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The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
ACUTE LEUKEMIA AND MYELODYSPLASTIC SYNDROME
ATRA plus ATO in low-risk acute promyelocytic leukemia (April 2016)
Prospective trials in acute promyelocytic leukemia (APL) suggest that the chemotherapy-free combination of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) yields at least equivalent outcomes compared with ATRA with anthracycline-based chemotherapy (eg, AIDA) and is better tolerated. Longer follow-up is now available for the Intergroup APL0406 randomized phase III trial, which compared ATRA plus ATO versus AIDA in 156 adults with newly diagnosed APL with a total white blood cell count ≤10 x 109/L (ie, low- or intermediate-risk APL) . ATRA plus ATO resulted in superior estimated rates of event-free survival (96 versus 81 percent) and overall survival (99 versus 88 percent) at four years. This provides further support for the use of this combination in APL, and we now give a stronger recommendation for the use of ATRA plus ATO for patients with low- or intermediate-risk APL. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'Arsenic trioxide plus ATRA'.)
Minimal residual disease in NPM1-mutated AML (February 2016)
Testing for minimal residual disease (MRD) is commonly used to monitor patients with acute promyelocytic leukemia (APL) in complete remission (CR). The value of MRD monitoring in non-APL acute myeloid leukemia (AML) is less clear. MRD monitoring was assessed in a large study of patients with NPM1-mutated AML treated within a clinical trial . When compared with MRD negative cases, those with detectable MRD at the time of first CR had higher relapse rates and inferior overall survival. Assessment of MRD at other time points did not provide additional prognostic value, nor did the coexistence of mutations usually associated with poor prognosis (eg, FLT3-ITD and DNMT3A). While these results support the prognostic value of MRD in non-APL AML, the use of NPM1 and other markers for MRD testing needs to be confirmed using validated techniques before such results can be used to escalate or de-escalate post-remission therapy. (See "Remission criteria in acute myeloid leukemia and monitoring for residual disease", section on 'Use in non-APL AML'.)
Declining mortality among long-term survivors of childhood cancer (January 2016)
Rates of late mortality among survivors of childhood cancer have improved over time. One study evaluated late mortality among over 34,000 survivors of childhood cancer who had been treated between 1970 and 1999, with a median follow-up of 21 years . Overall, mortality rates were lower in the later decades of follow-up, reflecting fewer deaths due to recurrence and long-term toxicities. Long-term treatment-related mortality decreased significantly over time among survivors of acute lymphoblastic leukemia, Hodgkin lymphoma, Wilms’ tumor, and astrocytoma, but not among survivors of other cancer subtypes. (See "Overview of the outcome of acute lymphoblastic leukemia in children and adolescents", section on 'Treatment-related mortality'.)
Addition of rituximab to induction therapy in CD-20 positive acute lymphoblastic leukemia (December 2015)
Nonrandomized prospective studies have suggested that the addition of rituximab to standard induction regimens improves outcomes in adults with CD20-positive acute lymphoblastic lymphoma (ALL). In a multicenter randomized trial, presented at the American Society of Hematology meeting, 220 adults with previously untreated CD20-positive, Philadelphia chromosome negative, precursor B cell ALL were randomly assigned to the pediatric inspired GRAALL regimen with or without the addition of rituximab . The addition of rituximab resulted in superior event-free survival and overall survival when patients who received transplantation in first complete remission were censored at the time of transplant. These results support our preference to use rituximab in addition to induction therapy in patients with CD20-positive ALL. (See "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults", section on 'Addition of rituximab for CD20+ ALL'.)
Midostaurin in FLT3 mutation-positive acute myeloid leukemia (December 2015)
Mutations in the FLT3 gene are common in acute myeloid leukemia (AML) and associated with worse survival following standard intensive chemotherapy. In a multicenter, phase III trial presented at the American Society of Hematology meeting, 717 adults <60 years old with previously untreated FLT3 mutation-positive AML were randomly assigned to standard induction 7+3 chemotherapy plus either the FLT3 inhibitor midostaurin or placebo . The addition of midostaurin improved event-free and overall survival without increasing the rates of severe toxicity or treatment-related deaths. Midostaurin is being evaluated by drug regulatory agencies for use in this setting but is as yet unavailable. (See "Induction therapy for acute myeloid leukemia in younger adults", section on 'FLT3 mutation positive AML'.)
Genetic predisposition in pediatric cancer (December 2015)
The prevalence and spectrum of mutations predisposing to cancer are not clear in pediatric cancer patients. In a study that used next-generation sequencing to determine the contribution of known germline predisposition mutations in over 1000 children and adolescents with cancer, pathogenic or probably pathogenic mutations were identified in 8.5 percent of cases . Mutations were most common in patients with adrenocortical cancers and osteosarcoma, but were also identified among patients with retinoblastoma, Ewing sarcoma, central nervous system tumors, rhabdomyosarcoma, leukemia, and neuroblastoma. Importantly, family history did not predict an underlying predisposition syndrome in most patients. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Hereditary cancer syndromes' and "Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology", section on 'Inherited conditions'.)
ANEMIA AND OTHER RED CELL DISORDERS
Stroke prevention in sickle cell disease (March 2016)
Individuals with sickle cell disease (SCD) are at risk for ischemic and hemorrhagic stroke. Transcranial Doppler (TCD) measures blood flow rate in intracranial arteries and is used to assess stroke risk in children with SCD. Children with increased TCD velocities are treated with chronic prophylactic transfusions to reduce the risk of ischemic stroke. The recently published TWiTCH trial (TCD With Transfusions Changing to Hydroxyurea) randomly assigned 121 children who had completed a period of chronic transfusions and who met study criteria (related to hemoglobin S levels with transfusion, TCD velocities, magnetic resonance angiographic findings, ability to comply with treatment and monitoring, and response to hydroxyurea) to transition to hydroxyurea therapy or to continue transfusions . After approximately two years of follow-up, TCD velocities were similar in both groups and there were no strokes in either group. For children who would have met criteria for the TWiTCH trial, we suggest transitioning to hydroxyurea after two or more years of chronic transfusion, with transfusions tapered and hydroxyurea dosing gradually increased during the transition, as done in the trial. We continue to recommend chronic transfusions for all patients with SCD who have had an ischemic stroke (ie, for secondary prevention). (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Chronic transfusion followed by transition to hydroxyurea'.)
Erythropoiesis-stimulating agents may not improve quality of life in chronic kidney disease (February 2016)
While many clinicians believe that maintaining hemoglobin levels above 10 to 12 g/dL with erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease (CKD) improves quality of life, particularly in younger individuals with active lifestyles, a meta-analysis calls this into question. The meta-analysis included studies that examined the effect of ESAs on changes in health-related quality of life using validated instruments including the 36-item Short Form Health Survey (SF-36; 13 studies) and the Kidney Disease Questionnaire (KDQ; four studies) . The achieved hemoglobin was 7.4 to 12 g/L in the placebo-treated and/or lower hemoglobin target group and 10.2 to 13.6 g/L in the higher hemoglobin target group. Overall, there were no significant differences between groups in any SF-36 or KDQ domains. These data suggest that the use of ESAs to treat anemia may not result in significant changes in health-related quality of life among CKD patients. (See "Anemia of chronic kidney disease: Target hemoglobin/hematocrit for patients treated with erythropoietic agents", section on 'Quality of life'.)
CHRONIC LEUKEMIAS AND THE MYELOPROLIFERATIVE NEOPLASMS
Bcl-2 inhibitor venetoclax in relapsed/refractory CLL (December 2015, Modified May 2016)
Venetoclax is an orally available, selective, small molecule inhibitor of Bcl-2. In a phase I dose-escalation study of venetoclax in 116 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the overall response rate was 79 percent . Tumor lysis syndrome (TLS) was the dose-limiting toxicity and resulted in a protocol amendment requiring a reduced initial dose and hospitalization for the first one or two days, followed by gradual dose escalation. High response rates were also seen in a subsequent phase II trial in patients with relapsed or refractory CLL with 17p deletion (overall response rate 79 percent, 8 percent complete response) . These findings have led to the approval of venetoclax by the US Food and Drug Administration for the treatment of patients with CLL with 17p deletion who have received at least one prior therapy. The US prescribing information includes risk-stratified recommendations for TLS prophylaxis (hydration and antihyperuricemics), as well as the setting and frequency of blood chemistry monitoring. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Venetoclax'.)
Risk of Pneumocystis pneumonia and cytomegalovirus infections with idelalisib (March 2016)
Idelalisib is a phosphatidylinositol 3-kinase inhibitor used for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Seven clinical trials of idelalisib used in combination with other agents have been halted due to an increase in serious adverse events and fatalities in patients receiving idelalisib . The majority of adverse events were infections, including sepsis and pneumonia. In particular, an increased number of cases of Pneumocystis pneumonia and cytomegalovirus (CMV) infection was observed in the idelalisib groups of three trials . The manufacturer has suggested that patients taking idelalisib receive Pneumocystis prophylaxis. They have also suggested that patients taking idelalisib be monitored for CMV reactivation and that idelalisib be discontinued in patients with evidence of infection or viremia. Changes to the prescribing information are expected, pending review by the US Food and Drug Administration. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Idelalisib' and "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Ibrutinib and idelalisib'.)
Ibrutinib in older adults with newly diagnosed CLL (March 2016, Modified March 2016)
Ibrutinib is commonly used for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and for the initial treatment of patients with CLL who carry a deletion in chromosome 17. Until now, there was little data regarding its use in other patients with previously untreated disease. In a phase III trial (RESONATE-2), 269 older adults with previously untreated CLL were randomly assigned to initial therapy with ibrutinib or chlorambucil . Ibrutinib was better tolerated and resulted in higher response rates and superior rates of progression-free and overall survival at two years. These results led to the approval of ibrutinib by the US Food and Drug Administration for the initial treatment of CLL . Ibrutinib is now our preferred therapy for previously untreated older adults with CLL. We continue to use fludarabine-based therapies for younger patients. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia", section on 'Ibrutinib'.)
Ofatumumab maintenance in relapsed CLL (January 2016)
The anti-CD20 monoclonal antibody ofatumumab has a mild toxicity profile and induces a partial remission in approximately half of patients with relapsed or refractory chronic lymphocytic leukemia (CLL). In a phase 3, open-label trial, patients with relapsed CLL in complete or partial remission after second- or third-line treatment were randomly assigned to receive maintenance ofatumumab for up to two years versus observation . The superior progression-free survival seen with ofatumumab maintenance resulted in US Food and Drug Administration approval for maintenance ofatumumab in this population. However, given the higher rate of neutropenia and infections and lack of an overall survival benefit with maintenance, we prefer observation with treatment at the time of progression rather than maintenance. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Anti-CD20 monoclonal antibodies'.)
Idelalisib, bendamustine, and rituximab in CLL (December 2015)
The combination of idelalisib plus rituximab is one of our treatments of choice for patients with refractory or early relapsing chronic lymphocytic leukemia (CLL). In a multicenter phase III trial, patients with relapsed or refractory CLL were randomly assigned to bendamustine plus rituximab (BR) plus either idelalisib or placebo . The addition of idelalisib to BR resulted in improved response rates, progression-free survival and overall survival. Idelalisib increased the rate of severe (grade >3) toxicity, including neutropenia, pyrexia, diarrhea, nausea, vomiting, and rash. This provides further support for the efficacy of idelalisib in CLL. It is not known whether bendamustine provides additional benefit over that seen with idelalisib plus rituximab. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Idelalisib'.)
Selective BTK inhibitor acalabrutinib in relapsed CLL (December 2015)
Acalabrutinib (previously ACP-196) is an investigational, orally available, irreversible Bruton’s tyrosine kinase (BTK) inhibitor that was designed to be more selective than ibrutinib. In a small, phase 1/2 multicenter study, responses were seen in the vast majority of patients with relapsed CLL treated with acalabrutinib, including all of the patients with chromosome 17p deletions . The treatment was well tolerated with no dose-limiting toxicities during the dose-escalation phase. Additional studies of acalabrutinib are underway. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Acalabrutinib (ACP-196)'.)
HEMATOPOIETIC CELL TRANSPLANTATION
Defibrotide for hepatic sinusoidal obstruction syndrome (April 2016)
Hepatic sinusoidal obstruction syndrome (SOS) is an uncommon but serious complication of allogeneic hematopoietic cell transplantation (HCT). It accounts for a significant fraction of transplant-related mortality and, in its severe form, is almost always fatal when treated with supportive care alone. Small single-arm prospective trials have demonstrated modest improvement in patients with severe SOS treated with defibrotide. In the largest international study, 102 adults and children with SOS and multiorgan failure were treated with defibrotide . When compared with historical controls, defibrotide was associated with higher response rates and improved survival (38 versus 25 percent at day +100). Based on this and other studies, defibrotide has been approved by the US Food and Drug Administration for the treatment of severe SOS . It is our preferred therapy for such patients. (See "Treatment and prevention of hepatic sinusoidal obstruction syndrome following hematopoietic cell transplantation", section on 'Defibrotide'.)
Zika virus and tissue/gamete donation (March 2016)
Zika virus has been detected in a number of tissues and body fluids. To avoid possible transmission of Zika virus infection, the US Food and Drug Administration (FDA) has issued donor deferral recommendations for hematopoietic stem cells, tissues, and donor sperm or eggs; the recommendations do not apply to solid organs . Living donors with Zika virus infection or relevant epidemiologic exposure (residence in or travel to an area where mosquito-borne transmission of Zika virus infection has been reported, or unprotected sexual contact with a person who meets these criteria) should be considered ineligible for donation for six months. Deceased donors with Zika virus infection in the preceding six months should also be considered ineligible. The deferral period recommended by the FDA for blood donors with risk factors for Zika virus infection remains at four weeks. (See "Zika virus infection: An overview", section on 'Blood/tissue donation'.)
Antilymphocyte globulin for chronic GVHD prevention (January 2016)
Chronic graft versus host disease (GVHD) is the leading cause of later mortality after hematopoietic cell transplantation (HCT), and interventions to prevent it are needed. In a multicenter, open-label, phase 3 trial, patients with acute leukemia undergoing myeloablative allogeneic HCT were randomly assigned to receive their conditioning regimen with or without the addition of antilymphocyte globulin . All patients received cyclosporine and methotrexate for acute GVHD prophylaxis. Rates of acute GVHD, relapse-free survival, viral reactivation, and overall survival at two years were similar between the two groups. However, the addition of antilymphocyte globulin dramatically reduced the rate of chronic GVHD and allowed more patients to discontinue cyclosporine. These results support the incorporation of antilymphocyte globulin into the preparative regimens for patients at high risk of developing chronic GVHD such as those with an unrelated donor or haploidentical donor. (See "Treatment of chronic graft-versus-host disease", section on 'Prevention'.)
Myeloablative versus reduced intensity conditioning in AML and MDS (December 2015)
Small nonrandomized trials have evaluated the use of reduced intensity conditioning (RIC) regimens in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). A phase III trial comparing standard myeloablative conditioning (MAC) versus RIC in 272 adults with AML or MDS was closed early, and initial results have been reported in abstract form . Despite greater treatment-related mortality, patients with AML assigned to MAC had superior survival rates due to dramatically lower relapse rates. In contrast, in patients with MDS, the lower relapse rates with MAC did not translate into a survival advantage. Based on these and other data, MAC is preferred over RIC in younger adults with AML undergoing allogeneic HCT. (See "Post-remission therapy for acute myeloid leukemia in younger adults", section on 'Nonmyeloablative or reduced intensity HCT'.)
HEMOSTASIS AND THROMBOSIS
Long-acting factor IX for hemophilia B (May 2016)
Long-acting clotting factor products are appealing for replacement therapy in individuals with hemophilia because they can reduce the frequency of injections. A long-lasting recombinant factor IX-albumin fusion protein (rIX-FP) was approved by the US Food and Drug Administration in 2016 for prophylaxis or treatment of bleeding in individuals with hemophilia B . The half-life is five to sixfold longer than unmodified factor IX products. (See "Treatment of hemophilia", section on 'Longer lasting products'.)
New approach to treating hemophilia A (May 2016)
The mainstay of treatment for hemophilia A is replacement with exogenous factor VIII, which interacts with factor IX to activate factor X in the coagulation cascade. In a new approach, investigators have created a monoclonal antibody (ACE910) that binds simultaneously to factors IX and X, bringing them together and bypassing the role of factor VIII. This product has now undergone the first stage of testing in humans. In 64 healthy volunteers, ACE910 was well tolerated and did not cause major adverse events . It was able to correct a prolonged activated partial thromboplastin time (aPTT) in the volunteers' plasma that had been depleted of factor VIII in vitro. The half-life was four to five weeks. Clinical trials in people with hemophilia are ongoing. (See "Treatment of hemophilia", section on 'Novel proteins'.)
Vorapaxar for lower extremity peripheral artery disease (March 2016)
Patients with peripheral artery disease (PAD) are at increased risk of limb ischemic events. In a randomized trial of the protease-activated receptor 1 antagonist vorapaxar in symptomatic stable patients with PAD, the event rate for acute limb ischemia (ALI) at one year (1.3 percent) was similar to that for ischemic stroke (0.9 percent) and myocardial infarction (1.9 percent) . Vorapaxar reduced the rate of ALI at three years (2.3 versus 3.9 percent with placebo) regardless of the cause, although most patients (71 percent) had a prior vascular intervention. Given the serious risks associated with ALI (prolonged hospitalization, limb loss, reperfusion surgery, mortality), these results suggest a need for additional trials to determine whether vorapaxar is beneficial following revascularization. (See "Surgical management of claudication", section on 'Antithrombotic therapy'.)
Protamine for heparin reversal following carotid endarterectomy (March 2016)
Following open carotid endarterectomy, whether to reverse the anticoagulant effects of heparin is controversial. A recent systematic review and meta-analysis of protamine use after anticoagulation for carotid endarterectomy assessed outcomes in over 10,000 patients from 12 studies (one randomized trial, a large registry study, and 10 other observational studies) . Use of protamine reduced the risk of major bleeding complications requiring reoperation compared with not using protamine, without increasing the risk of stroke, myocardial infarction, or mortality. These results support our practice of heparin reversal after endarterectomy. (See "Carotid endarterectomy", section on 'Endarterectomy procedure'.)
Updated guidelines for the treatment of venous thromboembolism (March 2016)
The American College of Chest Physicians (ACCP) has published new guidelines on antithrombotic therapy for venous thromboembolic (VTE) disease that include guidance on choice of anticoagulant, indications for extended anticoagulation, and indications for thrombolytic therapy in patients with acute pulmonary embolism (PE) . In addition to a preference for direct oral anticoagulants for the treatment of VTE, the ACCP suggests extending anticoagulation beyond three months (ie, no scheduled stop date) in patients with unprovoked VTE or active cancer. For most patients with small subsegmental pulmonary embolism (SSPE), anticoagulation is suggested; however, clinical surveillance with lower extremity Doppler ultrasound may be appropriate for select patients with a low burden of SSPE who have no evidence of thrombus elsewhere and in whom the risk of recurrence is low. The guidelines suggest administration of systemic thrombolytic therapy, rather than catheter-directed thrombolysis (CDT), for patients with hemodynamically-significant PE; CDT may be appropriate for those who fail systemic thrombolysis or who are at high risk of bleeding. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Indications' and "Venous thromboembolism: Anticoagulation after initial management", section on 'Selection of agent' and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Patients likely to benefit' and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Patients with subsegmental PE'.)
Agent selection for anticoagulation in venous thromboembolism (March 2016)
Guidelines for the treatment of acute venous thromboembolism (VTE) were issued by The American College of Chest Physicians (ACCP) . Compared with earlier versions of the guidelines, the direct oral anticoagulants (DOACs) apixaban, edoxaban, rivaroxaban, or dabigatran are now the preferred agents for long-term anticoagulation in patients who are not pregnant and do not have active cancer or severe renal insufficiency. This preference was based upon randomized trials that consistently reported similar efficacy, a lower bleeding risk, and improved convenience when compared with warfarin. We agree with this preference for DOACs in patients with acute VTE, understanding that choosing among anticoagulants frequently depends upon availability and cost as well as patient comorbidities and preferences. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Selection of agent'.)
Preoperative aspirin in patients undergoing CABG (February 2016)
In recent years, aspirin has been given preoperatively to stable patients undergoing coronary artery bypass graft surgery (CABG) despite the absence of strong evidence to do so. The ATACAS trial randomly assigned 2000 stable CABG patients to aspirin (100 mg) or placebo administered one to two hours before surgery . At 30 days, there was no significant difference in the rate of the combined end point of death, nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction, nor was there a difference in the rate of major hemorrhage. For stable patients not at high bleeding risk who are scheduled for CABG, we continue aspirin preoperatively, and we individualize the decision regarding starting aspirin in those not taking it. (See "Medical therapy to prevent complications after coronary artery bypass graft surgery", section on 'Preoperative aspirin'.)
Venous thromboembolism risk with central versus peripheral insertion of central venous catheters (January 2016)
There is accumulating evidence that peripherally-inserted central venous catheters (PICCs) are associated with a greater risk for upper extremity deep vein thrombosis (UEDVT) compared with centrally-inserted central venous catheters (CICCs). The Medical Inpatients and Thrombosis (MITH) Study evaluated catheter use in 299 venous thromboembolism cases compared with controls without venous thromboembolism at a single institution . Central catheter use was associated with a 14-fold increased risk for UEDVT, without a significantly increased risk for pulmonary embolism. PICCs were associated with a higher cumulative risk compared with CICCs (8.1 versus 4.8 per 1000 admissions). Given the higher risk for UEDVT with PICCs, we generally avoid them in patients for whom maintaining vascular patency and integrity for long-term vascular access options (eg, future hemodialysis access) is essential. (See "Catheter-related upper extremity venous thrombosis", section on 'Peripheral versus central insertion' and "Overview of central venous access".)
Recombinant von Willebrand factor (October 2015, Modified December 2015)
Patients with von Willebrand disease (VWD) may require von Willebrand factor (VWF) replacement therapy for serious bleeding or surgery. A recombinant VWF product has now been tested in patients with VWD during bleeding episodes and found to be highly effective in restoring hemostasis . Adverse effects were minor, and the half-life of the product is longer than that of plasma-derived concentrates. This product was approved by the United States Food and Drug Administration in December 2015 . (See "Treatment of von Willebrand disease", section on 'VWF preparations'.)
Allergic reactions with REG1, an investigational factor IXa-based anticoagulant (November 2015)
A variety of new anticoagulants are under development. REG1 consists of an injectable RNA fragment that inhibits coagulation factor IXa and a complementary fragment that can be used to reverse the effects (ie, a fast-acting antidote). However, a recent trial comparing REG1 with bivalirudin in patients undergoing percutaneous coronary intervention was terminated early due to an unacceptably high rate of allergic reactions with REG1 . A primary ischemic endpoint was similar between the two therapies. (See "Direct oral anticoagulants: Dosing and adverse effects", section on 'Anticoagulants in development'.)
Reversal agent for factor Xa inhibitors (November 2015)
Lack of reversal agents for the direct oral anticoagulants has been a concern. Andexanet alfa is a recombinant protein designed to reverse factor Xa inhibitors by binding to the drugs and sequestering them away from endogenous factor Xa. In a randomized trial in healthy volunteers, an andexanet bolus reduced anti-factor Xa activity by 94 percent and 92 percent for volunteers taking apixaban or rivaroxaban, respectively, compared with reductions of 21 and 18 percent for a placebo bolus . A study evaluating andexanet efficacy in patients with factor Xa inhibitor-associated bleeding is ongoing. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Antidotes under development'.)
LYMPHOMA: HODGKIN AND NON-HODGKIN
Nivolumab for Hodgkin lymphoma (May 2016)
Patients with Hodgkin lymphoma (HL) that has relapsed or progressed following autologous hematopoietic cell transplantation (HCT) and post-transplantation brentuximab vedotin have limited treatment options. Initial data from two prospective studies have reported high response rates with the programmed death 1 (PD-1) inhibitor nivolumab, which has been beneficial in the treatment of melanoma. Based on this, the US Food and Drug Administration has approved the use of nivolumab in this patient population . Serious adverse effects seen in this population include those reported in patients with melanoma (pneumonitis, colitis, hepatitis, nephritis, renal dysfunction, and thyroid dysfunction). In addition, patients treated with nivolumab who proceed to allogeneic HCT have a high rate of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, and hepatic sinusoidal obstruction syndrome. Further study is needed to see if these high response rates translate into a survival benefit and to clarify the role of this agent in the treatment of multiply relapsed HL. (See "Second and third line chemotherapy regimens and biologic therapy for relapsing or resistant classical Hodgkin lymphoma", section on 'PD-1 blockade'.)
Rituximab in Burkitt lymphoma (April 2016)
Rituximab is an attractive addition to conventional chemotherapy for Burkitt lymphoma (BL) given its efficacy in other CD20-positive non-Hodgkin lymphoma subtypes, the expression of CD20 in most cases, and the results of several uncontrolled, prospective trials which suggested improved outcomes with rituximab. In a multicenter, open-label trial, 260 adults with previously untreated HIV-negative BL were randomly assigned to receive dose-dense chemotherapy with or without rituximab . After a median follow-up of 38 months, the addition of rituximab improved event-free and overall survival without increased toxicity. These results provide stronger evidence to support the use of rituximab in BL. To lessen the risk of tumor lysis syndrome, we wait until the second cycle of chemotherapy before incorporating rituximab into the treatment program. (See "Treatment of Burkitt leukemia/lymphoma in adults", section on 'Incorporation of rituximab'.)
Lenalidomide in mantle cell lymphoma (March 2016)
Data supporting the use of lenalidomide in patients with relapsed or refractory mantle cell lymphoma (MCL) come from uncontrolled phase II trials. In an international phase II trial (SPRINT), 254 patients with relapsed MCL who were not candidates for intensive therapy were randomly assigned to receive lenalidomide versus a single agent of the investigator’s choice (rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine) . After a median follow-up of 16 months, lenalidomide improved progression-free survival (median 9 versus 5 months). Toxicities were similar to those seen in other trials. These results provide further support for the efficacy of lenalidomide in this population. Given the availability of effective agents not used in this trial (eg, ibrutinib, bendamustine plus rituximab), we usually reserve lenalidomide for patients with multiply relapsed disease. (See "Treatment of relapsed or refractory mantle cell lymphoma", section on 'Lenalidomide'.)
Bendamustine plus obinutuzumab for follicular lymphoma (February 2016)
It is not known whether the novel anti-CD20 monoclonal antibody obinutuzumab is better than rituximab for the treatment of relapsed or refractory follicular lymphoma (FL). Preliminary results are available from a trial in which 321 patients with relapsed or refractory FL were randomly assigned to six cycles of bendamustine alone versus six cycles of bendamustine plus obinutuzumab, followed by obinutuzumab maintenance for two years . The addition of obinutuzumab improved progression-free survival, leading to the approval of this regimen by the US Food and Drug Administration for FL relapsed or refractory after a rituximab-containing regimen. However, we do not routinely use this regimen, as it has not demonstrated an overall survival benefit and requires longer follow-up to better clarify potential long-term toxicities. In addition, it has not been compared directly with rituximab-containing regimens in this setting. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Chemoimmunotherapy'.)
Second cancers in Hodgkin lymphoma survivors (January 2016)
While the majority of patients with Hodgkin lymphoma (HL) are cured, second malignancies result in significant morbidity and mortality among survivors. In response, practice has shifted towards radiation fields and doses that limit exposure. In a retrospective analysis of almost 4000 patients with HL treated in the Netherlands between 1965 and 2000, the cumulative incidence of second solid tumor did not differ by treatment period . While the use of radiation fields that spared the axilla was associated with lower rates of breast cancer, less extensive supradiaphragmatic field radiotherapy was not associated with lower lung cancer rates. While these results are disheartening, the standardization of even smaller radiation fields (ie, involved site and involved node radiation) and doses did not occur until after the patients in this study were treated. As such, this study did not assess whether the most modern radiation techniques result in lower cancer risks. (See "Second malignancies after treatment of classical Hodgkin lymphoma", section on 'Effect of treatment given'.)
Brentuximab vedotin in mycosis fungoides and Sézary syndrome (December 2015)
Given that the majority of mycosis fungoides (MF) and Sézary syndrome (SS) cases have some expression of CD30, there has been interest in the potential efficacy of brentuximab vedotin, an anti-CD30 monoclonal antibody conjugated with an antineoplastic drug, which is currently used for refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Two phase II multicenter trials of brentuximab vedotin in MF/SS have reported objective responses for the majority of patients, with a median duration of response greater than six months [39,40]. Randomized trials evaluating brentuximab vedotin in MF/SS are underway. (See "Treatment of Sézary syndrome", section on 'Brentuximab vedotin'.)
Ibrutinib versus temsirolimus in relapsed mantle cell lymphoma (December 2015)
Ibrutinib was approved for use in the United States and Europe for multiply relapsed mantle cell lymphoma (MCL) based on data from a small uncontrolled prospective trial that showed high response rates and good tolerability. Data are now available from a phase III, open-label, multicenter randomized trial comparing ibrutinib versus temsirolimus in 280 patients with relapsed or refractory MCL . Ibrutinib was better tolerated and resulted in improved response rates and progression-free survival. An analysis of overall survival was limited by the use of ibrutinib in approximately one-quarter of patients who progressed on temsirolimus. This provides further support for the use of ibrutinib in this patient population. (See "Treatment of relapsed or refractory mantle cell lymphoma", section on 'Ibrutinib'.)
Lenalidomide plus rituximab in previously untreated mantle cell lymphoma (November 2015)
Phase II trials have demonstrated the activity of lenalidomide in patients with relapsed or refractory mantle cell lymphoma (MCL). Its good tolerability makes it a reasonable option for older or frail patients who are unlikely to tolerate more intensive chemotherapy regimens. The combination of lenalidomide plus rituximab was evaluated in a small prospective trial of patients with previously untreated MCL . Initial results demonstrated overall and complete response rates of 92 and 64 percent, respectively. Although promising, data from randomized trials are needed prior to incorporating this combination into the standard management of this patient population. (See "Initial treatment of mantle cell lymphoma", section on 'Clinical trials'.)
MULTIPLE MYELOMA AND OTHER PLASMA CELL DISORDERS
Ixazomib plus lenalidomide and dexamethasone for relapsed multiple myeloma (November 2015, Modified March 2016)
The US Food and Drug Administration has approved the oral proteasome inhibitor ixazomib for use in combination with lenalidomide and dexamethasone (IRd) for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy . Approval was based on an interim analysis of a multicenter phase 3 trial (Tourmaline-MM1), which included over 700 adults with relapsed MM not refractory to lenalidomide or proteasome inhibitor-based therapy . The addition of ixazomib to lenalidomide and dexamethasone resulted in superior response rates and progression-free survival (median 21 versus 15 months). Overall survival data are not yet mature. Common toxicities with IRd include neutropenia, thrombocytopenia, gastrointestinal distress, peripheral neuropathy, peripheral edema, and rash. IRd offers an all-oral treatment option for patients with relapsed MM. (See "Treatment of relapsed or refractory multiple myeloma", section on 'Ixazomib'.)
Bortezomib, lenalidomide, and dexamethasone (VRd) for previously untreated multiple myeloma (December 2015)
Until now, only phase II trials had evaluated bortezomib, lenalidomide, and dexamethasone (VRd) in the treatment of previously untreated multiple myeloma (MM). In a multicenter phase III trial (SWOG S0777), reported in abstract form only, 525 patients with previously untreated MM were randomly assigned to receive six months of induction therapy with either VRd or lenalidomide plus dexamethasone (Rd), each followed by Rd maintenance until progression or unacceptable toxicity . VRd resulted in higher response rates and improved both progression-free and overall survival. We now prefer VRd for the initial treatment of most patients with standard risk MM. Given that VRd is associated with greater toxicity, Rd is an acceptable alternative for frail adults, especially those with preexisting neuropathy, and patients age 75 years or older who are expected to have higher rates of toxicity with VRd. (See "Selection of initial chemotherapy for symptomatic multiple myeloma", section on 'Bortezomib, lenalidomide, dexamethasone (VRd)'.)
Reducing transmission of malaria by blood transfusion using a pathogen inactivation technology (May 2016)
Pathogen inactivation technologies are treatments that can be applied to blood products before they are transfused, to reduce transmission of viable infectious agents. In Ghana, where malaria is endemic and testing of donated blood for parasitemia is not routinely available, a randomized trial demonstrated that treatment of whole blood with one of these methods (riboflavin [vitamin B2] plus ultraviolet [UV] light) was able to significantly reduce transfusion-transmitted malaria . (See "Pathogen inactivation of blood products", section on 'Potential benefits'.)
Investigational laboratory test for Zika virus in donated blood (April 2016)
A laboratory test that detects Zika virus RNA is under investigation in the United States to screen donated blood for Zika . This test has been implemented under a US Food and Drug Administration (FDA)-approved investigational new drug application (IND) for all blood that is collected in Puerto Rico, a jurisdiction defined by the Centers for Disease Control (CDC) as an active Zika virus transmission area. In areas without active transmission, the donor medical and travel history is used to disqualify individuals who may be infected with Zika. (See "Blood donor screening: Laboratory testing", section on 'Zika virus'.)
Zika virus and blood donation (March 2016, Modified April 2016)
The blood donor medical and travel history is used to identify and disqualify individuals who may be infected with Zika. Several agencies including the US Food and Drug Administration (FDA), World Health Organization (WHO), and AABB (an international organization) have issued guidance to reduce the risk of transmission in affected and unaffected areas [48-51]. These vary slightly but all include recommendations for deferral of individuals at risk of infection based on travel, symptoms, or sexual contacts, and recall and destruction of products if the donor develops symptoms of infection or diagnosis of Zika following donation. The WHO also recommends consideration of temporarily stopping collections and/or quarantining units until lack of symptoms can be confirmed. Currently used donor questionnaires are likely to identify individuals with symptomatic infection at the time of donation. (See "Blood donor screening: Medical history", section on 'Zika virus'.)
New guidance on blood donation deferral for men who have sex with men in the United States (December 2015)
The US Food and Drug Administration has updated its guidance on blood donation for men who have sex with men (MSM). The new guidance specifies a deferral period of 12 months since the last MSM sexual contact rather than indefinite deferral . Prospective donors are instructed not to donate if they have other risk factors for human immunodeficiency virus (HIV) infection such as a recent needle stick injury or blood splash, and permanent deferral remains in place for individuals who have tested positive for HIV, used non-prescription injection drugs, or engaged in sex in exchange for money or drugs. The 12-month deferral has already been in place for other donors who have sex with at-risk individuals, and it aligns the US policy with that of Australia and the United Kingdom. Other countries have deferral periods ranging from six months to indefinite. (See "Blood donor screening: Medical history", section on 'Human immunodeficiency virus'.)
Oritavancin interference with coagulation tests (February 2016)
Oritavancin is a glycopeptide antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). Although oritavancin has no effect on the coagulation system in vivo, it falsely prolongs the activated partial thromboplastin time (aPTT), prothrombin time/international normalized ratio (PT/INR), and activated clotting time (ACT) by binding to phospholipid reagents used in laboratory testing. In 2016, the US Food and Drug Administration (FDA) labeling was revised to include new time frames for concern as to interference with coagulation tests of up to five days for aPTT, 12 hours for PT/INR, and 24 hours for ACT, following a single intravenous (IV) dose of oritavancin . Coagulation test interference can make the monitoring of unfractionated heparin (UFH) and warfarin unreliable within these time frames. For patients who require aPTT monitoring within five days of oritavancin, anti-factor Xa activity testing may be used. Patients who require a heparin anticoagulant and do not have access to anti-factor Xa testing could be treated with low molecular weight (LMW) heparin instead of UFH. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Prolonged baseline aPTT' and "Pharmacology of antimicrobial agents for treatment of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus", section on 'Drug interactions' and "Oritavancin: Drug information".)
Caplacizumab for acquired TTP (February 2016)
Thrombotic thrombocytopenic purpura (TTP) is a medical emergency that is almost always fatal without treatment. Even with plasma exchange (PEX), mortality is as high as 10 percent. Caplacizumab is a monoclonal antibody fragment designed to block binding of platelets to the ultralarge multimers of von Willebrand factor (VWF) that form in TTP. In a randomized trial in which 75 patients with acquired TTP received caplacizumab or placebo (all patients received PEX), caplacizumab was associated with a faster time to response, fewer days of PEX, and greater frequency of remission . This therapy is not yet available outside of a clinical trial. (See "Acquired TTP: Initial treatment", section on 'Anti-VWF (caplacizumab)'.)
Glucocorticoid dose in ITP (February 2016)
Many adults with immune thrombocytopenia (ITP) do not require treatment. For those who do, glucocorticoids are used, but the optimal dosing has been unclear. A new trial supports our preference for high-dose dexamethasone rather than prednisone for most patients and illustrates differences in side effect profiles. In this trial, 195 adults with newly diagnosed ITP requiring therapy were randomly assigned to receive either oral dexamethasone at 40 mg daily for four days without a taper or oral prednisone at 1 mg/kg daily for four weeks followed by a gradual taper . High-dose dexamethasone was associated with a higher response rate, more rapid responses, and fewer adverse events. Common dexamethasone side effects included insomnia and mood disturbance, while prednisone more often caused dizziness, hypertension, hyperglycemia, and weight gain. (See "Immune thrombocytopenia (ITP) in adults: Initial treatment and prognosis", section on 'Glucocorticoids'.)
Early volume expansion in STEC-hemolytic uremic syndrome (January 2016)
Fluid management of patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) has been based on assessment of intravascular volume, which can be increased or decreased. However, a prospective Italian study of 38 children with STEC-HUS from 2012 and 2014 compared with historical controls from 2006 to 2009 reported that routine early volume expansion targeted to increase body weight by 10 percent improved outcome (lower rate of renal replacement therapy, shorter hospital course, and shorter duration of intensive care) . Although these results are promising, further investigation is needed due to the potential bias from the use of historical controls and the relatively small number of patients and adverse events in the study. Until confirmatory data are available, we recommend assessment of intravascular volume status and renal function, with administration of fluids to rapidly correct documented volume depletion. We recommend not routinely providing volume expansion, especially if there is evidence of increased intravascular volume. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children", section on 'Fluid management'.)
Low risk of anaphylaxis with intravenous iron (December 2015)
Many clinicians are reluctant to use intravenous (IV) iron due to concerns about anaphylaxis. We believe the risk is overestimated, largely due to experience with older products such as high molecular weight iron dextran (HMW ID), which is no longer used, and to the practice of aggressively treating non-allergic infusion reactions with diphenhydramine and other therapies that convert the reaction to a more serious event. A recent review addressed the frequency of anaphylaxis in nearly 700,000 older adults who received an IV iron product . Overall risk of anaphylaxis was low (<0.07 percent), although some deaths were recorded. However, we believe this may overestimate serious reactions because the criteria for anaphylaxis were based on medical coding data that may not have distinguished adverse drug events from effects of premedications. The rates with iron dextran may also be an overestimate, since they included HMW ID. Further, findings from this population may not be directly applicable to younger patients. We continue to use IV iron in a variety of settings, and we do not premedicate with diphenhydramine (or in most cases, with any medications). (See "Treatment of iron deficiency anemia in adults", section on 'Risks/prevention'.)
No benefit to intravenous magnesium or prasugrel for sickle cell pain (October 2015, Modified December 2015)
Acute pain episodes in sickle cell disease are severe, and opioids are usually required. Two new trials have now been performed to test additional therapies for vasoocclusive pain. Magnesium was considered a possible adjuvant therapy because of its vasodilatory and antiinflammatory properties. However, a randomized trial to evaluate the efficacy of magnesium in the setting of acute pain (MAGnesium for children in Crisis [MAGiC]) did not show any benefit in the length of hospital stay, opioid use, quality of life, or markers of inflammation . The antiplatelet agent prasugrel was thought to have a possible role in preventing vasoocclusive pain due to its antiinflammatory and vascular effects, but in a randomized trial in children prasugrel did not reduce the frequency of acute painful events . (See "Vasoocclusive pain management in sickle cell disease", section on 'Therapies we do not use'.)
Eltrombopag for chronic ITP in children (November 2015)
Approximately 10 to 20 percent of children who present with immune thrombocytopenia (ITP) go on to have chronic ITP with ongoing bleeding risk. In adults with refractory chronic ITP, thrombopoietin (TPO) receptor agonists increase platelet counts and reduce bleeding events, although the effect generally lasts only as long the drug is continued. A recent study found similar effects in pediatric patients. In a multicenter, randomized, double-blind trial of 92 children with chronic ITP, 40 percent of patients in the eltrombopag group achieved a sustained response in their platelet count compared with 3 percent in the placebo group . Bleeding events occurred less frequently in the eltrombopag group (37 versus 55 percent). During the subsequent 24-week open-label treatment period, 81 percent of patients achieved a response. The drug was well tolerated and serious adverse events did not differ between the treatment and placebo groups. Due to cost considerations and limited pediatric experience with TPO receptor agonists in children, UpToDate reserves these agents for children with chronic ITP who fail or are ineligible for treatment with splenectomy and/or rituximab and for those requiring a high platelet count for surgery when this cannot be achieved with other therapies (eg, steroids, intravenous immune globulin). (See "Immune thrombocytopenia (ITP) in children: Management of chronic disease", section on 'Thrombopoietin receptor agonists'.)
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