patients. Overall survival was good, at 83% (similar between AIC patients and control subjects). In conclusion, we identified chemo-naivety before HCT, preceding aGVHD grades II to IV, and serotherapy as predictors for development of AIC. Increasing levels of IgM, IgA, and IgG preceded AIC development. These data provide clues to further study the biology of AIC.

A recent extensive analysis encompassing data on more than 2000 patients with PID in French national register revealed that about a quarter of those patients suffer from at least one autoimmune and inflammatory (A/I) conditions. The manifestations spanned through all known A/I symptoms with autoimmune cytopenia being the most frequent one, followed in frequency by gastrointestinal disorders, skin ailments, and rheumatic conditions. About a third of the affected patients did experience more than one A/I manifestation. The relative risk of developing A/I manifestation was 3- to 14-fold higher in patients with PIDs compared to the normal population. The A/I manifestations occurred throughout the life; by the age of 50 years, 40% of the patients were affected.

Evans syndrome is defined by bilineal autoimmune cytopenia, typically coombs positive hemolytic anemia and thrombocytopenia. Corticosteroids are the mainstay of treatment, with rituximab and/or mycophenolate mofetil often used in steroid-refractory cases. However, no treatment methodology has ever evaluated by a randomized clinical trial. We present a 15-year-old boy with Evans syndrome and common variable immunodeficiency who experienced a severe, refractory flare 16 months postsplenectomy. After failing to respond to multiple other agents, he achieved a durable response to a bortezomib-based regimen. Bortezomib may be a reasonable second or third line option, especially before high-morbidity therapies such as splenectomy or stem cell transplantation.