Low Blood Counts Research Articles

P079 Are patients with unexplained blood dyscrasias being tested for hiv?

IntroductionThe purpose of our audit was to determine whether our hospital is following the BHIVA National Guidelines (2008) and testing for HIV in patients presenting with unexplained blood dyscrasias.MethodsOur initial sample consisted of all inpatients coded as having lymphopenia, thrombocytopenia or neutropenia between 1/1/16 and 1/11/16. We excluded patients with a known cause of cytopenia and those with mild cytopenias (platelets >80, neutrophils >1, lymphocytes>1). In our final sample of 82 patients, we used the electronic ordering system to collect patient and admission information and to determine whether a HIV test was ordered.Results37% of patients with unexplained blood dyscrasias were tested for HIV. 60% of patients with neutropenia were tested compared with 42% with thrombocytopenia, 25% with lymphopenia and 20% with mixed cytopenias. Patients with lower blood counts were more likely to be tested for HIV. Patients were more likely to be tested for HIV if they were admitted under the haematology team (55%) compared with those admitted under general medical (31%) or surgical teams (27%). HIV testing declined with increasing age of patients with 67% of those aged under 30 being tested compared with 60%, 56%, 22% and 0% of patients between 31–50, 51–70, 71–90 and over 90 respectively.DiscussionWe found that the majority of patients with unexplained blood dyscrasias were not tested for HIV. Our study highlighted several factors that influence whether testing is performed. These include the nature and severity of cytopenia, patient age and the admitting medical team.

HIV INTEGRASE INHIBITORS: THE BASIS OF EFFECTIVE AND SAFE ANTIRETROVIRAL THERAPY

The article examines the efficacy and safety of HIV integrase inhibitors (raltegravir, dolutegravir) in antiretroviral therapy (ART) regimens in various groups of HIV-infected patients: patients with high HIV RNA blood levels, patients with low CD4-lymphocytes blood count, pregnant women, patients with tuberculosis or chronic hepatitis C, and patients in later years and /or with high cardiovascular risk, neurocognitive disorders. Particular attention is paid to the minimal risk of developing delayed ART complications in using raltegravir in ART regimens and combining raltegravir and drugs of various classes.

Chronic hepatitis C as an adverse prognostic factor in myelodysplastic syndromes.

e18557 Background: Chronic hepatitis C virus (HCV) infection has been associated with hematologic malignancies such as B-cell non-Hodgkin lymphoma. In contrast, there is very little known about the relationship between HCV and myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). To determine the effect of HCV on MDS/AML clinical outcomes we conducted a retrospective analysis in a large inner city cohort of patients (pts) Methods: 478 pts with MDS and MDS-transformed AML were identified between 1997 and 2016; 13 pts were HCV-positive (HCV+/MDS) and 465 were HCV-negative (HCV-/MDS). Demographics, hematologic parameters, cytogenetics, IPSS-R scores and molecular profiles were compared for both groups (grp). Survival (surv) analysis was done using the Kaplan-Meier method Results: HCV+/MDS had significantly worse surv than HCV-/MDS pts on univariate analysis (UA) (median surv 16 vs 52 months, HR 2.8, 95% CI 1.4-5.5, p < 0.01). Difference remained strongly significant after exclusion of HIV-coinfected pts (HR 2.7, p = 0.02) and pts w/ AML on presentation (HR 3.1, p < 0.01). Cytopenias were worse in HCV+/MDS (mean Hgb level 8.2 vs 9.4 g/dl, p = 0.04; mean plt count 64 vs 139 103/µL, p = 0.03). Average IPSS-R score was higher in HCV+/MDS pts (5.5 vs 3.8, p = 0.02). IDH1 mutation was more prevalent in HCV+/MDS (25% vs 2%, p < 0.01). Differences in age between HCV+/MDS and HCV-/MDS were non-significant (mean 64 vs 69 respectively, p = 0.2). Male-to-female ratio was higher in HCV+/MDS but difference was non-significant (2.3 vs 0.9, p = 0.2). Interestingly, high HCV viral load and cirrhosis did not correlate with poor surv in the HCV+/MDS grp, suggesting deleterious effect occurs even in early stages of HCV infection. Conclusions: Our analysis suggests that chronic HCV infection strongly correlates with worse surv in UA and is associated with lower blood counts and higher IPSS-R scores at the time of diagnosis of MDS. We observed a high rate of MDS refractory to standard therapies and speculate that HCV may affect biology of the disease. Larger studies are warranted to determine the effect of HCV on surv in this population and to provide a rationale for trials of anti-HCV drugs concomitantly with MDS Tx.

Early platelet and leukocyte decline in patients with neuroinflammatory disorders after intravenous immunoglobulins.

Intravenous immunoglobulins (IVIGs) are a common therapy in patients with neuroinflammatory disorders, especially chronic inflammatory demyelinating polyradiculoneuropathy or Guillain-Barré syndrome. Hematological toxicities upon IVIG infusion are a known side effect and still an important subject of investigation. Laboratory results and data for clinical efficacy and tolerability of 62 patients with neuroinflammatory disorders treated with IVIG (0.4 g/kg bodyweight per day over 5 days) at the Department of Neurology, University of Duisburg-Essen, Germany, were retrospectively analyzed. Blood samples were taken before and 1 day after IVIG administration. In pre-treated and first-time treated patients, there was a significant decrease in white blood cell count (WBC) (8.10 ± 2.85/nl to 5.61 ± 2.50/nl, P < 0.001, n = 57) and platelets (255 ± 72/nl to 215 ± 66/nl, P < 0.001, n = 57). Mild hemolysis of red blood cells was found in patients who received IVIG for the first time (red blood cell count 4.61 ± 0.67/pl to 4.28 ± 0.52/pl, hemoglobin 13.7 ± 1.7 g/l to 13.0 ± 1.7 g/l, P < 0.001, n = 40). Hemolysis was associated with less tolerability of IVIG treatment and clinical efficacy was accompanied with a higher decline of WBC (not significant). Next to mild hemolysis, a significant decrease in WBC and platelets can be detected early after high dose IVIGs in patients with neuroinflammatory disorders. Changes in blood counts may be possible markers for clinical efficacy and tolerability. Patients with low blood counts in advance should be particularly closely monitored whilst on IVIG treatment.

Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells.

Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS.

Safety of Symptom-Based Modification of Physical Therapy Interventions in Pediatric Oncology Patients With and Without Low Blood Counts

Background: Pediatric patients being treated for cancer often have low blood counts, yet physical therapy (PT) intervention and activity during treatment are thought to be important. The current practice at one institution is to modify PT interventions based on symptoms rather than relying on complete blood cell (CBC) counts. Purpose: This study investigates the safety of a symptomatic, rather than count-based, approach to modification of PT interventions in a pediatric cancer population at least 2 months into treatment. Methods: A retrospective chart review was performed to investigate the number and type of adverse events that occurred within 48 hours of a PT session in pediatric oncology patients. Information related to CBC values and type of interventions was abstracted from medical records. Associations between adverse events and low hemoglobin, platelets, and white blood cell (WBC) counts were assessed, and risk ratios were calculated. Results: CBC values were often abnormal. Adverse events occurred during or after 37 of 406 PT sessions, with the most common event being tachycardia not requiring medical intervention. No serious adverse events occurred. While an increased number of events occurred in those with low hemoglobin levels, this was nonsignificant when tachycardia was removed. A higher rate of adverse events did occur when platelets were below 20 000/mm3 (χ2 = 11.08, P = .001; Risk Ratio = 4.91; 95% confidence interval, 1.76-13.67), although none were bleeding-related. Low WBC count was not associated with an increased risk of adverse events. Conclusion: PT interventions can be safely incorporated into patient care when symptoms, rather than CBC values, guide clinical decision making about treatment modification.

Chronic Pancytopenia and Increased Bone Density Due to TBXAS1 Deficiency

Non-dysmorphic 32-year old Caucasian female developed malaise, fluctuating body aches and progressive transfusion-dependent pancytopenia with peripheral blood morphology consistent with myelodysplastic syndrome (MDS). Reportedly, she had an episode of "low blood counts" of unclear etiology 23 years prior. Multiple attempts at bone marrow biopsy were unsuccessful due to technical difficulties with penetrating the bone, necessitating surgical biopsy by an orthopedic surgeon. Bone densitometry revealed increased bone density with Z-score of 4.5, consistent with mild thickening of long bone diaphysis noted via x-ray. Strikingly, the bone marrow biopsy revealed haphazard ossification, immature cartilage formation and thickened trabeculae replacing hematopoiesis within the marrow cavity. Next-generation sequencing revealed two novel biallelic mutations within the thromboxane synthase gene TBXAS1 (c.266T>C; c.989T>C). Both mutations affected conserved amino acid residues and were predicted to be disruptive to the protein function by two independent bioinformatics algorithms (Provean and PolyPhen-2).Thromboxane cascade regulates pathways of inflammation, coagulation and osteoclast activation, suggesting a mechanistic explanation of how thromboxane synthase malfunction causes abnormal bone remodeling and bone marrow failure. TBXAS1 disruption had been described in a rare autosomal recessive syndrome Ghosal hematodiaphyseal dysplasia (GHDD) associated with increased bone density and bone marrow failure. GHDD due to TBXAS1 mutations was genetically confirmed only in four families of Northern African and Middle Eastern descent (Nat Genet 2008; 40: 284-286). To our knowledge, this is the first genetically validated case of TBXAS1-/- Ghosal syndrome in the Caucasian population.Consistent with the well-established role of thromboxane in platelet function, our patient's platelets displayed impaired aggregation in response to arachidonic acid and structural abnormalities by transmission electron microscopy, revealing a functional platelet defect. Steroid therapy rendered the patient transfusion-independent and alleviated chronic pain and inflammation. A long-term follow-up will be needed to determine whether steroid treatment will result in stable improvement in hematopoiesis and decreased bone density, similar to other GHDD patients. This case illustrates how establishing the diagnosis of an underlying rare inherited bone marrow failure syndrome allows personalized, evidence-based treatment with lower risk of morbidity compared to cytotoxic chemotherapy and hematopoietic stem cell transplantation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Vorinostat Does Not Improve Outcome in Patients with Acute Myeloid Leukemia and High Risk Myelodysplasia Treated with Azacitidine: Results of the UK Trials Acceleration Programme Ravva Trial

Introduction:Azacitidine (AZA) represents a significant advance in the treatment of adults with acute myeloid leukaemia (AML) (Dombret et al Blood 2016 126:291-9) and myelodysplasia (MDS) (Fenaux et al Lancet Oncol 2009) 10:223-32) ineligible for intensive chemotherapy. However complete response (CR) rates remain modest and disease progression is almost inevitable. Consequently, additional agents which improve the clinical activity of AZA and other hypomethylating agents are urgently required. Pre-clinical and Phase II studies have identified the potential of co-administration of histone deacteylase inhibitors, notably vorinostat (VOR), with AZA as a strategy to improve its clinical activity. We have therefore compared outcomes after AZA monotherapy or combined AZA and VOR in a prospective randomized trial in adults with high risk AML and MDS.Patients and Methods: 259adults with AML or high risk MDS deemed ineligible for intensive chemotherapy were randomized to receive either AZA (75 mg/m2) x 7 days every 28 days or AZA in combination with VOR 300 mg bd days 3-9 po for a minimum of 6 cycles. Patients were assessed for response, using modified Cheson criteria, after 3 and 6 cycles of therapy. Patients who achieved a major clinical response (CR, CRi or PR) were eligible to receive continued treatment until loss of response, toxicity or death. Major response after 6 cycles and overall survival (OS) were co-primary endpoints. 219 patients had AML (newly diagnosed n= 108) and 44 had MDS (newly diagnosed n= 30).Results: Co-administration of VOR did not increase either the major response rate at 6 months compared with AZA monotherapy (33% AZA v 37% AZA+VOR, OR (95% CI)=1.2 (0.7,2.0), p=0.55) or improve OS (1 year OS AZA 43% versus AZA/VOR 44%, HR (95% CI)=1.06 (0.8, 1.4), p=0.68). No benefit of addition of VOR was observed in any patient subgroup. In multivariate analysis of the study population, a low presentation white blood count (p=0.029) and a diagnosis of MDS vs AML (p=0.0048) was associated with significantly improved survival, whilst disease status (CR v advanced disease) (p=0.023) and low presentation white blood count (p=0.034) significantly improved major response rates. Presentation karyotype was not predictive of either survival or response. Both adverse events (AE) and serious adverse events (SAE) were balanced between treatment arms with 64 and 89 patients in the AZA arm experiencing AE and SAEs respectively versus 75 and 97 in the combination arm respectively.Discussion: To our knowledge this is the largest randomized study of epigenetic therapy in AML and MDS. We conclude that the addition ofVOR to AZA therapy does not increase either major response rates or overall survival in patients with AML and high risk MDS. Alternative therapeutic strategies with the potential to increase response to AZA are required in this patient population. DisclosuresFerguson:Celgene: Consultancy. Raghavan:Celgene: Consultancy. Quek:Celgene: Research Funding. Cavenagh:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. McMullin:Novartis: Honoraria, Speakers Bureau. Pillai:Celgene: Honoraria. Vyas:Celgene: Honoraria, Research Funding.

Learning Not to Judge a Book By Its Cover: A Case Series of Malignancy Masquerading As Common Presentations of Sickle Cell Disease

Background: Sickle cell disease affects 100,000 people in the United States. Cancer does not appear to be more common in individuals with sickle cell disease however many presenting signs and symptoms of cancer overlap with signs and symptoms of sickle cell disease, complicating diagnosis. Furthermore, sickle cell disease can complicate surgical, chemo- and radio- therapies for malignancy.Methods: We reviewed the past 46 years experience of cancers in children with sickle cell at a large urban pediatric referral center. We identified 5 cases and reviewed the presentations, treatments, response to therapy, sickle cell complication and laboratory values, including transfusion needs and effect of chemotherapy on fetal hemoglobin levels.Results: We identified five cases of malignancies in children with sickle cell disease including cases of acute lymphoblastic leukemia (ALL), Hodgkin's lymphoma, Non-Hodgkin's lymphoma (NHL), Wilms tumor and renal cell carcinoma. An additional patient with sickle cell trait was diagnosed with metastatic renal medullary carcinoma. The patients were ages 6-18 years old at diagnosis and 4 were female. All had delays in diagnosis as their initial signs and symptoms overlapped with sickle cell disease (abdominal mass mimicking splenomegaly, low blood counts, fever and posterior reversible encephalopathy syndrome, hematuria). All five achieved complete remission with multi-modality therapy (excluding stem cell transplants) and are currently doing well 1- 20 years after treatment. Admissions for pain were reduced during and for some period after cancer therapy and 2 patients had marked, and in one case, prolonged elevation of fetal hemoglobin after therapy.Discussion: Children with sickle cell develop cancers that can be confused for sickle cell related complications. Cancer therapy can be well tolerated and successful in children with sickle cell. Sickle cell complications are decreased during cancer therapy likely secondary to frequent therapy related transfusion and therapy induced increases in fetal hemoglobin. DisclosuresCallaghan:Biogen: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria; Baxalta: Honoraria, Research Funding; Grifols: Honoraria; Roche: Honoraria, Research Funding.

Asparaginase May Affect Mercaptopurine Tolerability in the Context of Multi-Agent Therapy for Acute Lymphoblastic Leukemia

▪Background: Mercaptopurine (MP) and asparaginase (ASP) are critical components in the treatment of acute lymphoblastic leukemia (ALL). Dose-limiting toxicities of the two drugs are common, resulting in therapy interruption, which has been associated with inferior treatment outcome in some studies. However, the interaction between these drugs has not been clearly identified. Merryman et al (Pediatr Blood Cancer 2012) reported that in DFCI ALL 05-01, patients had lower blood counts and more dosage reductions of MP during consolidation therapy (with concomitant ASP treatment) than during continuation therapy (identical treatment without concomitant ASP). Among groups of homogeneously treated patients with ALL, variability in ASP exposure due to inactivating antibodies can affect ASP pharmacodynamics: we have reported that ASP antibodies were associated with lower plasma ASP activity and higher dexamethasone (DEX) clearance, leading to a lower risk of osteonecrosis and a higher risk of CNS relapse (Liu, Leukemia 2012; Kawedia, Blood 2012). Here we studied the possible effect of ASP antibodies on MP tolerability in St. Jude Children's Research Hospital Total XV, a clinical trial featured intensive ASP treatment.Methods: A total of 390 children with ALL treated on St. Jude Total XV protocol were evaluable. TPMT genotype was used to guide starting doses of MP. During maintenance treatment, planned MP doses were higher on the low-risk arm (LR; n = 202) than on the standard/high-risk arm (SHR; n = 188). MP dose intensity was estimated as (prescribed dose)/(protocol dose) for weeks 1-146 (boys) or 1-120 (girls) for patients on the LR and SHR arms of maintenance therapy.Native E.coli-ASP (Elspar) was administered intramuscularly at 10000 U/m2 thrice weekly for 6 or 9 doses during remission induction. During maintenance therapy, patients on the LR arm received ASP only during reinductions I (weeks 7-9) and II (weeks 17-19), whereas those on the SHR arm received 19 weekly doses at 25000 U/m2 during weeks 1-19. Patients were tested for serum anti-Elspar antibodies at days 5, 19, 34 of remission induction, day 1 of reinduction I and day 1 of reinduction II, and were grouped based on whether they were ever positive for antibodies at any time during therapy or not. The area under the antibody concentration-time curve (AUC) for the entire period up to week 19 was also estimated in 360 patients.Result: Overall MP dose intensity was higher in those with vs without ASP antibodies in patients on the LR (median 83 vs 75%, P = 0.003) and SHR arms (median 86 vs 76%, P = 3.3 × 10-5; Figure 1A), and MP dose intensity was correlated with ASP antibody AUC in patients on both treatment arms (LR, P = 7.7 × 10-3 and SHR, P = 2.4 × 10-4; Figure 1B). In a multivariate model including age, sex, risk arm, ancestry, TPMT status, NUDT15 genotype and ASP antibody status, TPMT genotype was the strongest determinant of MP dose intensity (-17% in heterozygotes, P = 1.9 × 10-8), followed by ASP antibody positivity (+8.9% dose intensity in those with antibodies, P = 5.8 × 10-6). The model also confirmed previously identified associations of higher MP dose intensity with higher African ancestry (Bhatia et al. Blood 2014) (P = 1.8 × 10-4) and lower Asian ancestry (P = 0.05) (Yang et al. J Clin Oncol 2015).Conclusion: Interindividual differences in ASP systemic exposure, as reflected by ASP antibodies, had a strong impact on MP tolerance, especially in patients on the SHR arm who received intensive ASP therapy. We have previously shown that patients who are positive for ASP antibodies not only have lower exposure to ASP but also to dexamethasone (Kawedia, Blood 2012; Liu, Leukemia 2012). These data further emphasize the capacity for variation in ASP exposure to impact yet another critical component of ALL therapy. [Display omitted] DisclosuresEvans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Erythropoietin and thrombopoietin mimetics: Natural alternatives to erythrocyte and platelet disorders.

Erythropoietin (EPO) and thrombopoietin (TPO) plays a major role in the regulation of hematopoietic development. Though, blood transfusion was the most widely used method to treat low blood count, over the years with advancements in recombinant technology and drug designing, the EPO and TPO mimetics are dominating the therapeutics industry. On the other hand, the recombinant human EPO and TPO are associated either with reduced half-life or immune reactions. The restoration of alternate medicine in recent years has the hope to overcome limitations associated with recombinant technology, to treat various disorder including blood diseases, with low to no side effects. The work in recent years on plant derived mimetics suggests a paradigm shift in the way diseases are treated. Here, we are providing a comprehensive review on the EPO and TPO recombinant counterparts and synthetic mimetics studied till date with a focus on the need for more natural alternatives.

Patient reported outcome of tyrosine kinase inhibitor related side effects and their impact on daily life in Chinese patients with chronic myeloid leukemia in the chronic phase

目的评估中国慢性髓性白血病（CML）慢性期（CP）患者报告的酪氨酸激酶抑制剂（TKI）相关不良反应及其对日常生活的影响。方法2014年5月至11月在全国范围内向正在接受TKI治疗的成年CML患者发放无记名调查问卷。TKI不良反应对患者日常生活的影响程度采用自我报告的形式，以1分（没有影响）至5分（严重影响）进行评估。结果731例CML-CP受访者报告了TKI相关不良反应影响其日常生活评分，中位年龄41 (18~88）岁，男性407例（56%），560例（77%）确诊至TKI治疗时间< 1年。中位TKI治疗时间为3（<1~13）年，549例（75%）获得完全细胞遗传学反应，301例（41%）获得完全分子学反应。TKI最多见的不良反应依次为水肿（44%）、乏力（38%）、胃肠道不适（32%）、面部颜色改变（19%）、肌肉痉挛（19%）、皮疹（14%）、肝功能异常（12%）、体重增加（12%）和血细胞计数降低（8%）。多因素分析显示，TKI服药时间<4年是乏力的独立影响因素；女性、年龄≥40岁、服用一代TKI者容易发生水肿；服用一代TKI容易发生胃肠道不适；服用二代TKI容易出现皮疹及肝功能异常；女性容易出现体重增加；确诊至TKI治疗时间≥1年、服用一代TKI者较易出现肌肉痉挛；服用仿制品是血细胞计数降低的独立影响因素。患者自我报告TKI相关不良反应影响日常生活的评分显示218例（30%）没有影响（1分），375例（51%）受轻中度影响（2~3分），138例（19%）受严重影响（4~5分）。多因素分析显示，仅将人口学特征纳入分析时，女性、年龄≥40岁、服用仿制品、TKI服药时间<4年与受访者较高的日常生活受影响程度显著相关；将不良反应也纳入多因素分析后，未接受高等教育、TKI服药时间<4年、服用仿制品以及以下不良反应：水肿、乏力、胃肠道不适、面部颜色改变、皮疹和肝功能异常与较高的日常生活受影响程度相关。结论服用TKI的中国CML-CP患者中，水肿、乏力、胃肠道不适、皮疹、面部颜色改变和肝功能异常是最常见的、影响其日常生活的药物不良反应。女性、年龄≥40岁、未接受高等教育、服用仿制品和TKI治疗时间较短与患者日常生活受影响显著相关。

The Interactions Between Diabetes Mellitus and Myelodysplastic Syndromes: Current State of Evidence and Future Directions.

Diabetes mellitus (DM) and cancer are disorders of global importance. Multiple epidemiologic studies show that diabetic patients have an increased risk of developing cancer of different types. Myelodysplastic syndromes (MDS) are among the most common hematologic malignancies and include a heterogeneous group of hematopoietic neoplasms characterized by dysplastic changes, low blood counts, and an increased risk of progression to acute myeloid leukemia. Potential epigenetic and metabolic interferences between DM and MDS have been reported but are poorly understood. DM and MDS share some predisposing risk factors such as obesity. Patients with MDS and DM can experience worsening of diabetic control due to multiple factors that exacerbate hyperglycemia and insulin resistance such as stress, infections, adjunct drugs (e.g. steroids to control nausea), and others. In addition, accurate assessment of glucose control in diabetic patients who have MDS can be complicated. Alternatively, DM when associated with end-organ damage can complicate management of MDS, increase risks of complications, and limit the applicability of intensive therapeutic interventions. Here we review the current knowledge of the interactions between DM and MDS at the pathogenetic, clinical and epidemiologic levels, discuss how this knowledge could be used therapeutically to improve the outcome of patients affected by both conditions, and delineate important unmet needs that should be addressed in future research.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

Benefit of chemotherapy (CT) in patients (pts) with Merkel cell carcinoma (MCC) with distant metastases (mets) and visceral organ involvement.

e21000 Background: MCC is a rare skin cancer with a propensity for distant mets, yet the ability of palliative CT to impact survival is unknown. Methods: Pts with MCC were identified from an institutional database from 1990-2015. Demographic and clinical data were abstracted from the medical record. Pts with distant mets were analyzed for survival. Genomic testing by Foundation Medicine, if performed, is reported. Results: 205 pts with MCC were identified; 43 (21%) developed distant mets. Median age was 69 years (range 52-93, 36 male). Median time of follow up was 1.7 years. For initial treatment, 41 pts had surgery and 30 pts had adjuvant radiotherapy. Location of distant mets included: skin (n = 26), liver (n = 17), distant lymph nodes (n = 10),), bone (n = 7) lung (n = 2), heart (n = 2), kidney (n = 1), stomach (n = 1), pancreas (n = 1), and testes (n = 1). Visceral mets were seen in 23 pts. 24 pts received chemotherapy for metastatic disease and 19 did not. CT regimens were platinum/etoposide (n = 21) and doxorubicin, cyclophosphamide, and vincristine (n = 7). At last follow-up, 16 pts were alive and 27 were dead. For the whole cohort, 2-year overall survival (OS) was not increased with the use of CT (41% no CT, 68% with CT; p = 0.222). 2-year OS was 61% for pts without visceral involvement and 49% for pts with visceral mets (p = 0.127). However, 2-year OS of pts with visceral mets who received CT was better than those pts with visceral mets who did not receive CT (77% versus 0%; p = 0.0016). Genomic testing was available for 5 pts. Two pts had no targetable mutations. One pt had a mutation in HRAS G12S. One pt had a PTEN R335 mutation and was treated with temsirolimus but had to stop due to low blood counts after 2 doses so response could not be assessed. One pt had several genomic alterations: CD274 (PD-L1) amplification, JAK2 amplification, KDR G49E, PDCD1LG2 (PD-L2 amplification, and PIK3R2 W165. Conclusions: CT may have a survival benefit in pts with MCC with distant visceral mets. Further genomic testing is needed to inform the role of targeted therapies for pts with metastatic MCC.

Réintroduction de la clozapine après neutropénie dans la schizophrénie résistante : revue des données de la littérature

IntroductionClozapine is an atypical antipsychotic known for its efficacy in refractory schizophrenia. One of the adverse effects is neutropenia. This dysplasia is a rare but major side effect which leads to a discontinuation and constitutes further contraindication. Thereafter, therapeutic options decrease dramatically. Mechanisms involved are not well known at this time and can be combined. A toxic hypothesis may be more likely than an immune-allergic one. MethodsWe have reviewed publications on Medline describing procedures that allowed clozapine rechallenge after blood dyscrasia in refractory schizophrenia. Three different procedures were found: simple rechallenge, rechallenge with lithium and rechallenge with Granulocyte - colony stimulating factor (G-CSF). Rechallenge could be simple or multiple. ResultsThese past years, clozapine have been rechallenged successfully after neutropenia thanks to different procedures, the different options being simple rechallenge, rechallenge with lithium and/or rechallenge with G-CSF. Lithium as G-CSF are used to increase neutrophil blood rate and prevent neutropenia recurrence after clozapine rechallenge. G-CSF was first used within the context of chemotherapy and extends now to clozapine-induced neutropenia. Both for lithium and G-CSF, numerous procedures are reviewed and cannot be compared. DiscussionPublications are limited but increasing, and they point out that a careful rechallenge can be successful. However, interesting data can be extracted. First, clozapine is more likely to be incriminated in neutropenia when patients receive many drugs, but a careful study could prevent some discontinuation. Indeed, other drugs or a hematologic disease could be involved. Moreover, several contributing factors have been found such as HLA group and drug interaction. Ethnic origin also affects neutrophil rate. That is why, in Great Britain, a subgroup of patients “benign ethnic neutropenia” has been introduced to enlarge threshold and allow these patients to access clozapine despite lower blood counts. Then, rechallenge choice has to be done on a case-by-case basis and only after considering the benefits and risks of such a treatment. Most of the time, clinical advice of rechallenge arises from the inefficiency of other antipsychotics and even sismotherapy failure. Patients and sometimes families have to be informed and give their consent. Preventive measures have been found such as taking a hematologic recommendation and doing twice-a-week blood sample monitoring. With regards lithium and G-CSF, some efficient doses are assumed (lithium: 0,4–1,1 mEq/L and G-CSF>0,3 mg/week). Lithium as G-CSF may have other adverse effects which need to be considered. There is no successful rechallenge reported after agranulocytosis. Some publications highlight that if neutropenia occurs on rechallenge, it will do so more quickly and more severe than at the time of initial trial of clozapine. ConclusionThere is emerging evidence of successful clozapine rechallenging. However, further investigations are required as randomized controlled trials to reassess guidelines and establish the safety and effectiveness of the different procedures. Because of the practical and ethical difficulties of designing such studies, referral hospitals could be elected, and common background writing proposed in order to ease data comparison.

Analysis of plasma microRNA expression profiles in a Chinese population occupationally exposed to benzene and in a population with chronic benzene poisoning.

Circulating microRNA (miRNA) has attractive interests as a non-invasive biomarker of physiological and pathological conditions. Our study aimed to investigate the potential effects of chronic benzene poisoning (CBP) and benzene exposure on miRNA expression, and identify CBP-related miRNAs. In the discovery stage, we used a microarray assay to detect the miRNA expression profiles among pooled plasma samples from ten CBP patients, ten healthy benzene-exposed individuals and ten non-benzene exposed individuals. Subsequently, we conducted an expanded validation of six candidate miRNAs in 27 CBP patients- low blood counts, 54 healthy benzene-exposed individuals and 54 non-exposed individuals. Moreover, we predicted the biological functions of putative target genes using a Gene Ontology (GO) function enrichment analysis and KEGG pathway analysis. In the discovery stage, compared with non-exposures, 36 and 12 miRNAs demonstrated at least a 1.0-fold differential expression in the CBP patients and the benzene exposures, respectively. And compared with benzene exposures, 58 miRNAs demonstrated at least a 1.0-fold differential expression in the CBP patients. In the expanded validation stage, compared with non-exposures as well as exposures, miR-24-3p and miR-221-3p were significantly up-regulated (1.99- and 2.06-fold for miR-24-3p, 2.19- and 3.93-fold for miR-221-3p, P<0.01) while miR-122-5p and miR-638 were significantly down-regulated (-3.45- and -2.60-fold for miR-122-5p, -1.82- and -3.20-fold for miR-638, P<0.001) in the CBP patients; compared with non-exposures, the plasma level of miR-638 was significantly up-regulated (1.38-fold, P<0.01) while the plasma levels miR-122-5p and miR-221-3p were significantly down-regulated (-0.85- and -1.74-fold, P<0.01) in the exposures, which were consistent with the results of microarray analysis. The four indicated plasma miRNAs may be biomarkers of indicating responses to benzene exposure. Further studies are warranted to verify our findings with a large sample and to confirm the underlying mechanisms.

A Pilot Study of Continuous Infusion of Mycophenolate Mofetil for Prophylaxis of Graft-versus-Host-Disease in Pediatric Patients

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose-escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC0-24 of 40 to 80 μg·hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 μg/mL. During the CI schedule, MPA AUC0-24 was maintained at a mean of 40.1 μg·hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 μg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in pediatric HCT recipients compared with stable pediatric renal transplant patients or adult transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation.

Disrupted Lymphocyte Homeostasis in Hepatitis-Associated Acquired Aplastic Anemia Is Associated with Very Low Telomere Lengths

Acquired aplastic anemia (AA) is a hematologic disorder characterized by low blood counts and a hypocellular bone marrow, caused by autoimmune destruction of early hematopoietic cells. The diagnosis of AA is made by excluding other disorders that can present with bone marrow failure (BMF). Such disorders include dyskeratosis congenita (DC), a multisystem BMF syndrome, caused by an inherited defect in telomere maintenance. Although classical DC presents in childhood with stereotypical mucocutaneous changes, milder forms of telomere dysfunction associated with mutations in TERT and TERC genes can present with non-syndromic bone marrow failure clinically indistinguishable from AA. In clinical practice, lymphocyte telomere length measurements are used as a first-line screen for inherited telomeropathies before initiating treatment for AA.In our BMF center, we have observed that several patients with features of hepatitis-associated AA (HAA) had lymphocyte telomere lengths at diagnosis at or below the first percentile of age-matched controls, in the range similar to inherited telomere disorders. To confirm our initial observation, we performed a retrospective analysis of telomere lengths of consecutively enrolled HAA patients with non-hepatitis associated AA patients in our institution.A total of 30 patients with AA were included in this study: 10 had HAA and 20 had other AA (Table 1). The median age at telomere testing was 8.0 years (range 1-19 years). There was no significant difference in age or disease severity between the two groups (p=0.827). The patients' median lymphocyte telomere length (TL) was significantly lower in the HAA patients compared to AA (7.4kb versus 9.1kb, P= 0.021); the difference remained significant after adjusting for patient age (p<0.001). Strikingly, 5 of 10 HAA patients had telomeres at or below the 1st percentile of age-matched normal controls, within the diagnostic range for telomeropathies (Figure 1A). None of these 5 patients had clinical features of DC. As a comparison, TL measurements of genetically-confirmed DC patients (Figure 1) demonstrated TL below the 1st percentile for age-matched controls, and within a similar range to that seen in the HAA patients. To ensure that the significantly lower telomere lengths in the HAA patients were not caused by an occult TERT or TERC gene mutation, the five HAA patients with TL below the 1st percentile were screened for germline mutations in TERT and TERC. A known heterozygous polymorphism, Ala1062Thr was found in one patient, a known variant with no known telomere defect and no effect on telomere length.Because differences in lymphocyte activation and subset composition are known to impact telomerase activity, we hypothesized that alterations in lymphocyte populations caused by the unique inflammatory state of HAA could partly account for significantly shorter TL in this population. HAA patients exhibited significantly lower absolute lymphocyte counts and lower lymphocyte subsets across the board, as well as the decreased CD4/CD8 ratio compared to non-hepatitis AA patients (Figure 2). The median telomere length in the two groups was significantly correlated with lymphocyte counts (Pearson correlation coefficient 0.52, p=0.003).An altered lymphocyte homeostasis such as the one characteristic for HAA limits the specificity of telomere measurements as a screening method to identify patients with AA due to a genetic defect in telomere maintaining genes. As such, short telomeres in HAA in the absence of other features suggestive for DC does not necessarily warrant genetic testing for telomere length. Longitudinal studies of telomeres and study of clonal hematopoiesis in this population is ongoing.Table 1Overall (n = 30)AA (n=20)HAA (n=10)P value*Patient CharacteristicGender, female n (%)12 (40)9 (45)3 (30)0.694Gender, male n (%)18 (60)11 (55)7 (70)Age at diagnosis, y, median (range)8.0 (1-19)8.3 (1-19)7.5 (3-17)0.827Disease Severity, n (%)0.999Moderate6 (20)4 (20)2 (20)Severe22 (73)15 (75)7 (70)Very Severe2 (7)1 (5)1 (10)Median Lymphocyte Telomere Length, kb (range)8.9 (5.9-11.3)9.1 (7.5-11.3)7.4 (5.9-9.8)0.021≤ 1st percentile of age-matched controls5051-10th percentile of age-matched controls550> 10th percentile of age-matched controls20155*P-values are obtained by Fisher's exact test for gender and disease severity and by Wilcoxon test for age and telomere length. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Persistent Elevation of Plasma Thrombopoietin Levels in Severe Aplastic Anemia, Even with Hematologic Recovery

In bone marrow failure, levels of circulating hematopoietic growth factors (HGFs) are extremely elevated, in compensation for low blood counts. In general, administration of recombinant HGFs is not effective in aplastic anemia (AA) and related syndromes. We have established the utility of eltrombopag, a thrombopoietin (Tpo) mimetic, in severe AA (SAA) refractory to immunosuppression (IST) (Olnes, N Engl J Med, 2012; Desmond, Blood, 2014). Eltrombopag in combination with standard IST also appears to increase the rate and speed of recovery in treatment-naive SAA (Townsley, EHA. 2015). These clinical results are surprising, as plasma Tpo is markedly increased in SAA (Feng, Haematologica, 2011). In investigating possible mechanisms of action of eltrombopag, we studied HGF dynamics over time in SAA patients undergoing various treatment regimens and manifesting a range of hematologic responses. In a cohort of 37 treatment-naive SAA patients who were treated with either standard IST (horse antithymocyte globulin/cyclosporine A:ATG/CsA, n = 10) alone or with the addition of eltrombopag (n = 27), among whom 8 were non-responders and 29 responders at 6 months, we measured plasma Tpo, granulocyte-colony stimulating factor (G-CSF) and erythropoietin (Epo) using magnetic multiplex assays. Concentrations of these HGFs were greatly elevated before treatment. In a majority of patients, G-CSF declined rapidly to the normal range by 6 months, with no difference between responders and non-responders, and no correlation between G-CSF and absolute neutrophil counts. Epo concentrations decreased to the normal range at 6, 12, and 24 months post treatment in responders, to a significantly greater degree than in non-responders (p = 0.001, 0.0012, 0.038, respectively). There was a negative correlation between Epo and hemoglobin (r2 = 0.3126, p<0.0001). Tpo levels did decrease by 6 months and later, but remained much higher than the normal range, however Tpo levels in responders were significantly lower than in non-responders at 6, 12, and 24 months, respectively (p = 0.0009, 0.0477, 0.0036), with Tpo in non-responders remaining at high baseline levels (Figure 1A). These data suggest that a decrease in Tpo and/or Epo levels following initial IST therapy is an indicator of hematologic response. Linear regression analysis reveals a negative correlation between Tpo levels and platelet counts (r2 = 0.3243, P < 0.0001), consistent with previous reports. In a cohort of 7 SAA patients refractory to IST but who achieved a clinical response to eltrombopag, Epo and G-CSF levels in plasma decreased to the normal range at 3-4 months post initiation of eltrombopag treatment, but Tpo levels remained significantly elevated over the normal range for up to 5 years of follow-up, despite sustained clinical response (Figure 1B). Regression analysis revealed a negative correlation between Tpo and platelet counts (r2 = 0.3696, p < 0.0001). We asked if persistently elevated levels of Tpo even in responders are due to incomplete recovery of platelets or megakaryocytes, and thus followed up Tpo levels up to 7 years post horse ATG/CsA treatment in a cohort of 9 patients who obtained stable complete remission with platelet counts greater than 100 K/uL. Tpo levels in these patients had declined by 3 and 6 months post treatment, gradually decreased, then stabilized at levels still higher than healthy controls (Figure 1C) despite platelet counts of 102-314 K/uL (median, 174 K/uL) by 6 months and later post treatment, and recovery of bone marrow megakaryocyte frequency to normal or only mildly decreased. Tpo levels in these patients negatively correlated with platelet counts (r2 = 0.3904, p < 0.0001. Figure 1D). In conclusion, Epo and G-CSF levels fall promptly in patients with SAA who recover blood counts. In contrast, circulating Tpo levels remain markedly elevated for long periods even after complete response to treatment. Likely, Tpo is high due to low megakaryocyte mass. The consequences of sustained high Tpo levels on primitive progenitors and stem cells in these circumstances are unclear, and may play a role in stem cell exhaustion and clonal evolution. [Display omitted] DisclosuresTownsley:Novartis: Research Funding; GSK: Research Funding. Winkler:Novartis: Research Funding; GSK: Research Funding. Dumitriu:Novartis: Research Funding; GSK: Research Funding. Young:Novartis: Research Funding; GSK: Research Funding.