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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: May 2022. | This topic last updated: Jun 13, 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'.)

ANEMIA AND OTHER RED CELL DISORDERS

Mitapivat for pyruvate kinase deficiency (April 2022)

Pyruvate kinase (PK) is an enzyme in red blood cells needed for energy production and metabolism. Hereditary PK deficiency is associated with hemolytic anemia of variable severity, ranging from mild and asymptomatic to transfusion dependent. Mitapivat is an oral small molecule that enhances PK activity. In a new trial, 80 adults with PK deficiency who had symptomatic anemia and were not receiving regular transfusions were randomly assigned to mitapivat or placebo for 24 weeks [3]. Of the 40 assigned to mitapivat, 16 (40 percent) had an increase in hemoglobin (mean increase, 3.5 g/dL); none of the patients in the placebo arm had a response. Mitapivat was approved earlier this year by the US Food and Drug Administration for adults with PK deficiency. (See "Pyruvate kinase deficiency", section on 'Mitapivat for symptomatic anemia'.)

Anemia and pregnancy outcome (April 2022)

Some degree of dilutional anemia is normal in pregnancy, but nonphysiologic anemia, often due to iron deficiency, can be associated with serious adverse outcomes for mother and child. In a new retrospective study involving >18 million pregnancies in China, anemia correlated with several adverse outcomes including placental abruption, preterm birth, severe postpartum hemorrhage, maternal shock, and maternal intensive care unit admission [4]. The likelihood of the outcomes correlated with anemia severity. While this study does not demonstrate cause and effect, it does highlight the scope of the problem and the need for greater attention to treatment and prevention. (See "Anemia in pregnancy", section on 'Supporting evidence'.)

Safety of intravenous (IV) iron (April 2022)

In two new observational studies evaluating >200,000 iron infusions, the safety of intravenous (IV) iron was evaluated using case definitions of anaphylaxis or infusion reaction based upon billing codes or chart review [5,6]. In one study, administration of antihistamines and other anaphylaxis treatments was used as a surrogate for an infusion reaction. Overall, rates of anaphylaxis were extremely low (from 0.0005 to 0.098 percent). However, these are likely overestimates since antihistamines were sometimes administered as premedication before the IV iron infusion, rather than after the infusion in response to a reaction. Generalizability was hampered by exclusion of certain populations (hemodialysis, inflammatory bowel disease, younger individuals). In general, the availability of IV iron formulations with improved safety profiles has lowered the threshold at which many patients would consider switching from an oral to an IV iron preparation. (See "Treatment of iron deficiency anemia in adults", section on 'Risks/prevention'.)

Mortality from pulmonary hypertension in thalassemia (April 2022)

Individuals with thalassemia are at risk for pulmonary hypertension due to a combination of risk factors, especially hemolysis and iron overload. A new study monitored 24 individuals with thalassemia who had right heart catheterization-documented pulmonary arterial hypertension (PAH) [7]. The median age was 46.5 years. During a median of four years of follow-up, 13 patients died, and 10 of the deaths were attributed to PAH. Survival strongly correlated with PAH therapy. Patients with thalassemia and PAH need routine monitoring and multidisciplinary treatment by clinicians with expertise in treating PAH [8]. (See "Management of thalassemia", section on 'Pulmonary hypertension'.)

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 [9]. 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 [10]. Hematopoietic stem cell transplantation with myeloablative chemotherapy is required. (See "Management of thalassemia", section on 'Gene therapy and other stem cell modifications'.)

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 [11]. 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'.)

CHRONIC LEUKEMIAS AND THE MYELOPROLIFERATIVE NEOPLASMS

Pacritinib for symptom relief in myelofibrosis with thrombocytopenia (May 2022)

Thrombocytopenia caused by marrow fibrosis, hypersplenism, or prior treatments often limits use of ruxolitinib or fedratinib for symptom relief in patients with primary myelofibrosis (PMF). In a phase 3 trial in patients with PMF and platelets <100,000/microL, the JAK2 inhibitor, pacritinib, more effectively reduced splenomegaly and other PMF-associated symptoms than best available therapy (eg, ruxolitinib, hydroxyurea, observation) [12]. Pacritinib has been associated with bleeding and cardiovascular events and should not be given with CYP3A4-modulating drugs or to patients with limited renal or liver function, but it recently received fast-track approval by the US Food and Drug Administration for high-risk PMF with platelets <50,000/microL. We consider pacritinib an acceptable treatment for symptom relief in patients with symptomatic PMF and thrombocytopenia. (See "Management of primary myelofibrosis", section on 'Pacritinib'.)

Development of BTK mutations in CLL/SLL on BTK inhibitors (May 2022)

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) that progresses on the Bruton tyrosine kinase (BTK) inhibitors ibrutinib or acalabrutinib frequently demonstrates new point mutations that disrupt the covalent binding of these agents to BTK (eg, BTK C481). Noncovalent, reversible-binding BTK inhibitors that are not blocked by the BTK C481 mutation are under development (eg, pirtobrutinib). However, in a recent study, CLL/SLL that progressed on pirtobrutinib demonstrated novel, non-C481 BTK mutations that confer resistance to noncovalent BTK inhibitors and some covalent BTK inhibitors [13]. Further study is needed to better understand these mutations, how treatment sequence may impact the likelihood of their development, and how they might impact treatment selection. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'BTK, PLCg2, and BCL2 mutations'.)

A Bruton tyrosine kinase inhibitor plus venetoclax in CLL (March 2022)

For patients with chronic lymphocytic leukemia (CLL), initial treatment commonly employs either continuous therapy with a Bruton tyrosine kinase (BTK) inhibitor (ibrutinib or acalabrutinib) or fixed duration therapy with venetoclax plus obinutuzumab. In several single-arm trials, the investigational combination of a BTK inhibitor plus venetoclax with or without an anti-CD20 monoclonal antibody resulted in deep responses, with a sizeable percentage of patients achieving undetectable measurable residual disease [14,15]. Further study is needed before incorporating these combinations into routine practice. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia", section on 'BTK inhibitor plus venetoclax (investigational)'.)

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 [16]. 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

Abatacept for prophylaxis of graft-versus-host disease (May 2022)

Prophylaxis of graft-versus-host disease (GVHD) in allogeneic transplantation generally includes a calcineurin inhibitor (CNI; ie, tacrolimus or cyclosporine) plus an antimetabolite (eg, methotrexate [MTX]), but there is no preferred regimen. In a randomized trial in children and adults who received 8/8 antigen-matched unrelated donor grafts, addition of abatacept (a selective inhibitor of T cell costimulation) to CNI/MTX reduced acute GVHD compared with placebo (43 versus 62 percent); there was no difference in overall survival (OS) or nonrelapse mortality [17]. A companion study in patients who received 7/8 antigen-matched unrelated donor grafts reported that abatacept/CNI/MTX was associated with improved two-year OS (74 versus 45 percent) and less nonrelapse mortality (16 versus 40 percent) and acute GVHD, compared with historic controls who received CNI/MTX. Abatacept is the first drug approved by the US Food and Drug Administration for acute GVHD prophylaxis. We consider abatacept/CNI/MTX an acceptable prophylaxis regimen for transplantation using an unrelated donor graft. (See "Prevention of graft-versus-host disease", section on 'Abatacept'.)

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 [18]. 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".)

HEMOSTASIS AND THROMBOSIS

Apixaban versus warfarin for thrombotic antiphospholipid syndrome (May 2022)

Warfarin is recommended for patients with thrombotic antiphospholipid syndrome (APS) based on data showing superiority of warfarin over the direct oral anticoagulant (DOAC) rivaroxaban. In a new trial that randomly assigned 48 patients with thrombotic APS to receive warfarin or the DOAC apixaban, there were no strokes in the 25 patients assigned to warfarin; 6 of 23 patients assigned to apixaban had a stroke [19]. Although the trial had important limitations including early termination, small sample size, and an initially low dose of apixaban, these findings add to the evidence that warfarin is more effective than DOACs for recurrent thrombosis prevention in patients with thrombotic APS. (See "Management of antiphospholipid syndrome", section on 'Long-term anticoagulation'.)

Increased bleeding with apixaban and systemic fluconazole (May 2022)

Direct oral anticoagulants (DOACs) have fewer drug interactions than warfarin, but interactions do occur. In a large series involving nearly 100,000 individuals receiving a DOAC, individuals receiving apixaban plus fluconazole, a moderate inhibitor of the P450 cytochrome CYP3A4, had a 3.5-fold increased risk of bleeding compared with periods when they were receiving apixaban without fluconazole [20]. The increase was greatest in gastrointestinal bleeding requiring hospitalization. The risk was only seen with systemic fluconazole plus apixaban; it did not occur with topical fluconazole plus apixaban or systemic fluconazole plus another DOAC. This study highlights the importance of possible drug interactions and of considering alternatives that might be equally effective, such as topical therapy. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Dosing, monitoring, risks (apixaban)'.)

Efficacy and safety of tranexamic acid in noncardiac surgery (May 2022)

The antifibrinolytic agents epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) prevent fibrinolysis by plasmin, thereby supporting hemostasis. In a randomized trial comparing TXA (administered at the start and end of surgery) with placebo in over 9500 noncardiac surgical patients, a composite bleeding outcome (life-threatening or major bleeding, or bleeding into a critical organ) occurred less frequently in the TXA group (9 versus 12 percent) at 30 days [21]. The composite safety outcome (myocardial injury, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism) was similar in both groups. We use an antifibrinolytic agent routinely in cardiac surgery requiring cardiopulmonary bypass and in selected noncardiac surgical procedures with a high risk of bleeding. (See "Perioperative blood management: Strategies to minimize transfusions", section on 'Antifibrinolytic agents'.)

Investigational BTK inhibitor for ITP (April 2022)

Rilzabrutinib is an investigational Bruton tyrosine kinase (BTK) inhibitor. In a series of 60 individuals with immune thrombocytopenia (ITP) who had a platelet count <30,000 that was not raised by other therapies, 24 individuals (40 percent) had a response after treatment with rilzabrutinib, defined as a platelet count >50,000/microL and at least >20,000/microL over baseline on at least two occasions [22]. Unlike other BTK inhibitors used for lymphoid malignancies, rilzabrutinib does not appear to cause bleeding by inhibiting platelet aggregation. Further data are awaited. (See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'Rilzabrutinib (investigational BTK inhibitor)'.)

Gene therapy for hemophilia A (March 2022)

Data continue to emerge on the safety and efficacy of gene therapy for hemophilia. A new study that evaluated the factor VIII gene therapy construct valoctocogene roxaparvovec in 134 individuals with hemophilia A reported a decrease in the annualized bleeding rate from 4.8 episodes per year with factor VIII prophylaxis to 0.8 episodes per year after gene therapy [23]. Factor VIII activity remained increased through the end of the first year. For 17 participants who were followed beyond two years, the mean factor VIII activity was 42 percent at the end of the first year and 24 percent at the end of the second year. The declining trend in factor VIII activity raises concerns about durability of therapy. Longer-term follow-up is needed. (See "Gene therapy and other investigational approaches for hemophilia", section on 'Hemophilia A'.)

Fixed versus variable dose PCC for warfarin reversal (March 2022)

Four-factor prothrombin complex concentrate (4-factor PCC) is used to reverse warfarin anticoagulation with serious bleeding. Dosing can be calculated based on weight and international normalized ratio (INR). A new randomized trial compared fixed-dose versus weight-based dosing in 199 adults with major extracranial bleeding associated with vitamin K antagonist anticoagulation and found equivalent outcomes [24]. Effective hemostasis was seen in 88 percent of the fixed-dose group and 89 percent of the calculated-dose group. The fixed-dose group received treatment more rapidly (109 versus 142 minutes). UpToDate authors generally suggest a fixed-dose regimen due to ease of use and faster treatment; institutions should determine their own protocols and make them readily available. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Dosing'.)

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) [25]. 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) [26]. 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".)

LYMPHOMAS: HODGKIN AND NON-HODGKIN

CAR-T therapy for relapsed follicular lymphoma (June 2022)

There are limited data regarding the CD19-directed chimeric antigen receptor T (CAR-T) tisagenlecleucel (tisa-cel) in follicular lymphoma (FL). In an interim analysis of a single-arm trial of tisa-cel (ELARA), responses were seen in 77 of 90 evaluable patients with multiply relapsed FL, and 71 percent were progression free at one year [27,28]. Toxicity included cytokine release syndrome in most patients. Based on these and other data, the US Food and Drug Administration has granted accelerated approval for tisa-cel in adults with relapsed or refractory FL after ≥2 lines of systemic therapy. However, the quality of supporting evidence is low, and there is substantial associated toxicity, complexity, and expense. Since most patients with relapsed FL have favorable outcomes with other, less-toxic treatments, we reserve CAR-T therapy for patients with multiply relapsed FL with short prior remission durations (eg, <24 months). (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Chimeric antigen receptor T cells'.)

Polatuzumab vedotin in initial treatment of advanced-stage diffuse large B cell lymphoma (DLBCL) (May 2022)

For decades, initial treatment for diffuse large B cell lymphoma (DLBCL) has been R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) every 21 days. An international phase 3 trial (POLARIX) of 879 patients with advanced-stage DLBCL reported that substituting polatuzumab vedotin (pola) for vincristine (R-pola-CHP) achieved similar overall survival, but superior two-year progression-free survival, compared with R-CHOP; toxicity (cytopenias, infections, neuropathy) was similar with both regimens [29]. For patients with advanced-stage DLBCL, we suggest initial treatment with six cycles of either R-CHOP or R-pola-CHP (rituximab, polatuzumab vedotin, doxorubicin, prednisone). (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Initial therapy'.)

PI3K inhibitor drug withdrawals in relapsed lymphoma (April 2022)

The landscape of phosphoinositide 3'-kinase (PI3K) inhibitors in relapsed lymphoma is changing due to safety concerns and increased risk of death in some randomized trials. For follicular lymphoma (FL), copanlisib is now the only available PI3K inhibitor approved by the US Food and Drug Administration (FDA). While previously approved, the FL indications for duvelisib, idelalisib, and umbralisib were voluntarily withdrawn by manufacturers in December 2021, January 2022, and April 2022, respectively [30-33]. The manufacturers of umbralisib also voluntarily withdrew the indication for marginal zone lymphoma; no other PI3K inhibitor has FDA approval for this indication. Idelalisib and duvelisib maintain approval for chronic lymphocytic leukemia/small lymphocytic lymphoma. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Copanlisib'.)

Worsened survival from follicular lymphoma, if progression within 24 months of initial therapy (March 2022)

Previous studies have suggested that, among patients with follicular lymphoma, progression of disease within 24 months of initial therapy (POD24) identifies a subset of patients with an aggressive disease course and decreased overall survival (OS). In a pooled analysis of 13 international clinical trials with >5000 patients, POD24 was associated with worse OS regardless of initial therapy; however, patients with POD24 after chemoimmunotherapy had a clearly worsened OS relative to those with POD24 after single agent rituximab [34]. We offer aggressive therapy to patients with POD24 after chemoimmunotherapy or progression within 12 months of single agent rituximab, as these patients do poorly with standard therapies (algorithm 1). (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Recognize early treatment failure'.)

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) [35]. 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 [36,37]. By contrast, another CD-19 CAR-T cell product, tisagenlecleucel, did not improve outcomes or toxicity relative to HCT [38]. 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'.)

MULTIPLE MYELOMA AND OTHER PLASMA CELL DISORDERS

Benefit of autologous transplant in multiple myeloma (June 2022)

Autologous hematopoietic cell transplantation (HCT) is a key component of multiple myeloma (MM) therapy in eligible patients, although its role has been questioned given advances in induction therapy that produce deep responses. In the DETERMINATION trial, >1400 patients were randomly assigned to initial treatment with bortezomib, lenalidomide, and dexamethasone (VRd) induction alone versus VRd plus high-dose melphalan and HCT, each followed by lenalidomide maintenance [39]. A first or second HCT was allowed at relapse. HCT was associated with short-term toxicities and a temporary decrease in quality of life, but improved median progression-free survival by 22 months (68 versus 46 months). Overall survival data are immature. These results provide further support for the use of HCT in MM, either as part of the initial therapy or at the time of first relapse. (See "Multiple myeloma: Overview of management", section on 'Autologous HCT versus chemotherapy alone'.)

Limitations in use of ixazomib in multiple myeloma (June 2022)

Ixazomib, lenalidomide, and dexamethasone (IRd) is an all-oral, three-drug regimen that is a treatment option for relapsed multiple myeloma (MM). Despite limited data regarding efficacy, it has been used as initial therapy in transplant-ineligible patients who place a high value on limiting visits to an infusion center during the COVID-19 pandemic. However, a recent update to the United States prescribing information states that ixazomib is not recommended for use in the maintenance setting or in newly diagnosed MM as part of IRd outside of clinical trials [40]. Consequently, we generally do not use IRd for the initial treatment of MM but recognize that there may be select scenarios where its use may be reasonable. (See "Multiple myeloma: Initial treatment", section on 'Ixazomib, lenalidomide, dexamethasone (IRd)'.)

Minimal residual disease testing in multiple myeloma (March 2022)

For patients with multiple myeloma, achieving undetectable minimal residual disease (MRD) has been proposed as a surrogate marker for progression-free survival (PFS) and overall survival. In a meta-analysis that combined data from >2500 patients enrolled on four phase 3 trials, patients who achieved a complete response (CR) or better with undetectable MRD had superior PFS when compared with patients who did not achieve a CR and/or had detectable MRD [41]. While patients with undetectable MRD do better than those with detectable MRD, it is not known whether altering therapy based on MRD status will improve outcomes. As such, we typically reserve MRD assessment for patients on clinical trials. (See "Multiple myeloma: Evaluating response to treatment", section on 'Minimal residual disease assessment'.)

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 [42]. (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) [43]. 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'.)

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 [44]. 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

Thromboprophylaxis during hospitalization for COVID-19 (May 2022)

COVID-19 is a hypercoagulable state, and thromboprophylaxis with low molecular weight (LMW) heparin is appropriate during hospitalization. The intensity of anticoagulation (prophylactic versus therapeutic dosing) is individualized based on the patient's thrombotic and bleeding risks. UpToDate contributors generally suggest therapeutic dose LMW heparin for medical inpatients who are not critically ill (non-intensive care unit [ICU]), consistent with new guidelines from the American Society of Hematology and National Institutes of Health [45,46]. Individuals in the ICU and those hospitalized with another illness who are incidentally found to be infected with SARS-CoV-2 are generally treated with prophylactic dose LMW heparin. Many factors influence the degree of hypercoagulability, including viral variants, underlying medical conditions, and available therapies. (See "COVID-19: Hypercoagulability", section on 'Inpatient VTE prophylaxis'.)

Tixagevimab-cilgavimab for pre-exposure prophylaxis against COVID-19 (May 2022)

The monoclonal antibody combination tixagevimab-cilgavimab is a potential option for pre-exposure prophylaxis against COVID-19 for certain immunocompromised individuals (table 2) who may not benefit maximally from vaccination and for those who have a contraindication to vaccination. In a placebo-controlled, randomized trial of over 5000 unvaccinated adults, a single dose of tixagevimab-cilgavimab reduced the risk of symptomatic infection by 77 percent [47]. Overall, serious adverse event rates were similar to those with placebo. However, among individuals with cardiovascular risk, severe cardiac events were rare but more frequent with tixagevimab-cilgavimab. For those who meet eligibility criteria, we individualize the decision to use tixagevimab-cilgavimab, taking into account risk of exposure and severe disease, underlying comorbidities, and patient preference. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Pre-exposure prophylaxis'.)

Convalescent plasma in outpatients with COVID-19 (April 2022)

Accumulating evidence supports the efficacy of high-titer convalescent plasma for the treatment of outpatients with nonsevere COVID-19. In a new trial that randomly assigned 1181 outpatients with nonsevere COVID-19 (80 percent unvaccinated) to receive high-titer convalescent plasma or control plasma within nine days of symptom onset, the risk of hospitalization was lower in the convalescent plasma group (2.9 versus 6.3 percent) [48]. Pneumonia was more common with control plasma, and three deaths all occurred in the control group. Although other effective therapies are available for nonsevere COVID-19, high-titer convalescent plasma administered early in the disease course has a role for treating individuals at high risk of disease progression who lack access to these other therapies. (See "COVID-19: Convalescent plasma and hyperimmune globulin", section on 'Optimal timing and titer (or antibody level)'.)

New juvenile hemochromatosis gene (April 2022)

A recent report has identified a new cause of juvenile hemochromatosis in three children with neurologic abnormalities and iron overload [49]. Each child had a pathogenic variant in the PIGA gene, which encodes the first enzyme in the pathway that adds a glycophosphatidylinositol (GPI) anchor to certain plasma membrane proteins to maintain their cell surface attachment. The hemojuvelin protein is GPI-anchored, suggesting a possible mechanism of iron overload; the mechanism of the neurologic findings remains unexplained. (See "HFE and other hemochromatosis genes", section on 'PIGA'.)

Revaccination after an episode of VITT (March 2022)

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is an extremely rare syndrome that occurs after certain adenoviral vectored COVID-19 vaccines. New evidence is emerging that some individuals with VITT have subsequently received an mRNA-based vaccine, often while taking an anticoagulant for VITT, and these individuals do not have recurrent thrombosis or increases in VITT antibodies [50,51]. This suggests that when a second dose or booster dose is indicated, individuals with prior VITT may receive an mRNA vaccine. Adenoviral vectored vaccines should be avoided. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'Characteristics of VITT antibodies' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'Second dose (for two-dose vaccines) or booster dose'.)

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 [52,53]. 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 [54]. 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 introduced four new suffixes to be used instead of "mab" for antibodies developed from 2022 onward [55]. 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 [56]. 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'.)

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References