Pretransplant bone marrow cellularity and blood count recovery are not associated with relapse or survival risk following allogeneic stem cell transplant for AML in CR.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) can be curative for acute myeloid leukemia (AML). Novel therapies may render patients' bone marrow hypocellularity and lead to prolonged post-therapy pancytopenia. Patients' bone marrow cellularity (BMC) at pretransplant assessment and post-treatment pancytopenia (classification CR-incomplete [CRi]) may manifest AML persistence. METHODOLOGY: We retrospectively examined the impact of BMC and ELN response (ELNr) on a single-center cohort of 337 patients who underwent allogeneic HCT for AML in CR1. RESULTS: Median follow-up was 33 months. Overall survival (OS) for the whole cohort was 55.8% at 2 years, while cumulative incidence of relapse (CIR) was 20.8%, and non-relapse mortality was 27.5%. OS and CIR were not significantly different between BMC groups; and neither was ELNr. ELNr CRi was associated with BMC aplastic and hypocellular marrow states (P < 2.6e-8). Multivariate analysis confirmed neither BMC nor attainment of ELNr CR vs CRi affected OS or relapse. Significant factors for survival included age at transplant, cytogenetic risk, development of acute Gr II-IV GvHD, and moderate-severe chronic GvHD, while cytogenetic risk and chronic GvHD affected relapse. CONCLUSION: Neither ELNr status nor pretransplant BMC influenced relapse post-HCT or OS. Hypocellularity and CRi are not negative prognostic factors for post-HCT outcomes of AML.

Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.

BACKGROUND: We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation. RESULTS: The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved. CONCLUSIONS: Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.

Massive gingival bleed: a rare manifestation of cyclosporine toxicity.

A 12-year-old patient of thalassaemia major developed autoimmune cytopaenia after undergoing haematopoietic stem cell transplantation. She was started on cyclosporine (CsA) in view of poor response to steroids. She developed CsA toxicity manifesting as gum hyperplasia with multiple episodes of gum bleed. During endotracheal intubation for an elective splenectomy, she developed significant bleeding from gums requiring massive transfusion. Postoperatively the gum bleed persisted even after embolisation of facial artery and multiple transfusions. The catastrophic sequelae include transfusion-related lung injury, acute circulatory failure with subsequent cardiac arrest and death. Gum hyperplasia is a commonly reported toxic effect of CsA. Lethal presentations of this toxicity with such severity are limited in the medical literature. Evaluation of the patient's medical and laboratory records, along with a review of literature, was very helpful in understanding more about the toxicity of CsA.

Tacrolimus is effective in relapsed/refractory autoimmune cytopenias: results of a single-center retrospective study.

BACKGROUND: The standard therapies for autoimmune cytopenias, including idiopathic thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES), are corticosteroids and intravenous immunoglobulin G. However, the recurrence rate is high. METHOD: Data from 80 patients with ITP, AIHA and ES who were refractory to corticosteroids/relapsed and were treated with tacrolimus from January 2018 to January 2019 in Peking Union Medical Colleague Hospital were reviewed retrospectively. RESULTS: There were 24 males and 56 females, with a median age of 43 (14-81) years, including 66 with ITP, 11 with AIHA and 3 with ES. The median disease duration before tacrolimus was 16 (2-432) months. The complete response (CR) rates were 30.3%, 63.6% and 0%; the overall response (OR) rates were 63.6%, 72.7% and 66.7% for ITP, AIHA and ES, respectively; and the median time to response was 3 (2-10) months. In a median of 18 (10-24) months of follow-up time, 21.4% of ITP patients relapsed at a median time of 7 months. No relapse was found for patients with AIHA and ES. Side effects occurred in 16.3% of patients, including elevated creatinine (N = 3, 3.8%), gastrointestinal reactions (N = 3, 3.8%), and pulmonary infection (N = 2, 2.5%), and resulted in 3 patients stopping tacrolimus. The OR rate was found to be related with age (P = 0.01) but not with sex (P = 0.62), the duration of disease (P = 0.66), tacrolimus concentration (P = 0.99) or disease type (P = 0.84). CONCLUSION: Tacrolimus can achieve a durable response with mild side effects in patients with steroid-refractory/relapsed autoimmune cytopenias. Patients with younger age had a better response.

Rowell's syndrome: a rare but distinct entity in rheumatology.

Rowell's syndrome is a rare disorder characterised by an association of lupus erythematosus with erythema multiforme (EM)-like skin lesions. EM as the initial clinical presentation of systemic lupus erythematosus is also atypical and even rarer. We report the case of an 18-year-old girl admitted to our hospital with fever and polyarthralgia along with multiple discrete ill-defined target lesions with crust formation over forehead, cheek, external ears, scalp, upper chest and back (predominantly over sun-exposed areas) with ulceration over hard palate. Investigations revealed pancytopaenia, a positive rheumatoid factor, positive antinuclear antibody with a speckled pattern, anti-Smith antibody and strongly positive anti-Ro. Patient was diagnosed with Rowell's syndrome as per clinical and laboratory features. Majority of skin lesions including oral ulcerations subsided gradually after treatment with steroids and hydroxychloroquine.

Autoimmune pancytopenia occurring late after simultaneous pancreas and kidney transplantation.

A 35-year-old woman presented with a widespread petechial rash and pancytopenia. She underwent simultaneous pancreas and kidney transplantation for type 1 diabetes 8 years previously followed by a renal transplant 1 year prior to presentation, and was taking tacrolimus as long-term immunosuppression. The full blood count showed haemoglobin 97 g/L, platelet count 2×109/L and neutrophil count 0.22×109/L. Peripheral blood film examination confirmed genuine thrombocytopenia in the absence of any haemolytic or malignant features. Serological testing identified autoantibodies against all three blood lineages, consistent with a diagnosis of autoimmune pancytopenia. Treatment with steroids, intravenous immunoglobulins, romiplostim and mycophenolate mofetil achieved only fleeting remissions. Blood counts eventually normalised following the administration of rituximab and a change from tacrolimus to ciclosporin immunosuppression. Cytopenias are a well-recognised complication of post-transplantation care but we believe this to be the first reported case of autoimmune pancytopenia following solid organ transplantation. In this case report, we discuss the approach to investigation of haematological abnormalities post-transplant and the rationale for, and outcome of, the management of this rare case.

Antibodies specific to ferritin light chain polypeptide are frequently detected in patients with immune­related pancytopenia.

Immuno-related pancytopenia (IRP) is characterized by pancytopenia resulting from bone marrow suppression or destruction mediated by auto­antibodies. In our previous study, a K562 cDNA library was established, which was used to screen for seven possible auto­antigens produced by hematopoietic cells in patients with IRP, including ferritin light chain (FTL). In the present study, FTL was expressed and purified, and the levels of the auto­antibodies specific to FTL were measured. Through ELISA, it was shown that the titer of anti­FTL antibodies was higher in patients with IRP without treatment compared with those who had recovered from IRP, those with severe aplastic anemia (SAA), those with myelodysplastic syndrome (MDS) and the healthy controls. Furthermore, the expression levels of FTL­mRNA were upregulated in patients with IRP without treatment compared with those who had recovered from IRP, those with MDS and the normal controls. The results suggest that FTL antibody expression is upregulated in patients with IRP. Detecting FTL antibodies may therefore have certain clinical value in differentiating between IRP, SAA and MDS. Furthermore, in specific patients with IRP, FTL as an auto­antigen may induce immune attack on hematopoietic stem cells.

Insensitive to PTH of CD8+ T cells regulate bone marrow mesenchymal stromal cell in aplastic anemia patients.

Aplastic anemia (AA) is a rare disorder characterized by the suppression of bone marrow function resulting in progressive pancytopenia. The pathogenesis of AA is complex and involves an abnormal hematopoietic microenvironment, hematopoietic stem cell/progenitor cell deficiencies, and immunity disorders. However, the underlying mechanism of the disease is still not fully uncovered. In this research, we collected both donor and patient samples and found suppressed proliferation, abnormal differentiation as well as increased apoptosis of patient mesenchymal stem cells (MSCs). Considering the close relationship of parathyroid hormone (PTH) and MSCs differentiation, further studies showed that although patients maintained normal serum PTH level, their CD8+ T cells possessed lower PTH receptors. The insensitive to PTH of patients' CD8+ T cells finally lead to reduced expression of key Wnt factors. In all, bone marrow CD8+ T cells may play an important role in inducing MSCs adipogenesis and osteogenesis imbalancement.

Roles of immune responses in the pathogenesis of immunorelated pancytopenia.

Some patients with pancytopenia do not conform to any diagnostic criteria of known haematological or non-haematological diseases; however, they respond well to corticosteroid, high-dose intravenous immunoglobulin and rituximab treatment. This abnormality is termed immunorelated pancytopenia (IRP). Later studies indicated that IRP might be a kind of autoimmune disease in which T helper (Th) type 2 cell function is enhanced, resulting in the hyperfunction of B lymphocytes, which then produce excess autoantibodies that attack the bone marrow (BM) and cause cytopenia. Hypofunction of regulatory T (Treg) cells and enhanced Th17 cell function, an elevated percentage of plasmacytoid dendritic cells (pDCs) and a decreased percentage of natural killer (NK) cells help to promote the process. Moreover, increased expression of a synergistic stimulator of B lymphocytes, CD70 and the reactive overexpression of the BCR inhibitory coreceptor CD22 also support this claim. Candidate autoantigens targeted by autoantibodies on haematopoietic cell membranes have also been reported in IRP. This review is focused on studies that demonstrate the role of immune responses in the pathogenesis of IRP. Current diagnostic criteria and treatments for IRP are also referenced to provide a thorough understanding. Distinguishing IRP from idiopathic cytopenias of undetermined significance (ICUS) and other haematological disorders, for example myelodysplastic syndrome (MDS), aplastic anaemia (AA), paroxysmal nocturnal hemoglobinuria (PNH) and Evans syndrome, may help patients with pancytopenia benefit from proper treatment. Further studies are required to achieve new insight into the pathophysiology of IRP with regard to the immune system, which will be instrumental for the development of novel therapies for inhibiting disease initiation and/or progression.

Th9 Cells in Peripheral Blood Increased in Patients with Immune-Related Pancytopenia.

BACKGROUND: Immune-related pancytopenia (IRP) is a kind of autoimmune disease mediated by autoantibodies in bone marrow. T helper 9 (Th9) cell is a new subset of T cell discovered recently, which mainly expresses cytokine interleukin-9 (IL-9) to exert immune function. Th9 cells are associated with a variety of inflammatory diseases, but the role of Th9 cells in IRP remains unclear. METHODS: Fifty patients with IRP and 20 healthy controls were enrolled. The percentage of Th9 cells was detected by flow cytometry (FCM) and ELISA. CD4+ lymphocytes were sorted by magnetic beads, and the mRNA expression levels of Th9 cells related transcription factors PU.1 and BATF were detected by RT-PCR. RESULTS: The percentage of Th9 cells in CD3+CD4+ cells was 2.73 ± 1.96% in the untreated group, which was significantly higher than those in the remission group (1.21 ± 0.86%) (p < 0.01) and the control group (0.68 ± 0.40%) (p < 0.001). And that in the remission group was significantly higher than that in the control group (p < 0.05). The level of IL-9 in the untreated group was 183.91 ± 112.42 pg/mL, which was significantly higher than that in the remission group (105.96 ± 64.79 pg/mL) (p < 0.01) and control group (56.03 ± 14.49 pg/mL) (p < 0.001). That in the remission group was also significantly higher than that in the control group (p < 0.01). They were negatively correlated with hemoglobin, red blood cell, white blood cell, and platelet counts and positively correlated with the percentage of CD19+B cells and CD5+CD19+/CD19+B cells, respectively. The mRNA expression levels of PU.1 and BATF in IRP patients were higher than those in controls (p < 0.05). CONCLUSIONS: The percentage of Th9 cells in the peripheral blood and the level of IL-9 in the serum of patients with IRP were increased, which was related to the severity of the disease.

Spatial distribution and incidence of bovine neonatal pancytopenia in Bavaria, Germany.

BACKGROUND: Bovine neonatal pancytopenia (BNP) is a haemorrhagic disease of neonatal calves. BNP was first described in Germany in 2009, later on also in other European countries, and in New Zealand in 2011. The disease is characterised by spontaneous bleeding, pancytopaenia in the bone marrow, and a high case fatality ratio. The causal role of a specific bovine viral diarrhoea virus (BVDV) vaccine (PregSure®BVD, then Pfizer Animal Health, now Zoetis, Berlin, Germany) has been established over the last years, causing the production of alloantibodies in some vaccinated cattle, which in the case of pregnant cattle, are transferred to the newborn calf via the colostrum. However, striking regional differences in the incidence of the disease were observed within Germany and other countries, but as the disease was not notifiable, no representative data on the spatial distribution are available. In this study, we address the spatial distribution and incidence of BNP using the results of two representative surveys amongst cattle practitioners in Bavaria, Germany. The surveys, asking about the occurrence of BNP, were conducted in 2009 and 2010. Answers were analysed spatially by testing for clusters using space-time models. Practitioners were also asked how many cows they serve in their practice and this number was used to estimate the incidence of BNP. Furthermore, in the survey of 2010, practitioners were also asked about usage of vaccine against BVDV. RESULTS: From the results of the surveys, three clusters were identified in Bavaria. These clusters also coincided with the usage of the specific BVDV vaccine as indicated by the veterinary practices. Furthermore, the representative surveys allow the estimation of the incidence of BNP to be in the order of 4 cases per 10,000 calves at risk. CONCLUSIONS: The study is the only representative survey conducted on BNP. Despite the fact that BNP is a non-infectious disease, regional clusters were identified.

Parvovirus B19: un nuevo patógeno emergente en pacientes con SIDA. Presentación de 3 casos / PARVOVIRUS B19: HUMAN PARVOVIRUS B19: A NEW EMERGING DISEASE IN PATIENTS WITH AIDS. REPORT OF THREE PATIENTS

El Parvovirus humano B19 puede presentarse con una amplia variedad de manifestaciones clínicas, con distinto compromiso y evolución según el huésped afectado. En pacientes inmunocomprometidos se asocia con cuadros hematológicos prolongados y graves. Se describen 3 casos de pacientes con antecedentes de infección por virus de la inmunodeficiencia humana (VIH) que desarrollaron infecciones agudas por Parvovirus B19 que se presentaron con síndrome febril, citopenias (anemia, plaquetopenia y disminución de reticulocitos) y esplenomegalia. En todos los casos el diagnóstico se confirmó por la serología específica. Todos recibieron tratamiento con inmunoglobulina humana (Ig) intravenosa (IV); 2 pacientes tuvieron buena respuesta clínica y mejoría de citopenias mientras que el restante falleció. La infección por Parvovirus B19 debe incluirse en el diagnóstico diferencial de los pacientes VIH positivos con fiebre y citopenias, principalmente anemia persistente y compromiso linfoganglionar con esplenomegalia

Human Parvovirus B 19 is presented as a variety of diseases with different compromise and evolution according to the affected host. In immunocompromised patients the acute infection due to Parvovirus B19 is associated with severe and prolonged hematological clinical pictures. Three cases of patients with a history of infection with human immunodeficiency virus (HIV) co-infected with Human Parvovirus B19 are presented. All of they presented with febrile syndrome, cytopenias (anemia, platelet count and reticulocyte reduction) and lymphadenopathy and splenomegaly. In all cases the diagnosis was confirmed by serology. All were treated with intravenous human immunoglobulin (IVI G; 2 patients had good clinical response and better cytopenias while the other died. We consider thinking about Parvovirus B19 infection in HIV immunocompromised hosts with haematological involvement, mainly persistent anemia and lymph node involvement with splenomegaly

Does rehabilitation pose a risk to patients suffering from haemato-oncological diseases? Results of a monocentric, retrospective analysis in Germany.

OBJECTIVE: Patients suffering from haemato-oncological diseases tend to have a weakened immune system after the end of their therapy. To avoid infections, patients are advised to limit contact with other people. This poses the question whether a stay at a rehabilitation facility can be recommended. METHODS: We report about 134 rehabilitation stays of patients. Premature discontinuation of the rehabilitation stay was selected as the criterion for a serious complication during the rehabilitation, and the underlying reasons were analysed. RESULTS: Compared to the discontinuation rates of patients suffering from solid tumours (2.4%), the percentage of haemato-oncological patients ending prematurely their rehabilitation stay (8.2%) is significantly increased. This rises to 17.1% for patients who have undergone an allogeneic stem cell transplantation. The analysis of the discontinuation reasons revealed that they were not directly connected to the rehabilitation. Apart from the already known risk factors for premature termination of the rehabilitation stay, we have identified the period (days) between the last therapy and the beginning of the rehabilitation stay as a risk factor. CONCLUSIONS: We show for the first time that a rehabilitation stay does not pose additional risks for patients suffering from haemato-oncological diseases.

Febrile Hashimoto's encephalopathy associated with Graves' disease and acute pancytopenia: A case report.

RATIONALE: Hashimoto's encephalopathy (HE) is an autoimmune-mediated encephalopathy rarely seen in Graves' disease, with <20 cases reported previously, associated with elevated concentration of circulating serum anti-thyroid antibodies usually responsive to steroid therapy. PATIENT CONCERNS: We present a HE case (25-year-old male) with Graves' disease, complicated by fever and pancytopenia. The patient presented with fever, gait impairment, delirium, agitation and disorientation. DIAGNOSES: Thyroid-related antibodies were elevated and brain magnetic resonance imaging confirmed symmetrical white-matter lesion. There was no evidence of infection or other reasons to explain all of his clinical manifestations. Hashimoto's encephalopathy (HE) is an autoimmune encephalopathy with various manifestations and the characteristic of elevated anti-thyroid antibodies and has no relationship to thyroid function. INTERVENTIONS: The patient had nonspecific clinical manifestations and excellently respond to glucocorticoid therapy.The symptoms and the radiographic abnormalities disappeared after glucocorticoid therapy. OUTCOMES: We followed up with him for 5 years, in which there was no recurrence and his thyroid function continued to be normal. LESSONS: It is important to evaluate thyroid function and related antibodies in patients present with neuropsychological symptoms to avoid delay in diagnosis.

Yeast (1 → 3)-(1 → 6)-ß-d-glucan alleviates immunosuppression in gemcitabine-treated mice.

Gemcitabine (2'-deoxy-2',2'-difluorocytidine, dFdC) is one of the most effective chemotherapy drugs commonly used for treatment of various tumors. Despite its significant anticancer effects, some adverse effects create obstacles to treatment. The main toxicity of gemcitabine is myelosuppression, which not only reduces patient quality of life, but also hinders further anticancer treatment. In this respect, immunotherapy can address these drawbacks because of its ability to enhance the patient's immune system. To improve immune system function, yeast-derived ß-glucans, which are well-known biologic response modifiers, were administered to gemcitabine-treated mice. The in vivo experiment revealed that orally administered yeast (1 → 3)-(1 → 6)-ß-d-glucan effectively alleviated myelosuppression associated with gemcitabine-induced pancytopenia. Moreover, analysis of myelopoiesis-related cytokine expression through real-time PCR demonstrated that ß-glucan treatment significantly upregulated hematopoietic responses in gemcitabine-treated mice. Furthermore, orally administered ß-glucan significantly induced the expression of IFN-γ and IL-2 in splenocytes of gemcitabine-treated mice. It also restored the cytotoxicity of splenocytes against YAC-1 in gemcitabine-treated mice and displayed a positive effect on gemcitabine-damaged bone marrow tissue. In conclusion, yeast ß-glucans have the potential to be used as adjuvants for alleviating chemotherapy-induced immunosuppression in patients.

A Functionally Different Immune Phenotype in Cattle Is Associated With Higher Mastitis Incidence.

A novel vaccine against bovine viral diarrhea (BVD) induced pathogenic antibody production in 5-10% of BVD-vaccinated cows. Transfer of these antibodies via colostrum caused Bovine neonatal pancytopenia (BNP) in calves, with a lethality rate of 90%. The exact immunological mechanisms behind the onset of BNP are not fully understood to date. To gain further insight into these mechanisms, we analyzed the immune proteome from alloreactive antibody producers (BNP cows) and non-responders. After in vitro stimulation of peripheral blood derived lymphocytes (PBL), we detected distinctly deviant expression levels of several master regulators of immune responses in BNP cells, pointing to a changed immune phenotype with severe dysregulation of immune response in BNP cows. Interestingly, we also found this response pattern in 22% of non-BVD-vaccinated cows, indicating a genetic predisposition of this immune deviant (ID) phenotype in cattle. We additionally analyzed the functional correlation of the ID phenotype with 10 health parameters and 6 diseases in a retrospective study over 38 months. The significantly increased prevalence of mastitis among ID cows emphasizes the clinical relevance of this deviant immune response and its potential impact on the ability to fight infections.