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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
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 . 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) . 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 . 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 . 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 . 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'.)
ANEMIA AND OTHER RED CELL DISORDERS
Frequency for dosing of oral iron (November 2017)
For many years, iron deficiency has been treated with oral iron given at least once per day, despite significant gastrointestinal side effects in the majority of individuals. A small, unblinded randomized trial has now demonstrated that giving oral iron every other day rather than every day resulted in greater iron absorption and fewer gastrointestinal side effects . Alternate-day dosing is also supported by mechanistic studies that showed favorable effects on hepcidin, a negative regulator of intestinal iron absorption and iron release from macrophages. We now suggest that patients treated with oral iron for iron deficiency take the iron every other day rather than daily. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)
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 [7,8]. 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 . 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
Letermovir for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplant recipients (November 2017)
Letermovir, a novel anti-cytomegalovirus (CMV) agent with intravenous and oral formulations, was approved by the US Food and Drug Administration and Health Canada in November 2017 for CMV prophylaxis in adult CMV-seropositive (CMV R+) allogeneic hematopoietic cell transplant (HCT) recipients [10-12]. Unlike ganciclovir and valganciclovir, letermovir is not myelosuppressive. In a phase III trial that has not yet been published, all-cause mortality among CMV-seropositive allogeneic HCT recipients was lower with letermovir than placebo . In addition, fewer patients receiving letermovir developed clinically significant CMV or were considered to have failed prophylaxis. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Primary prophylaxis'.)
Hematopoietic stem cell gene therapy for adrenoleukodystrophy (October 2017)
Childhood cerebral adrenoleukodystrophy (ALD) is a severe neurologic disease that rapidly progresses to total disability and death unless treated with allogeneic hematopoietic cell transplantation (HCT), which has considerable morbidity and mortality. Gene therapy with autologous hematopoietic stem cells is emerging as a possible alternative treatment. A study of 17 boys with early-stage cerebral ALD enrolled to undergo transplantation with autologous CD34+ cells transfected with Lenti-D (a lentiviral vector containing manufactured ABCD1 complementary DNA) reported 88 percent were alive with no major functional disabilities at 24 months posttransplantation . One boy died from disease progression that began during pretransplantation conditioning, and one was withdrawn from the study and died from complications of subsequent allogeneic HCT. None of the survivors had evidence of graft failure or graft-versus-host disease. These results suggest that autologous hematopoietic stem cell gene therapy may be as effective as, and safer than, HCT for treatment of early cerebral ALD. The treatment has not received regulatory approval. The clinical trial is ongoing and important uncertainties remain. (See "Adrenoleukodystrophy", section on 'Gene therapy'.)
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 . 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  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
Emicizumab for prophylaxis in hemophilia A with an inhibitor (November 2017)
Emicizumab, a bifunctional monoclonal antibody that can substitute for factor VIII (figure 1), was approved by the US Food and Drug Administration in November 2017 for prophylaxis against bleeding in individuals with hemophilia A who have an inhibitor . It is administered subcutaneously once per week. In a randomized trial comparing emicizumab with standard therapy in 109 individuals with hemophilia and an inhibitor, emicizumab reduced the annualized bleeding rate from 23 to 3 events . Three patients receiving emicizumab plus an activated prothrombin complex concentrate (aPCC) developed a thrombotic microangiopathy, and two had a thrombosis in an unusual site. Emicizumab cannot be used for acute bleeding. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab'.)
Evidence-based guidelines for pediatric antiphospholipid syndrome (October 2017)
The first evidence-based guidelines for pediatric antiphospholipid syndrome (APS) and catastrophic APS have been published by the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative . The panel concluded that the existing adult criteria for APS, while specific, may lack sensitivity for pediatric APS. Thus, the guideline calls for new pediatric classification criteria to be developed, which would incorporate both non-thrombotic and thrombotic manifestations in children. The recommendations also provide guidance on risks of perinatal thrombosis and neurodevelopmental abnormalities in children born to mothers with APS. (See "Diagnosis of antiphospholipid syndrome", section on 'Diagnosis'.)
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 . 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 . 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 adult 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) . 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'.)
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 . 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 . 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 . 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".)
LYMPHOMA: HODGKIN AND NON-HODGKIN
Obinutuzumab versus rituximab for advanced stage follicular lymphoma (October 2017, Modified November 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 . The obinutuzumab-based strategy had more adverse events but resulted in superior progression-free survival, leading to approval by the US Food and Drug Administration in this setting. 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'.)
CAR-T therapy for relapsed DLBCL after autologous transplantation (October 2017)
Optimal treatment is not well defined for patients with diffuse large B cell lymphoma (DLBCL) that relapses after autologous hematopoietic cell transplantation (HCT). Axicabtagene ciloleucel (axi-cel) is a CD19-directed, chimeric antigen receptor T (CAR-T) cell autologous immunotherapy that was recently approved by the US Food and Drug Administration (FDA) for treatment of adults with relapsed or refractory DLBCL after two or more lines of systemic therapy . In a preliminary report, a single infusion of axi-cel achieved complete and partial remissions in 51 and 21 percent of patients, respectively, with an estimated median response duration of nine months. Treatment is associated with potentially life-threatening neurologic events and cytokine release syndrome, and axi-cel is only available under a Risk Evaluation and Mitigation Strategy (REMS) in the United States. (See "Treatment of relapsed or refractory diffuse large B cell lymphoma", section on 'Chimeric antigen receptor T (CAR-T) cells'.)
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 . 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 . 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 . 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 . 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 [32-34]. 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 . (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 [36,37]. In the StiL trial, BR demonstrates a clear progression-free survival (PFS) advantage with 10-year follow-up . In the BRIGHT trial, PFS with BR is at least equivalent, and may be superior to, R-CHOP in those with MCL . 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
Light chain (AL) amyloidosis and advanced chronic kidney disease (December 2017)
In patients with light chain (AL) amyloidosis, response to chemotherapy is associated with improved patient and renal survival. However, little is known about the benefits of chemotherapy in patients who present with advanced chronic kidney disease (CKD). In a study of 84 patients with AL amyloidosis and an estimated glomerular filtration rate (eGFR) of <20 mL/min/1.73 m2 at the time of diagnosis, patients who achieved ≥90 percent reduction in the amyloidogenic free light chain within three months of baseline had better overall survival and a prolonged time to dialysis compared with those who achieved a smaller response at three months; chemotherapy benefit was not seen for patients who achieved ≥90 percent light chain reduction but only after three months . Thus, patients with AL amyloidosis and advanced CKD at presentation may benefit from treatment, but the magnitude and time to hematologic response appear to be critical factors in determining outcome. (See "Renal amyloidosis", section on 'Response to therapy'.)
Carfilzomib versus bortezomib in relapsed multiple myeloma (November 2017)
Carfilzomib is a second generation proteasome inhibitor used for relapsed or refractory multiple myeloma (MM). In a multicenter, phase 3 trial (ENDEAVOR), over 900 patients with relapsed MM were randomly assigned to receive carfilzomib plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd) . Kd resulted in deeper responses and improved both progression-free and overall survival; there was less neuropathy and a low but increased frequency of heart failure, acute renal failure, and hypertension. These results confirm the efficacy of carfilzomib in relapsed MM, but it is not known how initial treatment with Kd compares with initial use of Vd followed by Kd at the time of progression. (See "Treatment of relapsed or refractory multiple myeloma", section on 'Efficacy and toxicity'.)
Cross-sectional imaging for suspected multiple myeloma (November 2017)
Imaging is a key part of the evaluation of all patients with suspected multiple myeloma (MM). Until recently, a skeletal survey using plain radiographs had been the preferred modality for detecting bone lesions that would trigger the institution of therapy. Low-dose computerized tomography (CT), FDG positron emission tomography (PET)/CT, and magnetic resonance imaging (MRI) are all more sensitive than plain radiographs for the detection of most skeletal lesions in myeloma. Accumulating data suggest that patients who previously would have met criteria for smoldering myeloma based on negative skeletal surveys, but who have lesions detected by one of these modalities, have a shorter time to progression than similar patients with negative cross-sectional imaging . We now prefer cross-sectional imaging with one of these modalities for patients with suspected MM. The preferred modality depends upon availability, cost, institutional preference, and clinical features. (See "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma", section on 'Choice of modality' and "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma", section on 'CT, MRI, and PET'.)
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 . 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 . 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 . 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'.)
Red blood cell transfusion threshold in patients undergoing cardiac surgery (November 2017)
While the optimal red blood cell transfusion threshold for patients undergoing cardiac surgery with cardiopulmonary bypass is not known, experts have generally recommended transfusion for hemoglobin values less than 8 g/dL. In the TRICS III trial, over 5000 adults at high risk of death were randomly assigned to a restrictive red cell transfusion threshold (transfuse if hemoglobin <7.5 g/dL) or a liberal threshold (transfuse if hemoglobin <9.5 g/dL) . There was no difference in the rate of the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis while, as expected, the rate of transfusion was higher in the group with the higher transfusion threshold. This trial confirms findings in smaller randomized trials and supports our practice to transfuse to maintain the hemoglobin level above 8 g/dL, recognizing that individual patient factors may alter this threshold. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Blood transfusion'.)
RBC transfusions from multiparous female donors (October 2017)
A large observational study involving almost one million red blood cell (RBC) transfusion recipients found that the age and sex of the RBC donor did not affect mortality in the recipient. A new study has raised the possibility that RBC transfusion from a multiparous female donor might be associated with a small increase in mortality in male recipients . However, methodological issues raise some questions about the validity of these results, and the findings would need to be replicated before any changes in RBC donor screening procedures are considered. (See "Red blood cell transfusion in adults: Storage, specialized modifications, and infusion parameters", section on 'Effect of donor characteristics (eg, donor sex and age) on transfusion outcomes'.)
Living donor kidney transplantation without eculizumab for complement-mediated hemolytic uremic syndrome (November 2017)
Eculizumab is used to prevent recurrent complement-mediated hemolytic uremic syndrome (HUS) after kidney transplantation, but its high cost has led to evaluation of alternative transplant strategies. A case series reported outcomes of 17 patients with complement-mediated HUS who underwent a living donor kidney transplant protocol (basiliximab induction, low-dose tacrolimus, high-dose mycophenolate mofetil, and strict blood pressure control) with no eculizumab prophylaxis . At a median of 25 months, all patients had stable graft function without significant proteinuria; one patient developed recurrent HUS but was successfully treated with eculizumab. Longer-term studies are required to confirm the efficacy and safety of this approach. (See "Recurrent and de novo HUS after renal transplantation", section on 'Prophylactic therapy'.)
Methemoglobinemia from antifreeze (November 2017)
Methemoglobinemia, which may be fatal, can be caused by exposure to a number of medications as well as certain solvents, pesticides, and dyes (table 2); the product label or safety data sheet may not always include information about these chemicals. As an example, an individual who drank antifreeze was found to have methemoglobinemia due to nitrites or nitrates that were not listed on the safety data sheet . Clinicians should maintain a high level of suspicion for methemoglobinemia in patients with cyanosis and findings related to tissue hypoxia (eg, tachycardia, headache, lethargy). (See "Clinical features, diagnosis, and treatment of methemoglobinemia", section on 'Other chemicals'.)
Thrombotic microangiopathy due to quinine ingestion (October 2017)
Quinine is a common cause of drug-induced thrombotic microangiopathy (DITMA). A new report illustrates common features among the largest series of individuals (18 women and 1 man) with quinine-associated DITMA . Most of the patients had a prior history of quinine-induced fever, nausea, headache, or confusion. Many reported symptoms within four hours of quinine ingestion. All had acute kidney injury. Eighteen required dialysis, and two underwent renal transplantation. Eighteen had quinine-dependent antibodies. Individuals presenting with thrombotic microangiopathy require specific questioning about quinine ingestion since the source may be a beverage or an over-the-counter tablet. (See "Drug-induced thrombotic microangiopathy", section on 'Quinine'.)
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 . 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 , confirming similar findings from an earlier trial . 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) [52-54]. 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 [55,56]. 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 . 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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