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What's new in hematology
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What's new in hematology
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Oct 11, 2017.

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

Tisagenlecleucel gene therapy for relapsed/refractory ALL (September 2017)

Relapsed/refractory lymphoblastic leukemia (ALL) generally requires achievement of complete remission prior to potentially curative allogeneic hematopoietic cell transplantation, but the optimal means of achieving remission is uncertain. Tisagenlecleucel is a novel immunotherapy in which the patient's own T cells are genetically modified to express a chimeric antigen receptor directed against CD19 on the leukemic cells. Based on an 83 percent response rate to a single treatment with tisagenlecleucel, it was approved by the US Food and Drug Administration (FDA) for treatment of patients up to 25 years old with relapsed/refractory B cell precursor ALL [1]. Tisagenlecleucel is associated with severe neurologic events and cytokine release syndrome (CRS), and is available only in specially certified facilities. Tisagenlecleucel is the first US FDA-approved gene therapy product, and it is an acceptable approach for achieving remission in children and young adults with relapsed or refractory B cell precursor ALL. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Chimeric antigen receptor T cells'.)

Gemtuzumab ozogamicin plus 7+3 induction therapy for AML (September 2017)

Addition of a third agent to anthracycline plus cytarabine induction therapy (so-called "7+3" regimens) for newly diagnosed acute myeloid leukemia (AML) has generally been disappointing. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 antibody linked to the cytotoxic agent calicheamicin. In a phase III study of adults with de novo CD33+ AML, addition of GO to 7+3 improved event-free survival, leading to its approval in this setting by the US Food and Drug Administration (FDA) [2]. It is also FDA approved as a single agent for relapsed or refractory AML in adults and in children ≥2 years old, irrespective of CD33+ status. GO has a boxed warning regarding hepatotoxicity (including potentially fatal sinusoidal obstructive syndrome) and may cause other severe adverse events (eg, infusion reactions, hemorrhage, teratogenicity). (See "Induction therapy for acute myeloid leukemia in younger adults", section on 'Adding a third agent'.)

Liposomal daunorubicin-cytarabine for treatment-related AML (August 2017)

Optimal management of treatment-related acute myeloid leukemia (t-AML) is not well defined. Based on preliminary results of a phase III trial in which liposome-encapsulated daunorubicin-cytarabine improved median overall survival compared with conventional "7+3" administration of daunorubicin and cytarabine (10 versus 6 months), and had tolerable adverse effects (eg, bleeding, infections, mucositis), the US Food and Drug Administration approved this product for patients with newly diagnosed t-AML [3]. For patients with t-AML whose performance status permits an aggressive therapeutic approach, we offer liposome-encapsulated daunorubicin and cytarabine as an alternative to conventional 7+3 therapy. (See "Therapy-related myeloid neoplasms: Acute myeloid leukemia and myelodysplastic syndrome", section on 'Treatment'.)

Enasidenib is effective for relapsed or refractory acute myeloid leukemia (August 2017)

Relapsed or refractory acute myeloid leukemia (AML) is generally treated with intensive chemotherapy in order to achieve complete remission (CR) prior to hematopoietic cell transplantation. In a multicenter phase I/II trial, daily oral treatment with enasidenib, an inhibitor of IDH2 (isocitrate dehydrogenase-2), achieved responses in 40 percent of patients (19 percent with CR), with median overall survival of nine months [4]. Grade 3-4 differentiation syndrome (DS) occurred in <10 percent of patients, including two possible DS-related deaths. Other toxicities included elevated bilirubin and nausea, but hematologic toxicities were modest. For patients whose relapsed or refractory AML has a mutation of IDH2, treatment with enasidenib is an acceptable alternative to intensive chemotherapy, with careful monitoring and prompt intervention for potential DS. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction' and "Differentiation (retinoic acid) syndrome".)

Updated guidelines for empiric antifungal therapy for children with fever and neutropenia (June 2017)

Updated guidelines from the International Pediatric Fever and Neutropenia Guideline Panel consider children with cancer or hematopoietic cell transplant as high risk for invasive fungal infection if they have acute myelogenous leukemia, high-risk acute lymphoblastic leukemia, relapsed acute leukemia, neutropenia for >10 days, or are receiving high-dose corticosteroids [5]. In contrast to the previous guideline, they weakly recommend against initiating empiric antifungal therapy for low-risk patients, using serial galactomannan to guide antifungal therapy, and obtaining computed tomography images of the sinuses before initiating antifungal therapy unless the patient has localizing signs or symptoms. They also now suggest abdominal imaging before initiation of antifungal therapy in high-risk patients. (See "Fever in children with chemotherapy-induced neutropenia", section on 'Antifungal therapy'.)

Midostaurin approved for induction therapy of AML with FLT3 mutations (April 2017)

Mutations of the FLT3 gene are found in approximately one-third of adults with acute myeloid leukemia (AML) and are associated with worse outcomes in patients undergoing induction therapy with cytarabine and daunorubicin. In a phase III trial of over 700 patients, the multitargeted small molecule FLT3 inhibitor midostaurin improved event-free and overall survival when added to standard induction therapy in adults with AML demonstrating FLT3 mutations [6]. Midostaurin is now approved by the US Food and Drug Administration in this setting [7], and we suggest the addition of midostaurin to induction therapy for treatment of adults with newly diagnosed AML who are FLT3 mutation-positive. (See "Induction therapy for acute myeloid leukemia in younger adults".)

ANEMIA AND OTHER RED CELL DISORDERS

Oral glutamine for sickle cell disease (July 2017)

In July of 2017, the US Food and Drug Administration approved an L-glutamine formulation (Endari) for reducing vaso-occlusive complications in individuals with sickle cell disease (SCD). Approval was based on a trial (as yet unpublished) in which 230 individuals with SCD who had frequent pain episodes were treated with daily oral glutamine or placebo for a year [8,9]. Compared with placebo, glutamine reduced the frequency of pain episodes, acute chest syndrome, and hospitalization. We await publication of the trial before incorporating L-glutamine into routine clinical care for individuals with SCD. (See "Vaso-occlusive pain management in sickle cell disease", section on 'L-glutamine'.)

Low-dose ferrous sulfate for iron deficiency anemia (June 2017)

For infants and children with iron deficiency anemia, standard oral iron dosing is 3 to 6 mg/kg elemental iron per day, but the optimal dose and preparation have not been established. Now, a study reports that ferrous sulfate 3 mg/kg once daily without food was effective in most patients and was more effective than an equivalent dose of an iron polysaccharide complex formulation [10]. These findings support administering ferrous sulfate at the low end of the standard dose range as first-line treatment for nutritional iron deficiency in children. (See "Iron deficiency in infants and children <12 years: Treatment", section on 'Dose and scheduling'.)

HEMATOPOIETIC CELL TRANSPLANTATION

Ibrutinib for treatment of chronic GVHD (August 2017)

Optimal management of patients with steroid-refractory (SR) chronic graft-versus-host disease (GVHD) is poorly defined. Preliminary results of a phase II trial of ibrutinib in 42 such patients reported multiorgan responses (eg, skin, mouth, gastrointestinal tract, liver) in two-thirds, which, for the majority of patients, permitted reduction in steroid dose and improved quality of life [11]. Reported side effects included fatigue, bruising, stomatitis, nausea, diarrhea, cytopenias, and infections. Ibrutinib was approved by the US Food and Drug Administration for treatment of chronic GVHD [12] and is an acceptable alternative to calcineurin inhibitors (eg, cyclosporin, tacrolimus) and other agents for treatment of SR-chronic GVHD. (See "Treatment of chronic graft-versus-host disease", section on 'Ibrutinib'.)

HEMOSTASIS AND THROMBOSIS

Safety of arthrocentesis and joint injection in patients on direct oral anticoagulants (October 2017)

Until recently, the safety of joint aspiration or injection in patients on anticoagulation was based on studies with warfarin, which reported only a small risk of increased bleeding. The first study to provide data on the risk of bleeding in patients on direct oral anticoagulants (DOACs) undergoing joint aspiration or injection is a retrospective review of 1050 consecutive procedures from Mayo Clinic over a six-year period [13]. There were no bleeding complications during the median follow-up period of five days. Of the 1050 procedures, 22 percent were performed in patients receiving a DOAC plus aspirin, and 1 percent were performed in patients on a DOAC plus clopidogrel. These findings support the safety of arthrocentesis and joint injection in patients receiving uninterrupted DOACs and/or antiplatelet therapy. (See "Joint aspiration or injection in adults: Technique and indications", section on 'Approach to the patient on anticoagulants'.)

Evaluation for occult cancer in unprovoked venous thromboembolism (August 2017)

Whether patients with a diagnosis of unprovoked venous embolism (VTE) should be evaluated for occult cancer with an extensive or more limited strategy is controversial. In a meta-analysis of 10 prospective studies (over 2000 patients with unprovoked VTE), the prevalence of cancer at one year was 5 percent [14]. Extensive screening, performed in nearly 60 percent of patients, detected more cancer initially than limited evaluation, but the difference was not significant at one year. The effect on long-term mortality is unknown. Until the benefits of extensive evaluation strategies are proven, we suggest evaluating patients with a single episode of unprovoked VTE using a limited strategy (clinical examination, routine laboratory studies, chest radiography, and age-appropriate screening) for the detection of occult cancer. (See "Evaluating patients with established venous thromboembolism for acquired and inherited risk factors", section on 'First episode of uncomplicated unprovoked VTE'.)

Anticoagulant therapy in patients with cirrhosis and portal vein thrombosis (August 2017)

Anticoagulant therapy may be beneficial for patients with cirrhosis and portal vein thrombosis. In a meta-analysis of eight studies including over 350 such patients, patients treated with anticoagulants (ie, low molecular-weight heparin or warfarin) had higher rates of either partial or complete recanalization compared with untreated patients (71 versus 42 percent) [15]. In six studies, the overall rate of bleeding was similar with or without anticoagulation (11 percent in both groups). We individualize the decision to anticoagulate in this setting, taking into account several factors including the risk of bleeding, the risk of further thrombosis, and whether the patient is awaiting liver transplantation. (See "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management", section on 'Cirrhotic patients'.)

Two new investigational therapies for hemophilia (July 2017, Modified July 2017)

Prophylaxis to reduce bleeding in hemophilia currently relies on administration of the deficient clotting factor. Two new investigational strategies have been demonstrated to reduce bleeding:

Emicizumab, a bifunctional monoclonal antibody that substitutes for the function of factor VIII, decreased bleeding in people with factor VIII deficiency (hemophilia A) who have factor VIII inhibitors (annualized bleeding rate reduced from 23 to 3 events) [16].

Fitusiran, an antisense oligonucleotide that reduces levels of antithrombin, decreased bleeding in an observational study in people with hemophilia A or hemophilia B (annualized bleeding rate reduced from 3 to 0 events) [17]. In September 2017, in the open-label extension study, a patient with hemophilia A without inhibitors developed a fatal thrombotic event [18]. Pending further safety review and development of a mitigation strategy, fitusiran administration has been suspended in all ongoing studies.

These therapies are not yet available for clinical use. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Prophylactic therapies under development'.)

Confirmatory data on idarucizumab for dabigatran reversal (July 2017)

Idarucizumab (pronounced "I-dare-you-cizumab") is a monoclonal antibody fragment against dabigatran that can reverse the anticoagulant effect within minutes. A preliminary report suggested good efficacy in patients with dabigatran-associated bleeding or those undergoing emergency surgery. In a new report of over 500 patients treated with idarucizumab, most had cessation of bleeding or underwent surgery without abnormal bleeding [19]. We continue to suggest idarucizumab for clinically significant bleeding or emergency surgery in patients on dabigatran with a history or laboratory testing that suggest they are actively anticoagulated. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.)

New oral direct factor Xa inhibitor betrixaban approved (June 2017)

The US Food and Drug administration has approved a new oral direct factor Xa inhibitor, betrixaban, for venous thromboembolism prophylaxis in acutely ill medical patients [20]. Betrixaban (brand name Bevyxxa) is taken at a dose of 160 mg on day 1 followed by 80 mg once daily for the duration of thromboprophylaxis. In a trial in which over 7500 patients hospitalized for an acute medical illness were randomly assigned to receive betrixaban or the low molecular weight heparin enoxaparin for 35 to 42 days, betrixaban was associated with a trend towards greater efficacy and a similar risk of bleeding compared with enoxaparin. (See "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects" and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

Neuraxial anesthesia in parturients with thrombocytopenia (June 2017)

The risk of spinal epidural hematoma (SEH) associated with neuraxial anesthesia (NA) techniques in patients with thrombocytopenia is poorly defined because SEH is rare. In a systematic review of over 1500 NA procedures in parturients with platelet counts less than 100,000 /microL, no cases of epidural hematoma requiring decompressive laminectomy were identified [21]. A statistical analysis based on data from this cohort suggests that the incidence of epidural hematoma may range from 0.2 percent (for platelet counts 70 to 100,000/microL) to 11 percent (for platelet counts <49,000/microL). These estimates may inform clinical decision-making regarding performance of NA in parturients with thrombocytopenia. (See "Adverse effects of neuraxial analgesia and anesthesia for obstetrics".)

Tranexamic acid for management of postpartum hemorrhage (May 2017)

Tranexamic acid, an antifibrinolytic drug, reduces bleeding in surgical and trauma patients. In a pragmatic randomized trial involving over 20,000 women with postpartum hemorrhage in over 20 countries (the World Maternal Antifibrinolytic Randomized Trial [WOMAN]), tranexamic acid, compared with placebo, reduced the relative risk of death due to bleeding by 20 to 30 percent, reduced the incidence of laparotomy to control bleeding, and was not associated with an increase in adverse effects [22]. Overall mortality was not reduced. We now recommend administration of tranexamic acid as a component of the treatment for postpartum hemorrhage. (See "Postpartum hemorrhage: Medical and minimally invasive management".)

Rivaroxaban for treatment of superficial vein thrombosis (May 2017)

Short-term anticoagulation is recommended for treatment of superficial vein thrombosis (SVT) in patients at high risk for venous thromboembolism (VTE). The phase 3b SURPRISE trial randomly assigned over 400 patients with SVT to oral rivaroxaban (a direct factor Xa inhibitor) or subcutaneous fondaparinux and found that both groups had similar rates of symptomatic VTE, progression or recurrence of SVT, and all-cause mortality at 45 days [23]. There were no major bleeds in either group, but clinically relevant nonmajor bleeding occurred more often in the rivaroxaban group. Thus, rivaroxaban appears to be an effective anticoagulant for patients with SVT and may be a more convenient and less expensive option than subcutaneous therapy. (See "Phlebitis and thrombosis of the superficial lower extremity veins", section on 'Increased risk for thromboembolism'.)

LYMPHOMA: HODGKIN AND NON-HODGKIN

Obinutuzumab versus rituximab for advanced stage follicular lymphoma (October 2017)

While it is clear that the addition of an anti-CD20 monoclonal antibody to standard chemotherapy improves outcomes in patients with follicular lymphoma (FL), it is not known whether next generation antibodies (eg, obinutuzumab, ofatumumab) are superior to rituximab. The GALLIUM study was an international, open-label, randomized phase III trial comparing an obinutuzumab-based induction and maintenance strategy versus a rituximab-based induction and maintenance strategy in >1200 patients with previously untreated advanced stage FL [24]. The obinutuzumab-based strategy had more adverse events but resulted in superior progression-free survival. It is not known whether this will translate into an overall survival benefit with longer follow-up. While we generally prefer rituximab-based regimens, these results suggest that obinutuzumab-based regimens are an acceptable alternative for the initial treatment of advanced-stage follicular lymphoma. (See "Initial treatment of advanced stage (III/IV) follicular lymphoma", section on 'Choice of anti-CD20 antibody'.)

Rituximab maintenance therapy after autologous transplantation for mantle cell lymphoma (October 2017)

Until recently, it has been unclear whether maintenance therapy is beneficial for patients with mantle cell lymphoma (MCL) treated with autologous hematopoietic cell transplantation (HCT) as part of initial management. A Lymphoma Study Association (LYSA) Group trial randomly assigned 240 patients with MCL who had undergone autologous HCT to three years of maintenance rituximab versus observation [25]. With median follow-up >4 years since randomization, maintenance therapy with rituximab improved progression-free survival and overall survival. Based on these results, we now suggest three years of rituximab maintenance therapy for patients with MCL who have undergone autologous HCT. (See "Initial treatment of mantle cell lymphoma", section on 'Maintenance therapy'.)

Copanlisib for relapsed follicular lymphoma (September 2017)

Most patients with follicular lymphoma (FL) are not cured with conventional therapies and will experience serial relapse requiring treatment with many different regimens over the disease course. The US Food and Drug Administration (FDA) has approved copanlisib for the treatment of patients with relapsed FL who have received at least two prior systemic therapies [26]. Copanlisib is an intravenous inhibitor of PI3K alpha and delta isoforms. In small, nonrandomized studies of patients with multiply relapsed FL treated with copanlisib, approximately half of patients achieved at least a partial response, but complete responses were uncommon [27]. Serious toxicities included opportunistic infections, hypertension, hyperglycemia, noninfectious pneumonitis, cutaneous reactions, and neutropenia. We reserve the use of copanlisib as one option for patients with multiply relapsed disease. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Copanlisib'.)

Brentuximab vedotin for CD30-expressing cutaneous lymphomas (July 2017)

Mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (PC-ALCL) are CD30-expressing tumors that frequently relapse after surgical resection, radiation therapy, and/or topical therapies. In an international, phase III trial of 128 patients with MF or PC-ALCL that had progressed despite earlier methotrexate or radiation, brentuximab vedotin (BV; anti-CD30 monoclonal antibody conjugated with chemotherapy) was more effective at controlling skin disease, achieving durable responses (at least four months), maintaining progression-free survival, and providing symptomatic relief than the physician’s choice of bexarotene or methotrexate [28]. Peripheral neuropathy occurred in two-thirds of patients. BV is now an acceptable alternative for treatment of MF or PC-ALCL that relapses after initial systemic treatment. (See "Primary cutaneous anaplastic large cell lymphoma", section on 'Brentuximab vedotin' and "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Brentuximab vedotin'.)

Subcutaneous formulation of rituximab for certain lymphomas (June 2017)

Most studies evaluating the efficacy of the anti-CD20 monoclonal antibody rituximab in the treatment of B-cell lymphomas have utilized intravenous administration. A subcutaneous formulation (rituximab-hyaluronidase) has been developed, which can be administered over a shorter time and uses a fixed dose that varies with histology and chemotherapy regimen. Randomized trials have demonstrated comparable efficacy and safety of the two formulations in patients with follicular lymphoma, diffuse large B cell lymphoma, or chronic lymphocytic leukemia [29-31]. The subcutaneous formulation (rituximab-hyaluronidase) is now an option for patients with these lymphoma subtypes who have tolerated at least one full dose of intravenous rituximab [32]. (See "Initial treatment of advanced stage (III/IV) follicular lymphoma", section on 'Immunotherapy-based treatment'.)

Bendamustine plus rituximab in mantle cell or clinically indolent lymphoma (June 2017)

The preferred initial chemotherapy regimen for patients with mantle cell lymphoma (MCL) or clinically indolent lymphoma is not known, and clinical practice varies. Initial reports of two randomized trials that together included over 900 patients suggested that bendamustine plus rituximab (BR) is less toxic than and at least equally efficacious to cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP). Long-term follow-up confirms these results with no new toxicity signals [33,34]. In the StiL trial, BR demonstrates a clear progression-free survival (PFS) advantage with 10-year follow-up [33]. In the BRIGHT trial, PFS with BR is at least equivalent, and may be superior to, R-CHOP in those with MCL [34]. Neither study demonstrates a survival difference between arms. These results support our preference for the off-label use of BR in clinically indolent lymphoma or MCL. (See "Initial treatment of mantle cell lymphoma", section on 'Conventional chemoimmunotherapy' and "Initial treatment of advanced stage (III/IV) follicular lymphoma", section on 'Chemoimmunotherapy'.)

MULTIPLE MYELOMA AND OTHER PLASMA CELL DISORDERS

Post-transplant lenalidomide maintenance in multiple myeloma (August 2017)

Three large randomized trials have shown a progression-free survival (PFS) benefit with lenalidomide maintenance versus placebo or observation in patients undergoing autologous hematopoietic cell transplantation (HCT) for newly diagnosed multiple myeloma (MM), but in each, estimates in overall survival (OS) were imprecise. In a meta-analysis using data from the >1200 patients enrolled in these three trials, post-transplant maintenance with lenalidomide improved both PFS and OS [35]. Although lenalidomide maintenance showed a survival benefit in most subgroups, a survival benefit could not be demonstrated in patients with high-risk cytogenetics. These results support our preference for post-HCT lenalidomide maintenance in patients with standard-risk MM; in contrast, we offer post-HCT bortezomib maintenance to patients with intermediate- or high-risk MM. (See "Autologous hematopoietic cell transplantation in multiple myeloma", section on 'Standard-risk disease'.)

Daratumumab, pomalidomide, and dexamethasone for relapsed multiple myeloma (August 2017)

The anti-CD38 monoclonal antibody daratumumab is one of our preferred agents for the treatment of patients with relapsed or refractory multiple myeloma (MM). In a prospective trial of daratumumab, pomalidomide, and dexamethasone in multiply relapsed MM, this regimen had an overall response rate of 60 percent and a median progression-free survival of 8.8 months, and was well tolerated [36]. Based on this and other data, the US Food and Drug Administration has approved this regimen for patients with MM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. We reserve this regimen for patients with multiply relapsed disease unresponsive to lenalidomide (table 1). (See "Treatment of relapsed or refractory multiple myeloma", section on 'Efficacy'.)

Denosumab versus zoledronic acid in multiple myeloma (June 2017)

Denosumab is a monoclonal antibody used for the treatment of solid tumor bone metastases. Its efficacy in patients with multiple myeloma (MM) is unclear. In preliminary results of a trial of 1700 patients with previously untreated MM and measurable bone lesions, those randomly assigned to denosumab versus zoledronic acid experienced similar time to first skeletal-related event and overall survival, longer median progression-free survival, and lower rates of renal toxicity, but had higher rates of osteonecrosis of the jaw [37]. Despite these data, further follow-up is needed to determine the role of denosumab for patients with MM. (See "The use of osteoclast inhibitors in patients with multiple myeloma", section on 'Denosumab'.)

Early versus delayed transplant for multiple myeloma (April 2017)

Autologous hematopoietic cell transplantation (HCT) extends the survival of, though does not cure, patients with multiple myeloma. Timing for HCT was evaluated in a trial of 700 adults ≤65 years of age who had completed induction therapy with bortezomib, lenalidomide, and dexamethasone (VRD) [38]. Early transplant, following induction with VRD, was compared with delayed transplant (consolidation VRD and transplant at the time of first relapse). Approximately 80 percent of patients assigned to further VRD underwent HCT at relapse. With a median follow-up of 44 months, early HCT resulted in a longer progression-free survival, but no difference in overall survival. We take patient preference, age, genetic risk profile, and logistic factors into account to individualize the timing of HCT. (See "Autologous hematopoietic cell transplantation in multiple myeloma", section on 'Timing of first HCT'.)

OTHER HEMATOLOGY

Subcutaneous C1 inhibitor for hereditary angioedema (April 2017, Modified September 2017)

Patients with hereditary angioedema (C1 inhibitor deficiency) develop attacks of angioedema affecting the skin, gastrointestinal tract, and airway, which can be prevented with intravenous infusions of C1 inhibitor, typically given twice weekly. Subcutaneous administration should significantly facilitate self-treatment. In a randomized multicenter trial of 90 children and adults, participants injected a subcutaneous formulation of C1 inhibitor or placebo twice weekly for 16 weeks [39]. Therapy was well tolerated and participants receiving active drug had fewer attacks per month (mean 0.5 versus 4.0 attacks). This formulation was approved for prophylaxis by the US Food and Drug Administration (FDA) in June 2017 and is an appropriate option for patients who prefer this form of administration. Approval in Europe is anticipated in the near future. (See "Hereditary angioedema: General care and long-term prophylaxis", section on 'Subcutaneous C1 inhibitor'.)

Rituximab in acquired TTP (August 2017)

Acquired thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening condition; standard treatment includes plasma exchange (PEX) and glucocorticoids. The role of additional up-front rituximab in acquired TTP is evolving, as evidence continues to accumulate suggesting that rituximab may reduce the risk of relapse and refractory disease and may hasten initial response. The latest evidence comes from a retrospective study from the United Kingdom TTP Registry, which found low rates of relapse in patients treated with rituximab as part of initial therapy, although patients were only observed for a median of 15 months [40]. Based on this and other studies, we now use rituximab as a component of initial therapy for acquired TTP. Some experts may reasonably omit rituximab due to concerns about toxicity, pending additional data. Other considerations for rituximab use In TTP include the optimal dose, timing relative to PEX, and risk of hepatitis B reactivation. (See "Acquired TTP: Initial treatment", section on 'Rituximab'.)

Midostaurin for advanced systemic mastocytosis (August 2017)

Cytoreductive treatment of advanced systemic mastocytosis (SM) can mitigate organ dysfunction, improve quality of life, and limit disease progression until a suitable donor for allogeneic hematopoietic cell transplant is identified. Midostaurin is a multikinase inhibitor that is effective against SM with wild type or mutant KIT (eg, KIT D816V). A recent phase II study found that midostaurin was associated with improved measures of organ damage (eg, cytopenias, liver function studies) in two-thirds of patients with advanced SM, with median overall survival >3 years [41], confirming similar findings from an earlier trial [42]. The drug was well tolerated, with primarily grade 1 to 2 nausea/vomiting or modest cytopenias. The US Food and Drug Administration approved midostaurin for treatment of advanced SM earlier this year. We now suggest midostaurin for initial systemic therapy of advanced SM. (See "Systemic mastocytosis: Management and prognosis", section on 'Choice of therapy'.)

Opana ER withdrawn from the US market (July 2017)

A long-acting abuse-deterrent formulation of oxymorphone, Opana ER, is being voluntarily withdrawn from the United States (US) market at the request of the US Food and Drug Administration due to concerns related to injection abuse, including reports of thrombotic microangiopathy (TMA) when the oral formulation is injected intravenously (IV) [43-45]. The TMA is thought to be due to an inert component that was added to the formulation to make it crush-resistant and thus deter IV injection. Generic extended-release oxymorphone products remain on the US market. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Oxycodone, hydrocodone, hydromorphone, and oxymorphone' and "Drug-induced thrombotic microangiopathy", section on 'Drugs of abuse'.)

Discontinuation of eculizumab in complement-mediated hemolytic uremic syndrome (June 2017)

Eculizumab is an effective treatment for complement-mediated hemolytic uremic syndrome (HUS). Monthly intravenous maintenance administration has been the standard of care for patients attaining complete remission. Now, two case series have reported successful discontinuation of eculizumab in most patients, with successful remission after early resumption of therapy in those who relapsed [46,47]. Although these results are promising, further studies are needed to determine the optimal time to discontinue eculizumab therapy and the patient population in whom therapy can be safely discontinued. Until these data are available, the decision to withdraw eculizumab therapy should be made in conjunction with a clinician with expertise in managing patients with complement-mediated HUS. Close monitoring after withdrawal is required so eculizumab can be reinitiated if relapse occurs. (See "Complement-mediated hemolytic uremic syndrome", section on 'Discontinuation'.)

Eltrombopag for adults with acquired severe aplastic anemia unable to undergo HCT (May 2017)

Acquired aplastic anemia (AA) has a high morbidity, and allogeneic hematopoietic cell transplantation (HCT) is suggested as therapy for patients healthy enough to tolerate HCT who have a suitable donor. Immunosuppressive therapy (IST) is offered to those for whom HCT is not an option but is often ineffective in improving outcomes over the long term. A prospective cohort study in adults with acquired severe AA evaluated the effectiveness of IST plus eltrombopag, a thrombopoietin receptor agonist that acts on platelet precursors and hematopoietic stem cells [48]. Eltrombopag plus IST produced higher rates of overall hematologic response at six months compared with responses in a historical cohort (80 to 94 percent versus 66 percent for the historical group). Based on these findings, we now suggest administration of eltrombopag plus IST for individuals with acquired severe AA who are not candidates for allogeneic HCT. (See "Treatment of aplastic anemia in adults", section on 'Evidence for efficacy'.)

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