Autoimmune Anemia Research Articles

T-cell expression of Bruton\u2019s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia

The role of Bruton’s tyrosine kinase (BTK) in BCR signaling is well defined, and BTK is involved in B-cell development, differentiation, and malignancies. However, the expression of Btk in T cells and its role in T-cell function remain largely unknown. Here, we unexpectedly found high expression and activation of BTK in T cells. Deficiencies in BTK resulted in the impaired activation and proliferation of autoreactive T cells and ameliorated bone marrow failure (BMF) in aplastic anemia. Mechanistically, BTK is activated after TCR engagement and then phosphorylates PLCγ1, thus promoting T-cell activation. Treatment with acalabrutinib, a selective BTK inhibitor, decreased T-cell proliferation and ameliorated BMF in mice with aplastic anemia. Our results demonstrate an unexpected role of BTK in optimal T-cell activation and in the pathogenesis of autoimmune aplastic anemia, providing insights into the molecular regulation of T-cell activation and the pathogenesis of T-cell-mediated autoimmune disease.

Ghosal hematodiaphyseal dysplasia with autoimmune anemia in two adult siblings

Ghosal hematodiaphyseal dysplasia (GHDD) is an autosomal recessive inherited disorder associated with biallelic mutations in the TBXAS1 gene located on the chromosome 7q33-34, which encodes thromboxane-A-synthase. GHDD is characterized by defective hematopoiesis due to bone marrow fibrosis and metadiaphyseal dysplasia of long bones. The accurate diagnosis of this rare syndrome is critical since it reduces the need of blood transfusions by corticosteroid therapy, leading to a significant improvement in anemia and bone changes. The aim of this study is to report two adult siblings diagnosed as GHDD, who admitted with pancytopenia and treated with steroids treatment in adult hematology clinic.

PRESENCE OF ALBUMIN IN ERYTHROCYTE LYSATE OF AUTOIMMUNE HAEMOLYTIC ANAEMIA PATIENTS OBSERVED IN ELECTROPHORETOGRAM

Autoimmune haemolytic anaemia is a condition in which autoantibodies present against self erythrocytes which leads to severe haemolysis and loss of haemoglobin. In the present study we compared the electrophoretic band patterns between control and autoimmune haemolytic anaemia and non autoimmune iron deficiency anaemia erythrocyte lysate samples. We observed the presence of a band which was specific to autoimmune haemolytic erythrocyte lysates in the region of 70 Kd which was later identified as albumin and was distinctly absent in control as well as iron deficiency non autoimmune haemolytic samples. In addition, we have noticed that the catalase in the region of 60 Kd was found to be decreased in its band intensity in haemolytic anaemia samples compared to control. The presence of both albumin and catalase in the respective positions in the electrophoretic gel was confirmed by in gel trypsin digestion followed by mass spectrometry. The other erythrocyte proteins visible in the region of 25 Kd were found to have an overall decrease in band intensity in haemolytic anaemia samples compared to control. The specific presence of albumin in autoimmune haemolytic erythrocyte lysate is the main highlight of the work which was not reported till date and further studies could reveal the exact role of albumin in autoimmune haemolytic conditions.
 Key words: Autoimmune haemolytic anaemia, erythrocytes, electrophoresis, albumin, catalase

Characteristics and Outcomes of Critically Ill Pediatric Patients with Posterior Reversible Encephalopathy Syndrome.

Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiologic entity, typically manifesting as reversible neurological symptoms and signs of white matter edema on magnetic resonance imaging. PRES has been widely described in adults. Studies of PRES in children are mostly limited to case series and case controls. Retrospective chart review of patients under 21years with PRES admitted at a tertiary children's hospital from 2011 to 2016. They were compared to controls matched for age and mortality risk using the Pediatric Index of Mortality-2 score. RESULTS: Sixteen cases of PRES were identified in 13 patients (ages 5-17years, 46% male). PRES presented with altered mental status (75%), seizures (77%), headache (31%), and vision changes (23%). In patients who recovered (n = 11), median days to symptom resolution was three (range 1-8). PRES patients had a higher mortality rate (15% vs. 5%, p < 0.05) and higher mean length of stay (13.1 vs. 4.6days) and were more likely to have autoimmune disease (p < 0.05), immunosuppression (p < 0.05), and anemia (p < 0.05). No PRES patients were diagnosed with epilepsy by last known follow-up, and all of whom had been started on an antiepileptic drug were discontinued within 13months. Sepsis was suspected in 53% of PRES patients and 59% of controls (p = 1.00). All PRES patients had stage II hypertension, versus 41% of controls (p < 0.05). Average creatinine in PRES was 2.35mg/dL compared to 0.90mg/dL in controls (p < 0.05). PRES patients had lower serum calcium (p < 0.05). After correcting for albumin, no association between PRES and hypocalcemia remained. PRES patients had a higher length of stay (13.1 vs. 4.6days, p < 0.05) and mortality rate (15% vs. 3%, p < 0.05). Immunosuppression, autoimmune disease, renal insufficiency, anemia, and hypertension are associated with PRES after controlling for mortality risk in critically ill children. There was no association between corrected serum calcium and sepsis with PRES.

Alexion to acquire autoimmune drug firm

Alexion Pharmaceuticals will acquire the Boston-based biotech firm Syntimmune for $400 million plus up to $800 million in potential milestone payments. Syntimmune says its lead antibody drug candidate, SYNT001, has the potential to treat autoimmune disease by facilitating the destruction of human immunoglobulin G antibodies that cause the disease. SYNT001 is already undergoing testing in people with a rare autoimmune blistering disease called pemphigus and a rare form of autoimmune anemia.

Sex-specific risk factors for cardiovascular disease in women-making cardiovascular disease real.

Sex-specific differences in pathophysiology, prevalence, and impact of cardiovascular disease (CVD) risk factors may explain the high cardiovascular mortality rates in women. We review the sex differences in traditional risk factors (dyslipidemia, hypertension, diabetes, and smoking) and nontraditional risk factors (menopause and hormones, pregnancy, inflammation and autoimmune diseases, anemia, depression, and migraines) and their prognostic and therapeutic implications. Recent research indicates that with respect to traditional risk factors such as dyslipidemia, hypertension, diabetes, and smoking, women appear to have a similar risk of CVD when compared to men. The risk is accelerated after menopause, possibly because of vascular and lipid profile changes. Pregnancy offers a unique opportunity and window to screen otherwise healthy women who may be at an increased risk of CVD in the future. Clinicians should be aware of other novel risk factors including inflammation, anemia, migraines, and depression, and further studies are warranted in order to identify therapeutic implications for these conditions and CVD risk.

IL-27: Friend or Foe in the Autoimmune Diseases

Abstract: Background: Autoimmune diseases, with emerging clinical concerns, are caused by imbalances in immune system functions. Cytokines are critical components of the immune system produced by various immune and non-immune cells. Objective: We will review the newly-introduced cytokine known as interleukin-27 (IL-27), which has both pro- and anti- inflammatory roles in immunity. Methods: Literature review of the field of immunology and cytokines in autoimmune diseases. Results: IL-27 alters the balance between the different types of T helper (Th) cells through reduction or promotion of their responses to autoimmune diseases including multiple sclerosis, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis, autoimmune diabetes, systemic lupus erythematosus, Sjogren's syndrome, Behcet’s disease, and autoimmune aplastic anemia. Conclusions: The functions of IL-27 are currently unclear because it appears to affect different cells, cytokines, and signaling pathways differently. Further investigations are needed to clarify the role of IL-27 in autoimmune diseases. Hence, this article reviewed the multiple roles of IL-27 in autoimmune diseases and describe the influence of IL-27 on the immune system.

Evaluation of Clinical and Immunological Characteristics of Children with Common Variable Immunodeficiency.

Background Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder (PID) that typically presents with hypogammaglobulinemia and impaired antibody production. Objectives This study aimed to promote the awareness of CVID, whose clinical spectrum is quite broad. Methods The demographic, clinical, and laboratory characteristics of 12 children (seven males and five females) with CVID were analyzed retrospectively. The patients were diagnosed using the diagnostic criteria of the European Society for Primary Immunodeficiencies. Results The median disease onset age was 7.2 ± 4.1 years, and the mean diagnosis age was 11.6 ± 3.7 years. The diagnosis delay was 4.3 ± 2.6 years, and the parental consanguinity rate was 75%. Most patients presented with recurrent infections, including upper respiratory tract infections (n = 8), lower respiratory tract infections (n = 9), and gastroenteritis (n = 5). In addition, growth retardation (n = 9) and bronchiectasis (n = 5) were common comorbidities. Two patients presented with autoimmune thrombocytopenia and anemia, and one patient exhibited lung empyema. All the patients had immunoglobulin G deficiencies. Conclusion CVID is a heterogeneous disease, so the diagnosis is frequently delayed. In the CVID patients with pulmonary complications, relationships were seen with the diagnosis delay, symptom onset age, and lung infection prevalence. Overall, the early diagnosis and treatment of PIDs can preclude life-threatening complications.

Maternal and neonatal vitamin B12 deficiency detected by expanded newborn screening

Infant vitamin B12 deficiency can manifest as a severe neurodegenerative disorder and is usually caused by maternal deficiency due to vegetarian diet or pernicious anaemia. Its early recognition and treatment can prevent potentially serious and irreversible neurologic damage. Biochemically, vitamin B12 deficiency leads to an accumulation of methylmalonic acid, homocysteine, and propionylcarnitine. Expanded newborn screening using tandem mass spectrometry may identify neonatal and maternal vitamin B12 deficiency by measurement of propionylcarnitine and other metabolites in the dried blood spot sample of newborns. To summarize our experiences gained by screening for vitamin B12 deficiency. Clinical and laboratory data of vitamin B12-deficient infants diagnosed in Szeged Screening Centre were retrospectively analysed. In Hungary, expanded newborn screening was introduced in 2007. Since then approximately 395 000 newborns were screened in our centre and among them, we identified four newborns with vitamin B12 deficiency based on their screening results. In three cases an elevated propionylcarnitine level and in the fourth one a low methionine level were indicative of vitamin B12 deficiency. We also detected an additional vitamin B12-deficient infant with neurological symptoms at 4 months of age, after a normal newborn screening, because of elevated urinary methylmalonic acid concentration. Vitamin B12 deficiency was secondary to maternal autoimmune pernicious anaemia in all the five infants. As a result of the recognized cases the incidence of infant vitamin B12 deficiency in the East-Hungarian region was 1.26/100 000 births, but the real frequency may be higher. Conslusions: Optimizing the cut off values of current screening parameters and measuring of methylmalonic acid and/or homocysteine in the dried blood spot, as a second tier test, can improve recognition rate of vitamin B12 deficiency. Orv Hetil. 2017; 158(48): 1909-1918.

Plasmodium DNA-mediated TLR9 activation of T-bet+ B cells contributes to autoimmune anaemia during malaria

Infectious pathogens contribute to the development of autoimmune disorders, but the mechanisms connecting these processes are incompletely understood. Here we show that Plasmodium DNA induces autoreactive responses against erythrocytes by activating a population of B cells expressing CD11c and the transcription factor T-bet, which become major producers of autoantibodies that promote malarial anaemia. Additionally, we identify parasite DNA-sensing through Toll-like receptor 9 (TLR9) along with inflammatory cytokine receptor IFN-γ receptor (IFN-γR) as essential signals that synergize to promote the development and appearance of these autoreactive T-bet+ B cells. The lack of any of these signals ameliorates malarial anaemia during infection in a mouse model. We also identify both expansion of T-bet+ B cells and production of anti-erythrocyte antibodies in ex vivo cultures of naive human peripheral blood mononuclear cells (PBMC) exposed to P. falciprum infected erythrocyte lysates. We propose that synergistic TLR9/IFN-γR activation of T-bet+ B cells is a mechanism underlying infection-induced autoimmune-like responses.

Complex karyotype involving six chromosomes, with one dicentric and three yet unreported acquired chromosomal aberrations in a case of splenic marginal zone lymphoma

BackgroundSplenic marginal zone lymphoma (SMZL) is an extremely rare low-grade malignancy of the B-cells, comprising <2% of all non-Hodgkin lymphoma (NHL). SMZL occurs at a median age of 65years while the median survival has been recorded to be approximately 10.5years. Clinically, it is associated with splenomegaly, moderate lymphocytosis and sometimes autoimmune thrombocytopenia and/or anemia; also cytopenias and are frequently observed.The pathogenesis of SMZL still remains unclear. Approximately 70–80% of cases have been reported to exhibit detectable cytogenetic and/or molecular genetic abnormalities. The most frequent cytogenetic abnormalities are deletions in 7q22–q32, followed by gain of chromosomes 3/3q, 5q, 9q, 12q and 20q, and deletion in 17p. Complex karyotypes are common: the most frequently involved chromosomes are 1, 3, 7, 8, and 14. However, the incidence of specific recurrent clonal cytogenetic abnormalities in SMZL has not been established yet. ResultsBone marrow of a 78-year-old male patient with a 1month history of umbilical abdominal pain, cough, pallor, vomiting, fever, pancytopenia, anemia and enhanced serum lactate dehydrogenase (LDH) level was studied by banding cytogenetics, refined by fluorescence in situ hybridization including array-proven multicolor banding. A complex karyotype involving, among others both chromosomes 13, was detected. An unbalanced translocation der(13)t(1;13)(q21;p11.2) led to partial trisomy of 1q21-qter and a dicentric dic(13)t(3;13)(p11.2;p11.2) caused partial trisomy of 3q11.2-qter. Besides there were inversion inv(1)(p12q12) and a balanced translocation t(9;14)(p13;q32.3) as yet unreported abnormalities in an adult SMZL case at diagnosis. The immunophenotype was consistent with marginal zone lymphoma according to World Health Organization (WHO) recommendations. ConclusionsTo the best of our knowledge, a comparable adult SMZL case with complex karyotype, anemia and elevated LDH was not previously reported. Besides the involvement of yet unreported genetic regions in SMZL, also this case is one of the rare examples for a malignancy with a stable dicentric chromosome.

Concomitant Case of Primary Biliary Cirrhosis and Autoimmune Hemolityc Anemia Responding to Corticosteroid and Ursodeoxycholic Acid in Young Woman

Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology and is characterized by chronic progressive cholestasis with destruction of the small intrahepatic bile ducts and associated most commonly with antimitochondrial antibodies. PBC is most common in women and is often associated with other autoimmune disease such as autoimmune hemolityc anemia (AIHA), rheumatoid arthritis, thyroiditis, and systemic lupus eritomatosus. We report one case, a 20 years old woman with AIHA have been treated by corticosteroid since last year and she came to the outpatient department (OPD) with fatique and jaundice. The result of laboratory were haemoglobin 8.7 mg/dL, white blood cell 8700 mg/dL, coomb test +2, total bilirubin 33.2 mg/dL, direct bilirubin 29.3 mg/dL, γGT: 297 mg/dL and alkalyphospatase: 158 mg/dL. The result of Abdominal CT scan showed the size of liver and spleen increased and normal common bile duct (CBD). The result of ANA test, anti-nuclear (ANA) and antimitochondrial M2 (AMA M2) antibodies were positive. From the physical examination, laboratory and CT scan Abdomen; the diagnose of this patient was AIHA with PBC. After treatment with corticosteroid (prednison 1mg/kg/day) and ursodeoxicholic acid (UDCA) for several weeks, the clinical manifestation of PBC such as jaundice getting better (the laboratory result: total bilirubin 2.7 mg/dL, direct bilirubin 1.5 mg/dL, gamma GT 80 mg/dL).

Anti-Interleukin-6 Receptor Tocilizumab for Severe Juvenile Idiopathic Arthritis-Associated Uveitis Refractory to Anti-Tumor Necrosis Factor Therapy: A Multicenter Study of Twenty-Five Patients.

To assess the efficacy of tocilizumab (TCZ) for the treatment of juvenile idiopathic arthritis (JIA)-associated uveitis. We conducted a multicenter study of patients with JIA-associated uveitis that was refractory to conventional immunosuppressive drugs and anti-tumor necrosis factor (anti-TNF) agents. We assessed 25 patients (21 female; 47 affected eyes) with a mean ± SD age of 18.5 ± 8.3 years. Uveitis was bilateral in 22 patients. Cystoid macular edema was present in 9 patients. Ocular sequelae found at initiation of TCZ included cataracts (n = 13), glaucoma (n = 7), synechiae (n = 10), band keratopathy (n = 12), maculopathy (n = 9), and amblyopia (n = 5). Before TCZ, patients had received corticosteroids, conventional immunosuppressive drugs, and biologic agents (median 2 [range 1-5]), including adalimumab (n = 24), etanercept (n = 8), infliximab (n = 7), abatacept (n = 6), rituximab (n = 2), anakinra (n = 1), and golimumab (n = 1). Patients received 8 mg/kg TCZ intravenously every 4 weeks in most cases. TCZ yielded rapid and maintained improvement in all ocular parameters. After 6 months of therapy, 79.2% of patients showed improvement in anterior chamber cell numbers, and 88.2% showed improvement after 1 year. Central macular thickness measured by optical coherence tomography in patients with cystoid macular edema decreased from a mean ± SD of 401.7 ± 86.8 μm to 259.1 ± 39.5 μm after 6 months of TCZ (P = 0.012). The best-corrected visual acuity increased from 0.56 ± 0.35 to 0.64 ± 0.32 (P < 0.01). After a median follow-up of 12 months, visual improvement persisted, and complete remission of uveitis was observed in 19 of 25 patients. Significant reduction in the prednisone dosage was also achieved. The main adverse effects were severe autoimmune thrombocytopenia in 1 patient, pneumonia and then autoimmune anemia and thrombocytopenia in 1 patient, and viral conjunctivitis and bullous impetigo in 1 patient. TCZ appears to be a useful therapy for severe refractory JIA-associated uveitis.

Partial and simultaneous remission of nephritis and autoimmune hemolytic anemia in patients with lupus after treatment with biological agent: a case report

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, systemic, of unknown cause and autoimmune nature. It features variable prognosis, depending on the affected organ or system. The renal impairment is the condition most often related to morbidity and mortality. This manuscript aims to contribute to the further evidence that early diagnosis of lupus associated with quickly aggressive therapy could increase the success outcome rate. Also, immediate recognition of therapeutic failures and change the treatment strategy must be applied. In this regard, a new therapeutic option seems to be the biological drug rituximab described in this study and which it is emphasised because of its possible and still supposed ability to act as a rescue agent for nephritis and hemolytic lupus anaemia, simultaneously, with effectiveness and safety. This article presents the case of female lupus patient with both severe refractory hematologic disorder and renal impairment, which had an evolution of the simultaneous restoration of urine output, and clinical and laboratory improvement of autoimmune anaemia after rituximab administration. The persistence of renal damage could not be ruled out, so the response to treatment was considered to be partial

Development of red blood cell autoantibodies following treatment with checkpoint inhibitors: a new class of anti-neoplastic, immunotherapeutic agents associated with immune dysregulation

Ipilimumab, nivolumab, and pembrolizumab represent a new class of immunotherapeutic drugs for treating patients with advanced cancer. Known as checkpoint inhibitors, these drugs act to upregulate the cellular and humoral immune response to tumor antigens by inhibiting T-cell autoregulation. As a consequence, they can be associated with immune-related adverse events (irAEs) due to loss of self-tolerance, including rare cases of immune-related cytopenias. We performed a retrospective clinical chart review, including serologic, hematology, and chemistry laboratory results, of two patients who developed red blood cell (RBC) autoantibodies during treatment with a checkpoint inhibitor. Serologic testing of blood samples from these patients during induction therapy with ipilimumab and nivolumab, respectively, showed their RBCs to be positive by the direct antiglobulin test (IgG+, C3+) and their plasma to contain panreactive RBC autoantibodies. Neither patient had evidence of hemolysis. Both patients developed an additional irAE during treatment. A literature review for patients who had developed immune-mediated cytopenia following treatment with a checkpoint inhibitor was performed. Nine other patients were reported with a hematologic irAE, including six with anemia attributable to autoimmune anemia, aplastic anemia, or pure RBC aplasia. Hematologic irAEs tend to occur early during induction therapy, often coincident with irAEs of other organs. In conclusion, checkpoint inhibitors can be associated with the development of autoantibodies, immune-mediated cytopenias, pure RBC aplasia, and aplastic anemia. Immunohematology reference laboratories should be aware of these agents when evaluating patients with advanced cancer and new-onset autoantibodies, anemia, and other cytopenias.

Actualización en anemias hemolíticas

IntroductionHemolytic anemias (HA) are a complex group of disorders resulting in premature destruction of red blood cells or hemolysis. Common laboratory data are: anemia with increased reticulocyte, elevated values for indirect bilirubin and lactate dehydrogenase (LDH), as well as decreased level of haptoglobin and hemopexin. ClasificationHemolytic anemias are grouped in two big categories: hereditary HA, due to a half-life reduction of red cells as consequence to congenital structural defects (membranopathies, erythro-enzymopathies, thalassemia and hemoglobinopathies); and acquired HA which are divided in immune and non-immune mediated, highlighting its frequency the autoimmune anemias and its severity the thrombotic microangiopathies. Its distinctive features require different management strategies.

Development of a Risk Score for Extraintestinal Manifestations of Coeliac Disease.

The aim of this study was to identify indicators of coeliac disease (CD) in an Australian cohort, beyond the known gastrointestinal symptoms.Individuals were recruited from the general population and at the 2014 Gluten Free Expo in Sydney and in Melbourne, Australia. Data on their current health status including medical history, diagnosis for CD, and family history were collected. Multivariable logistic regression was used to identify independent predictors of CD. A weighted risk score system was then generated for the independent predictors, and a risk score was calculated for each individual.A total of 301 individuals were included in the study. We found an association between CD and having a family history of CD (odds ratio [OR] 7.6, 95%confidence interval [CI] 3.7–15.6), an autoimmune disorder (OR 2.1, 95%CI 1.1–4.1), anemia (OR 5.8, 95%CI 2.8–11.9), lactose intolerance (OR 4.5, 95%CI 1.2–17.7), and depression (OR 4.8, 95%CI 1.9–11.6). Risk score analysis found individuals in the medium (OR 4.8, 95%CI 2.5 to 9.3) and high-risk (OR 36.6, 95%CI 16.4 to 81.6) groups were significantly more likely to report having CD compared with those in the low-risk group.This study identifies a set of factors more commonly observed in individuals with CD, beyond the traditional gastrointestinal complaints. These include a family history of CD, the presence of another autoimmune disorder, anemia, lactose intolerance, and depression. A risk score was developed (Coeliac Risk COMPARE) which scores individuals based on the presence or absence of these additional symptoms and provides an additional screening tool when assessing whether the patient requires follow-up testing for CD.

Prevalence of vitamin B-12 deficiency among patients with thyroid dysfunction.

Due to the non-specificity of symptoms and possibly severe consequences of untreated vitamin B-12 deficiency, screening is important for at-risk patients to ensure the prompt delivery of treatment. In this review, studies assessing the prevalence of vitamin B-12 deficiency in thyroid dysfunction are evaluated to determine whether regular vitamin B-12 screening is necessary. A literature search was conducted using multiple electronic databases. Only original studies assessing the prevalence of vitamin B-12 deficiency in thyroid dysfunction that reported their findings as percentages of the sample were eligible for inclusion. From a total of 7091 manuscripts generated, 6 were included in this review. The prevalence of vitamin B-12 deficiency in hypothyroidism was reported as 10, 18.6, and 40.5% in three separate studies. The prevalence of deficiency in autoimmune thyroid disease was reported as 6.3, 28, and 55.5% in three studies. The prevalence of vitamin B-12 deficiency in hypothyroidism and autoimmune thyroid disease are reflective of the nutrition status of the population. Autoimmune thyroid disease is also associated with the autoimmune disorders pernicious anemia and atrophic gastritis which may lead to malabsorption of vitamin B-12. Vitamin B-12 screening is recommended upon initial diagnosis with autoimmune thyroid disease and then periodically thereafter. There is not enough evidence to recommend regular screening for patients with hypothyroidism unless the underlying cause is autoimmune thyroid disease.

A Phase 3 Study to Evaluate the Efficacy and Safety of Dinaciclib Compared to Ofatumumab in Patients with Refractory Chronic Lymphocytic Leukemia

Abstract Introduction: Abnormalities of cell cycle regulation have an important role in the pathogenesis of cancers. Cyclin dependent kinase (CDK) inhibitors have shown potent activity in patients with chronic lymphocytic leukemia (CLL) and other cancers. Dinaciclib (MK-7965/SCH 727965) is a novel, selective inhibitor of CDK1, CDK2, CDK5, and CDK9. Prior studies show that dinaciclib has anti-leukemic activity against CLL. The present study compared the efficacy and safety of dinaciclib with ofatumumab in patients with refractory CLL. Methods: This Phase 3 randomized, open-label, active-controlled, balanced, multi-site, group sequential confirmatory trial evaluated the progression-free survival (PFS; primary objective), overall response rate and overall survival (secondary objectives), and safety of dinaciclib vs. ofatumumab in patients with refractory CLL. Patients with a confirmed diagnosis of CLL (based on 2008 International Workshop on CLL criteria) and fludarabine or chemoimmunotherapy refractory disease were enrolled if they had no central nervous system involvement, prior allogenic bone marrow transplant or uncontrolled autoimmune anemia or thrombocytopenia. Patients previously treated with dinaciclib, ofatumumab, or other CDK inhibitors were excluded. In Cycle 1, dinaciclib was administered intravenously (IV) over 2 hours at doses of 7 mg/m2 on Day 1, 10 mg/m2 on Day 8 and 14 mg/m2 on Day 15. In Cycle 2 and thereafter, dinaciclib was dosed at 14 mg/m2 on Days 1, 8, and 15 of each 28-day cycle for a total of 12 cycles. Ofatumumab was administered IV once-weekly for 8 weeks starting in Cycle 1 on Day 1, followed by 9 monthly doses as follows: 300 mg in Cycle 1 on Day 1; 2000 mg in Cycle 1 on Days 8, 15, and 22, Cycle 2 Days 1, 8, 15, and 22, and 5 weeks later on Day 1 of Cycles 4-12. Efficacy results are from the intent to treat (ITT) population, and safety results are from the all-subjects-as-treated population. Results: In total, 44 patients were randomized (ITT) and 42 were treated (20 dinaciclib and 22 ofatumumab) due to early study termination not attributed to safety. At study entry, the median age was 62 years (range, 43-77), 32/42 (76.2%) patients were male, 26/42 (62.0%) were RAI stage III-IV, 24/42 (57.1%) had bulky disease, 40/42 (95.2%) were ECOG ≤ 1, the median number of prior therapies was 3 (range, 1-20), and 39/42 (92.9%) patients received prior fludarabine. Deletion 17p (del 17p) was present in 17/42 (38.6%) patients, 7 dinaciclib and 10 ofatumumab. Median follow-up (range) was 16.7 (0.4-26.1) months. In the dinaciclib and ofatumumab groups, respectively, 11 (55.0%) and 17 (70.8%) patients had PFS events, and median (95% CI) PFS was 59.7 (45.0, 92.1) and 25.7 (9.3, 40.7) weeks. Overall response (all partial responses) was recorded for 8 (40.0%) dinaciclib and 2 (8.3%) ofatumumab patients. Stable disease was achieved by 7 (35.0%) dinaciclib and 11 (45.8%) ofatumumab patients. Median survival (95% CI) was 21.2 (16.6, NR) months with dinaciclib and 16.7 (2.3, 20.2) months with ofatumumab; 6 (30.0%) and 11 (45.8%) patients have died in each group, respectively. There were 2 treatment-related deaths in the dinaciclib arm (pneumonia and febrile neutropenia) and none in the ofatumumab arm. Median survival (95% CI) in the del 17p population was 21.2 (1.4, 21.2) months with dinaciclib and 5.4 (0.4, NR) months with ofatumumab. Overall, 17 (85.0%) dinaciclib and 13 (59.0%) ofatumumab patients had a grade 3-5 adverse event (AE). The most common grade ≥ 3 AEs with dinaciclib and ofatumumab, respectively, were neutropenia, 7 (35.0%) vs. 2 (9.1%); thrombocytopenia, 4 (20.0%) vs. 2 (9.1%); decreased neutrophil count, 4 (20.0%) vs. 1 (4.5%); pneumonia, 1 (5.0%) vs. 3 (13.6%); sepsis, 1 (5.0%) vs. 3 (13.6%); and febrile neutropenia, 2 (10.0%) vs. 1 (4.5%). One dinaciclib patient developed tumor lysis syndrome that was deemed not treatment-related. Ten (50.0%) dinaciclib and 13 (54.2%) ofatumumab patients discontinued from the study for the following reasons: AE, 3 (15.0%) vs. 1 (4.2%); disease progression, 4 (20.0%) vs. 4 (16.7%); death, 1 (5.0%) vs. 5 (20.8%); and other/unknown, 2 (10.0%) vs. 4 (16.7%). Conclusion: The limited data from this study demonstrate potential anti-cancer activity and tolerability of dinaciclib compared with ofatumumab in patients with refractory CLL. Based on these results and given the distinct mechanism of action, combinations of dinaciclib with other novel therapies should be explored. Disclosures Ghia: Janssen: Consultancy; Acerta Pharma BV: Research Funding; Adaptive: Consultancy; Pharmacyclics: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding. Pathiraja:Merck &amp; Co., Inc.: Employment, Other: stock/stock options. Derosier:Merck &amp; Co., Inc.: Employment, Other: stock/stock options. Small:Merck &amp; Co., Inc.: Employment, Other: stock/stock options.

Autologous Hematopoietic Stem Cell Transplantation (AHSCT) in Severe Auto-Immune Disease Adult Patients: Analysis of Outcomes from the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGMT-TC) in Light of the European Society for Blood and Marrow Transplantation (EBMT) Activity

IntroductionAutologous Hematopoietic Stem Cell transplantation (AHSCT) is used since 1994 worldwide to treat severe autoimmune disease (AD) refractory to standard therapy. Despite early release and regular update of the European Society for Blood and Marrow Transplantation (EBMT) practice guidelines (Snowden JA et al BMT 2012, Alexander T et al BMT 2014) along with 3 randomised Clinical trials (CTs) for Systemic Sclerosis (SSc) ASTIS, Crohn's Disease (CD) ASTIC and Multiple sclerosis (MS) ASTIMS, the uptake of this approach varies according to each ADs and between countries. We therefore design this retrospective study to evaluate patients (pts) outcomes as reported to the French Bone Marrow Transplantation Society registry (SFGMT-TC) in light of the other States activity published or reported to the EBMTregistry.Materials and methodsAll AHSCT for adult AD pts (> 18 years (yrs)) reported in France from 1997 to 2013 with at least one yr follow-up after AHSCT were included in the study. Primary data were derived from the EBMT registry (MED-A/B forms) with additional data obtained through a specific questionnaire (MED-C) for the study. Primary end point is overall survival (OS), defined as time since the day of transplant to death, irrespective of the cause. Secondary end points are Progression Free Survival (PFS), 100 day treatment related mortality (100-day TRM) and non-relapse related mortality (NRM). The probabilities were estimated using the Kaplan-Meier estimator for OS and PFS, cumulative incidence for NRM, relapse/progression being the competing event. All tests were two-sided. Statistical analyses were performed with IBM SPSS Statistics 22.0 and R version 3.1.2 (R Development Core Team, Vienna, Austria) software packages.Results96 adult pts (55% Female), median age 45 yrs [20-71], underwent a first AHSCT for ADs in 19 HSCT Units. Most of the ADs were rheumatological(72%) with 55 SSc, 7 polymyositis-dermatomyositis, 3 polychondritis, 2 Lupus Erythematosus, 1 Rheumatoid Arthritis (RA), 1 Ankylosing Spondylitis, or neurological (15%) with 14 MS, whereas the others were 5 CDs, 5 immune thrombocytopenic purpura, 1 hemolytic autoimmune anemia, 1 IgM neuropathy and 1 POEMS syndrome. Two pts had 2 simultaneous ADs (1 SSc and RA, 1 CD and RA). Median duration between AD diagnosis and AHSCT was 3.5 yrs [1-33]. With a median follow-up of 7 yrs [<1- 17], 5 yrs OS and PFS were 79.4% [95% CI: 70.8-88] and 49.3% [95% CI: 38.7-59.9] while 10 yrs OS and PFS were 70.2% [95% CI: 58.9-81.7] and 41.9 % [95% CI: 30.6-53.2], respectively. The 100 days NRM was 7.4% [95% CI: 3.2-13.9]. 5 and 10 yrs NRM was 9.6% [95% CI: 4.7-16.6] and 13.6% [95% CI: 6.9-22.7] respectively. At the end of follow-up, 28 pts (29%) had died, for whom the causes of death were: relapse or progression (n=12), AHSCT related cause (n=7 with 3 infections, 2 cardiac toxicity, 1 renal toxicity, 1 respiratory failure), secondary malignancies (n=3), aspiration pneumonia in polychondritis (n=1) or unknown causes (n= 5).ConclusionAHSCT for severe ADs, has progressively developed in France, allowing 5y OS equal to 79.4%, similar to UK (Snowden JA et al, BJH 2012) and EBMT data. In rapidly progressive severe SSc, where the proof of efficacy of AHSCT was obtained (Van Laar J and Farge D et al, JAMA 2014) and in MS (Pasquini MC et al BBMT 2010) where long-term responses are confirmed worldwide, the French and the EBMT registry activities have increased over the past 14 years, with sustained positive clinical results despite non negligible NMR, which remains lower than spontaneous AD evolution. Meanwhile, AHSCT activity has become exceptional in RA due to the availability of safe and effective biological therapies, and other indications remain rare, such as for CD or SLE where the risk of AHSCT in highly immunosuppressed patients has to be balanced with ADs severity. More than half of French pts were treated on an individual basis, outside CTs, underlying the need to evaluate national activity and to promote education of HSCT Unit members. At each French or other European state levels, like in the US, the indications for AHSCT in ADs remain low due to other competing therapies. Combined study using European and American data registry will allow analysis of a larger number of AD pts treated by AHSCT and would offer more clues to better understand the determinants of the response and to refine indications for each AD type. DisclosuresLeblond:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria. Snowden:MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau; Sanofi: Consultancy.