Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis

Background Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. Objective To compare the effects of factor replacement therapies in patients with hemophilia. Methods We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). Results Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. Conclusions Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

Thrombosis and Bleeding After Implementation of an Intermediate-Dose Prophylactic Anticoagulation Protocol in ICU Patients With COVID-19: A Multicenter Screening Study

Thrombosis and bleeding after implementation of an intermediate-dose prophylactic anticoagulation protocol in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19): a multicenter screening study Background: Venous thromboembolism (VTE) is common among critically ill patients with COVID-19. Information regarding VTE prevalence and bleeding complications after implementation of intermediate-dose prophylactic anticoagulation in such patients is, however, limited. Methods: We performed a prospective, observational study in 6 ICUs in 2 university-affiliated teaching hospitals in Sweden. After implementation of an intermediate-dose prophylactic anticoagulation protocol, we performed ultrasound screening for proximal lower-extremity deep vein thrombosis (DVT) and collected routine computed tomography pulmonary angiography exam results. Results: A total of 100 COVID-19 patients were included from June 21, 2020, through February 18, 2021. During a median follow-up of 120 (IQR, 89-134) days, we found VTE in 37 patients with the majority (78.4%) being diagnosed after ICU arrival. Overall, 20 patients had proximal lower-extremity DVT with 95% being detected on ultrasound screening; 22 patients had pulmonary vascular thrombosis; and 4 patients had venous thrombosis at other sites. A total of 6 patients had both proximal lower-extremity DVT and pulmonary vascular thrombosis. On univariate logistic regression analysis of 14 baseline characteristics, only pre-existing heart failure was associated with VTE (OR 4.67, 95% CI 1.13-19.34). Major and non-major bleeding occurred in 10 and 18 patients, respectively. Conclusions: In our cohort of ICU patients with COVID-19, we observed a high prevalence of VTE and bleeding complications after implementation of intermediate-dose anticoagulation. In approximately half of patients, VTE was identified on screening ultrasound.

Intermediate-dose cytarabine is an effective therapy for adults with non-Langerhans cell histiocytosis

Background Non-Langerhans cell histiocytosis, including Erdheim–Chester disease (ECD), Rosai–Dorfman disease (RDD), indeterminate cell histiocytosis (ICH), and unclassified histiocytosis, is a rare disorder lacking a standard treatment strategy. We report our experience using intermediate-dose cytarabine as the first or subsequent therapy in non-Langerhans cell histiocytosis. Results Eight ECD patients, 5 RDD patients, 1 ICH patient and 1 unclassified histiocytosis patient were enrolled. Intermediate-dose cytarabine therapy was administered as 0.5-1.0 mg/m2 of intravenous cytarabine every 12 hours for 3 days every 5 weeks. The median age at cytarabine initiation was 45 years (range, 18–70 years). The median number of cycles of cytarabine administered was 6 (range, 2–6). The overall response rate (ORR) was 86.7% in the overall cohort, including 6.7% with complete response and 80.0% with partial response. All patients (n=10) with CNS involvement achieved disease improvements. One patient experienced disease recurrence 19 months after cytarabine therapy. The median follow-up duration for the entire cohort was 12 months (range, 4-61 months). The 1-year progression-free survival (PFS) and overall survival (OS) rates were 85.6% and 92.3%, respectively. The most common toxicity was haematological adverse events, including grade 4 neutropenia and grade 3-4 thrombocytopenia. No treatment-related deaths occurred. Conclusions Intermediate-dose cytarabine is a cost-effective treatment option for non-Langerhans cell histiocytosis patients, especially for those with CNS involvement.

Standard- versus intermediate-dose enoxaparin for anti-factor Xa guided thromboprophylaxis in critically ill patients with COVID-19

The prevalence of venous thromboembolism (VTE) is high in critically ill patients with COVID-19. Dosing of Low Molecular Weight Heparin (LMWH) for thromboprophylaxis in patients with severe COVID-19 is subject to ongoing debate.In this brief report, we describe our study where we retrospectively examined the efficacy of standard- versus intermediate-dosing of enoxaparin in attaining and maintaining accepted prophylactic levels of anti-Factor Xa (anti-FXa) in critically ill patients with COVID-19.We collected data for all patients with confirmed COVID-19 who were treated with enoxaparin for thromboprophylaxis in a single Intensive Care Unit (ICU) in the United Kingdom between 31st March and 16th November 2020. Standard-dose of enoxaparin was 40 mg subcutaneously once daily for patients with normal renal function and body weight between 50 and 100 kg; the intermediate-dose was 40 mg subcutaneously twice daily. Anti-FXa peak concentrations between 0.2-0.4 IU/ml were considered appropriate for thromboprophylaxis.Age, sex, weight, Body Mass Index, APACHE II score, ICU length of stay, initial P/F ratio and creatinine were not statistically significantly different between standard- and intermediate-dose thromboprophylaxis cohorts. In the standard-dose group, the median initial anti-FXa level was 0.13 (interquartile range 0.06-0.18) compared to 0.26 (0.21-0.33) in the intermediate-dose cohort (p < 0.001). On repeated measurement, in the standard dose cohort, 44 of 95 (46%) anti-FXa levels were < 0.2 IU/ml compared with 24 of 132 (18%) levels in the intermediate-dose cohort even after dose-adjustment. There was one radiologically confirmed pulmonary embolism (PE) on computed tomography pulmonary angiogram during hospital admission in each cohort.Our study supports starting intermediate-dose thromboprophylaxis for critically ill patients with COVID-19 to achieve anti-FXa levels in the accepted thromboprophylactic range although further study is required to investigate whether anti-FXa guided thromboprophylaxis is safe and effective in reducing the incidence of VTEs in critically ill patients with COVID-19.

Results of Hematopoietic Stem Cells Transplantation with Tcrαβ and CD19-Depletion from Matched Related Donors and Infusions of CD45RA Depleted Donor Lymphocytes in Pediatric Severe Aplastic Anemia

Introduction HSCT from matched family donors results in most favorable outcomes among children with severe aplastic anemia (SAA). Despite overall success, morbidity, associated with acute and chronic graft-versus-host disease (GVHD) is not completely prevented with current standard of pharmacologic prophylaxis. Depletion of ab T cells from the graft prevents GVHD, and improves outcome of hematopoietic stem cell transplantation from haploidentical donors, while infusions of donor memory lymphocytes (mDLI) (CD45RA-depleted) are able to transfer pathogen-specific immunity without the risk of GVHD. We evaluated the outcomes of ab T cell depletion and add-back of intermediate-dose mDLI among the pediatric SAA recipients of matched related grafts. Materials and methods A total of 16 children with SAA (8 female, 8 male, median age 10,9 y) underwent allogenic HSCT from matched family donors (MFD) between february 2015 and may 2021. For 15 (94%) pts it was the first allo HSCT, for 1 pts it was the second HSCT. TCR αβ+/CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells was 7,1 x10 6/kg (range 2,6-13), αβ T cells - 28x10 3/kg (range 5,6-184). All pts received an additional injection of memory T-cell (CD45RA-depleted) on day 0 at 1 million T cells per kg. All patients received cyclophosphamide at 100 mg/kg, fludarabine at 100 mg/m 2, rituximab 100mg/m 2 and serotherapy with either rabbit ATG at 5 mg/kg (n-2) or horse ATG at 100 mg/kg (n-14). Post-transplant GVHD prophylaxis included calcineurin (CNI)-based regimen and abatacept 10mg/kg on days -1, +7, +14 and +28. All pts received a graft from a 10/10 HLA-matched sibling. Median time of follow-up for survivors was 1,1 years (range: 0.14 - 6.38). Results Primary engraftment was achieved in all evaluable patients (100%) with full donor chimerism, and the median time to neutrophil and platelet recovery was 11 (10-20) and 14 (11-20) days, respectively. One patient had aGVHD grade I, there were no incidence of grade II-IV aGVHD and TRM. Event-free and overall survival were 100%. CMV viremia was detected among two patients after a median of 40 (35-73) days after HSCT. No cases of ADV and Epstein-Barr virus (EBV) viremia and EBV disease were recorded. The median recovery of T cells on day+60 was 0,26 (0,04-0,9). Conclusion ab T cell-depleted transplantation with intermediate dose memory T cell add-back definitively prevents GVHD and provides a platform for safe HSCT from matched family donors in patients with SAA. Disclosures Maschan: Miltenyi Biotec: Speakers Bureau.

Cyclophosphamide, Etoposide, and Intermediate-Dose of Carboplatin; An Efficient Preparative Regimen for Autologous Transplantation for Patients with Lymphoma, a Good Alternative to Those Based on Carmustine. Experience with 108 Patients

Autologous Stem Cell Transplantation (ASCT); is a universal accepted therapy for rescuing relapsed Hodgkin (HL) and non-Hodgkin (NHL) lymphoma patients and for consolidation of mantle cell lymphoma (MCL). The most used preparative regimens in this setting are BEAM and CBV. both of them include carmustine, a medication with serious shortage and cost problems, therefore , is very important to find alternative regimens. During the nineties the combination of high dose of carboplatin plus cyclophosphamide and etoposide (CEC) was explored, however, it was abandoned due to high toxicity. We present our experience with 108 patients using this regimen but with intermediate dose of carboplatin (Inter CEC) Methods: We did a retrospective descriptive longitudinal observational study. All consecutive patients who met the inclusion criteria; age above 18 years, diagnosis of HL, NHL, M CL, and transplanted with Inter CEC were included. The preparative regimen consisted of carboplatin 900 mg/m2, etoposide 900 mg/m2, and cyclophosphamide 6.000 mg/m2, split in five days (fig 1). All patients received peripheral blood stem cells, and from d + 5 until neutrophil recovery, daily filgrastim. Every patient signed informed consent and the study was approved for institutional ethical committee. Results: From Oct 2013 to May 2020, 108 patients were included; median age was 45 years (18-70), 43.5% were female, 20% were older than 60 years and 79.6% had advanced disease at diagnosis. Thirty-five (32.4%) had HL, 35 (32.4 %) NHL (28 diffuse large B cell, 7 follicular), 29 (26,9%) had MCL, and 9 (8.3%) had other lymphomas. 34% of HL patients and 48% of cases were transplanted in CR1 after being refractory to first line therapy, while 44% and 14% of HL and NHL respectively had active disease at the time of transplantation. Regarding MCL cases; 21 (72,4%) had MIPI above 3 points and 96.5% were transplanted in first remission. All of the evaluable patients at day + 30 had hematopoietic recovery, median time to achieve 500 neutrophil /ul or more was 12.3 days (10-30) and for self-sustained platelet counts, 20.000/ul or more, was 15.3 (10-34). After a median follow up for surviving patients of 42,2 months the overall survival (OS) (Kaplan-Meier) at 48 months for the entire group was 74% (CI 63-82) and the event free survival (EFS) was 57% (CI 43-69). When the OS and EFS were discriminated for diseases, it was; for HL 76% (CI 56-88) and 43% (CI 17-66), for NHL 78% (CI: 57-90) and 68% (CI 42-83), and for MCL 69% (48-83) and 57% (CI 32-76) respectively (Fig 2). Eleven out of 18 patients (61%) transplanted with active disease achieved complete remission and 14 out of the entire group relapsed during the first years of transplant The transplant related mortality (TRM) at 1 year was 2.8%, the relapse associated deaths were 13% and, in 5 patients, who died after one year of transplant, the cause was not found. The main toxicity was mucositis; 46%, (grade II-IV: 22%), 30 patients (28%) had confirmed infections; bacteremia 17 cases, pneumonia 5, and others infections 6. Renal toxicity occurred in 24 cases (22%), grade 1; 15.8%, grade 2; 4.6% and grade 3; 1.8% Discussion Comparing results among trials is always difficult; however, despite that, in our series 58% of the cases were transplanted with active disease, our outcomes compare favorably with the results informed after the use of BEAM or CBV presented by CIBMTR in the largest trial published so far (table 1). The use of intermediate dose of carboplatin plus etoposide and cyclophosphamide produces a very good control of the lymphoma activity with acceptable toxicity, and achieves good OS and EFS. Other advantage of this regimen is that is carmustine free. The next step in our study is to do a matched paired analysis with patients transplanted with BEAM or CBV Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

RADT-08. A VOLUMETRIC ANALYSIS OF STEREOTACTIC RADIOSURGERY LOW DOSE VOLUMES IN PREVENTING FUTURE BRAIN METASTASES

PURPOSE/OBJECTIVE(S) Stereotactic radiosurgery (SRS), compared to whole brain radiotherapy is limited in its ability to prevent development of brain metastases in untreated areas. The purpose of this study is to assess whether low-dose volumes delivered to uninvolved regions of the brain during SRS can reduce the risk of developing brain metastases in those regions. MATERIALS AND METHODS Data were collected for 69 patients with brain metastases who were treated with SRS at least two occasions. The regions of uninvolved brain receiving a high, intermediate, and low dose of incidental radiotherapy were defined as the volume receiving at least 10, 5, and 2.5 Gy if the prescribed dose was &lt; 25 Gy (1-3 fraction plans) or the volume receiving at least 15, 7.5, and 5 Gy if the prescribed dose was ≥ 25 Gy (5 fraction plans). A second round metastasis was considered to occur within a given dose level if 20% or more of the tumor was found within that dose level. Probabilities were calculated based on the volume of each dose level as a percentage of total brain volume and were used to estimate the expected number of cases with at least one metastasis occurring in each dose level. RESULTS The average number of metastases treated in both rounds of SRS was two. The expected and observed number of cases with at least one second round metastasis were 0 and 2 for the high dose level (p=0.151), 7 and 3 for the intermediate dose level (p=0.018), and 17 and 11 for the low dose level (p=0.094). CONCLUSION We observed fewer than expected new metastases within prior SRS low dose levels based on volumetric probabilities, though this difference was only significant for the intermediate dose level. This suggests that low dose volumes from SRS may provide benefit in preventing future regional metastases.

Intermediate- vs. Standard-Dose Prophylactic Anticoagulation in Patients With COVID-19 Admitted in Medical Ward: A Propensity Score-Matched Cohort Study

Background: Microthrombosis and large-vessel thrombosis are the main triggers of COVID-19 worsening. The optimal anticoagulant regimen in COVID-19 patients hospitalized in medical wards remains unknown.Objectives: To evaluate the effects of intermediate-dose vs. standard-dose prophylactic anticoagulation (AC) among patients with COVID-19 hospitalized in medical wards.Methods and results: We used a large French multicentric retrospective study enrolling 2,878 COVID-19 patients hospitalized in medical wards. After exclusion of patients who had an AC treatment before hospitalization, we generated a propensity-score-matched cohort of patients who were treated with intermediate-dose or standard-dose prophylactic AC between February 26 and April 20, 2020 (intermediate-dose, n = 261; standard-dose prophylactic anticoagulation, n = 763). The primary outcome of the study was in-hospital mortality; this occurred in 23 of 261 (8.8%) patients in the intermediate-dose group and 74 of 783 (9.4%) patients in the standard-dose prophylactic AC group (p = 0.85); while time to death was also the same in both the treatment groups (11.5 and 11.6 days, respectively, p = 0.17). We did not observe any difference regarding venous and arterial thrombotic events between the intermediate dose and standard dose, respectively (venous thrombotic events: 2.3 vs. 2.4%, p=0.99; arterial thrombotic events: 2.7 vs. 1.2%, p = 0.25). The 30-day Kaplan–Meier curves for in-hospital mortality demonstrate no statistically significant difference in in-hospital mortality (HR: 0.99 (0.63–1.60); p = 0.99). Moreover, we found that no particular subgroup was associated with a significant reduction in in-hospital mortality.Conclusion: Among COVID-19 patients hospitalized in medical wards, intermediate-dose prophylactic AC compared with standard-dose prophylactic AC did not result in a significant difference in in-hospital mortality.