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  • American Society of Hematology  (6)
  • 1
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2068-2068
    Abstract: Background: Venous thromboembolism (VTE) is a leading cause of mortality and morbidity in cancer patients. The current standard of care is to treat cancer-associated VTE with Low Molecular Weight Heparin (LMWH), which is more effective than vitamin K antagonists, such as warfarin. However, LMWH injections are painful, expensive, and a burden in healthcare resource utilization. Further, many of these patients are referred to an emergency room for education on self-injection techniques, an added health care cost. The Hematology/Anticoagulation Management Service at Memorial Sloan Kettering Cancer Center is developing rivaroxaban as a safe and effective alternative to LMWH for cancer-associated VTE. In this report, we demonstrate a significant reduction in the referral of patients to the MSKCC Urgent Care Center (UCC), our in-house emergency room, to initiate anticoagulation, resulting in a significant reduction in resource utilization. Methods: As a Quality Assessment Initiative, we track all patients with cancer-associated VTE at MSKCC receiving rivaroxaban since January 2014, and have a similar database of cancer-associated VTE from June through December 2013, treated with enoxaparin. For this utilization of resources study we evaluated where anticoagulation was initiated for treatment of a new pulmonary embolism or lower extremity deep vein thrombosis, specifying either a single outpatient visit, two outpatient visits on the same day, a telephone call, or a visit to the UCC. When patients had a second outpatient visit on the same day as diagnosis of the VTE, the second visit was for patient education on injection technique and insurance authorization. The site of anticoagulation initiation was by the judgment and discretion of the physician managing the patient's cancer. Patients who developed a VTE during a hospital stay or were managed at an outside emergency room were not included in this analysis, as our program has no influence in those settings. Statistical analysis was with the Chi-square test. Comparison of safety and efficacy of rivaroxaban and LMWH is the subject of a separate study. Results: As anticipated, changing from a parenteral anticoagulant to rivaroxaban (an oral agent) resulted in significant changes in practice (Table). Significantly fewer rivaroxaban patients required visits to the UCC than with enoxaparin (p=0.009). Fewer patients required a second outpatient, as well. When viewed in the aggregate of UCC or second outpatient visit, 82% of patients treated with enoxaparin required additional medical resources for initiation of anticoagulation, beyond a single outpatient visit, which decreased to 59% with rivaroxaban (p 〈 0.001). Of note, 11% of rivaroxaban patients were initiated with a phone call only, typically after a recent medical visit and outpatient imaging. The reduction in UCC utilization was confined to weekday hours when the outpatient clinics are open. In all cases with enoxaparin and rivaroxaban, initiation of anticoagulation was in the UCC on weekends and between the hours of 6 PM and 8 AM on weekdays. Discussion: In addition to the burden of morbidity and mortality, management of cancer-associated VTE with LMWH is painful to the patient and expensive to the healthcare system. In our QAI we have been developing rivaroxaban as an oral alternative. Safety and efficacy are being analyzed separately. In addition to the markedly lower cost of rivaroxaban compared with enoxaparin, and patient quality of life preference, we also demonstrate a significant reduction in the healthcare resources associated with initiation of anticoagulation. Cancer patients tend to be higher risk and more complex than general medical patients and it remains appropriate for some to be evaluated in an emergency room for diagnosis and management. Despite this, we observed a reduction in emergency room visits for patients in this setting. One limitation to our findings is that our study was within a single institution, with a devoted Hematology/Anticoagulation Management Service. It would be appropriate to perform a similar analysis in other institutions, including non-cancer patients, to confirm these findings. Table 1. Sites of Initiation of Anticoagulation Enoxaparin Rivaroxaban UCC/Emergency Room (p=0.009) 127 (71%) 101 (57%) Two Outpatient Visits On The Same Day 20 (11%) 4 (2%) Outpatient, Single Visit 32 (18%) 53 (30%) Telephone 0 19 (11%) Total 179 177 Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 908-908
    Abstract: We and others have demonstrated the dysregulation of interleukin-6 (IL-6) early after experimental bone marrow transplantation (BMT) and protection from acute GVHD following the administration of an anti-IL-6 receptor (IL-6R) antibody. In these models, where GVHD prophylaxis is not administered, systemic IL-6, IFNγ and TNF levels peak 7 days after BMT before returning to baseline by the third week. We have determined cytokine dysregulation in a large clinical cohort of allogeneic stem cell transplant (SCT) recipients conditioned with myeloablative Cy/TBI (12 Gy, n = 25) or reduced intensity Flu/Mel (120mg/m2, n = 25) receiving standard GVHD prophylaxis with cyclosporine and MTX (d 1 at 15mg/m2, d 3, 6, 11 at 10mg/m2). IL-6 levels rose from pre-transplant levels of 6.4 ± 0.7 pg/ml to a peak of 58.8 ± 8.8 pg/ml at day 7 (P 〈 0.0001) with a fall at day 14 to 39.0 ± 12.5 pg/ml (P 〈 0.0001) and return to baseline by day 30 (6.2 ± 0.9 pg/ml), consistent with the preclinical data. IL-6 dysregulation was not different in recipients of matched sibling or unrelated donor grafts but was proportional to the intensity of conditioning (day 7 levels after Cy/TBI vs. Flu/Mel: 83.3 ± 12.2 pg/ml vs. 31.0 ± 10.1 pg/ml, P 〈 0.0001). In contrast to preclinical mouse data, no systemic increases were seen in any other cytokine including IFNγ, TNF, IL-17, IL-4, IL-13 and IL-10. We thus initiated a phase I/II study whereby a human neutralizing monoclonal antibody (mAb) against the IL-6R was administered on day -1 to patients receiving Cy/TBI or Flu/Mel conditioned allogeneic SCT from HLA (10/10)–matched sibling or unrelated donors with standard cyclosporine/MTX GVHD prophylaxis. There was no T cell depletion. The primary endpoint was the incidence of grade II-IV acute GVHD and the study has achieved its planned enrollment (n = 48). There was no toxicity attributable to IL-6R antibody administration. Pharmacokinetic analysis confirmed high levels of IL-6R Ab at day 3 (mean 64.7 ug/ml) which persisted in all patients 3 weeks after BMT (mean = 9.8 ug/ml) and remained above the level of detection (0.1ug/ml) in 75% of patients at day 30 (mean = 1.9 ug/ml). IL-6 levels were dramatically increased (relative to baseline) in patients receiving antibody due to the inability to excrete the inactive IL-6 – soluble IL-6R antibody complex (peak IL-6 levels at day 7 = 773.6 ± 207.9 pg/ml; P 〈 0.0001) and remained increased at day 30 (60.9 ± 24.4 pg/ml; P 〈 0.0001), returning to baseline by day 60 (9.5 ± 1.7 pg/ml), consistent with antibody clearance. Soluble IL-6R levels also rose over the first month of SCT and levels at day 30 correlated with residual antibody levels (r2 = 0.72, P = 0.02). Neutrophil ( 〉 0.5x109/L) and platelet ( 〉 20x109/L) recovery was normal relative to a matched untreated control cohort at a median of 16 and 18 days respectively. Donor chimerism and immune reconstitution (conventional T, regulatory T and B cells) was equivalent at day 30 in recipients of IL-6R inhibition versus the control cohort. In contrast, changes in innate immunity were seen in patients receiving IL-6R inhibition with increases in plasmacytoid DC (P = 0.002), CD1c+ conventional DC (P = 0.04) NKT cells (P =0.03) and marked reductions in inflammatory (CD14+CD16+) monocytes (P 〈 0.0001). Transcriptional profiling of T cell subsets is underway. With 36 patients evaluable (beyond day 100, median follow up of 297 days), the incidence of grade II-IV GVHD is 11.1% in recipients of IL-6R inhibition versus 39.6% in the matched (n = 53) control cohort (P = 0.004). The incidence of grade III/IV acute GVHD is 5.6% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.045). Protection from grade II-IV acute GVHD was noted in patients receiving both Cy/TBI (7.7% vs. 40.7%, P=0.045) and Flu/Mel conditioning (13.0% vs. 38.5%, P = 0.044). Rates of CMV reactivation were very low in the IL-6R neutralized patients (16.7% vs. 35.8% in controls, P = 0.04), likely due to the prevention of acute GVHD and its’ consequent therapy. At one year, the relapse incidence and disease free survival in patients receiving IL-6R inhibition versus the control cohort is 21.2% vs. 30.0% (P = 0.28) and 73.1% vs. 62.4% (P = 0.14) respectively. IL-6 is thus the principal inflammatory cytokine dysregulated after clinical allogeneic SCT and its inhibition appears to offer profound protection from acute GVHD despite robust immune reconstitution, without compromise of the GVL effect. Disclosures: Off Label Use: The use of Tocilizumab to prevent GVHD is experimental and an off label use.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 135, No. 24 ( 2020-06-11), p. 2171-2181
    Abstract: Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics, by coactivating serum response factor. Recently, the first human with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with 2 siblings with a homozygous frameshift mutation in MKL1. The index case died as an infant from progressive and severe pneumonia caused by Pseudomonas aeruginosa and poor wound healing. The younger sibling was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response by MKL1-deficient neutrophils. In addition to the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed actin and several actin-related proteins to be downregulated, confirming a role for MKL1 as a transcriptional coregulator. Degranulation was enhanced upon suboptimal neutrophil activation, whereas production of reactive oxygen species was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration under flow conditions. No apparent defect in phagocytosis or bacterial killing was found. Also, monocyte-derived macrophages showed intact phagocytosis, and lymphocyte counts and proliferative capacity were normal. Nonhematopoietic primary fibroblasts demonstrated defective differentiation into myofibroblasts but normal migration and F-actin content, most likely as a result of compensatory mechanisms of MKL2, which is not expressed in neutrophils. Our findings extend current insight into the severe immune dysfunction in MKL1 deficiency, with cytoskeletal dysfunction and defective extravasation of neutrophils as the most prominent features.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Blood Advances, American Society of Hematology, Vol. 3, No. 20 ( 2019-10-22), p. 3013-3019
    Abstract: Peg-IFNα is tolerated and induces disease response in patients who relapse after allogeneic SCT. Increased pretreatment MAIT and pDC proportions were associated with better progression-free and overall survival after peg-IFNα treatment.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 2876449-3
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  • 5
    Online Resource
    Online Resource
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 2619-2619
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2619-2619
    Abstract: Venous thromboembolism (VTE) is a leading cause of mortality and morbidity in cancer patients, and management represents a major cost to the healthcare system. We have previously presented in a cohort of 200 patients with cancer-associated thrombosis, rivaroxaban provides an alternative to low molecular weight heparin (LMWH), with 4.4% recurrent VTE and 2.2% major bleeding at 6 months (Mantha et al, ASH Abstract, 2015). Other recent publications have provided similar support for use of rivaroxaban in treatment of cancer-associated thrombosis (Bott-Kitslaar et al, Am J Med. 2016, Prins et al, Lancet Haem, 2014). In our early experience with rivaroxaban, fewer patients were sent to the Emergency Room (ER) for initiation of rivaroxaban than LMWH. We now characterize the site and cost of initiation of anticoagulation for the full 200 rivaroxaban patient cohort and a similar cohort of patients treated with LMWH demonstrating significant changes in practice and cost savings. In an IRB approved initiative we track all patients with cancer-associated thrombosis at MSKCC. We characterized the site of initiation of anticoagulation of the first 200 cancer patients with a pulmonary embolism (PE) or lower extremity deep vein thrombosis DVT since January 2014, treated with rivaroxaban. A similar cohort from June through December 2013 was treated with enoxaparin. We excluded patients whose VTE developed as an inpatient. Anticoagulation starts were classified as an emergency room (ER) visit or a second return outpatient visit on the same day for patient education and insurance authorization, a single outpatient visit, or telephone communication. Respective billing codes were then used as part of an economic evaluation to estimate the cost of the additional healthcare resources utilized, and therefore the costs saved by reduction in ER visits or second medical office visits. In the first 6 months of rivaroxaban availability, there was no decrease in ER utilization, compared with LMWH use. After 6 months of rivaroxaban availability, there was a significant decrease in ER visits for VTE management (p=0.008), which resulted in a decrease from baseline of 71% to 34% after one year (p=0.0001). Also of note, after one year of rivaroxaban availability, 18% of newly diagnosed VTE were managed by a simple telephone call to the patient or family member, typically after a recent outpatient visit. Only 2 patients who were started on rivaroxaban had required an additional outpatient visit to our Hematology clinic for evaluation. Based on 2016 Medicare billing codes, we calculated the cost for the additional resources utilized, beyond a single outpatient visit. During the first 6 months of rivaroxaban use, the cost of additional resources per 100 outpatient VTE patients ($47,067) was not significantly different than during the LMWH era ($43,144). However, as practice patterns evolved, ER utilization declined and more patients were managed without additional healthcare resources, resulting in an approximately 50% reduction in costs, for a savings of approximately $20,000 per 100 anticoagulation initiations. Management of cancer-associated thrombosis with LMWH is painful to the patient and expensive to the healthcare system. Patient quality of life is improved by treatment with rivaroxaban versus LMWH, with no evidence of loss of safety or efficacy. In this analysis, we expand on our prior observation that demonstrated a marked reduction in ER visits or hematology consults for the purpose of anticoagulation initiation and also show a substantial cost savings, of approximately $20,000 per 100 VTE patients. These changes in practice developed over an 18-month period, presumably reflecting a learning curve as healthcare providers became more familiar and comfortable with rivaroxaban. Of course, some patients with a new cancer-associated thrombosis should be sent to an ER for evaluation, based on their hemodynamic state or co-morbidities. However, our findings suggest that a majority of patients with cancer-associated thrombosis do not require ER visits, improving patient quality of life and sparing healthcare resources. Disclosures Soff: Janssen Pharmaceuticals: Other: Summer Student Internship. Mantha:Janssen Scientific Affairs, LLC: Research Funding. Soff:Janssen Scientific Affairs, LLC: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 884-884
    Abstract: Background: Sapacitabine, a 2′-deoxycytidine nucleoside analogue with unique ability to cause irreparable single-strand DNA breaks and as a result induce G2 cell cycle arrest, is undergoing clinical evaluation for the treatment of cancer. The recommended Phase II dose (RD) in patients with advanced solid tumors was 75 mg twice daily (b.i.d.) x 7 days orally every 21 days. The major DLT was myelosuppression. Here, we present the initial results of a Phase I study of sapacitabine in patients with advanced leukemias or MDS. The primary objective was to define the MTDs of two dosing schedules, b.i.d. x 7 days orally every 21 days or b.i.d. x 3 days per week for 2 weeks every 21 days. The secondary objectives were to characterize the PK/PD effects of sapacitabine and its major metabolite CNDAC. Methods: Eligible patients had relapsed/refractory leukemias or MDS, or untreated disease if not willing to proceed with conventional systemic chemotherapy, adequate organ functions and performance status of 0–2. At least 3 patients were enrolled at each dose level. The MTD was the highest dose level at which ≤2/6 patients experienced a DLT during the first treatment cycle. Results: Forty-seven patients received sapacitabine, including 35 treated with the 7-day schedule and 12 treated with the 3-day per week schedule. Median age was 65 (range: 36 – 91). The majority of patients had AML (n=36) or MDS (n=4). Median number of prior chemotherapies was 2 (range: 0 – 6). Cytogenetic abnormalities were present in 27; 30 had relapsed disease or were refractory to cytarabine or high-dose cytarabine regimens. MTD was reached at 375 mg b.i.d. on the 7-day schedule, and 475 mg b.i.d. on the 3-day per week x 2 schedule. DLTs consist of abdominal pain/small bowel obstruction (n=1), neutropenic colitis (n=2) and diarrhea (n=3). One patient died from complications of neutropenic colitis. Common non-hematologic adverse events (all grades, regardless of causality) included fatigue, nausea, vomiting, diarrhea, anorexia, cough, dyspnea, and abdominal pain, most of which were mild to moderate in intensity. PK and PD data are being analyzed. To date, 11 patients of 42 evaluable (9 AML, 2 MDS) had a reduction in bone marrow blast counts to ≤ 5% including 2 CRs, 2CRs with incomplete recovery of platelets, 1 CR of extramedullary disease, and 1 PR of extramedullary disease. 5/11 had relapse-resistance disease on prior cytarabine. Conclusion: The MTD of sapacitabine is 375 mg b.i.d. by the 7-day schedule and 475 mg b.i.d. by the 3-day per week schedule. The predominant DLT is gastrointestinal toxicity. Sapacitabine is well tolerated and has promising antileukemic activity in patients with relapsed or refractory AML and MDS.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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