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What's new in hematology

What's new in hematology
Authors:
Rebecca F Connor, MD
Jennifer S Tirnauer, MD
Alan G Rosmarin, MD
Literature review current through: Feb 2022. | This topic last updated: Feb 28, 2022.

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 LEUKEMIAS AND MYELODYSPLASTIC SYNDROMES

Routine premedication for PEGylated asparaginase (January 2022)

Asparaginase, a polypeptide of bacterial origin, is an important component of treatment for acute lymphoblastic leukemia, and PEGylated products (eg, pegaspargase, calaspargase) are now preferred for newly diagnosed patients. While they are less immunogenic than nonpegylated E. coli-derived asparaginase, infusion reactions still occur in up to one-third of patients. In 2021, the pegaspargase United States prescribing information was updated to recommend routine premedication with acetaminophen, an H1-receptor blocker, and an H2-receptor blocker administered 30 to 60 minutes prior to each dose [1]. The prescribing information for calaspargase has also been similarly updated [2]. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase'.)

No benefit of sapacitabine added to decitabine in myelodysplastic syndrome (November 2021)

The preferred initial treatment for myelodysplastic syndrome (MDS) in medically unfit patients generally includes decitabine or azacitidine plus another agent, but the favored second agent varies with pathologic features and drug availability. In a recent phase 3 trial of nearly 500 such patients, alternating cycles of sapacitabine (an investigational oral deoxycytidine analogue) with decitabine were associated with a modest increase in complete remissions compared with decitabine alone (17 versus 11 percent), but there was no improvement in overall survival, transfusions, or hospitalizations [3]. Severe cytopenias, infections, and disease progression were similar in both arms. Since sapacitabine did not improve survival or decrease toxicity, its role in MDS remains uncertain. (See "Acute myeloid leukemia: Management of medically-unfit adults", section on 'HMA plus other agents'.)

ANEMIA AND OTHER RED CELL DISORDERS

New consensus for managing alpha thalassemia major (January 2022)

Alpha thalassemia major (ATM; deletion of all four alpha globin genes) was once considered incompatible with life, but advances in prenatal and postnatal care have resulted in viability and good quality of life for an increasing number of individuals. A new consensus document outlines management principles for ATM, which include prenatal screening, confirmation of the diagnosis early in the pregnancy, nondirective counseling, and, for those who choose to continue the pregnancy with fetal therapy, intrauterine transfusions (IUTs) started as early as technically possible [4]. Delivery should occur in a facility that can provide high-level critical care. Some neonates may need aggressive resuscitation at birth, although this is generally unnecessary after serial IUTs. Education about options for future pregnancy should be provided. (See "Alpha thalassemia major: Prenatal and postnatal management".)

Gene therapy for thalassemia (December 2021)

Earlier studies of gene therapy for thalassemia determined that therapy is most effective when used for individuals with transfusion-dependent beta thalassemia who had some beta globin production (non-beta0/beta0 genotypes). A new gene therapy study restricted to this population has observed encouraging results, with transfusion independence in 20 of 22 evaluable patients (91 percent), including 6 of 7 children <12 years of age [5]. Hematopoietic stem cell transplantation with myeloablative chemotherapy is required. (See "Management of thalassemia", section on 'Gene therapy and other stem cell modifications'.)

Prevalence of iron deficiency during pregnancy (December 2021)

A new retrospective study involving over 44,000 pregnant individuals suggests that a large proportion have iron deficiency, many in the absence of anemia [6]. Ferritin was low in over half (<15 ng/mL in 24 percent, <30 ng/mL in 53 percent) and borderline (30 to 44 ng/mL) in another 25 percent. Individuals with lower household income were less likely to be screened. These data support having a high level of suspicion for iron deficiency during pregnancy, being aware of possible health care disparities, testing individuals at high risk, and evaluating the cause in all patients with anemia. Iron deficiency is correlated with adverse maternal and fetal outcomes. (See "Anemia in pregnancy", section on 'Whether to screen for iron deficiency'.)

Gene therapy for sickle cell disease (December 2021)

The largest study of gene therapy for sickle cell disease has been published, including data from 35 patients with a median follow-up of over 17 months [7]. The gene therapy construct uses an anti-sickling variant of beta globin, introduced into autologous hematopoietic stem and progenitor cells that are delivered by autologous hematopoietic stem cell transplant. After transplant, vaso-occlusive events decreased from a mean of 3.5 to 0 annually, and median hemoglobin increased from 8.5 to ≥11 g/dL. Transplant toxicities were as expected; one individual with underlying pulmonary hypertension and hypertrophic cardiomyopathy died after 20 months. Other gene therapy and gene editing approaches are under study. (See "Investigational therapies for sickle cell disease", section on 'Anti-sickling beta globin gene'.)

Daprodustat for anemia treatment in nondialysis chronic kidney disease (November 2021)

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs) are a novel class of oral erythropoiesis-stimulating agents (ESAs) that are being evaluated for treatment of anemia in patients with chronic kidney disease (CKD). In a trial of nearly 4000 patients with nondialysis CKD and anemia that compared the safety and efficacy of the HIF PHI daprodustat with darbepoetin, hemoglobin concentrations increased more with daprodustat at approximately two years [8]. However, major cardiovascular events (a composite of death, nonfatal stroke, and nonfatal myocardial infarction) were also more frequent with daprodustat, a difference that was statistically significant during the active treatment period but not by the end of post-treatment follow-up. Although these data indicate that anemia can be effectively treated with daprodustat, they raise some safety concerns about this drug. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Investigational agents'.)

Sickle cell disease pain management in infusion centers (August 2021)

Hematology-oncology infusion centers or day hospitals staffed by clinicians familiar with sickle cell disease (SCD) can provide rapid evaluation and treatment of uncomplicated pain using a plan tailored to the individual's analgesic history. A study comparing pain management in nearly 500 adults with SCD who were treated in an infusion center or an emergency department (ED) found infusion center treatment was associated with better outcomes, including administration of pain medication nearly twice as fast, rapid reassessment nearly four times more likely, and rate of hospitalization nearly four-fold less [9]. These data reinforce the practice of managing acute SCD pain in hematology-oncology clinics or dedicated day hospitals rather than EDs. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Day hospital/infusion center'.)

CHRONIC LEUKEMIAS AND THE MYELOPROLIFERATIVE NEOPLASMS

No role for ibrutinib in early stage CLL without active disease (January 2022)

For patients with early stage chronic lymphocytic leukemia (CLL) without "active disease" (table 1), chemotherapy increases toxicity relative to observation, without clinical benefit; but there is limited evidence regarding targeted therapies. The randomized CLL12 trial evaluated ibrutinib in >360 patients with early stage, asymptomatic CLL without active disease, but with prognostic markers associated with worse clinical outcomes [10]. Ibrutinib postponed the development of active disease and the need for additional CLL-directed therapy compared with placebo, but increased toxicity. It is unknown whether these improved short-term measures will translate into clinically meaningful benefits, including improved overall survival. Observation remains standard for early stage, asymptomatic CLL, with early treatment reserved for clinical trials. (See "Overview of the treatment of chronic lymphocytic leukemia", section on 'Initial observation as standard care'.)

HEMATOPOIETIC CELL TRANSPLANTATION

Ex vivo expansion of umbilical cord blood for allogeneic HCT (January 2022)

Umbilical cord blood (UCB) is an important alternative graft source for allogeneic hematopoietic cell transplantation (HCT), but its use for transplantation in adults is often limited by an inadequate cell dose, which can cause delayed engraftment. Ex vivo treatment of UCB using nicotinamide can increase the cell dose and may increase homing to marrow. In a recent phase 3 trial, allogeneic HCT using a single, ex vivo expanded UCB unit achieved faster engraftment, reduced infections, and shortened hospital stays compared with an unmanipulated UCB product [11]. There was no difference in graft-versus-host disease (GVHD) or overall survival. We consider allogeneic HCT using an ex vivo nicotinamide-expanded UCB graft to be acceptable when the cell dose appears to be limiting. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation".)

Belumosudil for steroid-refractory chronic graft-versus-host disease (GVHD) (December 2021)

More than two-thirds of patients with chronic graft-versus-host disease (cGVHD) require treatment beyond systemic corticosteroids, but there is no consensus treatment for steroid-refractory (SR) cGVHD and current approaches have limited efficacy and/or substantial toxicity. Belumosudil, a novel oral inhibitor of ROCK2, was associated with objective responses and significant symptomatic improvement in more than two-thirds of patients with SR-cGVHD, with mostly modest adverse effects [12]. Belumosudil was recently approved by the US Food and Drug Administration (FDA) for treatment of SR-cGVHD in patients who received two to five prior therapies. We consider belumosudil an acceptable later-line treatment for SR-cGVHD as we await studies that compare it with other available therapies. (See "Treatment of chronic graft-versus-host disease", section on 'Belumosudil'.)

Ruxolitinib for treatment of steroid-refractory (SR)-chronic graft-versus-host disease (cGVHD) (September 2021)

Treatment of steroid-refractory chronic graft-versus-host disease (SR-cGVHD; ie, an inadequate response or intolerance to prednisone) has generally been ineffective and/or associated with substantial toxicity. A recent randomized trial reported that adding ruxolitinib (JAK kinase inhibitor) to prednisone was superior to adding the best available treatment (BAT; investigator's choice of 10 treatments) to prednisone [13]. Compared with BAT, at 24 weeks ruxolitinib achieved superior overall responses (50 versus 26 percent, respectively), improved symptoms, and longer failure-free survival, with comparable rates of serious adverse events. Ruxolitinib can be associated with cytopenias, liver dysfunction, neurologic complaints, infections, and a "withdrawal syndrome" that resembles systemic inflammatory response syndrome when abruptly discontinued. For patients with SR-cGVHD, we suggest adding ruxolitinib to prednisone, rather than adding an alternative second agent. (See "Treatment of chronic graft-versus-host disease", section on 'Ruxolitinib'.)

HEMOSTASIS AND THROMBOSIS

Duration of anticoagulation for low-risk provoked venous thromboembolism in pediatric patients (February 2022)

The optimal duration of anticoagulant therapy for children with venous thromboembolism (VTE) is uncertain. Usual practice has been to treat for three months based largely upon evidence from adult studies. However, a recent clinical trial suggests that six weeks of therapy is sufficient for most pediatric patients with low-risk provoked VTE (ie, attributable to a transient risk factor) [14]. The trial enrolled 417 children with provoked VTE (catheter-associated in 50 percent; infection-related in 30 percent; surgery- or trauma-related in 20 percent) who were randomly assigned to six weeks or three months of anticoagulant therapy. At one year, rates of VTE recurrence were similarly low in both groups (1.1 and 1.6 percent, respectively). Based upon these findings, we now suggest a six-week course of treatment for pediatric patients with provoked VTE who met all of the following low-risk criteria:

No prior history of VTE

The VTE is not severe or life-threatening

The provoking risk factor resolves within six weeks

The thrombus resolves or is nonocclusive within six weeks

For patients with provoked VTE who do not meet these criteria, we continue to suggest three months of therapy. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Provoked VTE'.)

Updated guidelines on venous thromboembolism management (January 2022)

Updated guidelines on the treatment of venous thromboembolism (VTE) were published by the American College of Chest Physicians (CHEST) [15]. Many recommendations are similar to those in the 2016 guideline but either expanded in scope or changed in strength of the recommendation. As new recommendations, for most patients with cancer-related VTE, CHEST suggests a direct oral anticoagulant (DOAC) rather than low molecular weight heparin. For select patients without cancer who require extended anticoagulation beyond the conventional period of three to six months, CHEST suggests low-intensity anticoagulation with a DOAC. While CHEST did not promote aspirin for VTE prevention, they suggest that it may reduce the risk of recurrence when compared with no therapy. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Choosing apixaban or rivaroxaban for venous thromboembolism (December 2021)

Although several direct oral anticoagulants (DOACs) are available for treating patients with venous thromboembolism (VTE), no randomized trials support choosing one over another. A recent retrospective study reported that among 37,000 new users of apixaban or rivaroxaban, apixaban was associated with lower rates of recurrent VTE (hazard ratio [HR] 0.77, 95% CI 0.69-0.87) and bleeding (HR 0.60, 95% CI 0.53-0.69) [16]. While these data favor apixaban, we continue to favor an individualized choice among DOACs that also take into consideration cost, availability, and preference for once- versus twice-daily dosing. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Efficacy' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Gene therapy for hemophilia (December 2021)

Investigation of gene therapy for hemophilia continues to advance. In a new study in 18 individuals with severe hemophilia A who were treated with an adeno-associated virus (AAV) vector, stable expression of factor VIII was maintained for at least one year in 16 individuals [17]. The annualized bleeding rate for the entire cohort decreased from 8.5 to 0.3 events per year, and factor infusions decreased from 58 to 0.6 per year. Therapy was well tolerated, with one infusion reaction and seven transaminase elevations. Several other constructs for hemophilia A and B are under investigation. (See "Gene therapy and other investigational approaches for hemophilia", section on 'Hemophilia A'.)

Investigational DOAC targeting factor XIa (November 2021)

Milvexian is an investigational direct oral anticoagulant (DOAC) that targets the active form of factor XI. In a dose-finding trial in which various doses and schedules of milvexian were compared with standard prophylactic enoxaparin in adults undergoing knee arthroplasty, rates of postoperative venous thromboembolism (VTE) were lower with milvexian [18]. Bleeding rates were similar. Comparison with other DOACs would be informative. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Inhibitors of factor XI or factor XIa'.)

Safety of anticoagulation in factor XI deficiency (November 2021)

Factor XI deficiency is a bleeding disorder in which bleeding typically occurs with trauma but not spontaneously. Although factor XI deficiency provides partial protection from venous thromboembolism, antithrombotic therapy may be indicated in selected individuals (eg, if they develop atrial fibrillation [AF]). A new review of over 200 people with factor XI deficiency identified 15 individuals who were treated with anticoagulation, mostly with warfarin for AF [19]. There were no major bleeding events. Two patients had minor bleeds before starting warfarin, and two had minor bleeds after starting warfarin, suggesting no significant increase in bleeding. These findings are reassuring regarding the safety of anticoagulation when needed. (See "Factor XI (eleven) deficiency", section on 'Anticoagulation or antiplatelet therapy'.)

Neuraxial anesthesia and delivery in individuals with VWD (November 2021)

In a retrospective review of 106 deliveries among 71 individuals with von Willebrand disease (VWD) seen by a high-risk anesthesia consult service, neuroaxial anesthesia was used in 89 percent without complications [20]. Treatment with desmopressin (DDAVP) or a von Willebrand factor (VWF) concentrate was used in approximately one-third. Postpartum hemorrhage occurred in approximately 10 percent, mostly following cesarean delivery. We believe that most individuals with type I and mild-to-moderate type II VWD may receive neuraxial anesthesia, especially with good antepartum planning and as long as their VWF levels can be maintained at 50 to 100 international units (IU)/dL. VWF levels decline rapidly following delivery, and close monitoring is needed postpartum. (See "von Willebrand disease (VWD): Treatment of minor bleeding and routine care", section on 'Delivery and postpartum care'.)

Risk of GI bleeding with DOACs (October 2021)

Direct oral anticoagulants (DOACs) are generally preferred over warfarin in individuals with non-valvular atrial fibrillation or venous thromboembolism. A new study evaluated the risk of gastrointestinal (GI) bleeding in over 5000 individuals taking apixaban, rivaroxaban, or dabigatran [21]. Higher rates of GI bleeding were seen in individuals taking rivaroxaban (3.2 per 100 patient-years) than with the other agents (2.5 for apixaban and 1.9 for dabigatran). The once-daily dosing of rivaroxaban and higher peak levels may explain the higher bleeding risk; the other agents are dosed twice daily. These results may be a consideration when choosing among DOACs. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Differences between factor Xa inhibitors'.)

Plasma not helpful for mildly elevated INR (October 2021)

A new trial has documented the lack of benefit from using plasma to "correct" an increased prothrombin time (PT) and international normalized ratio (INR). The trial randomly assigned 57 hospitalized adults with an INR of 1.5 to 2.5 (approximately 60 percent with cirrhosis) who were undergoing a procedure outside the operating room to receive or not receive plasma [22]. There was little to no difference in post-procedure hemoglobin (a measure of bleeding), hospital length of stay, or adverse events. Although small, this trial adds further evidence that plasma should not be used to treat a mildly elevated INR. Appropriate uses of plasma include massive transfusion protocols, therapeutic plasma exchange, and treatment of bleeding due to one or more deficient clotting factors when a specific factor concentrate is unavailable. (See "Clinical use of plasma components", section on 'Settings in which plasma is not appropriate'.)

LMW heparin dosing in individuals with high BMI (September 2021)

Optimal dosing of low molecular weight (LMW) heparins for individuals with high body mass index (BMI) is unknown, and guideline recommendations are variable regarding whether to prefer fixed dosing or weight-based dosing for venous thromboembolism (VTE) prophylaxis. A new meta-analysis has evaluated data from 11 studies (nearly 20,000 medical and surgical patients with high BMI) treated with fixed-dose or weight-based dose LMW heparin and found little or no difference in the rates of recurrent VTE or bleeding [23]. Although more data are needed, these results are reassuring and suggest that both approaches are reasonable. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Dosing at extremes of body weight'.)

Direct oral anticoagulants for venous thromboembolism in children ≥2 years (August 2021)

In 2021, the US Food and Drug Administration approved two direct oral anticoagulants (DOACs), dabigatran and rivaroxaban, for treatment of venous thrombosis and thromboembolism (VTE) in children [24,25]. These regulatory approvals were based upon two large multicenter pediatric trials demonstrating that dabigatran and rivaroxaban have similar efficacy and bleeding risk compared with low molecular weight heparin (LMWH) and warfarin [26,27]. Adolescents made up most of the trial populations, and children <2 years were underrepresented. DOACs are an attractive option since they are orally administered and do not require drug monitoring. We now suggest one of the approved DOACs (dabigatran or rivaroxaban) for treatment of VTE in adolescents, after at least five days of initial parenteral therapy. For children ages 2 to 11 years, either a DOAC or LMWH is acceptable. For infants and children <2 years, the efficacy and safety of DOACs remain uncertain, and we continue to suggest LMWH. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Direct oral anticoagulants'.)

LYMPHOMAS: HODGKIN AND NON-HODGKIN

Prognostic scoring for patients with angioimmunoblastic T cell lymphoma (AITL) (January 2022)

Angioimmunoblastic T cell lymphoma (AITL) is an aggressive peripheral T cell lymphoma, but current prognostic scoring systems do not successfully stratify patients according to outcomes. The AITL score is a new prognostic scoring system that stratified 282 patients into three groups based on clinical and laboratory features: low-risk (63 percent five-year overall survival), intermediate-risk (54 percent), and high-risk (21 percent) [28]. The model was validated with a separate cohort of patients. We consider the AITL score the most accurate way to assess risk and outcomes in patients with AITL. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma", section on 'Prognosis'.)

Chimeric antigen receptor-T cell therapy for early relapse or refractory diffuse large B cell lymphoma (January 2022)

Although autologous hematopoietic cell transplantation (HCT) has long been standard treatment in medically-fit patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), recent phase 3 trials compared transplantation with CD19-directed chimeric antigen receptor (CAR)-T products in these settings. In patients with early first relapse (<12 months after initial therapy) or primary refractory DLBCL, lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) improved event-free and overall survival relative to autologous HCT, with acceptable toxicity [29,30]. By contrast, another CD-19 CAR-T cell product, tisagenlecleucel, did not improve outcomes or toxicity relative to HCT [31]. CAR-T cell therapy is restricted to approved institutions and can be associated with life-threatening cytokine release syndrome and neurologic toxicity. We now recommend liso-cel or axi-cel for early relapsed or primary refractory DLBCL, when available; note that this guidance does not apply to later relapses (≥12 months). (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients", section on 'Relapse <12 months or primary refractory DLBCL'.)

PI3K inhibitors in follicular lymphoma (December 2021, Modified January 2022)

The landscape of phosphoinositide 3'-kinase (PI3K) inhibitors in follicular lymphoma (FL) is changing, with umbralisib and copanlisib used for multiply relapsed disease, and regulatory approval recently withdrawn for duvelisib and idelalisib for this indication. While direct comparisons are not available, indirect comparisons suggest that umbralisib is similarly effective and better tolerated than the others. In a pooled analysis of >370 patients treated with umbralisib for FL and other non-Hodgkin lymphomas, adverse events led to drug discontinuation in 14 percent [32]. The most common toxicities were diarrhea, nausea, vomiting, and fatigue. Umbralisib is our preferred PI3K inhibitor for treatment of relapsed or refractory FL due to its oral administration and favorable toxicity profile. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Umbralisib'.)

MULTIPLE MYELOMA AND OTHER PLASMA CELL DISORDERS

Withdrawal of panobinostat from United States market (January 2022)

Panobinostat, an orally available histone deacetylase inhibitor, was granted accelerated approval by the US Food & Drug Administration in 2015 for the treatment of relapsed or refractory multiple myeloma in combination with bortezomib and dexamethasone. It is being withdrawn from the US market beginning December 2021; the manufacturer was not able to complete the required postapproval clinical studies as part of the accelerated approval process [33]. (See "Multiple myeloma: Treatment of third or later relapse", section on 'Panobinostat'.)

Progressive parkinsonism after BCMA-targeted CAR-T cell therapy (January 2022)

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a well-known acute and usually reversible complication of chimeric antigen receptor T (CAR-T) cell therapy, but long-term neurologic effects have not been well documented. A recent case report described the onset of progressive parkinsonism approximately 100 days after administration of ciltacabtagene autoleucel, an investigational CAR-T cell therapy for multiple myeloma targeting B-cell maturation antigen (BCMA) [34]. Based on postmortem studies, the syndrome appeared to be an on-target effect of CAR-T cells on BCMA-expressing astrocytes and neurons in the basal ganglia. Delayed parkinsonism has also been reported after idacabtagene vicleucel, another BCMA-targeted product. Further studies are needed to understand risk factors and treatment strategies. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)", section on 'Delayed parkinsonism'.)

Daratumumab plus lenalidomide and dexamethasone in transplant ineligible newly diagnosed MM (October 2021)

Most patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous hematopoietic cell transplantation (HCT) are treated with a three-drug regimen of lenalidomide plus dexamethasone (Rd) with bortezomib (VRd) or daratumumab (DRd). In updated results of the MAIA trial that compared DRd versus Rd in this patient population, DRd improved both progression-free and overall survival without major increases in toxicity [35]. For most patients, we prefer VRd given the well-established data on long-term efficacy and more convenient treatment schedule. DRd is a reasonable alternative for patients with standard-risk MM who are not HCT candidates, especially for patients who cannot receive or tolerate bortezomib. (See "Multiple myeloma: Selection of initial chemotherapy for symptomatic disease", section on 'Daratumumab, lenalidomide, dexamethasone (DRd)'.)

Melphalan flufenamide withdrawn from market (March 2021, Modified October 2021)

Melphalan flufenamide is a peptide-drug conjugate that showed promising outcomes in combination with dexamethasone among patients with relapsed refractory multiple myeloma (MM), which led to its accelerated approval by the US Food and Drug Administration (FDA) in combination with dexamethasone in heavily pretreated MM. However, following approval, the FDA raised concerns about its efficacy and safety based on a preliminary analysis of a randomized trial (OCEAN), which suggested inferior outcomes when compared with pomalidomide plus dexamethasone [36]. On October 22, the manufacturer announced its decision to withdraw melphalan flufenamide from the market, although it will provide access to the drug for patients who started treatment prior to its withdrawal. (See "Multiple myeloma: Treatment of first or second relapse".)

TRANSFUSION

Benefits of patient blood management (December 2021)

Patient blood management (PBM) programs provide guidelines for appropriate use of blood transfusion. In a new series involving >400,000 hospital admissions over an eight-year period, institution of a PBM program was associated with a 22 percent reduction in transfusions [37]. Hospital length of stay and adverse events were also reduced, and there was an estimated cost savings of USD $7 million. PBM programs should not supersede clinical judgment in transfusion decisions, but when well designed and thoughtfully implemented, they can improve quality of care and reduce risks, costs, and burdens associated with transfusion. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Hospital-wide oversight programs/patient blood management'.)

OTHER HEMATOLOGY

Additional COVID-19 vaccine primary series dose for immunocompromised individuals (August 2021, Modified February 2022)

COVID-19 vaccines are less effective among patients with certain immunocompromising conditions than in the general population; additional vaccine doses have been associated with improved effectiveness in this population. We agree with recommendations from the Advisory Committee on Immunization Practices (ACIP) in the United States that individuals with such conditions (table 2) receive an additional mRNA vaccine dose as part of their primary COVID-19 vaccine series (eg, following two doses of an mRNA vaccine or one dose of Ad26.COV2.S vaccine) [38,39]. This additional primary series dose is distinct from the booster dose, which such patients should additionally receive, although at a shorter interval than recommended for the general population. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

ITP after COVID-19 vaccination (January 2022)

Exacerbations of immune thrombocytopenia (ITP) as well as new-onset ITP have been reported after COVID-19 vaccination [40,41]. Individuals with ITP who receive any COVID-19 vaccine should be advised about this risk, and platelet counts should be monitored before and after vaccination. The benefits of vaccination outweigh the risks in almost all patients with ITP. Those in the midst of a flare can delay vaccination until the flare is controlled; flares that occur following vaccination tend to be transient and respond well to standard ITP therapy. ITP is distinct from the exceedingly rare syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT). (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'COVID-19 vaccination'.)

Addition of eltrombopag to immunosuppressive therapy for severe aplastic anemia (January 2022)

Immunosuppressive therapy (IST) using horse anti-thymocyte globulin (hATG) plus cyclosporine A (CsA) has been a standard treatment for decades in patients with severe aplastic anemia (SAA) who do not undergo allogeneic transplantation. Recently, a multicenter phase 3 trial that included nearly 200 patients age ≥15 years with SAA reported that addition of the thrombopoietin receptor agonist eltrombopag (EPAG) to hATG and CsA ("triple therapy") achieved significantly faster and higher rates of hematologic response compared with hATG plus CsA [42]. There was no difference in adverse effects between trial arms. We now suggest triple therapy with EPAG, hATG, and CsA for adults who require IST for SAA. (See "Treatment of aplastic anemia in adults", section on 'Patients ≥40 years'.)

New naming convention for therapeutic monoclonal antibodies (January 2022)

The number of therapeutic monoclonal antibodies (mAbs) continues to increase. In order to reduce sound-alikes and specify structural components of the immunoglobulins, the World Health Organization International Nonproprietary Names (INN) Programme has developed four new suffixes to be used instead of "mab" for antibodies developed from 2022 onward [43]. Unmodified immunoglobulins will end in "tug"; mAbs with an engineered constant region will end in "bart"; bifunctional mAbs will end in "mig"; and variable region fragments will end in "ment." (See "Overview of therapeutic monoclonal antibodies", section on 'Naming convention for therapeutic mAbs'.)

Prophylactic anticoagulation after discharge from COVID-19 hospitalization (December 2021)

Prophylactic-dose anticoagulation has become the standard of care during hospitalization for COVID-19, but the role of post-discharge prophylactic-dose anticoagulation is unclear. In the MICHELLE trial, 320 individuals hospitalized with COVID-19 and deemed at high risk for venous thromboembolism (VTE) were randomly assigned to receive post-discharge rivaroxaban 10 mg daily for 35 days or no anticoagulant after discharge [44]. Over two-thirds of the patients screened for the trial were ineligible, many because their thromboembolic risk was too low. The composite endpoint of VTE, symptomatic arterial embolism, and fatal cardiovascular events occurred in 3 percent of the rivaroxaban-treated patients and 9 percent of the controls. Despite this result, most clinicians are unlikely to provide post-discharge thromboprophylaxis until more data become available. (See "COVID-19: Hypercoagulability", section on 'Patients discharged from the hospital'.)

COVID-19 vaccination and hematopoietic cell transplant or CAR-T therapy (November 2021)

Immunocompromised individuals who are recipients of hematopoietic cell transplantation (HCT) or chimeric antigen receptor (CAR)-T-cell therapies are at risk for a suboptimal immune response to COVID-19 vaccination. Updated guidance from the United States Centers for Disease Control and Prevention (CDC) now recommends revaccination with a full primary series for patients who were vaccinated prior to receiving HCT or CAR-T-cell therapy and who are at least three months post-HCT or CAR-T-cell therapy. Our recommendations are in agreement with this guidance [45]. (See 'COVID-19: Considerations in patients with cancer', section on 'COVID-19 vaccination' and 'Immunizations in hematopoietic cell transplant candidates and recipients', section on 'COVID-19 vaccine'.)

No role for aspirin in inpatients with COVID-19 (November 2021)

The RECOVERY trial, which randomly assigned nearly 15,000 individuals hospitalized with COVID-19 to receive standard care with or without aspirin 150 mg, found no benefit of aspirin in reducing mortality or progression to mechanical ventilation [46]. The aspirin group had a small reduction in thrombosis (4.6 versus 5.3 percent) and a small increase in major bleeding (1.6 versus 1.0 percent). We continue to use aspirin for standard indications but do not prescribe aspirin for individuals admitted to the hospital with COVID-19. (See "COVID-19: Hypercoagulability", section on 'Aspirin/antiplatelet agents'.)

Oral agent for patients with paroxysmal nocturnal hemoglobinuria (PNH) (November 2021)

For most patients with paroxysmal nocturnal hemoglobinuria (PNH), treatment with a C5 inhibitor (C5i; ravulizumab or eculizumab) effectively reduces intravascular hemolysis, transfusions, and thromboses and improves quality of life (QoL). However, some patients treated with a C5i require ongoing transfusions due to extravascular hemolysis caused by opsonization of red blood cells by C3. Danicopan is an investigational oral agent that inhibits C3 production. Addition of danicopan to eculizumab for 24 weeks in 11 transfusion-dependent patients raised hemoglobin, nearly eliminated transfusions, and improved QoL; danicopan was associated with only minor headaches, cough, and nasopharyngitis [47]. Danicopan is under review by the US Food and Drug Administration for control of extravascular hemolysis in PNH. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria", section on 'Newer complement inhibitors'.)

Thromboprophylaxis does not improve outcomes in outpatients with COVID-19 (October 2021)

While prophylaxis for venous thromboembolism (VTE) is used routinely in individuals hospitalized with COVID-19, the role of thromboprophylaxis in outpatients has been unclear. A new randomized trial, ACTIV-4B, evaluated outcomes in 657 symptomatic outpatients with COVID-19 who were treated for 45 days with aspirin, prophylactic-dose apixaban, therapeutic-dose apixaban, or placebo [48]. There was no statistically significant difference in mortality, VTE, or arterial thromboembolism, with very low numbers in all groups. As expected, bleeding complications were higher with apixaban and aspirin. These results support our practice of not routinely using anticoagulation or aspirin in outpatients with COVID-19. Outpatient thromboprophylaxis may be appropriate in selected individuals with especially high thrombotic risk; if thromboprophylaxis is used, an oral anticoagulant is preferred over aspirin. (See "COVID-19: Hypercoagulability", section on 'Aspirin/antiplatelet agents'.)

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Topic 8359 Version 10977.0

References

1 : https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103411s5201lbl.pdf (Accessed on January 04, 2022).

2 : https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761102s008lbl.pdf (Accessed on January 04, 2022).

3 : Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS).

4 : Consensus statement for the perinatal management of patients withαthalassemia major.

5 : Betibeglogene Autotemcel Gene Therapy for Non-β0/β0 Genotypeβ-Thalassemia.

6 : Suboptimal iron deficiency screening in pregnancy and the impact of socioeconomic status in a high-resource setting.

7 : Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease.

8 : Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis.

9 : Treatment of Acute Pain in Adults With Sickle Cell Disease in an Infusion Center Versus the Emergency Department : A Multicenter Prospective Cohort Study.

10 : The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia.

11 : Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study.

12 : Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

13 : Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease.

14 : Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

15 : Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report.

16 : Risk for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data.

17 : Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.

18 : Milvexian for the Prevention of Venous Thromboembolism.

19 : Anticoagulant therapy in patients with congenital FXI deficiency.

20 : Anesthetic Management of Von Willebrand Disease in Pregnancy: A Retrospective Analysis of a Large Case Series.

21 : Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants : A Nationwide Propensity Score-Weighted Study.

22 : Plasma trial: Pilot randomized clinical trial to determine safety and efficacy of plasma transfusions.

23 : Weight-adjusted versus fixed dose heparin thromboprophylaxis in hospitalized obese patients: A systematic review and meta-analysis.

24 : Weight-adjusted versus fixed dose heparin thromboprophylaxis in hospitalized obese patients: A systematic review and meta-analysis.

25 : Weight-adjusted versus fixed dose heparin thromboprophylaxis in hospitalized obese patients: A systematic review and meta-analysis.

26 : Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial.

27 : Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

28 : Outcomes and prognostic factors in angioimmunoblastic T-cell lymphoma: final report from the international T-cell Project.

29 : Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Versus Standard of Care (SOC) with Salvage Chemotherapy (CT) Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Randomized Phase 3 Transform Study [#91]

30 : Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma.

31 : Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma.

32 : Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1εinhibitor, in relapsed/refractory lymphoid malignancies.

33 : Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1εinhibitor, in relapsed/refractory lymphoid malignancies.

34 : Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy.

35 : Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial.

36 : Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial.

37 : Implementation of a Comprehensive Patient Blood Management Program for Hospitalized Patients at a Large United States Medical Center.

38 : Implementation of a Comprehensive Patient Blood Management Program for Hospitalized Patients at a Large United States Medical Center.

39 : Implementation of a Comprehensive Patient Blood Management Program for Hospitalized Patients at a Large United States Medical Center.

40 : Severe immune thrombocytopenia after COVID-19 vaccination: Report of four cases and review of the literature.

41 : COVID-19 vaccination in patients with immune thrombocytopenia.

42 : Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.

43 : New INN nomenclature for monoclonal antibodies.

44 : Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial.

45 : Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial.

46 : Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.

47 : Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab.

48 : Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.