μL In Patients Research Articles

Risk of neutropenia among clozapine users and non-users: results from 5,847 patients

Objective:Clozapine is underprescribed due to neutropenia risk. Blood tests every 3 months in those on continuous treatment for > 1 year who have never had an absolute neutrophil count (ANC) < 2,000/µL has been proposed as a monitoring strategy; however, there are no South American data to support this recommendation. This study sought to investigate whether clozapine use and other variables could explain the occurrence of ANC < 1,000/µL in patients with severe mental disorders.Methods:A total of 5,847 subjects were included, 1,038 on clozapine. We performed a Cox regression considering the outcome as ANC < 1,000/µL at any time point. Predictors were sex, age, ethnicity, clozapine use, ANC > 2,000/µL during the first year of blood monitoring, and presence of a severe medical condition.Results:In the Cox regression model, ethnicity (white) (hazard ratio [HR] 0.53; 95%CI 0.29-0.99, p < 0.05) and ANC > 2,000/µL (HR 0.04; 95%CI 0.01-0.10, p < 0.001) were protective factors, while presence of a severe medical condition (HR 69.35; 95%CI 37.45-128.44, p < 0.001) was a risk factor for ANC < 1,000/µL. Other variables were not significant, including clozapine use (HR 1.33; 95%CI 0.74-2.39, p > 0.05).Conclusions:These findings suggest that clozapine does not increase the risk of neutropenia in subjects with ANC > 2,000/µL during the first year of use and in the absence of a severe medical condition. These results could help guide clinical and public-health decisions regarding clozapine blood monitoring guidelines.

TIME-DEPENDENT, LIFE-SAVING SUPPORTIVE TREATMENT IN AN UNORDINARY PULMONARY LEUKOSTASIS PRESENTATION: A CASE REPORT

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary leukostasis (PL) is a medical emergency defined by an extremely high white blood cell count (WBC) with pulmonary symptoms with or without imaging findings. This condition is seen more frequently in acute myeloid leukemia or chronic myeloid leukemia during a blast crisis and confers up to 30% mortality. Symptoms usually do not occur unless WBC exceeds 400x10ˆ3 / µL in patients with chronic lymphocytic leukemia (CLL). Here we present an atypical presentation of this dreaded disease. CASE PRESENTATION: An 80-year-old man with a history of atrial fibrillation, benign prostatic hyperplasia, diabetes mellitus, and a recent diagnosis of chronic lymphocytic leukemia came to the emergency room with tachypnea, hypoxia, headache, slurred speech, drowsiness, and confusion. Days before his arrival, he began with bradyphrenia, subjective fever, and dry cough. Vital signs with tachypnea and peripheral oxygen saturation of 90%. Routine laboratories stood out for 95.2 x10ˆ3 / µL white blood cells, with 65% immature blood cells, 17% lymphocytes, 10% neutrophils, and arterial blood gas with metabolic alkalosis and hypoxemia. Supportive therapy began with respiratory therapies every four hours, aggressive intravenous hydration, and empirical antibiotics. Chest radiography and chest computed tomography failed to show effusions, infiltrates, or consolidations. Brain studies negative for intracranial pathology. Debulking and leukoreduction therapies were discussed with the patient who decided to continue with supportive therapy, even with the risk of tumor lysis. After observation and aggressive hydration, there was a significant clinical improvement that correlated with the decrease in WBC from 95.2x10ˆ3 / µL to 69.9x10ˆ3 / µL. Noteworthy, cultures and respiratory panel were negatives. The following days the antibiotics were suspended and the patient was discharged with scheduled chemotherapy. DISCUSSION: Leukostasis is an emergency condition that, if overlooked or misdiagnosed, could be fatal if left untreated. In case of clinical suspicion, expeditious treatment is indicated since the mortality rate is approximately 20 to 40 percent regardless of the leukocytosis. CONCLUSIONS: Although it is less common in CLL and almost unthinkable with WBC less than 100x10ˆ3 / µL; L This case highlights the important role of high clinical suspicion of PL even if not all medical criteria are met and its response to supportive and symptomatic therapy when implemented in a rapid timely manner. REFERENCE #1: Kacar, D., Yarali, N., Candir, M. O., Kara, A., Ozbek, N., & Tunc, B. (2017). Pulmonary Leukostasis. Journal of Pediatric Hematology/Oncology, 39(2), 156–158. doi:10.1097/mph.0000000000000731 REFERENCE #2: Soares, F. A., Landell, G. A. M., & Cardoso, M. C. de M. (1992). Pulmonary leukostasis without hyperleukocytosis: A clinicopathologic study of 16 cases. American Journal of Hematology, 40(1), 28–32. doi:10.1002/ajh.2830400106 REFERENCE #3: Baer, M. R., Stein, R. S., & Dessypris, E. N. (1985). Chronic lymphocytic leukemia with hyperleukocytosis the hyperviscosity syndrome. Cancer, 56(12), 2865–2869. doi:10.1002/1097-0142(19851215)56:12<2865::aid-cncr2820561225>3.0.co;2-6 DISCLOSURES: No relevant relationships by Ian Da Silva Lugo, source=Web Response No relevant relationships by Arelis Febles, source=Web Response No relevant relationships by Juan Feliciano-FIgueroa, source=Web Response No relevant relationships by Heydee Fournier, source=Web Response No relevant relationships by Joel Gonzalez Chaple, source=Web Response No relevant relationships by Juan Santiago, source=Web Response

Eltrombopag for Post-Transplantation Thrombocytopenia: Results of Phase II Randomized, Double-Blind, Placebo-Controlled Trial

Prolonged thrombocytopenia occurs in up to 37% of patients after hematopoietic stem cell transplantation (HSCT) and is associated with adverse prognosis and increased risk of bleeding. Eltrombopag, a thrombopoietin receptor agonist, can increase platelet counts in thrombocytopenic patients. We conducted a phase II study, adaptively randomizing patients at ≥35 days post-HSCT to receive placebo or eltrombopag at a platelet count ≤20,000/µL for 7 days or platelet transfusion-dependent and a neutrophil count ≥1500/µL. Sixty patients were randomized to eltrombopag (n=42) or placebo (n=18) and received at least 1 dose. Fifteen patients (36%) in the eltrombopag arm achieved a platelet count of ≥30,000/µL, compared with 5 patients (28%) in the placebo arm, with a posterior probability of 0.75. (The protocol required this probability to be >0.975 to declare a winner; thus, the results are inconclusive.) However, 9 patients (21%) in the eltrombopag arm achieved a platelet count of ≥50,000/µL, compared with no patients in the placebo arm (P=.046). The overall survival, progression-free survival, relapse rate, and nonrelapse mortality were similar in the 2 arms. In conclusion, compared with placebo, treatment with eltrombopag led to a higher percentage of patients achieving a platelet count of ≥50,000/µL in patients with persistent thrombocytopenia after HSCT.

Effect of Vitamin D3 in combination with Omega-3 Polyunsaturated Fatty Acids on NETosis in Type 2 Diabetes Mellitus Patients.

An understanding of the consequences of oxidative/halogenative stress triggered by neutrophil activation is impossible without considering NETosis. NETosis, formation of neutrophil extracellular traps (NETs), is known to promote microthrombus formation and impair wound healing in type 2 diabetes mellitus (T2DM) patients. Therefore, there is a need to search for drugs and treatment approaches that could prevent excessive NET formation. We aimed to evaluate the effect of vitamin D3 in combination with omega-3 polyunsaturated fatty acids (vitamin D3/omega-3 PUFAs) on NETosis in T2DM patients with purulent necrotizing lesions of the lower extremities. Patients and healthy subjects had vitamin D3 deficiency. Patients received, beyond standard treatment, 6000 IU of vitamin D3 and 480 mg of omega-3 PUFAs, and healthy subjects 1000 IU of vitamin D3 and 240 mg of omega-3 PUFAs daily for seven days. Neutrophil activation in ex vivo blood by phorbol-12-myristate-13-acetate (PMA) was used as a NETosis model. The percentage of blood NETs relative to leukocytes (NETbackground) before vitamin D3/omega-3 PUFA supplementation was 3.2%-4.9% in healthy subjects and 1.7%-10.8% in patients. These values rose, respectively, to 7.7%-9.1% and 4.0%-17.9% upon PMA-induced NETosis. In addition, the leukocyte count decreased by 700-1300 per 1 μL in healthy subjects and 700-4000 per 1 μL in patients. For both patients and healthy subjects, taking vitamin D3/omega-3 PUFAs had no effect on NETbackground but completely inhibited PMA-induced NET formation, though neutrophils exhibited morphological features of activation. Also, leukocyte loss was reduced (to 500 per 1 μL). For patients on standard treatment alone, changes occurred neither in background NETs and leukocytes nor in their amount after PMA stimulation. The decreased ability of neutrophils to generate NETs, which can be achieved by vitamin D3/omega-3 PUFA supplementation, could have a positive effect on wound healing in T2DM patients and reduce the incidence and severity of complications.

Role of severe thrombocytopenia in preventing platelet count recovery in thrombocytopenic patients with chronic liver disease.

Certain thrombocytopenic patients with chronic liver disease have inadequate platelet count recovery after platelet transfusion or lusutrombopag administration. We aimed to identify the reasons for this phenomenon. We investigated 58 and 86 thrombocytopenic patients with chronic liver disease who received lusutrombopag (3 mg orally for up to 7 days) or underwent blood transfusions, respectively. Thirty patients underwent simultaneous hepatic surgery and splenectomy. Factors preventing platelet count recovery above 50 × 103 /μL were identified. The median patient age was 64 years. Eleven, 78, and 55 patients had hepatitis B, hepatitis C, or another etiology, respectively; 59, 69, and 16 had Child-Pugh classes A, B, and C, respectively. The median spleen volume was 432 mL, and a median of 10 blood units were transfused per patient. The median platelet count rose significantly (from 41.5 × 103 /μL to 81.0 × 103 /μL) after lusutrombopag administration but not after blood transfusion before invasive procedures. However, maximum platelet counts in patients who underwent splenectomy before platelet transfusion were markedly improved over those who did not. Increasing platelet counts above 50 × 103 /μL required baseline platelets > 30 × 103 /μL and lusutrombopag administration for all patients. Platelet count recovery was dependent on a spleen volume of < 300 mL and baseline platelets of > 40 × 103 /μL in patients who underwent platelet transfusions, while a baseline platelet count of > 30 × 103 /μL was required for patients administered with lusutrombopag. Neither blood transfusion nor lusutrombopag improves thrombocytopenia in patients with severe conditions; however, the degree of platelet count elevation following lusutrombopag administration is higher than that following blood transfusion.

The significance of platelet count in traumatic brain injury patients on antiplatelet therapy.

Platelet dysfunction has been attributed to progression of initial intracranial hemorrhage (ICH) on repeat head computed tomographic (RHCT) scans in patients on prehospital antiplatelet therapy. However, there is little emphasis on the effect of platelet count and progression of ICH in patients with traumatic brain injury. The aim of this study was to determine the platelet count cutoff for progression on RHCT and neurosurgical intervention in patients on antiplatelet therapy. We performed a prospective cohort analysis of all traumatic brain injury patients with an ICH on prehospital antiplatelet therapy. Antiplatelet therapy was defined as aspirin, clopidogrel, or a combination of both. Admission platelet count was recorded and used for analysis. Receiver operating characteristic curves were plotted to identify the optimal platelet count for progression on RHCT scan and neurosurgical intervention in patients on antiplatelet therapy. A total of 264 patients were enrolled. Platelet count of 135,000/µL or less (area under the curve, 0.80) and platelet count of 95,000/µL or less (area under the curve, 0.92) were the optimal threshold points for progression on RHCT scan and neurosurgical intervention, respectively. Patients with platelet count of 135,000/µL or less were 12.4 times (95% confidence interval, 7.1-18.4) more likely to have progression on RHCT scan and patients with platelet count 95,000/µL or less were 31.5 times (95% confidence interval, 19.7-96.2) more likely to require neurosurgical intervention. A platelet count of less than 135,000/µL in patients on antiplatelet therapy is predictive of both radiographic and clinical worsening. This is a clinically relevant target intended to help tailor and improve management in patients on antiplatelet therapy. Therapeutic study, level III.

Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial

Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. US National Institute of Allergy and Infectious Diseases.

English

INTRODUCTION: Tuberculosis is the most common HIV-related opportunistic infection in India, and caring for patients with both diseases is a major public health challenge, which places an immense burden on health care systems and poses particular diagnostic and therapeutic challenges, increasing the risk of treatment failure, relapse and death. Estimates by the World Health Organization (WHO) indicate that there are more than 9 million new active cases of TB and close to 2 million deaths per year. MATERIALS AND METHOD: The present retrospective study was conducted for a period of one year. HIV status was confirmed for patients attending voluntary counselling and testing centre (VCTC). HIV positive patients were referred to designated microscopic centre (DMC) for sputum examination for AFB and ART centre for estimation of CD4 count and necessary relevant investigations were carried out for extrapulmonary tuberculosis (EPTB). RESULTS: Out of 682 HIV positive patients, 93(13.6%) cases were diagnosed with pulmonary tuberculosis. Extrapulmonary tuberculosis was detected in16 (2.3%) patients. The commonest form of EPTB was cervical adenitis detected in13 (1.9%) of cases and pleural effusion in 3 (0.4%) of cases respectively. The mean CD4 count was 208 cells/µl in patients with pulmonary tuberculosis (PTB) and 192cells /µl , 162 cells /µl in patients with cervical adenitis and pleural effusion. CONCLUSIONS: Further reduction of CD4 count occurs in dually infected patients. Early diagnosis and prompt institution of ART and ATT reduces mortality and morbidity significantly. INTRODUCTION: Tuberculosis (TB) and human immunodeficiency virus (HIV) constitute the main burden of infectious disease in resource-limited Countries 1 . Persons infected with HIV are particularly susceptible to tuberculosis, both from the reactivation of latent infection and from new infection with rapid progression to active disease 2 . An individual who is HIV-positive has 10 times increased risk of developing TB compared to an HIV-negative person the life time risk is 50% for an HIV-positive person and 5-10% for an HIV-negative person3. Estimates by the World Health Organization (WHO) indicate that there are more than 9 million new active cases of TB and close to 2 million deaths per year and that 2.6 million new cases of HIV infection and 1.8 million AIDS- related deaths occur per year 1 . In India alone about 2.5 million people are currently infected with

Hepatitis B and C co-infection in HIV patients

Editor: Chronic viral infections with the human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) share similar routes of transmission, mainly through blood and blood products, sharing of needles to inject drugs, and sexual activity, enabling co-infection with these viruses [1–4]. HBV and HCV co-infections in HIV positive individuals are of clinical importance and have been shown to decrease the life expectancy of HIV infected patients [4]. We evaluated 100 HIV positive patients (ranging in age from 15 to 65 years) attending the HIV clinic, excluding those with a history of drug induced hepatitis and alcoholic hepatitis. Hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV) were detected using SD HBsAg kit and INSTACHK hepatitis C kit respectively. Ninety-eight patients had multiple sexual partners and unprotected sex as the major risk behavior, while two had possible transfusion related infection. None of them were intravenous drug users. Eight patients (8 %) were also positive for HBsAg and 2 (2 %) were positive for antiHCV. None of them were positive for both HBsAg and anti-HCV. The mean (SD) CD4 count of HBsAg reactive patients was 267 (180)/μL and that of anti-HCV reactive patients was 196 (94)/μL, compared to 276 (194)/μL in patients without HBV or HCV co-infection. None of these differences was statistically significant. The mean (SD) SGPT was 58 (40) IU/L in HBsAg reactive patients and 23 (6) IU/L in anti-HCV reactive patients (p0ns). The mean (SD) SGOT value in HBsAg reactive patients was 67 (79) IU/L and 28 (5) IU/L in anti-HCV reactive patients (p0 ns). The mean (SD) serum ALP value in HBsAg reactive patients was 234 (190) IU/L and 129 (24) IU/L in anti-HCV reactive patients. None of these differences was statistically significant. The prevalence of HBV co-infection in this study was 8.0 %. Various studies have shown prevalence from 2.19 % to 9 % [5–7]. In the present study the prevalence of HCV co-infection was 2 %. Other studies have shown prevalence from 1.61 % to 10.99 % [5–7]. In present study elevation of liver enzymes in patients who were co-infected with hepatitis B or hepatitis C was not statistically significant. In a study by Olanisun et al. [8], liver enzymes were elevated in all the patient groups, though there was no significant association. The mean level was highest for those co-infected with hepatitis B, followed by those co-infected with hepatitis C. Our study shows that the highest copositivity was seen in those patients having CD4 count <200/μL and HBeAg reactivity of 3 out of 8 HBsAg reactive patients indicated the need for change in highly active antiretroviral therapy regime in these patients. Since these viruses share common modes of transmission, we suggest that all HIV positive patients be investigated for hepatitis B and C co-infection so that appropriate management can be instituted.

Cumulative Response to Eltrombopag and Impact of the Number of Prior ITP Therapies: Interim Results of a Long-Term Extension Study,

Abstract 3297▪▪This icon denotes a clinically relevant abstract Background:Patients with chronic immune thrombocytopenia (ITP) have an increased risk of bleeding, ranging from minor to life-threatening. The goal of treatment is to increase and maintain platelets in a safe range to prevent bleeding. Guidelines state that achieving platelet counts of 30,000/μL to 50,000/μL in patients without other risk factors avoids the most serious complications of ITP, namely intra-cerebral or gastrointestinal hemorrhage (George 1996; Provan 2010). Many patients are refractory or relapse after multiple treatments. Eltrombopag is an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic ITP. In 6-week, and 6-month, placebo-controlled trials in patients with heavily pre-treated chronic ITP, eltrombopag increased platelets and reduced bleeding and the need for concomitant ITP therapy (Bussel 2007; Bussel 2009; Cheng 2011). Long-term treatment with eltrombopag is being evaluated in EXTEND, an extension study in chronic ITP patients who completed a previous eltrombopag study (Saleh 2010). Aims: To analyze in EXTEND the ability of eltrombopag to increase platelet counts to ≥50,000/μL in >50% and >75% of assessments and to determine whether the number of prior ITP therapies influences this ability. Methods: Patients in EXTEND received eltrombopag or placebo in 1 of the following prior studies of eltrombopag in chronic ITP: a 6-week phase 2 (TRA100773A; Bussel 2007) or phase 3 (TRA100773B; Bussel 2009) study, a 6-month phase 3 study (RAISE; Cheng 2011), or a phase 3 study of intermittent treatment (REPEAT; Psaila 2008). Dosing in EXTEND is individualized in order to maintain platelet counts ≥50,000/μL and <200,000/μL while minimizing the use of concomitant ITP medications. For the purpose of this analysis, response is defined as a platelet count ≥50,000/μL. Results: Among the 299 patients enrolled in EXTEND between June 2006 and February 2010, 67 (22%), 73 (24%), 47 (16%), and 112 (37%) patients had received 1, 2, 3, and ≥4 prior therapies (excluding eltrombopag). The most commonly used prior therapies were corticosteroids (81%), IVIg (45%), splenectomy (38%), and rituximab (23%). Of the 299 patients enrolled, 70% achieved response in >50% of study assessments and 46% achieved response in >75% of assessments. Among 210 patients treated ≥12 months, 79% achieved response in >50% of assessments and 56% in >75% of assessments. Among 138 patients treated for ≥24 months, 82% achieved response in >50% and 59% in >75% of assessments. Response in >50% and >75% of assessments by the number of prior therapies was similar between the groups (Figure 1). The proportion of patients who achieved a response in >50% of assessments was similar between splenectomized and non-splenectomized patients (65% and 73%, respectively). Conclusion: The majority of patients treated with eltrombopag for ≥12 months achieved a platelet count of ≥50,000/μL in >50% of study assessments. This response was observed even among patients previously treated with 4 or more ITP therapies, suggesting that eltrombopag may be a viable treatment option even for more refractory chronic ITP patients. [Display omitted] Disclosures:Bussel:Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership.

Use of IL15 Stimulated, CD3/19 Depleted Transplants From Haploidentical Donors In Pediatric Malignancies

AbstractAbstract 3548T and B cell depleted haploidentical grafts and a melphalan based intensity reduced regimen result in low toxicity and stable event free survival in patients with leukemias in CR1-3. However, patients with active disease or with second or subsequent transplantation show unacceptable relapse rates. In an ongoing study, 36 pediatric patients with acute leukemias and advanced MDS (median age: 11 years) received melphalan (2×70mg/m2), fludarabine (4×40mg/m2) or clofarabine (4×50mg/m2), thiotepa (10mg/kg) and OKT3 (0.1mg/kg). T and B cells were depleted by antiCD3/antiCD19 coated magnetic microbeads, whereas NK cells remained into the grafts (median number= 120×106/kg).Remission status was: CR1-3=18, NR=18, 18/36 already received previous allogeneic transplantations. Relapse rates at 2 years were 20% (CR patients) and 73% (active disease patients or 2nd trp). Thus, we investigated options to reduce the risk of relapse by increasing antileukemic activity of donor NK cells in the grafts in vitro. Over night incubation with Interleukin 15 increased NK activity most effectively (specific lysis at E:T=20:1 against K562: 28% prior to and 71% after stimulation, n=10). After additional IL2 stimulation a 22 fold increase in thymidine uptake indicated proliferation of NK cells (n=5). Due to the profound depletion, no T cell proliferation was detectable. Based on these results, we started a pilot study with ex vivo IL15 stimulated grafts in 4 patients at very high risk (ALL, 3rd relapse, active disease (n=1); ALL 2nd relapse, remission (n=1); AML 1st relapse, active disease (n=2)). All patients received a backbone of unstimulated cells at day 0 to ensure engraftment. Additionally, parts of the grafts were incubated over night, washed four times and afterwards infused at day +1 (median numbers: CD56+CD3- =9.4×106/kg (range 3.7–24.4); CD34=1.5×106/kg; CD14=34×106/kg, CD3=0.01×106/kg). No acute side effects occurred. All patients engrafted within 12 days. 3 patients had acute GvDH grade 0-I, 1 patient had GvHD grade III. Recovery of NK cells was remarkably fast (526 CD56+/μl at day 14 posttransplant versus 256 CD56+/μl in patients without IL15 stimulation (means)). After additional administration of IL2 in vivo (1×106 Units/m2/day s.c.) high NK activity (specific lysis>90% against K 562, E:T=20:1) was detectable in peripheral blood. Two patients are disease free (day 154 and 674 posttransplant), 2 patients died from relapse (day 56 and 64). Conclusions:ex vivo stimulation with IL15 strongly increases cytotoxic activity of NK cells in T and B cell depleted grafts from haploidentical donors and can counterbalance G-CSF mediated inhibitory effects. Those grafts were infused without any acute side effects and resulted in a fast recovery of functional donor NK cells. Potential interactions with stem cells and stem cell derived NK reconstitution have to be investigated. Further studies have to evaluate if this approach might contribute to reduce relapse rates in high risk patients. Disclosures:No relevant conflicts of interest to declare.

A Restrictive Platelet Transfusion Policy Allowing Long-Term Support of Outpatients With Severe Aplastic Anemia

The threshold for prophylactic platelet transfusions in patients with hypoplastic thrombopenia generally recommended in the standard literature is 20,000 platelets/microL. A more restrictive transfusion policy may be indicated in patients with chronic severe aplastic anemia (SAA) in need of long-term platelet support. We evaluated the feasibility and safety of a policy with low thresholds for prophylactic transfusions (</=5,000 platelets/microL in stable patients; 6,000 to 10,000 platelets/microL in cases with fever and/or hemorrhagic signs) combined with progressive lengthening of transfusion intervals (up to at least 7 days irrespective of the interim course of platelet counts). The study was based on a retrospective analysis of a total of 18,706 patient days with platelet counts </=10,000/microL in patients with chronic SAA treated (for more than 3 months) on an outpatient basis. Altogether, 1,135 platelet transfusions were given, 88% at counts </=10, 000/microL and 57% at counts </=5,000/microL. The mean transfusion interval was 10 days. During the period of observation, three major nonlethal bleeding complications occurred, which could be well controlled. We conclude that the restrictive policy with low transfusion thresholds and prolonged transfusion intervals proved feasible and safe in chronic SAA patients.

A Restrictive Platelet Transfusion Policy Allowing Long-Term Support of Outpatients With Severe Aplastic Anemia

AbstractThe threshold for prophylactic platelet transfusions in patients with hypoplastic thrombopenia generally recommended in the standard literature is 20,000 platelets/μL. A more restrictive transfusion policy may be indicated in patients with chronic severe aplastic anemia (SAA) in need of long-term platelet support. We evaluated the feasibility and safety of a policy with low thresholds for prophylactic transfusions (≤5,000 platelets/μL in stable patients; 6,000 to 10,000 platelets/μL in cases with fever and/or hemorrhagic signs) combined with progressive lengthening of transfusion intervals (up to at least 7 days irrespective of the interim course of platelet counts). The study was based on a retrospective analysis of a total of 18,706 patient days with platelet counts ≤10,000/μL in patients with chronic SAA treated (for more than 3 months) on an outpatient basis. Altogether, 1,135 platelet transfusions were given, 88% at counts ≤10,000/μL and 57% at counts ≤5,000/μL. The mean transfusion interval was 10 days. During the period of observation, three major nonlethal bleeding complications occurred, which could be well controlled. We conclude that the restrictive policy with low transfusion thresholds and prolonged transfusion intervals proved feasible and safe in chronic SAA patients.