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Background: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia mediated by immunoglobulin M autoantibodies that bind to the "I" antigen on erythrocytes. IgM binding results in either agglutination at ≤37°C, activation of the classical complement pathway, or both. Patients with CAD can have transient agglutination-mediated circulatory symptoms triggered by exposure to cold conditions. Separately, patients with CAD can experience complement-mediated symptoms such as anemia, hemolysis, and fatigue, but the effect of the season on these complement-mediated manifestations of CAD and clinical outcomes is not well understood., Methods: Using data from the Optum® de-identified Electronic Health Record dataset, we compared hemoglobin, markers of hemolysis (bilirubin and lactate dehydrogenase [LDH]), and healthcare resource utilization (HRU) between seasons for 594 patients (62% female; 66% aged ≥65 years) with CAD (defined as having CAD-related terms in their clinical notes on ≥3 separate occasions between December 2008 and May 2016). Laboratory parameters and HRU were compared between seasons using multivariate regression models., Results: Estimated median hemoglobin (9.87 g/dL in summer and 9.86 g/dL in winter; P = 0.944) and bilirubin (1.04 mg/dL in summer and 1.09 mg/dL in winter; P = 0.257) were similar in winter versus summer. While LDH was statistically significantly higher in winter compared with summer (P < 0.001), the estimated median value was above normal for both seasons (309 U/L in summer and 367 U/L in winter). HRU measures and transfusion and thromboembolism rates were similar across seasons., Conclusions: Patients with CAD had evidence of persistent chronic hemolysis, HRU, and thromboembolism risk year round., (© 2021 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Background: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway., Methods: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol., Results: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred., Conclusions: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.)., (Copyright © 2021 Massachusetts Medical Society.)

Aims: Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia associated with increased thromboembolism risk and early mortality. Healthcare resource utilization (HRU) in CAD has not been reported. We aimed to compare HRU of patients with CAD with a matched non-CAD cohort in the United States. Materials and methods: Patients with CAD were identified from 2006 to 2016 in the Optum-Humedica database using CAD terms in clinical notes and hematologist review. Patients were required to have Integrated Delivery Network records and ≥6 months' follow-up before and after the first CAD mention date (index date). Patients with CAD were matched to a non-CAD cohort based on demographics. Multivariate analyses assessed inpatient hospitalizations, outpatient visits, emergency room visits, and transfusion use between cohorts 6 months before and 12 months after the index date. Results: Of 814 patients with CAD, 410 met inclusion criteria and were matched to 3,390 patients without CAD. Mean age of patients with CAD was 68.0 years; approximately 62% were female. In the 12 months after the index date, mean inpatient hospitalizations (0.83 vs. 0.25), outpatient visits (17.26 vs. 6.77), emergency room visits (0.55 vs. 0.32), and transfusion days (1.05 vs. 0.05) were higher for patients with CAD than the matched non-CAD cohort (all p  < .0001). Similarly, in the 6 months before the index date, patients with CAD had higher HRU than matched patients without CAD for all measures evaluated. Limitations: Results of this study are based on patient information from the Optum-Humedica database, which is limited to commercially insured patients and may not represent the overall CAD population. Conclusions: CAD places a substantial burden on patients and healthcare systems. In addition, the high HRU for patients with CAD observed in the 6 months before diagnosis indicates that disease awareness and better diagnostic practices may be needed.

Introduction: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources., Aim: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors., Methods: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI., Results: Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported., Conclusions: Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Acquired hemophilia A is a very rare, serious bleeding disorder. We describe a 5-year-old female who developed an acquired factor VIII inhibitor, and while under treatment with steroids, had an intestinal perforation with peritonitis and septic shock, making her a poor candidate for further immunosuppression. She was treated with rituximab with rapid, complete eradication of the inhibitor. She represents the first published case of a pediatric patient with acquired hemophilia A successfully treated with rituximab.

T-cell acute lymphoblastic leukemia (ALL) accounts for 15% of ALL cases in children and has been associated with a worse prognosis. Cytogenetic studies show an abnormal karyotype in 50-60% of the T-cell ALL patients; ABL1 fusions are present in approximately 8% of the cases. Dasatinib, a second-generation tyrosine kinase inhibitor, directly targets the BCR-ABL gene. We describe a pediatric case of T-cell ALL with amplification of the ABL1 gene in which remission was achieved only after the addition of dasatinib to conventional chemotherapy., (Copyright © 2011 Wiley Periodicals, Inc.)

Stromal cell-derived Factor-1alpha (SDF-1alpha) stimulates the migration of bone marrow (BM) cells, similar to vascular endothelial growth factor (VEGF). We previously demonstrated that inhibition of VEGF(165) by small interfering RNA inhibited Ewing's sarcoma tumor growth, tumor vessel formation and recruitment of BM cells to the tumor. To determine the importance of BM cells in tumor vessel development, we investigated the effects of SDF-1alpha on VEGF-inhibited TC/siVEGF(7-1) Ewing's tumor neovasculature formation and growth. The effect of SDF-1alpha on CD34(+) progenitor cell chemotaxis was determined in vivo. Using a BM transplantation model with GFP(+) transgenic mice as BM donors and nude mice as recipients, we evaluated the effect of SDF-1alpha on the recruitment of BM-derived cells to VEGF(165)-inhibited TC/siVEGF(7-1) tumors, as well as its effect on neovasculature development, vessel morphology and tumor growth. SDF-1alpha stimulated the migration of CD34(+) progenitor cells to Matrigel plugs in vivo and promoted the retainment of BM-derived pericytes in close association with perfused, functional tumor vessels. Intratumor inoculation of Ad-SDF-1alpha into TC/siVEGF(7-1) tumors resulted in increased SDF-1 and PDGF-BB expression, augmented tumor growth, an increase in the number of large, lumen-bearing vascular structures, and enhanced vessel pericyte coverage, with no change in VEGF(165). SDF-1alpha stimulates BM cell chemotaxis and the association of these cells with functional tumor vessels. Furthermore, SDF-1alpha enhances tumor neovascularization and growth with no alteration in VEGF(165). Our work suggests that SDF-1-mediated vasculogenesis may represent an alternate pathway that could potentially be utilized by tumors to sustain growth and neovasculature expansion after anti-VEGF therapy., ((c) 2008 Wiley-Liss, Inc.)

Background: Ewing sarcoma (ES) is a highly vascular malignancy. It has been demonstrated that both angiogenesis and vasculogenesis contribute to the growth of ES tumors. Granulocyte-colony-stimulating factor (G-CSF), a cytokine known to stimulate bone marrow (BM) stem cell production and angiogenesis, is routinely administered to ES patients after chemotherapy. Whether ES cells and patient tumor samples express G-CSF and its receptor (G-CSFR) and whether treatment with this factor enhances tumor growth was examined., Methods: Human ES cell lines were analyzed for expression of G-CSF and G-CSFR in vitro and in vivo. Sixty-eight paraffin-embedded and 15 frozen tumor specimens from patients with ES were also evaluated for the presence of G-CSF and G-CSFR. The in vivo effect of G-CSF on angiogenesis and BM cell migration was determined. Using a TC/7-1 human ES mouse model, the effect of G-CSF administration on ES tumors was investigated., Results: G-CSF and G-CSFR protein and RNA expression was identified in all ES cell lines and patient samples analyzed. In addition, G-CSF was found to stimulate angiogenesis and BM cell migration in vivo. Tumor growth was found to be significantly increased in mice treated with G-CSF. The average tumor volume for the group treated with G-CSF was 1218 mm(3) compared with 577 mm(3) for the control group (P = .006)., Conclusions: The findings that ES cells and patient tumors expressed both G-CSF and its receptor in vitro and in vivo and that the administration of G-CSF promoted tumor growth in vivo suggest that the potential consequences of G-CSF administration should be investigated further.

Background: Increasing evidence suggests that lymphocyte recovery plays a major part in tumor control. Facilitating immune reconstitution might be a novel direction of cancer therapy. The purpose of this study was to determine if early lymphocyte recovery is an independent prognostic indicator for high-risk Ewing sarcoma outcome., Results: Data of 24 Ewing sarcoma patients were analyzed (age, 3 to 50 y; median, 16.5; male to female, 16:8). The 5-year overall survival (OS) of the total population was 47.9% [10.6 standard error (SE)]. Patients were separated into 2 groups: prolonged lymphopenia versus early lymphocyte recovery, using a threshold absolute lymphocyte count (ALC) of > or =500 cells/microL on day 15. The majority (67%; n=16) of the patients had an ALC > or =500 cells/microL, and of these 10/16 are alive with a 5-year OS of 58.7% (13.2 SE). In contrast, 33% (n=8) of patients had an ALC <500 cells/microL on day 15 and only 2/8 are alive with a 5-year OS of 25% (15.3 SE). This difference was significant (P=0.007 using the log rank test). When comparing patients with metastatic disease, patients with an ALC-15 < 500 cells/microL had a median survival of 13 months, whereas patients with an ALC-15 > or =500 cells/microL had a median survival of 29.5 months. All patients had an ALC before chemotherapy of >1000 cells/microL. The difference was significant (P value=0.001 using the log rank test). Univariate analysis of platelet counts, age, sex, and absolute neutrophil count showed no statistically significant association with OS., Conclusions: The data demonstrate that an ALC > or =500 cells/microL on day 15 of the first course of chemotherapy is an independent prognostic factor associated with superior OS in high-risk Ewing sarcoma.