Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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
Inotuzumab ozogamicin in acute lymphoblastic leukemia (June 2016)
Inotuzumab ozogamicin is an investigational anti-CD22 monoclonal antibody conjugated to calicheamicin; it has demonstrated activity in relapsed/refractory acute lymphoblastic leukemia (ALL). Early results are available from an international open-label, randomized phase 3 trial that compared inotuzumab ozogamicin versus intensive chemotherapy in 326 patients with relapsed/refractory ALL . Inotuzumab ozogamicin resulted in a higher percentage of patients achieving a complete response (81 versus 29 percent), many of whom attained minimal residual disease negativity. There was a small improvement in median progression-free survival (five versus two months) and overall survival (eight versus seven months). Inotuzumab ozogamicin results in high rates of deep response in this setting, but the majority of patients will relapse if no further therapy is given. Further study is necessary to better elucidate the best way to incorporate this drug into the treatment of patients with ALL. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Inotuzumab ozogamicin'.)
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'.)
ANEMIA AND OTHER RED CELL DISORDERS
Rhabdomyolysis and sickle cell trait (August 2016)
Sickle cell trait is a benign carrier condition with a normal life expectancy. However, concerns have been raised regarding an increased risk of rhabdomyolysis and sudden death with prolonged physical activity. These risks were addressed in a cohort study of almost 50,000 black soldiers in the United States army for whom sickle cell trait status and other clinical information was available . While the risk of rhabdomyolysis was increased (hazard ratio, 1.5), this magnitude of risk is similar to that conferred by obesity or smoking and less than that due to antipsychotic or statin medications. Mortality was not increased over that in black soldiers without sickle cell trait, and the sole death from rhabdomyolysis occurred in an individual without sickle cell trait. Interventions to reduce exertion-related injuries should be aimed at all athletes and members of the military, regardless of sickle cell trait status. (See "Sickle cell trait", section on 'Rhabdomyolysis and sudden death during strenuous physical activity'.)
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
Bendamustine plus rituximab versus FCR in CLL (July 2016)
Nonrandomized trials have suggested that the combination of bendamustine plus rituximab (BR) is slightly less effective, but better tolerated than, fludarabine, cyclophosphamide, and rituximab (FCR) for the initial treatment of chronic lymphocytic leukemia (CLL). In a multicenter, open-label noninferiority trial, 564 adults with previously untreated CLL without del(17p) and without significant comorbidities were randomly assigned to FCR versus BR . Despite being associated with more severe toxicities and dose reductions, FCR improved median progression-free survival by approximately 13 months. At a median follow-up of 37 months, this has not yet translated into an improvement in overall survival. FCR remains our preferred treatment regimen for younger adults with previously untreated CLL without del(17p). Given its better tolerability, BR is an acceptable alternative for younger adults with decreased renal function or other comorbidities. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia", section on 'Bendamustine-based therapy'.)
Midostaurin in systemic mastocytosis (June 2016)
Case reports have described dramatic responses in patients with systemic mastocytosis (SM) treated with the multikinase/KIT inhibitor midostaurin. Two prospective trials of midostaurin have now described responses in 60 to 70 percent of patients with advanced SM [7,8]. Treatment resulted in reversal of organ damage (cytopenias, liver dysfunction) and decreases in bone marrow mast cell burden and serum tryptase levels. Responses were observed regardless of KIT D816V status, prior therapy, or the presence of an associated hematologic neoplasm. Midostaurin is being evaluated by drug regulatory agencies, but is as yet unavailable. (See "Systemic mastocytosis: Treatment and prognosis", section on 'Midostaurin'.)
Vascular disease in patients with CML taking tyrosine kinase inhibitors (June 2016)
For the initial treatment of chronic myeloid leukemia (CML), the second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib are able to achieve faster and deeper responses than imatinib, but have a different toxicity profile, including increased cardiovascular toxicity. A retrospective cohort study used a Swedish population-based registry to analyze the risk of vascular events in 896 patients with chronic-phase CML treated with imatinib, dasatinib, or nilotinib . When compared with age- and sex-matched controls, patients treated with any TKI had an increased risk of vascular events, but the association was greater with the second-generation agents. Event rates for myocardial infarction among patients treated with nilotinib, dasatinib and imatinib were 29, 19, and 8 per 1000 person-years, respectively. These findings underscore the importance of screening for and optimal management of traditional cardiac risk factors. Although it is not known whether anticoagulation helps, many clinicians offer low-dose aspirin for general cardiovascular prophylaxis in patients taking TKIs. (See "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia", section on 'Vascular disease'.)
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'.)
HEMATOPOIETIC CELL TRANSPLANTATION
Virus-specific T cell infusions for patients with primary immunodeficiencies and hematopoietic cell transplant (June 2016)
Viral infections, particularly with cytomegalovirus, Epstein-Barr virus, and adenovirus, are a leading cause of death in patients with severe combined immunodeficiency (SCID) and other forms of moderate-to-severe primary immunodeficiency (PID), both before and after hematopoietic cell transplantation (HCT). Investigational infusions of virus-specific T cells (VST) from either stem cell donors or third-party donors have been evaluated to treat and/or prevent these life-threatening viral infections. One retrospective series examined 26 patients with a PID requiring HCT who had at least one documented serious viral infection and were treated with VST either before or after HCT . Complete or partial antiviral response was seen in 76 to 100 percent of patients, depending upon the particular virus. An additional 10 patients were treated preventively with VST prior to HCT. Of these, eight remained free of the most common serious viral infections. This therapy is still experimental, but commercial entities are developing these cellular products and they may be available for more widespread use in a few years. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Treatment'.)
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'.)
HEMOSTASIS AND THROMBOSIS
Dosing of direct oral anticoagulants in obese patients (June 2016)
Limited data are available to guide dosing of direct oral anticoagulants (DOACs; dabigatran, apixaban, edoxaban, rivaroxaban) in patients with obesity. The International Society of Thrombosis and Hemostasis (ISTH) has issued guidance on this subject . The major recommendations include use of DOACs at standard doses for those with a body mass index (BMI) ≤40 kg/m2 or weight <120 kg, and avoidance of DOACs in individuals with a BMI >40 kg/m2 or weight ≥120 kg. (See "Direct oral anticoagulants: Dosing and adverse effects".)
Risk of inhibitors in hemophilia A (June 2016)
Individuals with hemophilia who receive coagulation factor infusions are at risk of developing an autoantibody to the factor (a factor inhibitor); this occurs in approximately 25 to 30 percent of individuals with severe hemophilia A. The SIPPET trial (Survey of Inhibitors in Plasma-Product Exposed Toddlers) is the first randomized trial to evaluate the risk of inhibitors with recombinant versus plasma-derived factor VIII products . In SIPPET, 264 children who required factor VIII infusions were randomly assigned to receive a recombinant or a plasma-derived product. Inhibitors were seen more frequently with the recombinant products (37 versus 23 percent). The mechanism of this difference is unknown; the presence of von Willebrand factor in the plasma-derived products or the use of non-human cell lines to produce the recombinant products has been suggested. These results may not apply to recombinant products made in human cell lines or those engineered to have extended half-lives. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Recombinant versus plasma-derived products'.)
Investigational laboratory assay for multiple anticoagulants (June 2016)
The prothrombin time (PT) with international normalized ratio (INR) and the activated partial thromboplastin time (aPTT) are used to monitor warfarin and heparin therapy, but these tests are not adequate for assessing the presence or therapeutic effect of direct thrombin inhibitors or direct factor Xa inhibitors. A modified form of the PT that uses highly diluted thromboplastin, designated dFiix-PT, has been developed . In a preliminary study, this assay was able to detect and quantify unfractionated and low molecular weight heparins, vitamin K antagonists, and direct oral anticoagulants. If validated, this test could potentially greatly simplify anticoagulant testing. (See "Clinical use of coagulation tests", section on 'Prothrombin time (PT) and INR'.)
Role of platelet transfusions in bleeding associated with antiplatelet agents (May 2016)
The role of platelet transfusion in patients with antiplatelet agent-associated bleeding has been unclear. A recent randomized trial compared platelet transfusions with standard care in 190 individuals with intracerebral hemorrhage (ICH) in the setting of aspirin or other antiplatelet agents . Compared with those assigned to standard care, individuals who received platelet transfusions had a higher rate of a composite endpoint of death or lower score on the modified Rankin Scale for functional independence. When analyzed separately, the increase in mortality did not reach statistical significance. Serious adverse events were more frequent in the platelet transfusion arm, and ICH enlargement was similar in both arms at approximately 15 percent. Despite these results, such cases can be complex, and we continue to favor an individualized approach. (See "Clinical and laboratory aspects of platelet transfusion therapy", section on 'Platelet function defects'.)
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 investigational 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 (emicizumab; ACE910) that binds simultaneously to factors IX and X, bringing them together and bypassing the role of factor VIII. In a study involving 18 individuals with hemophilia A who had bleeding despite prophylactic or on-demand therapy, once-weekly subcutaneous administration of emicizumab markedly decreased bleeding rates; 11 of these individuals had factor VIII inhibitors . There were no serious adverse events or thrombotic complications. Additional studies 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'.)
Thromboembolic events in systemic sclerosis (February 2016)
Vascular dysfunction is a significant physiologic feature of systemic sclerosis (SSc). In a large population-based study, a threefold increased risk of venous thromboembolism (VTE, including pulmonary embolism and deep vein thrombosis) was observed among 1245 patients with incident SSc compared with matched non-SSc controls, after adjusting for relevant risk factors such as age, sex, and recent hospitalization . The increased risk of VTE was highest during the first year after SSc diagnosis. These findings support the relevance of increased vigilance for VTE risk factors among patients with SSc, regardless of a recent hospitalization. (See "Overview of the clinical manifestations of systemic sclerosis (scleroderma) in adults", section on 'Thromboembolic disease'.)
LYMPHOMA: HODGKIN AND NON-HODGKIN
PET/CT-adapted therapy in advanced Hodgkin lymphoma (June 2016)
Mid-treatment positron emission tomography/computed tomography (PET/CT) has prognostic value in patients with Hodgkin lymphoma (HL), and initial studies suggest that treatment may be safely deescalated in early responders. In a large trial, 935 patients with advanced-stage HL who achieved a "negative" PET/CT after two cycles of combination chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) were randomly assigned to receive four more cycles of ABVD or four cycles of doxorubicin, vinblastine, and dacarbazine (AVD) . AVD and ABVD resulted in similar rates of progression-free survival at three years (PFS, 84 versus 86 percent), although the 95% confidence intervals included a decrease in PFS with AVD of 5.3 percent. Decisions for an individual patient must take into account the risk of pulmonary toxicity with further bleomycin versus a potentially small increase in relapse with bleomycin omission. Omission in those with a "negative" PET/CT is most attractive for patients with additional risk factors for bleomycin toxicity (eg, older age, underlying pulmonary disease, active smokers). Application of this approach must pay careful attention to the methodology used including the timing of PET/CT and cutoff values used to determine "negative" scans. (See "Initial treatment of advanced (stage III-IV) classical Hodgkin lymphoma", section on 'Response adapted therapy'.)
Maintenance rituximab after bendamustine plus rituximab in mantle cell lymphoma (June 2016)
Maintenance rituximab improves progression-free survival (PFS) and may improve overall survival in patients with mantle cell lymphoma (MCL) treated with R-CHOP induction, but its role after induction with bendamustine plus rituximab (BR) is not well understood. In a preliminary report, presented in abstract form, a randomized phase 2 trial comparing two years of maintenance rituximab versus observation in 168 patients with newly diagnosed MCL treated with BR induction showed no significant difference in PFS at a median follow-up of 59 months (HR 0.71; 95% CI 0.41-1.23; median 55 versus 72 months) . For patients with newly diagnosed MCL who have had at least a partial response to initial therapy and are not eligible for autologous hematopoietic cell transplantation (HCT), the decision to use maintenance rituximab must take into account the initial therapy administered. Given the lack of a PFS benefit in this randomized trial, we suggest observation rather than maintenance following BR induction. In contrast, for those receiving R-CHOP induction, we suggest the use of maintenance rituximab until progression, rather than observation with treatment at the time of progression. (See "Initial treatment of mantle cell lymphoma", section on 'Maintenance therapy'.)
R-CHOP/R-DHAP for mantle cell lymphoma (June 2016)
Nonrandomized prospective trials have suggested high rates of deep responses in patients with mantle cell lymphoma (MCL) treated with alternating cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) followed by autologous hematopoietic cell transplantation (HCT). A randomized trial in 497 younger adults with previously untreated MCL compared six cycles of this regimen versus six cycles of R-CHOP, both followed by autologous HCT . After a median follow-up of six years, R-CHOP/R-DHAP resulted in longer time to treatment failure (median nine versus four years), but this has yet to translate into a statistically significant survival benefit (HR 0.78; 95% CI 0.57-1.07). R-CHOP/R-DHAP was associated with higher rates of hematologic toxicity, febrile neutropenia, and renal toxicity. We do not routinely use R-CHOP/R-DHAP due to toxicity concerns and lack of a proven survival benefit. (See "Initial treatment of mantle cell lymphoma", section on 'Conventional chemoimmunotherapy'.)
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). In one trial, 396 patients with relapsed or refractory indolent lymphoma (81 percent 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'.)
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'.)
Investigational laboratory test for Zika virus in donated blood (April 2016, Modified August 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, and in Florida, following reports of mosquito-borne transmission. 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'.)
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'.)
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 [43-46]. 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. The FDA has approved two investigational nucleic acid tests for Zika screening. (See "Blood donor screening: Medical history", section on 'Zika virus'.)
Danazol in telomere disorders (May 2016)
Telomeres are regions at the ends of chromosomes that maintain chromosomal integrity. Telomeres shorten with normal aging, but inherited disorders of premature telomere shortening can cause aplastic anemia (AA), pulmonary fibrosis, and certain malignancies. To date, no therapies have been developed to reverse premature telomere shortening. In the first prospective study to evaluate androgen therapy for telomere disorders, the androgen danazol was administered to 27 individuals with mutations that affect telomere length (most with AA) . Danazol was associated with improved hematologic parameters in those with cytopenias, stabilization of pulmonary status in those with pulmonary fibrosis, and reduced telomere shortening in all evaluable participants. Androgens are an attractive candidate for treating telomere disorders, although further study is needed. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis", section on 'Telomerase mutations and telomere length' and "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition'.)
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)'.)
- Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med 2016.
- Lo-Coco F, Di Donato L, GIMEMA, et al. Targeted Therapy Alone for Acute Promyelocytic Leukemia. N Engl J Med 2016; 374:1197.
- Nelson DA, Deuster PA, Carter R 3rd, et al. Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers. N Engl J Med 2016; 375:435.
- Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 2016; 387:661.
- Collister D, Komenda P, Hiebert B, et al. The Effect of Erythropoietin-Stimulating Agents on Health-Related Quality of Life in Anemia of Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2016; 164:472.
- Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016; 17:928.
- Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med 2016; 374:2530.
- Chandesris MO, Damaj G, Canioni D, et al. Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med 2016; 374:2605.
- Dahlén T, Edgren G, Lambe M, et al. Cardiovascular Events Associated With Use of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Population-Based Cohort Study. Ann Intern Med 2016; 165:161.
- Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2016; 374:311.
- Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 2016; 17:768.
- Important drug warning (Gilead). Decreased overall survival and increased risk of serious infections in patients receiving ZYDELIG (idelalisib). http://zydelig.com/Content/pdf/Zydelig-Safety-Info-FINAL.pdf (Accessed on March 29, 2016).
- Personal communication, Gilead Medical Information Department (25 March 2016).
- Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med 2015; 373:2425.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205552s007lbl.pdf (Accessed on March 11, 2016).
- Naik S, Nicholas SK, Martinez CA, et al. Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin Immunol 2016; 137:1498.
- Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood 2016; 127:1656.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208114lbl.pdf (Accessed on March 31, 2016).
- US Food and Drug Administration. Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products: Guidance for Industry, March 2016. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM488582.pdf (Accessed on March 07, 2016).
- Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14:1308.
- Peyvandi F, Mannucci PM, Garagiola I, et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med 2016; 374:2054.
- Letertre LR, Gudmundsdottir BR, Francis CW, et al. A single test to assay warfarin, dabigatran, rivaroxaban, apixaban, unfractionated heparin, and enoxaparin in plasma. J Thromb Haemost 2016; 14:1043.
- Baharoglu MI, Cordonnier C, Al-Shahi Salman R, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet 2016; 387:2605.
- http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM489301.pdf (Accessed on March 17, 2016).
- Shima M, Hanabusa H, Taki M, et al. Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med 2016; 374:2044.
- Bonaca MP, Gutierrez JA, Creager MA, et al. Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease: Results From the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50). Circulation 2016; 133:997.
- Newhall KA, Saunders EC, Larson RJ, et al. Use of Protamine for Anticoagulation During Carotid Endarterectomy: A Meta-analysis. JAMA Surg 2016; 151:247.
- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149:315.
- Myles PS, Smith JA, Forbes A, et al. Stopping vs. Continuing Aspirin before Coronary Artery Surgery. N Engl J Med 2016; 374:728.
- Schoenfeld SR, Choi HK, Sayre EC, Aviña-Zubieta JA. Risk of Pulmonary Embolism and Deep Venous Thrombosis in Systemic Sclerosis: A General Population-Based Study. Arthritis Care Res (Hoboken) 2016; 68:246.
- Johnson P, Federico M, Kirkwood A, et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma. N Engl J Med 2016; 374:2419.
- Rummel MJ, Knauf W, Goerner M, et al. Two years rituximab maintenance vs. observation after first-line treatment with bendamustine plus rituximab (B-R) in patients with mantle cell lymphoma: First results of a prospective, randomized, multicenter phase II study (a subgroup study of the StiL NHL7-2008 MAINTAIN trial). (abstract 7503). J Clin Oncol 2016; 34.
- Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet 2016.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125554s019lbl.pdf?utm_medium=email&utm_source=FDA-Alert-5-17-16&utm_campaign=FDA (Accessed on May 18, 2016).
- Ribrag V, Koscielny S, Bosq J, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet 2016.
- Trněný M, Lamy T, Walewski J, et al. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol 2016; 17:319.
- Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 2016.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125486s013lbl.pdf (Accessed on February 26, 2016).
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf (Accessed on November 20, 2015).
- Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016; 374:1621.
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm493081.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery (Accessed on April 06, 2016).
- Allain JP, Owusu-Ofori AK, Assennato SM, et al. Effect of Plasmodium inactivation in whole blood on the incidence of blood transfusion-transmitted malaria in endemic regions: the African Investigation of the Mirasol System (AIMS) randomised controlled trial. Lancet 2016; 387:1753.
- US Food and Drug Administration. FDA issues recommendations to reduce the risk for Zika virus blood transmission in the United States. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm486359.htm (Accessed on February 17, 2016).
- http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM486360.pdf (Accessed on February 18, 2016).
- http://apps.who.int/iris/bitstream/10665/204436/1/WHO_ZIKV_HS_16.1_eng.pdf (Accessed on February 22, 2016).
- AABB Association Bulletin #16-03. Zika, Dengue, and Chikungunya Viruses. February 1, 2016. (Available online at http://www.aabb.org/programs/publications/bulletins/Documents/ab16-03.pdf)
- Townsley DM, Dumitriu B, Liu D, et al. Danazol Treatment for Telomere Diseases. N Engl J Med 2016; 374:1922.
- ORBACTIV (oritavancin) for injection, for intravenous use. FDA package insert. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206334s002lbl.pdf (Accessed on February 02, 2016).
- Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med 2016; 374:511.