Search

We aim to identify predictors of therapy-related myeloid neoplasms (t-MN) in patients with breast cancer (BC) and cytopenias to determine the timing of bone marrow biopsy (BMBx). Patients with BC and cytopenias who were referred for BMBx between 2002-2018 were identified using the Memorial Sloan Kettering Cancer Center institutional database. Characteristics associated with the risk of t-MN were evaluated by multivariable logistic regression and included in a predictive model. The average area under the receiver operating characteristic curve (AUC) was estimated by 5-fold cross-validation. Of the 206 BC patients who underwent BMBx included in our study, 107 had t-MN. By multivariable analysis, white blood cell count 4-11 K/mcL, absolute neutrophil count (ANC) ≥1.5 K/mcL, hemoglobin ≥12.2 g/dL, red cell distribution width 11.5-14.5%, the presence of bone metastasis and a time from BC diagnosis to BMBx

Chemotherapy-induced thrombocytopenia (CIT) is common during treatment with antineoplastic therapies and may adversely impact chemotherapy dose intensity. There is no approved therapy for CIT. In our recent phase II randomized study, romiplostim led to correction of platelet counts in 85% of treated patients and allowed resumption of chemotherapy, with low rates of recurrent CIT in the first two cycles or 8 weeks of chemotherapy. However, there is a lack of long-term data on the efficacy and safety of romiplostim in CIT.To analyze efficacy and safety of romiplostim in the patients in the phase 2 study, who received romiplostim for ≥1 year.Twenty-one patients remained on romiplostim for ≥1 year. We analyzed the effect of romiplostim on platelet counts, absolute neutrophil counts, and hemoglobin, as well as impact on ongoing chemotherapy. We also tracked venous or arterial thrombotic events.During the study period, romiplostim was effective in preventing reduction of chemotherapy dose intensity due to CIT. Fourteen of the 20 (70%) analyzable patients experienced no episode of CIT, 4 subjects experienced a single chemotherapy dose delay due CIT, and 2 patients required a chemotherapy dose reduction. Platelet counts were preserved throughout the duration of the extension analysis. One patient experienced a proximal deep vein thrombosis, and one patient experienced multiple tumor-related ischemic events.Long-term use of romiplostim for treatment of CIT was effective and safe, with no evidence of resistance or increased risk of thrombosis.

Background Neutropenia is commonly encountered in cancer patients. Recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim), a cytokine that initiates proliferation and differentiation of mature granulocytes, is widely given to oncology patients to counteract neutropenia, reducing susceptibility to infection. However, the clinical impact of neutropenia and G-CSF use in cancer patients with coronavirus disease 2019 (COVID-19) remains unknown. Methods An observational cohort of 379 actively treated cancer patients with COVID-19 was assembled to investigate links between concurrent neutropenia and G-CSF administration on COVID-19-associated respiratory failure and death. These factors were encoded as time-dependent predictors in an extended Cox model, controlling for age and underlying cancer diagnosis. To determine whether the degree of granulocyte response to G-CSF affected outcomes, the degree of response to G-CSF, based on rise in absolute neutrophil count (ANC) 24 hours after growth factor administration, was also incorporated into a similar Cox model. Results In the setting of active COVID-19 infection, outpatient receipt of G-CSF led to an increased number of hospitalizations (hazard ratio [HR]: 3.54, 95% confidence interval [CI]: 1.25–10.0, P value: .017). Furthermore, among inpatients, G-CSF administration was associated with increased need for high levels of oxygen supplementation and death (HR: 3.56, 95% CI: 1.19–10.2, P value: .024). This effect was predominantly seen in patients that exhibited a high response to G-CSF based on their ANC increase post-G-CSF administration (HR: 7.78, 95% CI: 2.05–27.9, P value: .004). Conclusions The potential risks versus benefits of G-CSF administration should be considered in neutropenic cancer patients with COVID-19, because G-CSF administration may lead to worsening clinical and respiratory status.

Background: Chemotherapy induced thrombocytopenia (CIT) is common, adversely impacts chemotherapy relative dose intensity, and may adversely impact cancer control. There is no approved therapy for CIT. In our recent phase II study of solid tumor patients with CIT (Soff et al, J. Clin. Onc., 2019), romiplostim lead to correction of platelet counts in 85% of participants within 3 weeks. While on romiplostim maintenance, only 6.8% of participants experienced chemotherapy dose reduction or delay as a result of recurrent CIT within a minimum of two cycles of chemotherapy or 8 weeks. However, there is a lack of long-term data on the efficacy and safety of romiplostim in CIT. Objectives: This is an extension analysis of the phase II study for patients receiving romiplostim maintenance for 12 months or longer. Patients/Methods: In the phase II study, 44 patients successfully met the primary endpoint of correction of their platelet count within 3 weeks and resumed chemotherapy with romiplostim maintenance. 21 patients (48%) remained on romiplostim for 12 months or longer. Data were collected from one month prior to initiation of romiplostim to one month after the last dose of drug. Data extracted included complete blood count, chemotherapy doses and dates, romiplostim doses and dates, body weight, cancer diagnosis, age, gender, date of death and thrombotic events. Efficacy was demonstrated by persistent maintenance of platelet counts during long-term chemotherapy and avoidance of episodes of reduced chemotherapy dose intensity. Safety was assessed by two methods: tracking the rates of venous or arterial thrombosis; as well as development of marrow fibrosis and/or secondary hematologic malignancy. The mean romiplostim doses and lab values are calculated by month of study participation. Results: All participants had metastatic disease. Breast (N=6) and colorectal (N=6) were the most common cancers. No participant discontinued romiplostim therapy due to an adverse event or futility. One patient received romiplostim at our institution, but chemotherapy at an outside hospital; details of his chemotherapy were not available for this analysis. 14 of the 20 (70%) of the analyzable participants experienced no episode of CIT; 4 subjects experienced a single chemotherapy dose delay due CIT. No patient experienced multiple delays in chemotherapy due to CIT. Two patients required a chemotherapy dose reduction. The mean monthly platelet counts remained controlled throughout the period of analysis. (Figure 1A). The mean romiplostim doses were in the range of 3-5 mcg/kg through 35 months. There were insufficient participants beyond month 36 to allow meaningful interpretation of platelet counts or mean romiplostim doses. There was no evidence of adverse impact on absolute neutrophil count or hemoglobin levels (Figure 1B). No patient developed leukoerythroblastic changes indicative of marrow fibrosis, and no cases of secondary hematologic malignancy were identified. Two participants experienced thrombosis. One individual experienced a deep vein thrombosis. A second participant with an established history of congenital thrombophilia, experienced multiple tumor associated infarctions. The thrombotic events did not lead to discontinuation of participation in the trial for either participant. Of the 44 patients in the phase 2 study who resumed chemotherapy, 21 were alive at 12 months (48%) and 12 were alive at 24 months (27%). Conclusions: In this long-term analysis, romiplostim was effective and safe in the treatment of CIT with no evidence of drug resistance, marrow fibrosis, or secondary hematologic malignancy. The rates of thrombosis were no higher than expected for this patient demographic. There are some limitations to our analysis which includes our inability to accurately capture non-parenteral chemotherapy (oral or investigational agents) which were excluded from our analysis. We are unable to assess an impact on overall survival or cancer progression. However, the fact that half the participants were alive at 12 months and a quarter at 24 months is a reassuring signal. The analysis also is limited to the patients who were eligible for the initial phase 2 trial and corrected their platelet count within 3 weeks. Within these limitations, the extension study provides reassurance for long-term efficacy and safety of romiplostim treatment for CIT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Romiplostim is approved to increase platelet counts in ITP and pre-surgery. We are describing the results of a clinical trial.

PURPOSE Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment. METHODS We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/μL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/μL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point. RESULTS The mean platelet count at enrollment was 62,000/μL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/μL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/μL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT. CONCLUSION This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.

Autoimmune hemolysis (AH) and immune thrombocytopenic purpura (ITP) are recognized complications after cord blood transplantation (CBT). We evaluated the incidence and characteristics of AH/ ITP after double-unit CBT in a day 100 landmark analysis of 152 patients (median age 36 years, range 0.9–70) transplanted for hematologic malignancies with myeloablative or non-myeloablative conditioning and calcineurin-inhibitor (CNI)/ mycophenolate mofetil. With a median 5.2 year (range 1.6–9.7) survivor follow-up, 10 patients developed autoimmune cytopenias (8 AH, 1 ITP, 1 both) at a median of 10.4 months (range 5.8–24.5) post-CBT for a 7% cumulative incidence 3 years after the day 100 landmark. Six patients presented with severe disease (hemoglobin ≤ 6 g/dl and/ or platelets < 20 × 109/L). All AH patients were direct anti-globulin test positive. All 10 cases developed during immunosuppression taper with 8 having prior acute graft-versus-host disease. All 10 patients received rituximab 2–18 days after diagnosis, and corticosteroids combined with rituximab within < 7 days was the most effective. No patient died of AH/ ITP. AH/ ITP occurs infrequently after CBT but may be life-threatening requiring emergency therapy. Rituximab combined with corticosteroids at diagnosis is warranted in patients with severe disease.

Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. Rivaroxaban was approved in 2012 for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but no prior studies have been reported specifically evaluating the efficacy and safety of rivaroxaban for cancer-associated thrombosis (CAT). Under a Quality Assessment Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT and now report a validation analysis of our first 200 patients. A 200 patient cohort with CAT (PE or symptomatic, proximal DVT), whose full course of anticoagulation was with rivaroxaban, were accrued. In competing risk analysis, primary endpoints at 6 months included new or recurrent PE or symptomatic proximal lower extremity DVT, major bleeding, clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. In competing risk analysis, the 6 months cumulative incidence of new or recurrent VTE was 4.4 % (95 % CI = 1.4–7.4 %), major bleeding was 2.2 % (95 % CI = 0−4.2 %) and all-cause mortality 17.6 % (95 % CI = 11.7–23.0 %). In this cohort of 200 patients with active cancer and CAT the rates of new or recurrent VTE and major bleeding were comparable to the cancer subgroup analysis from the EINSTEIN studies. The results of our Clinical Pathway provide guidance on Rivaroxaban use for treatment of CAT, and suggest that safety and efficacy is preserved, compared with past-published experience with LMWH. Electronic supplementary material The online version of this article (doi:10.1007/s11239-016-1429-1) contains supplementary material, which is available to authorized users.

Anemia, which is highly prevalent in oncology patients, is one of the most established negative prognostic factors for several gynecologic malignancies. Multiple factors can cause or contribute to the development of anemia in patients with gynecologic cancers; these factors include blood loss (during surgery or directly from the tumor), renal impairment (caused by platinum-based chemotherapy), and marrow dysfunction (from metastases, chemotherapy, and/or radiation therapy). Several peri- and intra-operative strategies can be used to optimize patient management and minimize blood loss related to surgery. Blood transfusions are routinely employed as corrective measures against anemia; however, blood transfusions are one of the most overused healthcare interventions. There are safe and effective evidence-based blood transfusion strategies used in other patient populations that warrant further investigation in the surgical oncology setting. Blood is a valuable healthcare resource, and clinicians can learn to use it more judiciously through knowledge of the potential risks and complications of blood interventions, as well as the ability to properly identify the patients most likely to benefit from such interventions.

Venous thromboembolism (VTE) is a common complication in cancer patients and anticoagulation (AC) remains the standard of care for treatment. Inferior vena cava (IVC) filters may also used to reduce the risk of pulmonary embolism, either alone or in addition to AC. Although widely used, data are limited on the safety and efficacy of IVC filters in cancer patients. We performed a retrospective review of outcomes after IVC filter insertion in a database of 1270 consecutive patients with cancer-associated pulmonary embolism (PE) at our institution between 2008 and 2009. Outcomes measured included rate of all recurrent VTE, recurrent PE, and overall survival within 12 months. 317 (25%) of the 1270 patients with PE had IVC filters placed within 30 days of the index PE event or prior to the index PE in the setting of prior DVT. Patients with IVC filters had markedly lower overall survival (7.3 months) than the non-IVC filter patients (13.2 months). Filter patients also had a lower rate of AC use at time of initial PE. There was a trend towards higher recurrent VTE in patients with IVC filters (11.9%) compared to non-filter patients (7.7%), but this was not significant (p = 0.086). The risk of recurrent PE was similar between the IVC filter cohort (3.5%) and non-filter group (3.5%, p = 0.99). Cancer patients receiving IVC filters had a similar risk of recurrent PE, but a trend towards more overall recurrent VTE. The filter patients had poorer overall survival, which may reflect a poorer cancer prognosis, and had greater contraindication to AC; therefore these patients likely had a higher inherent risk for recurrent VTE. A prospective study would be helpful for further clarification on the partial reduction in the recurrent PE risk by IVC filter placement in cancer patients.

Chemotherapy-induced thrombocytopenia (CIT) can cause delay or reduction in subsequent courses of chemotherapy. Here, we report on a series of 20 patients who had protracted CIT and were treated with romiplostim, a thrombopoietin receptor agonist.We performed a retrospective review of the use of romiplostim for dose-limiting CIT at Memorial Sloan-Kettering Cancer Center from 2010-2012. Romiplostim was initiated at 1-2 mcg/kg weekly, with dose escalation by 1 mcg/kg per week until recovery of platelets (≥ 100 × 10(9)/L). If patients resumed chemotherapy, weekly romiplostim was continued.Romiplostim improved platelet counts in all 20 patients. In 19 of 20 patients, platelet counts of ≥ 100 × 10(9)/L were achieved. The mean dose of romiplostim to achieve adequate platelet recovery was 2.9 mcg/kg (range 1.0-5.1). Sixteen patients achieved platelet recovery by 2 weeks. Fifteen patients resumed cytotoxic chemotherapy with continued romiplostim support and 14 tolerated at least two subsequent cycles of chemotherapy, on schedule, without recurrence of dose-limiting CIT. Sepsis prevented continued chemotherapy in one patient. No resistance to romiplostim was observed. Three deep vein thromboses (DVT) were observed; one of which was a recurrent DVT in a patient who had previously experienced a DVT and was off anticoagulation. Three DVTs within 20 patients is within the anticipated thrombosis rates of patients with active cancer on chemotherapy.Romiplostim resulted in improvement in platelet counts, allowing resumption of chemotherapy without recurrence of dose-limiting CIT. No treatment-related toxicity was observed, but this would need to be confirmed in a larger, prospective trial. Our series differs from prior studies in that we selected only those patients who had already demonstrated persistent thrombocytopenia, and we continued weekly romiplostim during chemotherapy. Romiplostim may be a safe and effective treatment for CIT.

The purpose of this review was to highlight the more commonly used cardiac medications that should be closely monitored or possibly discontinued during cancer therapy. Often, older cancer patients are taking multiple pharmacotherapy agents for the treatment or prevention of cardiac disease when they face decisions about cancer treatment. Concurrent administration of drugs can result either in increased toxicity or decreased efficacy of either therapy. The benefits of the cardiac medications must be weighed against the effects of cancer therapy, and the role of drug metabolism also must be considered. For example, the benefits of cardiac medications such as anti-platelet agents, important in treating coronary artery disease, and anti-thrombotic agents, important for stroke prevention in atrial fibrillation, must be evaluated against an increased risk of bleeding during cancer therapy. It should be noted that some cardiac medications which act on hormonal receptors can theoretically stimulate growth of certain cancers. The concomitant management of cardiac therapy and cancer therapy is a common challenge in today's aging population.

Background Patients with hematologic malignancies are at risk for severe thrombocytopenia (sTP). The risk and benefit of aspirin are not known in thrombocytopenic cancer patients experiencing acute myocardial infarction (AMI). Materials and Methods Medical records of patients with hematologic malignancies diagnosed with AMI at Memorial Sloan Kettering Cancer Center during 2005–2014 were reviewed. sTP was defined as a platelet count Results Of 118 patients with hematologic malignancies who had AMI, 58 (49%) had sTP. Twenty-five patients (43%) with sTP received aspirin as a treatment for AMI. Compared with patients without sTP with AMI, patients with sTP with AMI were less likely to receive aspirin (83% vs. 43%; p = .0001) and thienopyridine treatment (27% vs. 3%; p = .0005). During median follow-up of 3.7 years after AMI, survival was lower in patients with sTP than in those with no sTP (23% vs. 50% at 1 year; log rank p = .003). Patients with sTP who received aspirin for AMI had improved survival compared with those who did not (92% vs. 70% at 7 days, 72% vs. 33% at 30 days, and 32% vs. 13% at 1 year; log rank p = .008). In multivariate regression models, aspirin use was associated with improved 30-day survival both in the overall patient cohort and in sTP patients. No fatal bleeding events occurred. Major bleeding was not associated with sTP or aspirin use. Conclusion Treatment of AMI with aspirin in patients with hematologic malignancies and sTP is associated with improved survival without increase in major bleeding.

Objective: Patients with hematologic malignancies are at risk for severe thrombocytopenia (sTP). The risk and benefit of aspirin therapy is not known in thrombocytopenic cancer patients who experience an acute myocardial infarction (AMI). Methods: Medical records of patients with hematologic malignancies diagnosed with AMI at Memorial Sloan Kettering Cancer Center during 2005-2014 were reviewed. sTP was defined as platelet count Results: 118 patients with hematologic malignancies had AMI. 58/118 (49%) had sTP. 25/58 (43%) of those with sTP received aspirin. Patients were mostly male (70%, n=83), mean age 69±11 years, mean follow up 3.6 years. Non-Hodgkin’s lymphoma was the most common hematologic diagnosis (36%, n=42). Survival was significantly worse in patients with sTP vs. no sTP (23% vs. 50% at 1 year, log rank p=0.008). When compared to no sTP with AMI, patients with sTP and AMI were less likely to receive aspirin (83% vs 43%, p=0.0001), thienopyridine (27% vs 3%, p=0.0005) and to undergo coronary angiography (30% vs. 5%, p=0.0005) and revascularization (17% vs. 3%, p=0.03). Cancer patients with sTP and AMI who received aspirin had improved survival when compared to those not treated with aspirin, (92% vs. 70% at 7 days, 72% vs. 33% at 30 days and 32% vs. 13% at 1 year, log rank p=0.008). No fatal bleeding events occurred. Thrombolysis in Myocardial Infarction (TIMI) major bleeding occurred in one patient without sTP. Conclusions: In hematologic malignancy patients with AMI and sTP the use of aspirin was associated with improved survival without increase in major bleeding.

Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120 mcg kg(-1) every 2-3 h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90-300 mcg kg(-1). High-dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrand's disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range:100, 100-150, 150-200 and200 mcg kg(-1). Investigator-reported efficacy for the first 72 h of treatment was evaluated. Thirty-eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1-55 years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72 h was 360 mcg kg(-1) (range: 40-4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (P0.001). Five patients experienced nine adverse events (AEs). AE rates were1% for100, 5% for 100-150, 0% for 150-200,1% for200 mcg kg(-1) dose group. Decreased therapeutic response accounted for eight of the nine AEs. These data, which represent the most comprehensive report of rFVIIa use since the USA licensure, demonstrate that bleeding episodes in HI patients can be treated safely and effectively at home and that doses up to 346 mcg kg(-1) appear to be well-tolerated. Additionally, rFVIIa doses200 mcg kg(-1) appear to significantly increase efficacy (97% in the high-dose group, compared with 84% in the lower dose groups). Optimal dosing remains to be determined; specifically, what the lowest effective dose is and whether a single high-dose bolus eliminates the need for repeated dosing. Recombinant FVIIa appears to have a wide safety margin that may allow dose escalation to address these questions.

To estimate the incidence of postoperative venous thromboembolism among patients undergoing minimally invasive surgery for endometrial cancer, and to characterize risk factors associated with the development of venous thromboembolism.Patients with newly diagnosed endometrial cancer who were scheduled to undergo a planned minimally invasive surgery procedure from May 1, 2007 to December 31, 2010 were identified. The incidence of symptomatic postoperative venous thromboembolism was estimated in the patients who did not require conversion to laparotomy. Various clinicopathologic variables were tested for an association with the development of a postoperative venous thromboembolism using standard statistical tests.A total of 573 cases were identified. Postoperative low molecular weight heparin was administered to 125 (22%) patients during their immediate postoperative hospital stay. All patients had sequential compression devices placed intraoperatively. Seven (1.2%) patients had development of a symptomatic venous thromboembolism. The factors associated with development of a postoperative venous thromboembolism were: body mass index (BMI) (P=.005); estimated blood loss (P=.03); and operative time (P=.01). A high-risk group was determined to be patients with BMIs of 40 or higher and an operative time of 180 minutes or more. In this group, the incidence of venous thromboembolism was 9.5% (4 of 42) compared with 0.6% (3 of 531) in all others (P=.001).The incidence of venous thromboembolism in patients with newly diagnosed endometrial cancer undergoing minimally invasive surgery is very low. There appears to be no clear justification for the routine use of a heparin for perioperative thromboprophylaxis in the majority of these patients. Thromboprophylaxis with heparin, however, may be a consideration in morbidly obese patients (BMI of 40 or higher) after a procedure that lasts 3 hours or more.II.

Purpose This study was designed to determine the incidence of venous and arterial thromboembolic events (TEEs) in patients treated with cisplatin-based chemotherapy and to analyze the prognostic value of patients' baseline and treatment characteristics in predicting TEE occurrence. Patients and Methods We performed a large retrospective analysis of all patients treated with cisplatin-based chemotherapy for any type of malignancy at Memorial Sloan-Kettering Cancer Center in 2008. A TEE was cisplatin-associated if it occurred between the time of the first dose of cisplatin and 4 weeks after the last dose. Results Among 932 patients, 169 (18.1%) experienced a TEE during treatment or within 4 weeks of the last dose. TEEs included deep vein thrombosis (DVT) alone in 49.7%, pulmonary embolus (PE) alone in 25.4%, DVT plus PE in 13.6%, arterial TEE alone in 8.3%, or DVT plus arterial TEE in 3.0%. TEEs occurred within 100 days of initiation of treatment in 88% of patients. By univariate analysis, sex, age, race, Karnofsky performance status (KPS), exposure to erythropoiesis-stimulating agents, presence of central venous catheter (CVC), site of cancer, stage of cancer, leukocyte and hemoglobin levels, and Khorana score were all identified as risk factors. However, by multivariate analysis, only age, KPS, presence of CVC, and Khorana score retained significance. Conclusion This large retrospective analysis confirms the unacceptable incidence of TEEs in patients receiving cisplatin-based chemotherapy. In view of the controversy associated with prophylactic anticoagulation in patients with cancer treated with chemotherapy, randomized studies are urgently needed in this specific cancer population treated with cisplatin-based regimens.

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 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.

Background: Venous thromboembolism (VTE) is a common complication in cancer patients. Anticoagulation (AC) remains the standard of care for treatment of cancer-associated VTE, but inferior vena cava filters (IVCF) are often used in place of or in addition to AC for various indications. Data are limited addressing the role for IVCF in cancer patients. We examine the efficacy of IVCF in a large cohort of cancer patients with prior pulmonary embolism (PE), to assess for rates recurrent VTE within 1-yr of initial VTE and overall survival (OS). Methods: This is a retrospective, single institution study. The study population comprised of all patients diagnosed with a PE at Memorial Sloan Kettering Cancer Center (MSKCC) from 2008-2009 (N= 1272). Patients had diverse primary tumors including lung (N= 246), colorectal (N= 139), gynecologic (N= 130), and breast (N= 103). The majority of patients (96%) were placed on therapeutic AC at time of diagnosis of PE (within 7 days of PE diagnosis). Subsequent interruptions in AC could not be captured. The cumulative incidence for recurrent DVT/PE was calculated from date of initial PE diagnosis to date of recurrent DVT/PE, death, or last followup. Deaths without recurrent DVT/PE were considered a competing event. Patients alive without event are censored at 12 months. Gray's k-test and Fine & Gray regression were used in analyzing the relationship between recurrent DVT/PE and IVCF placement. OS was calculated from date of initial PE diagnosis to date of death or last follow up. Log-rank test was used to compare OS by IVCF placement. Results: 25% (N=317) of the 1272 cancer-associated PE cohort had IVCF placed, either within 30 days following the initial PE (N=274), or prior to the initial PE (N=43). These 317 patients are compared to the 955 patients without IVCF. The indications for IVCF placement included AC contraindicated (39%), pre-operative (16%), AC failure (16%), poor cardiopulmonary reserve (6%) or indication unclear (23%). Composite 12-month rate of all recurrent VTE rate was higher with IVCF (14%) than non-IVCF (8%), (p = 0.016). Adjusting for whether patients were placed on AC at time of initial PE, this difference remained statistically significant with p = 0.014. After adjusting for AC, the risk of recurrent PE was similar between the IVCF cohort (5%) and non-IVCF (4%), (p = 0.43), but the risk of DVT was significantly higher in the IVCF group, 9% versus 5% (p = 0.014). Median OS for IVCF patients was 7.4 months, versus 13.5 months in non-IVCF patients, (p = Radiographic evidence IVCF thrombosis was observed in 13% (N= 42). Interestingly, 55% (N=23) of these patients were on AC at time of IVCF thrombosis, suggesting that AC is not fully protective against this complication. Other complications include filter projection to outside IVC walls (N=6), which in 1 case was associated with erosive changes to L3 vertebral body from the IVCF strut, and filter migration to right renal vein (N=1). Conclusions: In this population of cancer patients with newly diagnosed PE, IVCF use was common and was associated with poorer OS, higher rates of recurrent DVT and similar rates of recurrent PE, even when adjusting for AC at initial PE diagnosis. Limitations include the retrospective, non-randomized nature of this study. Further, we were unable to account for AC interruptions following initial PE diagnosis, which likely influenced the recurrent VTE rates. The poorer survival with IVCF may reflect poorer performance status and generally sicker nature associated with patients undergoing IVCF placement. Still, the absence of significant reduction in PE rates with the IVCF is noteworthy. A putative partial protective effect of IVCF on PE rates may have been counterbalanced by a higher VTE risk associated with poorer performance status in those receiving the IVCF. However, this large cohort study should give pause before placement of IVCF in many cancer patients, especially with advanced stage disease. Figure 1. Gray's k-test comparing the incidence curves by filter group is 0.0162. The p-value for filter (adjusting for AC at initial PE) is 0.014. Figure 1. Gray's k-test comparing the incidence curves by filter group is 0.0162. The p-value for filter (adjusting for AC at initial PE) is 0.014. Disclosures No relevant conflicts of interest to declare.

Background: Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. LMWH injections are painful and costly. Rivaroxaban, an oral direct factor Xa inhibitor, was FDA approved in 2012 for treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but there has been a knowledge gap for its use in patients with cancer-associated thrombosis (CAT). Under a Quality Assurance Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT, and began to offer rivaroxaban as an alternative to enoxaparin, in January 2014, for patients who met appropriate clinical criteria. We are tracking all cancer patients with PE or symptomatic proximal DVT, whose full course of anticoagulation is with rivaroxaban (allowing up to 3 days of initial parenteral anticoagulation). We now report the characteristics of the first 200 patients, and an outcome analysis of our first 100 patients, who have been treated for at least 6 months or otherwise reached an endpoint. Materials and Methods: The Clinical Pathway guidelines will be available on request, pending publication. Patients were not treated with rivaroxaban if they had active gastrointestinal or genitourinary lesions, or had undergone gastric resection due to anticipated excess bleeding risk or reduced absorption. This excluded under 5% of patients. The Pathway provided dosing guidelines in the setting of thrombocytopenia, advanced age, transient renal, or hepatic dysfunction. Primary endpoints include new or recurrent PE, symptomatic proximal lower extremity DVT, major bleeding (ISTH definition), clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. Considering those outcomes as competing risks, the cumulative incidence of each event type was calculated using R 3.2.0 for Windows and package "Survival". Results: The characteristics of our first 200 patients are in Table 1. 70% of the patients had PE. Of the solid tumor patients, 65.6% had metastatic disease. The first 100 patients have completed at least 6 months of rivaroxaban anticoagulation or otherwise reached a primary endpoint. At 6 months, the cumulative incidence of death was 14.4% (95% CI=6.8-21.4%), new or recurrent VTE was 4.3% (95% CI=0.1-8.4%), major bleeding was 1.1% (95% CI=0-3.1%), and clinically relevant non-major bleeding leading to rivaroxaban discontinuation was 7.9% (95% CI=2.1-13.3%). Conclusions: In the analysis of the first 100 patients entered into our QAI program, the rates of major bleeding, and new or recurrent VTE compare favorably to two published studies of LMWH for treatment of cancer associated thrombosis. In the CLOT study (Lee et al, NEJM, 2003) and the Daltecan study (Francis et al, JTH, 2015), the 6-month rates of new or recurrent VTE were approximately 9%, and the rates of major bleeding were 6% and 9.5% respectively. Our final analysis awaits the completion of 6 months follow-up on 200 patients, to be completed in December 2015. But the rates of major bleeding and recurrent VTE at this point suggest safety and efficacy to be at least non-inferior to LMWH, with the advantage of reduced patient burden, and support the ongoing use of our Clinical Pathway. Our low rate of major bleeding likely is influenced by the exclusion of patients with active GI or GU lesions, who would be expected to have a high bleeding risk with an oral direct anticoagulant. However, we estimate this excluded less than 5% of cancer patients with VTE. Further, we anticipated reduced drug clearance in the elderly, and used a reduced dose for patients greater than 75 years of age. This appeared to be associated with no loss in efficacy, and helped maintain a low rate of major bleeding. A randomized trial is the optimal approach to establish non-inferiority or superiority of rivaroxaban to LMWH for cancer associated thrombosis. However, our QAI Clinical Pathway provides guidance and reassurance for rivaroxaban use until a randomized trial is conducted. Table. Baseline Characteristics of Patients Characteristic Number of Individuals Gender Male 82 Female 118 Event Type PE, with or without DVT 140 Proximal, Symptomatic Lower extremity DVT 60 Cancer Type Solid Tumor 186 Hematologic Malignancy 14 Cancer Stage (Of Solid Tumors) No Evidence of Disease (Post-Cancer Surgery) 11 (5.9%) 1 1 (0.5%) 2 4 (2.2%) 3 16 (8.6%) 4 122 (65.6%) Unknown 32 (17.2%) Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Despite significant advances in the treatment of haemophilia, including availability of recombinant coagulation factor replacement products and the use of prophylactic infusion regimens, the segment of haemophilic patients who develop inhibitory antibodies remain at higher risk for morbidity and mortality associated with recurrent or uncontrolled bleeding events. Bypassing agents represent the mainstay of treatment and prevention of bleeding. The most commonly used of the currently available therapeutic agents are a plasma-based therapy, factor eight inhibitor bypassing activity, vapour heated, and a recombinant therapy, NovoSeven (recombinant activated factor VIIa). A substantial body of literature exists to document efficacy and adverse event profiles for these two products. There is, however, a paucity of data arising from adequately powered prospective trials to determine optimal treatment and dosing in various clinical situations. Certain clinical circumstances, patient profiles, individual responses, or provider predilection may lead to preferential use of one of these products over the other; however, the continued presence of both agents in the therapeutic armamentarium remains critically important to this fragile population. The historical use, clinical practice concerns, published comparative studies and methods for optimization of these two bypassing agents are reviewed.

Introduction: Autoimmune hemolysis (AH) & immune thrombocytopenic purpura (ITP) are recognized complications of CBT. However, the incidence, severity, treatment response, & prognosis of these autoimmune cytopenias are not established. Methods: We evaluated AH/ITP after CBT in a landmark analysis of 152 patients who received double-unit grafts, had sustained donor engraftment, & were disease-free at 100 days post-transplant. This landmark was chosen as no patient has developed AH/ITP prior to day 100. CBT recipients (median 38 years, range 0.9-70) were transplanted for hematologic malignancies with myeloablative (MA) or non-myeloablative (NMA) conditioning and calcineurin-inhibitor (CNI)/mycophenolate mofetil immunosuppression. Results: With a median follow-up of survivors in this cohort of 50.6 months (range 7.6-105.4) post-CBT, 9 patients [median age 42 years (range 2-54), 5 MA & 4 NMA conditioning] have developed autoimmune cytopenias (7 AH, 1 ITP, 1 both). All AH patients were IgG Direct Antiglobulin Test (Coombs) positive and ITP diagnosis was made by standard criteria. The cumulative incidence of AH/ITP is 6% (95%CI:3-11) at 3-years after the day 100 landmark with a median onset of 8.6 months (range 5.8-24.5) post-CBT (Figure). Six patients presented with severe disease (Hb 8 &/or plts >100): median 13 days (7-49 days) in 4 early rituximab patients vs 58 days (19-98 days) in 5 without early rituximab. Moreover, an initial IVIg/corticosteroids/rituximab combination was best (CR 7-13 days). Four patients flared after CR at 28-393 days & all patients achieved CR with further therapy. Three patients underwent splenectomy (2 with initial therapy & 1 with flare). Eight/9 AH/ITP patients are alive & disease-free (one patient died of GVHD in remission from AH). Seven/8 surviving patients are in CR from AH/ITP (median 30 months after AH/ITP diagnosis, range 9-102) & 1 has recurrent AH requiring therapy. Treatment was well tolerated although 4 patients required intermittent IVIg & 4 had transient neutropenia. Conclusions: AH/ITP occurs infrequently after CBT but is associated with sudden onset and may be life-threatening. The onset during immunosuppressant taper suggests the mechanism may be due to transient immune dysregulation at this time-point, and investigation of whether AH/ITP can be predicted from analysis of B-cell immune reconstitution is underway. IVIg/corticosteroid/rituximab combination is appropriate initial therapy in severe disease & our data suggests this is the most effective although the role of IVIg is unclear. Earlier treatment with Rituximab may reduce corticosteroid exposure & avoid early splenectomy. While the optimal treatment regimen is not established, our series suggests rituximab is essential to achieve & maintain CR & has an excellent safety profile. Finally, survival was high in AH/ITP patients with no deaths from this complication although this was likely contingent on aggressive supportive care in these patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The incidence of therapy related AML (t-AML) after adjuvant treatment of breast cancer has been estimated at 0.5%-1% of all patients in retrospective studies. While the absolute incidence of t-AML is low, the high prevalence of breast cancer in the United States – 2.8 million Americans are currently living with a diagnosis of breast cancer (http://seer.cancer.gov/statfacts/html/breast.html) - makes the burden of t-AML significant. Oncologists and hematologists are often confronted with a breast cancer patient who develops unexplained cytopenias. The differential diagnosis includes therapy-related myelodysplastic syndrome (t-MDS) or t-AML, chemotherapy effect, or breast cancer metastatic to the bone marrow. We evaluated factors that might inform whether a patient had t-MDS or t-AML to determine whether a bone marrow biopsy was indicated to aid diagnosis or whether a patient could be reassured and monitored with close outpatient follow up. 128 patients seen at Memorial Sloan-Kettering Cancer Center (MSKCC) who had a diagnosis of breast cancer, referred for a bone marrow biopsy between 2002 and 2012 were identified using the MSKCC institutional database and 126 patients were included in the analysis (2 excluded because of missing BM biopsy dates). Baseline characteristics of the patients are detailed in table 1. Patients were grouped based on bone marrow biopsy result: those who were found to have t-MDS or t-AML, those with breast cancer metastatic to the bone marrow, and those with a hypocellular marrow with no evidence of MDS, leukemia, or metastatic breast carcinoma. Logistic regression analysis was performed. In univariate analysis, low absolute neutrophil count (ANC) < 1.5K was significantly associated with increased likelihood of t-MDS/t-AML versus metastatic breast cancer or no disease compared to those who had an ANC ≥1.5k (OR=9.8, 95%CI(3.9, 24.5), p By multivariable analysis, both ANC and thrombocytopenia remained significantly associated with an increased likelihood of t-MDS/t-AML after controlling for hemoglobin and the receipt of any anthracycline or alkylating agent prior to BM biopsy (OR=9.8, 95%CI(3.7, 25.5), p In breast cancer patients with unexplained and persistent cytopenias, neutropenia Disclosures: No relevant conflicts of interest to declare.

1170 Thrombocytopenia is a common effect of cytotoxic chemotherapy regimens in cancer patients, often necessitating reduction or delay in subsequent cycles. While the thrombocytopenia typically resolves with time, a subset of patients (pts) with chemotherapy-induced thrombocytopenia (CIT) have prolonged thrombocytopenia, of idiopathic etiology, with interference with subsequent treatment. We describe the use of weekly romiplostim, a second generation thrombopoietin mimetic 'peptibody' in 7 pts who had prolonged thrombocytopenia beyond anticipated recovery from chemotherapy-induced platelet nadir. Five pts had metastatic solid tumors including soft tissue sarcoma on ifosfamide based therapy (n=2), colon cancer on 5-FU/ oxaliplatin based therapy(n=1), cholangiocarcinoma on gemcitabine therapy(n=1) and glioblastoma multiforme (GBM) on etoposide/CCNU (n=1). One patient had recurrent Non Hodgkin lymphoma (NHL) on rituximab and gemcitabine based therapy, and one pt had locally advanced gastric adenocarcinoma being treated with an irinotecan based regimen. All had isolated thrombocytopenia (< 60K/mcL) that persisted at least 5 weeks after the last dose of chemotherapy (range 5–48 weeks) causing chemotherapy delay. Five pts had received two or more previous lines of chemotherapy. Pre-treatment bone marrow biopsies were performed in six pts. Five showed normal cellularity with normal megakaryocytes while one showed 10% cellularity. In 2 pts, romiplostim was begun at 1 mcg/kg. All other pts were started at 2 mcg/kg. Doses were escalated by 1 mcg/kg weekly, as is done for chronic ITP, to a maximum of 4 mcg/kg. In all pts, platelets (plts) rose to greater than 100K/mcL between 2–4 weeks from initiation of romiplostim. Chemotherapy was re-instituted at full doses in six pts; the seventh pt with locally advanced gastric cancer was taken to surgery to attempt resection. Weekly romiplostim was continued throughout subsequent chemotherapy cycles in these six pts, maintaining counts adequate (>100K/mcL) to continue chemotherapy on schedule. Nadir platelet counts were maintained greater than 50K/mcL in 5/6 pts while on chemotherapy. In one pt with NHL, nadir platelet was 22K/mcL but demonstrated adequate recovery to receive next cycle on schedule. No treatment-related toxicity was observed. One pt, with prior history of thrombosis, developed new deep venous thrombosis while on romiplostim when platelet count was 278K/mcL. He has since been maintained for the next 12 months on both low molecular weight heparin and romiplostim titrated to platelet count 100–200K/mcL without further thrombotic events. This patient had a bone marrow biopsy performed after 14 months of therapy at maintenance dose of 4 mcg/kg. This was normal without reticulin deposition. No resistance to romiplostim was observed, and no pt required subsequent delay or reduction of chemotherapy due to thrombocytopenia. All pts received at least 4 additional cycles of chemotherapy. If chemotherapy was stopped or altered, it was due to oncologic considerations. One patient with stage IV sarcoma stopped romiplostim and chemotherapy at time of disease progression; no rebound thrombocytopenia was observed. No pts developed appearance of tear drop or nucleated red cells on review of peripheral smear morphology. Our case series is the first therapeutic interventional experience with a second-generation thrombopoietin agonist for CIT demonstrating benefit. Our series differs from prior studies in that we selected only those pts who had already demonstrated persistent thrombocytopenia, and we administered the romiplostim weekly, throughout the course of chemotherapy. We show promising clinical benefit in this situation, which supports the implementation of a larger study of weekly romiplostim for treatment of CIT.Pt number1234567Cancer typeColonSoft tissue sarcomaGastricSoft tissue sarcomaNHLCholangiocarcinomaGBMAge/Gender84/M71/M51/M44/F65/M62/M44/FNumber of lines of prior chemotherapy2212213Duration of prior thrombocytopenia (weeks)4851612141610Plt count at initiation of romiplostim (K/mcL)58535348485928Time to response in weeks. (plt ≥100 K/mcL)2344222Maintenance dose of romiplostim mcg/kg4443322 Disclosures: Off Label Use: Romiplostim for treatment of chronic idiopathic thrombocytopenia following chemotherapy for solid tumors.

High titer (HT), ≥1:32, anti-E, anti-c and anti-D Rh antibodies can cause hemolytic disease of the newborn (HDN). Maternal IVIG therapy may reduce need for intrauterine and exchange transfusions in HDN. Minimal data exists regarding optimal timing of therapy initiation, dose and frequency and fetal outcomes. Late administration of IVIG therapy beyond gestational age of 16 weeks have not been shown to improve fetal outcome. We describe the clinical course of 3 pregnant women with Rh AI. Two women with high titer Rh AI were treated with early IVIG dose of 1 gm/kg/week. A third woman with low titer Rh AI did not receive IVIG. Fetal status was monitored non-invasively with weekly Fetal Doppler ultrasound measurement of peak systolic velocity (PSV) of the middle cerebral artery (MCA). Patient 1 was a 38 year old Caucasian female with high anti- D (> 1:500) and history of HDN; second baby required 3 exchange transfusions and third baby required 3 intrauterine transfusions during pregnancy and 2 exchange transfusions post delivery. IVIG weekly infusion was started on week 11. Amniocentesis done at week 21 showed that baby was Rh(D) positive and the Kleihauer-Bethke test was negative. Serial fetal MCA PSV done weekly till labor induction did not show evidence of significant fetal anemia. The IVIG infusions were completed on 33rd week and the patient delivered healthy baby by cesarean section on the 35th week. The baby did not receive any intra uterine or exchange transfusions. Patient 2 was a 37 year old caucasian woman with anti-c AI. The patient’s husband is c antigen positive and she had seroconversion during her third pregnancy which manifested as positive antibody screen in a routine type and screen with her third delivery which was uneventful. She subsequently had a miscarriage of her fourth pregnancy at 9 weeks. Her peak anti –c titer was 1: 128. She received IVIG infusion from week 11 to week 33 with stable anti-c titer of 1: 64. Serial MCA PSV assesments did not reveal significant fetal anemia. She had a normal vaginal delivery on week 34 with a healthy baby not requiring any exchange transfusions. Patient 3 was a 41 year old caucasian woman with low titer anti-E AI (1:8). No IVIG was administered as her titers remained low during her pregnancy course. Her titers were monitored every 2 weeks; peak antibody titer was 1:8. Fetal anemia was ruled out with Serial MCA PSV assesments. She delivered a healthy baby by Ceserean section at 38 weeks, 4 days. Patient 1 Patient 2 Patient3 Gravid status G4 P2103 G5 P3013 G8, P4034 Blood group A- A+ O+ Antibody identification Anti D Anti c Anti E H/o documented HDN Yes No No Number of doses of IVIG 23 23 NA Age of Gestation IVIG started 10 weeks 11 weeks NA Cumulative dose of IVIG 1580 gms 1750 gms NA Peak antibody titer 1048 128 8 Serial Fetal Peak MCA velocity Normal Normal Normal Intra uterine/Exchange transfusions none None None Pregnancy outcome normal fetus normal fetus normal fetus IVIG adverse effects Headache, fatigue None N/A Patient 1 Weeks of gestation Anti D Titer IVIG –Cumulative No. of doses MCA PSV (cm/s) MoM= Multiples of Median 9 1:512 12 1:1048 1 17 1:512 7 20 1:512 10 21 (0.83 MoM) 21 1:512 11 28 (1.04 MoM) 22 1:512 12 21.3 (0.76 MoM) 23 1:512 13 28.1 (0.96 MoM) 24 1:512 14 22 (0.71 MoM) 25 1:512 15 25 (0.77 MoM) 26 1:512 16 32 (0.95 MoM) 27 1:512 17 28 (0.79 MoM) 28 1:512 18 35 (0.94 MoM) 30 1:512 20 45 (1.11 MoM) 32 1:512 22 61 (1.37 MoM) 33 1:512 23 51.9 (1.1 MoM) Patient 2 Weeks of gestation Anti c Titer IVIG – Cumulative number of doses MCA PSV (cm/s) MoM= Multiples of Median 11 1:128 1 14 1:64 4 20 1:64 10 22 1:64 11 22.3 (0.79 MoM) 24 1:64 13 23.7 (0.77 MoM) 25 1:64 14 22.7 (0.70 MoM) 26 1:64 15 30.1 (0.89 MoM) 27 1:64 16 34.3 (0.97 MoM) 29 1:64 18 37.9 (0.98 MoM) 30 1:64 19 33.3 (0.82 MoM) 31 1:64 20 27.9 (0.65 MoM) 32 1:64 21 28 (0.62 MoM) 33 1:64 22 59 (1.26 MoM) 34 1:64 23 35 (0.71 MoM) Patient 3 Weeks of gestation Anti E Titer IVIG - Cumulative No. of doses MCA PSV (cm/s) MoM= Multiples of Median Median – 1.29 MoM = No fetal anemia 1.29 – 1.5 MoM = Mild anemia >1.5 MoM = Severe anemia 12 1:8 0 19 1:8 0 26 1:8 0 28 1:8 0 40.6 (1.07 MoM) 29 1:4 0 39.7 (1.02 MoM) 32 1:4 0 42 (0.94 MoM 34 1:4 0 55 (1.12 MoM) Conclusion- Early initiation of weekly IVIg therapy at dose of 1 gm/kg at gestational age of 10 to 11 weeks in high titer (≥ 1:32) maternal Rh AI is well tolerated and can eliminate the need for invasive fetal monitoring, intrauterine transfusion and exchange transfusion.

Deficiency of ADAMTS-13, (A Disintegrin And Metalloprotease with 8 Thrombospondin like Domains), a Von Willebrandt Factor (VWF) cleaving protease, may be congenital (Upshaw Shulman syndrome) or acquired due to inhibitory autoantibodies and leads to the syndrome of Thrombotic Thrombocytopenic Purpura. Plasma exchange (PE) therapy is efficacious in therapy of TTP as it replenishes the deficient protease and at the same time removes the inhibitory antibody responsible for the enzyme deficiency. Few data exist effect of rising ADAMTS-13 inhibitor titers on the success of TTP therapy. We report a case of a 59 yr old African American woman who was diagnosed with TTP in October 2000 when she presented with altered mental status and focal weakness in right upper extremity. Initial labs showed Hemoglobin of 5.5 gm/dl, platelet count of 21,000/mm3, LDH of 4295. Peripheral smear showed moderate schistocytes and serum haptoglobin levels were decreased, renal function was normal. The patient received a total of 6 PE with FFP along with steroids and subsequently went into remission. The patient had a relapse after 10 months. She achieved remission with 5 PE. She was started on azathiaprine as an outpatient that was continued for five months. The patient remained asymptomatic for 5 years till her next relapse in the postoperative period after elective knee replacement surgery. The hospital course was complicated by development of transfusion related acute lung injury after receiving FFP. The patient again responded to PE (total 8 sessions) and IV steroids and went into remission. Prior to initiation of PE for this third relapse, tests showed ADAMTS -13 activity level was

DDAVP is effective therapy for VWD patients with documented adequate biologic response. Few data evaluating DDAVP exist in the less common type 2M VWD Seventy one members of an Amish kindred diagnosed with type 2 M VWD with abnormal VWF:Rco 50 kg); 9/11 were further evaluated for response to S.C. DDAVP (0.3 microgram/kg). These 9 patients included 5 males, 4 females; age range: 21 to 58 years; weight range: 59–101.8 kg. Response utilizing ristocetin cofactor activity (VWF:Rco), factor VIII activity (VIII:C), and VWF antigen (VWF:Ag). Was assessed at 90 minutes post Stimate® administration and at 60 and 120 minutes post S.C. administration; values were also obtained at 4 and 6 hours post S.C. DDAVP to assess pharmacokinetics. Response to DDAVP was defined as VWF:Rco >40%. Five people (55%) responded to Stimate®; three (33%) responded to S.C. DDAVP. There were no major adverse effects. Two males who had responded to I.N. route did not respond to S.C. route; one female who responded to S.C. DDAVP did not respond to Stimate®. Responses fell below 40% at 4 and 6 hours post-dose. Responses to DDAVP are thus observed in a subset of individuals with type 2M VWD. Although all individuals tested exhibit the 4120C>T mutation, the response to DDAVP as measured by VWF: Rco levels varied from 1.7 to 4.9 fold. Therefore response to DDAVP in these patients appears not to be solely based upon the mutation causing the VWD phenotype but may be modified by other environmental and genetic factors. DDAVP responsiveness is an interesting phenotypic trait to be studied. Response may vary based on route of administration; this report highlights the necessity of assessing response to a trial dose by the intended route of administration prior to clinical use. Both I.N. and S.C. DDAVP may be used for minor bleeding episodes in those patients with type 2M VWD with adequate response to a trial dose. Both may be self administered as home based first line hemostatic therapy and are well tolerated. | AGE/SEX | WEIGHT(KG) | PRE VWF:RCo(%) | POST VWF:RCo(%) | POST/PRE VWF:RCo RATIO | |:------- | ---------- | -------------- | --------------- | ---------------------- | | 58/M | 94.8 | 11 | 42 | 3.8 | | 26/M | 69.7 | 10 | 48 | 4.8 | | 48/M | 83.2 | 14 | 68 | 4.9 | | 29/M | 79.4 | 10 | 28 | 2.8 | | 49/F | 58.8 | 12 | 20 | 1.7 | | 43/F | 79 | 10 | 35 | 3.5 | | 21/F | 59.2 | 10 | 40 | 4.0 | | 22/F | 51.8 | 10 | 38 | 3.8 | | 27/M | 76.2 | 11 | 52 | 4.7 | RESPONSE TO I.N. DDAVP(2005) | AGE/SEX | WEIGHT (KG) | PRE VWF:RCo(%) | PEAK POST VWF:RCo(%) | POST/PRE VWF:RCo RATIO | |:------- | ----------- | -------------- | -------------------- | ---------------------- | | 58/M | 101.8 | 13 | 42 | 3.2 | | 26/M | 72.7 | 10 | 33 | 3.5 | | 48/M | 88.1 | 14 | 61 | 4.4 | | 29/M | 82.7 | 10 | 31 | 3.1 | | 49/F | 70.5 | 11 | 21 | 1.9 | | 43/F | 79.5 | 10 | 46 | 4.6 | | 21/F | 59 | 10 | 49 | 4.9 | | 22/F | 62.7 | 10 | 39 | 3.9 | | 27/M | 79 | 10 | 37 | 3.7 | RESPONSE TO S.C. DDAVP (2006)

CVD risk factors of age, hypertension, high cholesterol (HC), smoking, diabetes are expressed in the Framingham coronary risk score. Previous data suggest that hemophilia may protect against CVD. However, CVD risk factors may place HP at risk as they age. HIV infected patients are a rapidly developing group with CVD. No data address the effect of established risk factors on CVD prevalence in HP. We report an extensive analysis of a single hemophilia treatment center (HTC) database for CVD risk factors and prevalence in HP. Framingham coronary risk scores were calculated for HP patients with documented CVD events, using age at time of event to calculate risk. HTC population ≥40 yrs, used as denominator, comprised 156 with FVIII deficiency (63 severe, 16 moderate, 77 mild);109 with FIX deficiency (24 severe, 53 moderate, 31 mild). Forty-eight HP had HIV infection, 113 had hepatitis C, and 25 had HIV/hepatitis C coinfection. Twenty-one HP, 10 with viral infection, ranging 49 to75 years, experienced 23 CVD events. They included 11 FVIII (0 severe, 1 moderate, 10 mild),10 FIX (2 severe,6 moderate, 2 mild). CVD events included 13 myocardial infarction (MI); 5 cerebrovascular accidents (CVA); 1 patient with carotid stenosis and 4 HP with coronary artery disease on catheterization. Two patients each had both MI and CVA. Four patients underwent coronary artery bypass graft surgery. Of 8 patients on antiplatelet therapy, 2 had major bleeds (CNS and GI bleed); one had a minor bleed (epistaxis). Of these 21 HP with CVD, one patient had HIV disease; 8 had hepatitis C, 1 had co-infection with HIV and hepatitis C. One patient was on Vioxx® at the time of his CVD event.Six are deceased, all due to CVD. Overall, CVD affected 7.9% of HP aged >40 years in this population. Of all HP with viral infection in this HTC population, 40% experienced CVD. Ten-year CVD risk per Framingham model at time of event ranged from 10% to 37% (mean 20.1%; median 16%). All HP patients with CVD met the definition of high coronary risk per AHA guidelines with 10-year risk of CVD>10%. Management of established CVD in HP is difficult due to need for invasive procedures and bleeding risk with antiplatelet therapy. Primary prevention of CVD is thus crucial. Aggressive risk factor modification is indicated in all HP with 10-year risk score >10% for primary prevention of CVD. To our knowledge, this is the first application of the well validated Framingham score in the HP population.We conclude that the easily calculable Framingham score should be assessed in all HP over age 40, especially those with viral infections, and incorporated into the comprehensive care model.

DDAVP is effective treatment for VWD patients with adequate biologic response to administration of a trial dose. Intranasal therapy offers the advantage of ease of administration. Few prospective data evaluating response to intranasal DDAVP exist, especially in less common types such as type 2M VWD. As part of a study of a large Amish kindred of VWD in Northern Indiana, we conducted a prospective open label trial to assess response rate to a single dose of high concentration intranasal DDAVP in 11 affected individuals. Stimate® Nasal Spray (1.5 mg/ml) with weight based dosing was used. Laboratory parameters obtained prior to and 90 minutes after administration of Stimate® to assess for response included ristocetin cofactor activity (VWF:RCo), factor VIII activity(VIII:C), and VWF antigen (VWF:Ag) values. VWF:RCo ≥ 40% at 90 minutes post Stimate® administration was defined as adequate response. Of 212 evaluated members, 54 affected members were identified as defined by abnormally low VWF levels (VWF:RCo levels 50 kg; hence two intranasal Stimate® spray puffs were administered to each patient. Five of eleven patients had response to intranasal DDAVP as evidenced by ≥ 40% VWF:RCo levels 90 minutes after receiving Stimate® (Response range: 4.0 fold to 4.86 fold rise). The remaining patients did not meet definition of response (Response range: 1.6 fold to 3.8 fold rise). There were no major adverse effects. Nine patients had mild facial flushing alone; one patient had flushing and headache; one patient was asymptomatic. After Stimate® administration, the patient with gingival bleeding reported complete cessation of bleeding sustained for 24 hours. This is the first and largest report to date assessing response to intranasal DDAVP therapy in 2M VWD patients. High concentration intranasal DDAVP may be used for minor bleeding episodes in those patients with adequate response to a trial dose. It is easily self administered as home based first line hemostatic therapy. Intranasal DDAVP is well tolerated with minimal adverse effects. Prospective clinical correlation of efficacy is underway in this population. | AGE/SEX | BASELINE FVIII:C (%) | BASELINE VWF:AG(%) | BASELINE VWF:RCO(%) | 90 MINUTE FVIII:C(%) | 90 MINUTE VWF:AG(%) | 90 MINUTE VWF:RCO(%) | |:------- | -------------------- | ------------------ | ------------------- | -------------------- | ------------------- | -------------------- | | 56/M | 62 | 30 | 11 | 164 | 78 | 42 | | 25/M | 52 | 30

CVD, acute coronary syndrome (ACS)/cerebrovascular accident (CVA), is a leading cause of morbidity and mortality in the US. Risk factors are hypertension, hypercholesterolemia (HC), smoking and diabetes. Therapeutic advances allow PWBD to live longer; CVD may emerge as in the general population. No data address prevalence and treatment of CVD in PWBD. Previous data suggest that hemophilia may protect against CVD. A single HTC analysis of PWBD for CVD prevalence and outcome was performed. Query of HTC database identified patients with hemophilia/ von Willebrand disease(vWD) with CVD and retrospective chart analysis performed for risk factors. Coronary risk assessment score, expressed as a percentage(Framingham model), was calculated; unknown HC values assigned level 1 (scale maximum level 3) to avoid bias. Age at CVD event was used for risk comparison to age/ sex matched general population. HTC population was analyzed for bleeding disorder, severity, age ≥ 40 yrs, sex and utilized as the denominator for population event analysis. PWBD demographics ≥ 40 yrs revealed 146 with FVIII deficiency (60 severe, 18 moderate, 68 mild); 99 with FIX deficiency (20 severe, 52 moderate, 27 mild); 164 vWD (106 Type 1, 48 Type 2, 10 Type 3). Twenty-four PWBD, all ≥ 40 yrs of age, had experienced 26 CVD events. These PWBD included 8 FVIII (0 severe, 1 moderate, 7 mild), 6 FIX (2 severe, 4 moderate, 0 mild), and 10 vWD (5 Type 1, 4 Type 2, 1 Type 3). Events included 20 ACS; 6 were CVA; two patients each had both ACS and CVA. Six were deceased at time of analysis; five deaths due to CVD; one death (type III vWD) due to lung cancer. Framingham risk scores were comparable to expected general population scores. Eight patients received anti-platelet therapy. Of these, two had major bleeds (CNS and GI bleed); one had a minor bleed (epistaxis). Approximately one in 20 US population over age 40 yrs has CVD. Given this prevalence, we would expect 20 patients with CVD in our patient population. If bleeding disorders, specifically hemophilia and vWD, conferred protection against CVD, then we would expect decreased prevalence of CVD in our patient population. This putative protective effect would likely manifest in PWBD with severe deficiencies than in PWBD with mild deficiencies. Interestingly, we identified three patients with severe deficiency (two severe FIX; one type III vWD) with CVD; one of whom (type III vWD) had a higher calculated CVD risk score that age matched general population. CVD patients with mild/moderate deficiencies appear more similar to the general population for CVD risk than their severely affected counterparts. CVD prevalence in the former group could approach expected general population prevalence given Framingham scores equal to or higher than expected compared to the general population. In fact, Framingham score for identified CVD patients revealed 10 year comparative risk of CVD similar to general population risk. Accurate prevalence rates will be determined through prospective risk factor screening/CVD evaluation in PWBD over 40 yrs. Further study is warranted as prophylaxis becomes more widely utilized converting patients with severe disease to a more moderate disease state and possibly altering CVD prevalence. Invasive procedure outcome and optimal CVD therapy in PWBD require prospective investigation. This single center analysis represents the largest reported registry of PWBD analyzed for CVD to date.

Introduction Acquired factor VIII deficiency is a rare entity that can lead to severe and life-threatening bleeding. We describe a case of severe bleeding from the tongue secondary to acquired hemophilia and discuss treatment options, including aminocaproic acid and recombinant factor VIII, which have not been widely reported in the literature for the management of such patients. Case presentation A 94-year-old Caucasian man presented to our institution with diffuse bruising and extensive bleeding from the tongue secondary to mechanical trauma. He had no prior history of bleeding and his medical history was unremarkable except for dementia and hypertension. Coagulation studies revealed a prolonged activated partial thromboplastin time and a mixing study was consistent with the presence of an inhibitor. Quantitative assays revealed a reduced level of factor VIII activity (1%) and the presence of a factor VIII inhibitor, measured at seven Bethesda units, in the serum. Oral prednisone therapy (60mg/day) was given. He also received intravenous aminocaproic acid and human concentrate of factor VIII (Humate-P) and topical anti-thrombolytic agents (100 units of topical thrombin cream). His hospital course was prolonged because of persistent bleeding and the development of profuse melena. He required eight units of packed red blood cells for transfusion. Hospitalization was also complicated by bradycardia of unclear etiology, which started after infusion of aminocaproic acid. His activated partial thromboplastin time gradually normalized. He was discharged to a rehabilitation facility three weeks later with improving symptoms, stable hematocrit and resolving bruises. Conclusions Clinicians should suspect a diagnosis of acquired hemophilia in older patients with unexplained persistent and profound bleeding from uncommon soft tissues, including the tongue. Use of factor VIII (Humate-P) and aminocaproic acid can be useful in this coagulopathy but clinicians should be aware of possible life-threatening side effects in older patients, including bradycardia.

Background: The development of chemotherapy-induced thrombocytopenia (CIT) in the setting of therapeutic anticoagulation for venous thromboembolic (VTE) disease is a common problem in cancer patients. The current approach to low molecular weight heparin (LMWH) dosing in the setting of CIT (Lee, AYY. J. Clin. Onc. 2009) is empirical and based on limited published experience. This approach was never validated prospectively. Since 2011, Memorial Sloan Kettering Cancer Center (MSKCC) implemented a similar guideline: administer full dose LMWH for a platelet count >50,000/mcL, half dose for a platelet count 25,000/mcL to 50,000/mcL and hold LMWH temporarily for a platelet count Materials and Methods: In a Quality Assessment project, we evaluated cancer patients at MSKCC who were on a therapeutic dose of enoxaparin for a VTE during the years 2011 through 2013, who experienced at least one period of thrombocytopenia (platelet count ≤50,000/mcL) for at least 7 days. We assessed for adherence to the LMWH dose modification guidelines reflected by dose reduction and/or temporary hold for existing or anticipated thrombocytopenia. In addition, major bleeding, clinically relevant non-major bleeding, recurrent VTE events, and death were recorded during the episodes of thrombocytopenia. Results: We identified 101 patients with 144 episodes of thrombocytopenia, with an average duration of 21.3 days per episode. The LMWH dose was modified in 137 of the 144 episodes (95%), reflecting adherence to our institutional guidelines. The LMWH doses were reduced in 20 episodes, held in 90 episodes, and managed with combination of reduction/hold in 27 episodes. In general, the more severe thrombocytopenic episodes were managed with holding LMWH as opposed to dose reduction. The unweighted mean platelet count during episodes managed with holding LMWH was 27,000/mcL with a standard deviation (STD) of 16,000, while the mean platelet count during episodes of dose reduction was 36,000/mcL with a STD of 15,000. There were no recurrent VTE events or major bleeding episodes when the LMWH was reduced or held. In our cohort, there was only one major bleeding episode, a trauma-associated retroperitoneal hemorrhage, which occurred on the third day of a thrombocytopenic episode, prior to enoxaparin dose modification. That patient's platelet count was 28,000/mcL at the time of the event. There were 14 clinically relevant non-major bleeding episodes, of which 7 cases consisted of ecchymosis, epistaxis or gingival bleeding. Lastly, 10 patients died during the episode of thrombocytopenia. Discussion: This Quality Assessment project supports the safety and efficacy of our guidelines for therapeutic LMWH dose modification in the setting of CIT. In contrast to past case series, these patients were managed under direction of an institutional dosing guideline. We observed a 95% level of compliance with the guidelines. These data support the conclusion that the current LMWH dose reduction approach provides safety and efficacy, balancing the risks of recurrent thrombosis and bleeding during periods of CIT in cancer patients. It remains to be determined if a similar strategy would be appropriate for the new generation of oral anticoagulants. Disclosures No relevant conflicts of interest to declare.