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What's new in hematology

What's new in hematology
Authors:
Rebecca F Connor, MD
Alan G Rosmarin, MD
Jennifer S Tirnauer, MD
Literature review current through: Nov 2022. | This topic last updated: Dec 30, 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

Luspatercept for MDS with ring sideroblasts (November 2022)

Luspatercept can improve red blood cell transfusion-independence (TI) in patients with myelodysplastic syndromes (MDS) with ring sideroblasts who did not respond to an erythropoiesis-stimulating agent (ESA), but the duration of benefit has been uncertain. Longer follow-up (median >2 years) of the phase 3 MEDALIST trial now reports that benefits of luspatercept increased over time [1]. Compared with placebo, luspatercept achieved more ≥8-week TI (45 versus 16 percent, respectively); this and other hematologic outcomes improved over time, and there were no new toxicity signals. For patients with MDS with ring sideroblasts who fail to respond or are unlikely to respond to an ESA, luspatercept can achieve substantial, sustained TI. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Luspatercept'.)

New, competing classification systems for hematologic malignancies (November 2022)

By consensus among pathologists for more than two decades, successive World Health Organization (WHO) fascicles ("blue books") have been used for classification of hematologic malignancies. However, in addition to a new WHO fascicle (the WHO 5th edition, WHO5 [2,3]), another classification scheme was published in 2022, the International Consensus Classification (ICC) [4,5]. Both classify hematologic malignancies according to cellular lineage, morphology, immunophenotype, and genetic/molecular findings, but there are notable differences in classification of acute myeloid leukemia and myelodysplastic syndromes and numerous differences in specific diagnostic criteria and names of otherwise identical entities. There is no current consensus and many pathologists may provide diagnoses according to both systems. We favor use of either the ICC or the WHO5 scheme rather than earlier classification systems. (See "Classification of hematopoietic neoplasms", section on 'Overview'.)

Ivosidenib plus azacitidine for IDH1-mutated AML in medically-unfit patients (October 2022)

Most patients with newly diagnosed acute myeloid leukemia (AML) who are not fit for intensive induction therapy receive treatment that includes a hypomethylating agent (HMA; ie, azacitidine or decitabine). A randomized trial now reports that in such patients who have IDH1-mutated AML, treatment with azacitidine plus ivosidenib (an inhibitor of mutant IDH1) achieved superior median survival compared with azacitidine plus placebo (24 versus 8 months) [6]. The incidence of cytopenias and infections were similar in both trial arms. For patients with IDH1-mutated AML who are not eligible for intensive remission induction therapy, we recommend azacitidine plus ivosidenib, rather than an HMA alone. (See "Acute myeloid leukemia: Management of medically-unfit adults", section on 'IDH1-mutated AML'.)

Mutation-based models for estimating prognosis in MDS (September 2022)

Outcomes in myelodysplastic neoplasms/syndromes (MDS) are related to blood counts, percentage of marrow blasts, and various pathologic features. The International Prognostic Scoring System-Molecular (IPSS-M) is a validated mutation-based MDS prognostic model that incorporates more cytogenetic and molecular features than earlier models, such as the IPSS-Revised (IPSS-R) or the original IPSS. In an analysis of nearly 3000 patients with MDS, IPSS-M outperformed IPSS-R, reclassifying nearly half of patients and improving prognostic discrimination across all clinical end points [7]. Moreover, IPSS-M was applicable for both untreated and treated patients. Although we favor the IPSS-M and other mutation based prognostic models, we still consider the IPSS-R to be acceptable for estimating prognosis in MDS; we no longer endorse the use of the original IPSS. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'Choice of prognostic model'.)

ANEMIA AND OTHER RED CELL DISORDERS

Treatment of iron deficiency in patients with heart failure (November 2022)

Patients with heart failure (HF) who are iron deficient should receive iron replacement, but the benefit of this therapy in patients who are not anemic is unclear. In a recent trial in nearly 1900 patients with HF who had an ejection fraction ≤45 percent, hemoglobin ≥9 g/dL, and evidence of iron deficiency (ie, low ferritin or low transferrin saturation), patients assigned to receive intravenous ferric derisomaltose had lower rates of mortality and hospitalization that did not reach statistical significance when compared with placebo [8]. However, in aggregate, trials of iron replacement in similar patients suggest a favorable effect on reducing hospital admissions. Thus, for most patients with HF and iron deficiency (with or without anemia), we suggest iron replacement with intravenous iron. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure".)

Possible increased risks of complications in sickle cell trait (August 2022)

Sickle cell trait is considered a benign carrier state with normal life expectancy and rare increased risks of certain complications (renal medullary carcinoma, splenic infarction at high altitude). Previous studies of cardiovascular complications did not show an increased risk (or showed no increased risk). A new study from the United Kingdom Biobank raises the possibility of increased risks of diabetes, hypertension, heart disease, chronic kidney disease, and retinopathy [9]. The study was based on billing codes and lacked the intensity of monitoring in prior studies; thus, the true risks remain unclear. (See "Sickle cell trait", section on 'Inadequate evidence or conflicting results on the risk of hypertension, diabetes, heart disease, or stroke'.)

Mitapivat for thalassemia (August 2022)

Mitapivat is a small molecule that activates red blood cell pyruvate kinase, an enzyme involved in generating energy in the form of adenosine triphosphate. In a small study involving 20 patients with nontransfusion-dependent thalassemia, mitapivat was associated with increases in hemoglobin in 16, including all five participants with alpha thalassemia and 11 of 15 with beta thalassemia [10]. Future studies will evaluate optimal dosing and predictors of response. (See "Management of thalassemia", section on 'Mitapivat'.)

Sutimlimab for cold agglutinin disease (July 2022)

Cold agglutinin disease is a form of autoimmune hemolytic anemia caused by immunoglobulin M antibodies that fix complement and agglutinate red blood cells. Sutimlimab is a monoclonal antibody directed against complement component C1s that was previously shown to improve anemia and fatigue in single-arm studies. A randomized trial has now been conducted that clearly demonstrates benefit of sutimlimab in improving anemia and reducing symptoms, and a small observational study has demonstrated sustained responses for up to three years [11,12]. For anemia that requires transfusions or causes severe symptoms, we suggest sutimlimab. (See "Cold agglutinin disease", section on 'Sutimlimab (anti-C1)'.)

High prevalence of anemia in pregnancy (July 2022)

Nonphysiologic anemia in pregnancy can have serious adverse consequences for the mother and child and disproportionally affects some populations. The main cause is iron deficiency. A new report from the United States Special Supplemental Nutrition Program for Women, Infants, and Children documented a slight increase in pregnancy-associated anemia from 2008 to 2018 [13]. Nearly 50 percent of Black gravidas had anemia in the third trimester, a rate twice as high as in non-Black gravidas. This and previous studies highlight the importance of screening and treating iron deficiency in pregnancy. (See "Anemia in pregnancy", section on 'Epidemiology'.)

CHRONIC LEUKEMIAS AND THE MYELOPROLIFERATIVE NEOPLASMS

Zanubrutinib versus ibrutinib in relapsed CLL (December 2022)

The Bruton tyrosine kinase inhibitors ibrutinib, acalabrutinib, and zanubrutinib are effective treatments for chronic lymphocytic leukemia (CLL). In a multicenter, open label, phase 3 trial (ALPINE) of >650 patients with relapsed or refractory CLL, when compared with ibrutinib, zanubrutinib improved progression-free survival and had less overall toxicity, including less cardiotoxicity [14]. Overall survival data are immature. Based on these and other data, where available, we suggest zanubrutinib or acalabrutinib rather than ibrutinib. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Zanubrutinib'.)

Ibrutinib plus rituximab versus FCR in chronic lymphocytic leukemia (August 2022)

Targeted therapies, such as ibrutinib, are the preferred initial treatment for most patients with chronic lymphocytic leukemia (CLL). In the phase III ECOG-ACRIN E1912 trial that enrolled >500 younger adults with CLL without del(17)p, ibrutinib plus rituximab (IR) improved progression-free survival (PFS) and overall survival (OS) when compared with six cycles of fludarabine, cyclophosphamide, and rituximab (FCR) [15]. On subgroup analysis, patients with immunoglobulin heavy chain variable (IGHV)-mutated CLL had improved PFS, but not OS, and FCR remains a treatment option in such patients. As treatment with FCR is finite, approximately two-thirds of patients remain off therapy at five years following FCR. In contrast, approximately two-thirds of patients assigned to IR remain on ibrutinib. This longer-term follow-up favors ibrutinib in the initial treatment of most patients with CLL, while continuing to support FCR as an option for those with IGHV-mutated CLL. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia", section on 'Efficacy in younger patients'.)

Zanubrutinib versus bendamustine plus rituximab in chronic lymphocytic leukemia (August 2022)

Zanubrutinib is an oral, selective, irreversible inhibitor of Bruton tyrosine kinase. A multicenter, open label, phase 3 trial (SEQUOIA) compared continuous zanubrutinib versus six cycles of bendamustine plus rituximab (BR) in approximately 480 older adults with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) [16]. Zanubrutinib improved progression-free survival and was less likely to require dose reduction or treatment discontinuation due to toxicity. While these results suggest that zanubrutinib is well tolerated and effective, it has not been directly compared with other targeted therapies (eg, venetoclax, ibrutinib) for management of previously untreated CLL. We await further data prior to incorporating the off-label use of this agent in CLL. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia", section on 'Zanubrutinib'.)

HEMOSTASIS AND THROMBOSIS

Dose of LMW heparin for VTE prevention in pregnancy (November 2022)

Low molecular weight (LMW) heparin is used for venous thromboembolism (VTE) prophylaxis during pregnancy and postpartum, but optimal dosing has been unclear. The Highlow trial evaluated dosing in 1110 pregnant individuals with a prior VTE receiving LMW heparin for VTE prophylaxis from the first trimester to six weeks postpartum [17]. Compared with weight-adjusted intermediate dosing, those assigned to daily fixed low-dose (60 mg) LMW heparin had a slightly higher rate of VTE (1 percent in both groups antepartum, 2 versus 1 percent postpartum); the difference did not reach statistical significance. Bleeding risk was 4 percent in each group. While we continue to perform an individualized risk assessment for each patient, this trial provides reassurance for the efficacy of fixed low-dose LMH heparin, especially antenatally. (See "Use of anticoagulants during pregnancy and postpartum", section on 'LMW heparin'.)

Gastric protection during anticoagulation (November 2022)

Gastrointestinal (GI) bleeding can complicate anticoagulation, especially in individuals with prior GI bleeding, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and other risk factors. A new meta-analysis evaluating the benefit of proton pump inhibitors (PPIs) across six observational studies and one randomized trial found an association between PPI use and reduced upper GI bleeding (relative risk 0.67, 95% CI 0.61-0.74) [18]. The correlation was strongest in individuals with NSAIDs or aspirin use and/or with a high bleeding risk score. UpToDate contributors suggest a PPI in individuals at high risk of upper GI bleeding who require anticoagulation. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Gastric protection'.)

Platelet transfusion thresholds (November 2022)

Prophylactic platelet transfusions are used to reduce bleeding risk in individuals with severe thrombocytopenia, but the efficacy and the optimal platelet count threshold remain unclear. A new systematic review analyzed data from seven randomized trials in individuals with hematologic malignancies or dengue virus infection and found a reduction in clinically important bleeding and a nonsignificant trend towards improved survival with platelet transfusion (administered at a variety of platelet thresholds) [19]. The trials were conducted over several decades and had significant heterogeneity in populations and trial protocols. UpToDate contributors suggest prophylactic platelet transfusion for platelet counts (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Supporting evidence'.)

Progestogens and risk of venous thromboembolism (September 2022)

Historically, estrogens but not progestogens were avoided in patients at increased risk of venous thromboembolism (VTE) who desired contraception or experienced abnormal uterine bleeding. In a case-control study that matched >21,000 reproductive-age patients with acute VTE with patients without prior VTE, current use of depot medroxyprogesterone acetate (DMPA), norethindrone acetate, or MPA was associated with an increased risk of VTE compared with non-use; the levonorgestrel-releasing intrauterine device and oral norethindrone were not associated with increased risk [20]. Study limitations included potential bias from patient selection and treatment indication. When counseling any patient about use of DMPA or high dose oral progestogens, we discuss the possibly increased risk of VTE and consider the patient's other potential risk factors for VTE when making treatment decisions. (See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Cardiovascular and thromboembolic risk'.)

Aspirin versus enoxaparin to prevent venous thromboembolism after hip or knee arthroplasty (September 2022)

The role of aspirin as a sole agent for venous thromboembolism (VTE) prophylaxis in adult patients undergoing total hip or knee arthroplasty (THA, TKA) is debated. In a recent, randomized crossover trial of over 9700 patients following THA or TKA that compared aspirin (100 mg orally per day) to enoxaparin (40 mg subcutaneously per day), symptomatic distal deep vein thrombosis was more common in patients receiving aspirin (2.4 versus 1.2 percent) [21]. There was no difference in the rates of major bleeding (< 0.5 percent) and death. Study limitations include the trial being stopped early for harm and lack of blinding of hospitals to treatment allocation. Nevertheless, these findings indicate that aspirin alone is inferior to enoxaparin and supports our practice of not using aspirin as the sole agent for VTE prophylaxis in patients following THA or TKA. (See "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement", section on 'Aspirin'.)

Gene therapy for hemophilia B (July 2022)

Clinical trials continue to explore optimal delivery of gene therapy for hemophilia. For hemophilia B, many constructs use the Padua variant, a naturally occurring variant in the F9 gene that significantly increases factor IX enzymatic activity. A new trial in 10 people with hemophilia B used the Padua variant in a new viral vector with increased liver tropism [22]. The mean annualized bleeding rate decreased from 2.93 to 0.71, and only one individual resumed factor IX replacement therapy. Adverse effects were as expected; one individual with high factor IX activity developed a thrombosis. The first hemophilia B gene therapy (for a different product) was approved by the US Food and Drug Administration in November 2022 [23]. (See "Gene therapy and other investigational approaches for hemophilia", section on 'Hemophilia B'.)

LYMPHOMAS: HODGKIN AND NON-HODGKIN

Brentuximab vedotin for treatment of advanced classic Hodgkin lymphoma in children (November 2022)

Intensification of therapy for advanced classic Hodgkin lymphoma (cHL) in children can improve outcomes, but these benefits must be balanced against the risk for increased toxicity from combination chemotherapy, with or without radiation therapy. A recent randomized trial demonstrated that, for children with advanced cHL (stage IIB with bulky disease, stage III, stage IV), the addition of brentuximab vedotin (an anti-CD30 monoclonal antibody conjugate) to standard intensive combination chemotherapy improved three-year event-free survival (92 versus 83 percent) with no increase in toxicity [24]. Longer-term follow-up is needed to determine if there is a difference in overall survival or late toxicity, such as growth and development delays or second cancers. For children with advanced cHL, we recommend addition of brentuximab vedotin, when available, to the combination chemotherapy regimen. (See "Overview of Hodgkin lymphoma in children and adolescents", section on 'High-risk disease'.)

Mosunetuzumab for multiply relapsed follicular lymphoma (August 2022)

Mosunetuzumab is a bispecific T cell engager (BiTE) monoclonal antibody directed at both CD20 on follicular lymphoma (FL) cells and CD3 on cytotoxic T cells. In a single-arm, multicenter phase 2 study of mosunetuzumab in 90 patients with FL relapsed after at least two prior lines of treatment, there were high response rates (60 percent complete, 20 percent partial), with a median duration of response of 23 months [25]. The most common adverse event was cytokine release syndrome, which was predominantly grade 1 or 2 and confined to the first cycle. These results led to approval of mosunetuzumab by the European Medicines Agency for this population. Review by the US Food and Drug Administration is ongoing. Where available, we consider mosunetuzumab an option for patients with multiply relapsed FL with short prior remission durations (eg, "Treatment of relapsed or refractory follicular lymphoma", section on 'Mosunetuzumab'.)

MULTIPLE MYELOMA AND OTHER PLASMA CELL DISORDERS

Belantamab mafodotin withdrawn from market (December 2022)

Belantamab mafodotin is being withdrawn from the market beginning November 2022, although it remains accessible through the manufacturer for patients who started treatment prior to its withdrawal [26]. The antibody drug conjugate targeting B-cell maturation antigen (BCMA) had received accelerated approval in the United States for patients with relapsed or refractory multiple myeloma (MM) based on response data from two uncontrolled open-label trials (DREAMM-1 and DREAMM-2). However, initial results of a randomized phase 3 trial (DREAMM-3) of belantamab mafodotin versus pomalidomide and dexamethasone in relapsed or refractory MM have not confirmed clinical benefit, leading to market withdrawal. (See "Multiple myeloma: Treatment of third or later relapse", section on 'Belantamab mafodotin'.)

Bispecific T cell engager (BiTE) teclistamab in multiple myeloma (November 2022)

Therapies that target the B cell maturation antigen (BCMA) are a preferred treatment option for patients with penta-refractory multiple myeloma (MM), defined as disease refractory to an anti-CD38 monoclonal antibody, lenalidomide, pomalidomide, bortezomib, and carfilzomib (algorithm 1). In a single-arm, phase 2, multicenter trial (MajesTEC-1) of the first-in-class anti-BCMA bispecific T-cell engager (BiTE) teclistamab in multiply relapsed MM, objective responses were seen in 63 percent, with an estimated progression-free survival of 11 months [27]. At least one grade 3 or 4 toxicity was reported in 95 percent of patients, with hematologic toxicity being most common. Cytokine release syndrome occurred in 73 percent and was usually grade 1 or 2. Based on this data, teclistamab has received accelerated approval by the US Food and Drug Administration for treatment of adults with relapsed, refractory MM after four or more lines of systemic therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody [28]. The use of teclistamab and other BCMA-directed therapies is individualized, weighing disease tempo, availability of other treatments, and expected toxicity. (See "Multiple myeloma: Treatment of third or later relapse".)

TRANSFUSION

Prothrombin complex concentrate versus plasma for coagulopathy and bleeding after cardiopulmonary bypass (September 2022)

Unactivated prothrombin complex concentrate (PCC) is used to rapidly correct warfarin anticoagulation. Observational studies have described off-label use of PCC to treat surgical coagulopathic bleeding, but supporting data are limited. One randomized trial compared administration of PCC 15 International Units/kg with fresh frozen plasma (FFP) 10 to 15 mL/kg in 100 patients who had excessive microvascular bleeding with prothrombin time (PT) >16.6 seconds and international normalized ratio (INR) >1.6 after cardiac surgery with cardiopulmonary bypass [29]. Overall efficacy and safety were comparable between PCC and FFP, and patients receiving PCC had improved correction of PT and INR. Before considering administration of PCC or FFP, we treat other causes of intractable bleeding (eg, surgical sources, thrombocytopenia, low fibrinogen levels, platelet dysfunction). (See "Reversing anticoagulation and achieving hemostasis after cardiopulmonary bypass", section on 'Prothrombin complex concentrate (PCC) products'.)

Frequency of transfusion reactions in children and adults (August 2022)

Transfusion reactions range from bothersome to life threatening. A new meta-analysis of >1.3 million transfusion reactions has documented a nearly twofold higher frequency of acute transfusion reactions in children than in adults [30]. Children were more likely than adults to have reactions to red blood cells and platelets, but not to plasma. Allergic and febrile nonhemolytic transfusion reactions were most common. The only type of reactions seen more frequently in adults were delayed hemolytic and delayed serologic reactions. Early signs and symptoms may not distinguish between benign and more serious events, and all acute transfusion reactions must be considered potentially serious until fully evaluated. (See "Approach to the patient with a suspected acute transfusion reaction", section on 'Frequency of reactions'.)

OTHER HEMATOLOGY

Drainage or splenectomy for splenic abscess (November 2022)

Splenic abscess is an uncommon infection that typically results from a hematogenous source such as endocarditis. Along with broad-spectrum antibiotics, a procedure is often needed to remove the fluid collection. A new systematic review of splenic abscess treatment in nearly 600 patients found that approximately half were treated with percutaneous drainage and half with splenectomy [31]. There were no statistically significant differences in mortality or complications. Drainage is less invasive and was associated with trends toward lower mortality and complication rates, but this may have reflected differences in patient populations or local expertise. The choice of procedure is individualized; percutaneous drainage may be preferable to some individuals if feasible. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Management (abscess/infarction)'.)

IVIG for vaccine-induced immune thrombotic thrombocytopenia (October 2022)

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication of adenoviral-vectored COVID-19 vaccines that presents with thrombocytopenia and thrombosis. Emerging evidence on management continues to support a role for intravenous immune globulin (IVIG) as a component of therapy, along with anticoagulation. In a new nonrandomized study involving 99 individuals with VITT presenting with cerebral venous thrombosis, receipt of IVIG was associated with lower mortality (29 versus 70 percent) [32]. In contrast, the choice of anticoagulant (heparin versus a nonheparin agent) and receipt of a platelet transfusion were not associated with statistically different mortality rates. We continue to suggest IVIG plus a nonheparin agent, especially if there is concern for possible heparin-induced thrombocytopenia (HIT; including delayed or spontaneous HIT). (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'IVIG'.)

Potential benefit of genotyping for variants that affect neutrophil count (September 2022)

Duffy null-associated neutrophil count (DANC) refers to low baseline neutrophil counts due to variants in the ACKR1 gene, which encodes the Duffy chemokine receptor on red blood cells (RBCs). Neutrophil function is normal. DANC is more common in African Americans, and individuals with DANC may inadvertently be underdosed with myelosuppressive medications when low neutrophil counts are misattributed to hematologic toxicity. In a study of 1466 individuals receiving azathioprine, discontinuation was nearly threefold more likely in individuals with DANC [33]. Some experts have suggested that testing for DANC (or for absence of the Duffy antigen on RBCs, which may be faster) could reduce underdosing and lessen racial disparities in outcomes. (See "Overview of pharmacogenomics", section on 'Potential benefits of genotyping'.)

Thrombotic microangiopathy after gene therapy for spinal muscular atrophy (August 2022)

Spinal muscular atrophy is a rare genetic disorder characterized by progressive muscle weakness and atrophy; treatment is mainly supportive. Onasemnogene abeparvovec is an approved gene therapy that has demonstrated promising results in infants <2 years of age. Several recent reports have described thrombotic microangiopathy, with severe thrombocytopenia and microangiopathic hemolysis, following administration of this therapy. One case was fatal [34]. Further study is needed to determine the mechanisms, risk factors, and optimal treatment of this complication. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Gene therapy (mechanism unclear)'.)

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