What's new in hematology

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

Azacitidine plus abbreviated venetoclax for higher-risk myelodysplastic syndromes (March 2025)

Higher-risk (HR) myelodysplastic syndromes (MDS) primarily arise in older patients, who are often not candidates for allogeneic transplantation. In a recent trial of 107 treatment-naïve patients with HR MDS, treatment with azacitidine plus an abbreviated course of the BCL2 inhibitor venetoclax was associated with a complete response in one-third, hematologic improvement in one-half, and two-year survival in more than half of patients; 41 percent of transfusion-dependent patients became transfusion-independent [1]. Most patients required dose adjustment or interruption, but toxicity was consistent with known adverse effects, including febrile neutropenia and pneumonia. While these results are encouraging, we await results from an ongoing trial of azacitidine plus venetoclax before routinely using this regimen outside of a clinical trial. (See "Myelodysplastic syndromes/neoplasms (MDS): Treatment of higher-risk MDS", section on 'Azacitidine'.)

Blinatumomab in front-line treatment of acute lymphoblastic leukemia/lymphoblastic lymphoma in adults and children (February 2025)

The CD19 x CD3 bispecific antibody, blinatumomab, is being evaluated for the frontline treatment of acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL), given its proven efficacy with relapsed or refractory ALL/LBL.

●In a trial of 224 adults with Philadelphia chromosome (Ph)-negative ALL in complete remission (CR) with measurable residual disease (MRD) <0.01 percent, multiagent chemotherapy followed by blinatumomab achieved superior three-year overall survival (OS) compared with chemotherapy alone (85 versus 68 percent) [2]. There were more grade ≥3 neuropsychiatric adverse effects (AEs) with blinatumomab (23 versus 5 percent), but other AEs did not differ. For adults with standard-risk Ph-negative ALL in CR after induction therapy, regardless of the level of MRD, we suggest consolidating with blinatumomab-containing chemoimmunotherapy, rather than chemotherapy alone. (See "Philadelphia chromosome-negative acute lymphoblastic leukemia in adults: Post-remission management", section on 'Consolidation phase'.)

●A trial of pediatric ALL/LBL was stopped early when a planned interim analysis found that blinatumomab plus chemotherapy achieved better three-year disease-free survival (96 versus 88 percent) and fewer relapses (3.3 versus 11.8 percent) compared with chemotherapy alone [3]. There was no difference in OS, but infectious complications were increased in some children receiving blinatumomab. We encourage enrollment of children in a trial that incorporates blinatumomab into the initial treatment of pediatric ALL/LBL, but do not use it for such patients outside of a trial. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Consolidation/intensification therapy'.)

New prognostic model for patients with acute myeloid leukemia receiving less-intensive therapy (January 2025)

The European LeukemiaNet (ELN) 2022 classification is an effective prognostic tool for patients with acute myeloid leukemia (AML) receiving intensive therapy, but it has proven suboptimal for predicting outcomes in patients treated with less intensive therapies. Analysis of the mutation status of KRAS, NRAS, FLT3-ITD (internal tandem duplication), and TP53 in 279 patients who were treated with azacitidine and venetoclax identified three risk groups with distinctly different outcomes [4]. Median survival ranged from 5.5 months with mutated TP53, to 12.1 months for one or more of the other mutations, to 26.5 months with none of these mutations. We consider the ELN 2024 classification a valuable prognostic model for patients receiving less-intensive treatments for AML. (See "Acute myeloid leukemia: Risk factors and prognosis", section on 'ELN 2024 classification for less-intensive therapies'.)

Revumenib for relapsed or refractory KMT2A-rearranged acute lymphoblastic leukemia (January 2025)

Revumenib is a novel inhibitor of binding of the lysine methyltransferase KMT2A with menin, which is seen in chromosome 11q23/KMT2A-rearranged acute lymphoblastic leukemia (ALL) and is associated with an especially poor prognosis. In a study of 57 patients with relapsed/refractory (r/r) KMT2A-rearranged ALL, revumenib was associated with a 63 percent response rate, including 23 percent complete remissions; 40 percent of patients were able to proceed to allogeneic transplantation [5]. Adverse effects include differentiation syndrome, QT interval prolongation, febrile neutropenia, and embryo-fetal toxicity. Revumenib was recently approved by the US Food and Drug Administration based on these data, and we now suggest its use for treatment of KMT2A-rearranged r/r ALL in patients ≥1 year of age. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'KMT2A (chromosome 11q23) rearranged'.)

Obecabtagene autoleucel for relapsed/refractory CD19-positive B cell acute lymphoblastic leukemia (December 2024)

Obecabtagene autoleucel (obe-cel) is a new chimeric antigen receptor (CAR)-T cell therapy that uses an intermediate-affinity CD19-directed CAR as a strategy to reduce toxicity and possibly improve persistence. In a trial of obe-cel in 127 patients with relapsed or refractory (r/r) CD19-positive B cell acute lymphoblastic leukemia (ALL), the response rate was 76 percent, including a complete remission rate of 55 percent [6]. Rates of grade ≥3 cytokine release syndrome (2 percent) and neurologic adverse effects (7 percent) were low. Obe-cel was recently granted regulatory approval in the United States and Europe for treatment of r/r CD19-positive B cell ALL, and we consider it acceptable in this setting. Head-to-head comparisons among CAR-T cell therapies are lacking. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Obecabtagene autoleucel'.)

LYMPHOMAS

Epstein-Barr virus serostatus and risk of posttransplant lymphoproliferative disorder (April 2025)

Posttransplant lymphoproliferative disorders (PTLD) are a serious complication among solid organ or hematopoietic cell transplant recipients, with most cases being caused by Epstein-Barr virus (EBV)-positive B cell proliferation. Prior studies have found an increased risk for PTLD in cases where the donor is EBV seropositive and the recipient is EBV seronegative (EBV D+/R-). In a recent retrospective cohort study of over 100 EBV D+/R- and over 300 matched EBV-seropositive recipients (with any donor status), biopsy-proven PTLD occurred in 22 percent of EBV D+/R- recipients at a median of 202 days posttransplant, while none of the EBV seropositive recipients developed PTLD [7]. These findings confirm that EBV serostatus is a risk factor for PTLD and suggest that the incidence of PTLD in kidney transplant recipients may be higher than previously estimated. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'EBV serostatus'.)

Zanubrutinib for the initial treatment of chronic lymphocytic leukemia (April 2025)

The Bruton tyrosine kinase inhibitor zanubrutinib is one of our preferred initial therapies for chronic lymphocytic leukemia (CLL) based on a progression-free survival (PFS) benefit when compared with bendamustine plus rituximab in a randomized trial. Longer follow-up data now show a sustained PFS benefit (estimated five-year PFS 76 versus 40 percent) and fewer patients requiring dose reduction or drug discontinuation due to toxicity [8]. Rates of bleeding, cytopenias, and diarrhea were highest in the first year and decreased over time, whereas rates of hypertension increased over time. These results provide further support for zanubrutinib as a preferred option for previously untreated CLL. Our approach for an individual patient depends on genetic features of the tumor (algorithm 1), comorbidities, and patient preference. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Efficacy of zanubrutinib'.)

Mosunetuzumab in multiply relapsed or refractory follicular lymphoma (March 2025)

Bispecific antibodies (mosunetuzumab, epcoritamab, odronextamab) are used as single agents in multiply relapsed follicular lymphoma (FL) and target CD3 on the patient's T cells and CD20 on the tumor cells. Regulatory approvals were based on impressive response rates in single-arm trials with very short follow-up. In a follow-up report of 90 patients with multiply relapsed or refractory FL treated with the bispecific antibody mosunetuzumab, the median progression-free survival was 24 months and the median duration of response was 36 months [9]. There were no new toxicities. Based on these and prior data, we consider bispecific antibodies to be an appropriate option in multiply relapsed FL. However, bispecific antibodies have not been directly compared with other therapies (eg, chimeric antigen receptor [CAR]-T cell therapy, novel agents) or with each other, and longer follow-up is needed to better understand efficacy and long-term toxicity. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Bispecific antibodies'.)

Acalabrutinib plus venetoclax with or without obinutuzumab for the initial treatment of chronic lymphocytic leukemia (February 2025)

For patients with chronic lymphocytic leukemia (CLL), initial treatment commonly employs either continuous therapy with a Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib, zanubrutinib, or ibrutinib) or fixed-duration therapy (venetoclax plus obinutuzumab or venetoclax plus ibrutinib). In a three-arm, open-label, randomized trial (AMPLIFY) of >865 patients with previously untreated CLL without del(17p) or TP53 mutation, acalabrutinib plus venetoclax (AV) improved progression-free and overall survival when compared to six cycles of chemoimmunotherapy with either fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine plus rituximab (BR) [10]. The addition of obinutuzumab to acalabrutinib plus venetoclax (AVO) deepened responses at the cost of greater immunosuppression and infection. We now consider off-label AV and AVO as options for the initial treatment of CLL. Our approach depends on genetic features of the tumor (algorithm 1), comorbidities, and patient preference. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Acalabrutinib plus venetoclax (with or without obinutuzumab)'.)

Zanubrutinib, obinutuzumab, and venetoclax for TP53-mutated mantle cell lymphoma (February 2025)

There is no consensus treatment for mantle cell lymphoma (MCL) with mutated TP53, which is associated with poor outcomes even with intensive chemotherapy and hematopoietic cell transplantation (HCT). A recent study reported that treatment of 25 patients with TP53-mutated MCL using zanubrutinib, obinutuzumab, and venetoclax (BOVen) was associated with 96 percent response rate (most with deep molecular responses), with 76 percent overall survival and 72 percent progression-free survival at two years [11]. BOVen was associated with diarrhea, neutropenia, and infusion reactions, but toxicity was generally modest. While we strongly encourage participation in a clinical trial, we consider BOVen an acceptable option for treating MCL with mutated TP53. (See "Mantle cell lymphoma: Initial management", section on 'BOVen'.)

No role for ibrutinib in early-stage CLL without active disease (January 2025)

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. A double-blind, randomized trial compared ibrutinib versus placebo in >360 patients with early-stage, asymptomatic CLL with prognostic markers associated with worse clinical outcomes [12]. After a median follow-up of 69 months, ibrutinib postponed the development of active disease and the need for additional CLL-directed therapy; however, these benefits did not translate into improved overall survival and there was increased toxicity. Observation remains standard for early-stage, asymptomatic CLL, with early treatment reserved for clinical trials (algorithm 1). (See "Overview of the treatment of chronic lymphocytic leukemia", section on 'Initial observation as standard care'.)

Nivolumab plus doxorubicin, vinblastine, and dacarbazine for advanced-stage classic Hodgkin lymphoma (November 2024)

The immune checkpoint inhibitor, nivolumab (N), and brentuximab vedotin (BV) are both effective for relapsed classic Hodgkin lymphoma (cHL), but, until recently, they have not been directly compared for initial treatment of advanced-stage (stage III or IV) cHL. In a randomized trial in 970 patients with advanced-stage cHL, N plus doxorubicin, vinblastine, and dacarbazine (AVD) achieved better two-year progression-free survival compared with BV plus AVD (92 versus 83 percent), with comparable toxicity [13]. Given these data, in patients with advanced-stage cHL, we suggest N plus AVD for initial treatment of advanced-stage cHL. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'Nivolumab plus AVD (preferred)'.)

Longer follow-up of zanubrutinib for relapsed or refractory CLL (October 2024)

The Bruton tyrosine kinase (BTK) inhibitors ibrutinib, acalabrutinib, and zanubrutinib are all effective treatments for chronic lymphocytic leukemia (CLL). Zanubrutinib and acalabrutinib are preferred over ibrutinib based on early results of trials that demonstrated that they are at least as effective and better tolerated than ibrutinib. Now, with 3.5 years of follow-up of a randomized trial in patients with relapsed/refractory CLL, zanubrutinib still shows improved progression-free survival and less overall toxicity than ibrutinib, including less cardiotoxicity [14]. While overall survival data are immature, there were numerically fewer deaths reported in the zanubrutinib arm, although this difference was not statistically significant. These results provide further support for the use of zanubrutinib in CLL. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Zanubrutinib'.)

Glofitamab, gemcitabine, oxaliplatin for relapsed or refractory diffuse large B cell lymphoma in transplant-ineligible patients (January 2024)

There is no consensus for treating patients with relapsed or refractory (r/r) diffuse large B cell lymphoma (DLBCL) when neither chimeric antigen receptor (CAR)-T cell therapy nor hematopoietic cell transplantation (HCT) is an option. Glofitamab, a CD20 x CD3 bi-specific antibody, plus gemcitabine and oxaliplatin (GemOx) achieved superior overall survival and progression-free survival compared with rituximab plus GemOx in a recent trial in transplant-ineligible patients with r/r DLBCL [15]. Glofitamab-GemOx caused more hematologic toxicity, but severe cytokine release syndrome (CRS) and neurologic adverse effects were uncommon. We consider glofitamab-GemOx an acceptable option for r/r DLBCL when CAR-T cell therapy and transplantation are not options. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Glofitamab'.)

MULTIPLE MYELOMA AND OTHER PLASMA CELL DISORDERS

New consensus statement on plasma cell leukemia (April 2025)

Plasma cell leukemia (PCL) is a rare, yet aggressive variant of multiple myeloma (MM) and there are limited data to guide therapy. The European Myeloma Network has published an updated review and consensus statement on primary PCL [16]. Similar to the guidelines, we use induction therapy including an anti-CD38 monoclonal antibody, proteasome inhibitor, immunomodulatory agent, and dexamethasone, but we also typically add low-dose cyclophosphamide. Our postinduction management is consistent with the guidelines and includes tandem transplantation, consolidation based on response, and two-drug maintenance until progression or unacceptable toxicity. This approach is primarily based on data from small uncontrolled prospective studies, retrospective series, and extrapolation of data from patients with MM. (See "Plasma cell leukemia", section on 'Goals of care and overall strategy'.)

Daratumumab maintenance after transplant for multiple myeloma (March 2025)

Maintenance therapy is a standard component of multiple myeloma (MM) treatment and our preferred regimen differs by risk stratification and prior management (algorithm 2). In a randomized trial in patients naive to the anti-CD38 antibody daratumumab who had detectable minimal residual disease (MRD) after autologous hematopoietic cell transplantation (HCT), the addition of daratumumab to lenalidomide increased MRD negativity and improved progression-free survival, albeit with a modest increase in toxicity (cytopenias, infections) [17]. Our preferred maintenance regimens after HCT remain single-agent lenalidomide for standard-risk MM and lenalidomide plus a proteasome inhibitor for high-risk MM. However, based on this and other studies, maintenance with lenalidomide plus daratumumab is an acceptable alternative for patients with standard-risk MM who did not receive an anti-CD38 monoclonal antibody during induction and for those with high-risk MM who cannot tolerate a proteosome inhibitor. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'High-risk disease'.)

Bispecific antibody combination in multiple myeloma (January 2025)

Bispecific antibodies are used as single agents in multiply relapsed multiple myeloma and target CD3 on the patient's T cells and either BCMA (teclistamab or elranatamab) or GPRC5D (talquetamab) on the tumor cells. In an open-label, phase 1/2 multicenter trial in 94 patients, the combination of teclistamab plus talquetamab reported high response rates (78 percent), but significant toxicity, including serious infections in 64 percent and treatment-related death in 15 percent [18]. Use of bispecific antibody combinations should be reserved for clinical trials as further study is needed to assess efficacy and toxicity. (See "Multiple myeloma: Treatment of second or later relapse", section on 'Talquetamab'.)

Daratumumab for high-risk smoldering multiple myeloma (December 2024)

Early intervention is indicated for patients with high-risk smoldering multiple myeloma (SMM) based on randomized trials that demonstrated that time-limited lenalidomide-based early intervention prevents end-organ damage, delays more intensive myeloma-directed therapy, and improves overall survival (OS) (algorithm 3). In a multicenter randomized trial of 390 patients with high-risk SMM, three years of single-agent daratumumab improved progression-free survival, delayed the time to more intensive myeloma-directed therapy, and improved OS (93 versus 87 percent at 60 months, hazard ratio 0.52) [19]. There was a low rate of daratumumab discontinuation due to adverse events, no new safety concerns, and similar quality of life measures in the two study arms. Based on these results, we now consider single-agent daratumumab to be an option for early intervention in high-risk SMM. (See "Smoldering multiple myeloma", section on 'Single-agent daratumumab'.)

Improved survival with daratumumab plus CyBorD in stage I to IIIA AL amyloidosis (December 2024)

In patients with newly diagnosed stage I to IIIA immunoglobulin light chain (AL) amyloidosis, short-term follow-up of a randomized trial demonstrated deeper responses and delayed progression with the addition of daratumumab to cyclophosphamide, bortezomib, and dexamethasone (CyBorD). Now, an updated analysis available in abstract form with a median follow-up of 61 months reaffirmed the improvement in major organ deterioration progression-free survival and reported an overall survival benefit (five-year overall survival 76 versus 65 percent, hazard ratio 0.62) [20]. Based on this and other data, we recommend daratumumab plus CyBorD rather than CyBorD alone or other regimens in this population (algorithm 4). (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Mayo stage I to IIIA disease'.)

RED BLOOD CELL DISORDERS AND ANEMIAS

Hypophosphatemia with intravenous ferric carboxymaltose (April 2025)

Several intravenous iron formulations are available, with similar efficacy and mostly similar adverse effects profiles. However, recent reports have emphasized a high rate of hypophosphatemia with ferric carboxymaltose (FCM). A new systematic review reported high rates of hypophosphatemia with FCM in randomized trials (50 to 92 percent, versus 2 to 8 percent with other intravenous iron formulations) [21]. This supports our practice of monitoring serum phosphate in all patients receiving more than one dose of FCM, especially individuals with borderline phosphate levels at baseline or receiving repeated doses. (See "Treatment of iron deficiency anemia in adults", section on 'Hypophosphatemia and cardiac iron uptake'.)

Haploidentical transplantation in sickle cell disease (March 2025)

For adults with sickle cell disease who wish to pursue hematopoietic stem cell transplantation and lack a matched sibling donor, haploidentical donors (related donors who share at least one haplotype [50 percent of HLA loci] with the recipient) continue to show promise. A new study involving 42 adolescents and adults who underwent haploidentical transplantation using the Johns Hopkins platform reported a two-year event-free survival of 88 percent and overall survival of 95 percent [22]. Chronic graft-versus-host disease occurred in 22 percent and graft failure in three individuals. This adds to the literature supporting haploidentical donor transplantation as a viable alternative for individuals with sickle cell disease who lack a matched sibling donor. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy", section on 'Haploidentical related donor'.)

Pregnancy in beta thalassemia minor (February 2025)

Beta thalassemia minor is considered an asymptomatic (or minimally symptomatic) carrier state. A new study involving 347 pregnancies in individuals with beta thalassemia minor documented higher rates of anemia and associated risks than expected, including third-trimester anemia in 31 percent, postpartum hemorrhage in 9 percent, and transfusions in 4 percent antepartum and 4.3 percent postpartum [23]. Of concern, 26 individuals were treated with intravenous iron, which was deemed inappropriate in 12, presumably because they were misdiagnosed as having iron deficiency. These data emphasize the importance of considering and accurately classifying the cause of anemia in individuals with beta thalassemia minor. (See "Management of thalassemia", section on 'Pregnancy' and "Anemia in pregnancy", section on 'Causes of anemia'.)

Investigational use of pegcetacoplan for cold agglutinin disease (February 2025)

Pegcetacoplan is a complement inhibitor that targets complement factor C3, responsible for intravascular and extravascular hemolysis in immune-mediated hemolytic anemias. In a study in 13 individuals with cold agglutinin disease, treatment with pegcetacoplan resulted in sustained improvements in hemoglobin and reduced fatigue [24]. Adverse events included gastrointestinal symptoms and infections. Another study was terminated prematurely. We await further data before incorporating this drug into our treatment paradigm. (See "Cold agglutinin disease", section on 'Pegcetacoplan (anti-C3)'.)

High rate of iron deficiency in athletes (January 2025)

High-intensity athletics can cause iron deficiency by several mechanisms including reduced iron intake, gastrointestinal blood loss, iron loss in sweat, and traumatic hemolysis. A new meta-analysis including over 17,000 college athletes and military recruits reported iron deficiency in 31 percent, using a ferritin cutoff of 30 ng/mL [25]. Female athletes are more likely than male athletes to have iron deficiency; younger and older athletes are equally affected. These observations confirm that high-intensity athletics is a significant risk factor for iron deficiency and support a role for screening in this population. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Epidemiology'.)

Associations of preoperative anemia with frailty, cognitive dysfunction, and postoperative mortality (January 2025)

Anemia is common in older adults. In a retrospective study of more than 8500 patients older than 65 years who had elective surgery, preoperative mild anemia (hemoglobin 11 to 12 g/dL), moderate anemia (hemoglobin 8 to 11 g/dL), and severe anemia (hemoglobin <8 g/dL) were diagnosed in 17 percent, 10 percent, and 0.4 percent, respectively [26]. Lower preoperative hemoglobin values were associated with preoperative cognitive dysfunction and frailty and an increased risk of death within one year of surgery, compared with those who were not anemic. Since even mild anemia may have important perioperative ramifications, timely management of preoperative anemia is necessary. (See "Anesthesia for the older adult", section on 'Assessment for anemia'.)

Atrial arrhythmias as a cause of stroke in sickle cell disease (January 2025)

The main cause of stroke in individuals with sickle cell disease (SCD) is altered cerebral hemodynamics caused by vasculopathy. However, the risk of cardioembolic stroke may be underestimated. A recent study of 130 adults (mean age 45 years) with SCD who underwent 24-hour Holter monitor testing detected atrial arrhythmias in 26 percent, and atrial arrhythmias were independently associated with stroke risk in individuals without underlying vasculopathy [27]. These findings suggest the importance of increased vigilance for atrial arrhythmias in people with SCD as a component of primary stroke prevention. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Risk factors: Ischemic stroke'.)

Increased risk of pulmonary embolism in sickle cell trait (December 2024)

Sickle cell trait is an asymptomatic carrier state, but risks are increased for certain complications. A new study used genetic data from almost four million individuals to assess risks for venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT) [28]. Compared to individuals without sickle cell trait, those with sickle cell trait had an approximately 2-fold increased risk for PE; a definite increased risk for DVT was not identified, and the overall VTE risk was increased 1.5-fold. This VTE risk for sickle cell trait was less than that for factor V Leiden (3.3-fold) and is not great enough to warrant management changes. Appropriate VTE prophylaxis during hospitalization should be emphasized. (See "Sickle cell trait", section on 'Venous thromboembolism'.)

Gene therapy for beta thalassemia (December 2024)

Experience with gene therapy for beta thalassemia continues to accrue. While previous studies using betibeglogene autotemcel focused on patients with some hemoglobin A production (non-beta⁰/beta⁰ genotypes), a new study administered this therapy to 18 individuals with genotypes that cause severe disease, including 12 with beta⁰/beta⁰ thalassemia, and reported transfusion-independence in 16 (89 percent) at a median of nearly four years of follow-up [29]. This therapy was approved in the United States in 2022 and is approved but not available in Europe. (See "Hematopoietic stem cell transplantation and other curative therapies for transfusion-dependent thalassemia", section on 'Gene therapy'.)

THROMBOSIS AND HEMOSTASIS

Protein S deficiency in the general population (March 2025)

Data on hereditary thrombophilias generally come from kindreds with a high rate of venous thromboembolism (VTE), but it is unclear whether VTE risk estimates apply to individuals identified by general population screening. A new study involving over 600,000 participants in the UK Biobank and the All of US program in the United States now provides extensive data on prevalence of protein S deficiency and VTE risks [30]. Two categories of PROS1 gene variants were identified. High-risk genotypes were very rare (prevalence approximately 0.01 percent) and associated with a 14-fold increase in VTE risk; lower risk genotypes had a prevalence of approximately 0.2 percent and were associated with an approximately two-fold increase in VTE risk. This information may be helpful in evaluating and counseling patients. (See "Protein S deficiency", section on 'Epidemiology'.)

Competing risks when resuming direct oral anticoagulants after intracerebral hemorrhage (March 2025)

Patients with atrial fibrillation and intracerebral hemorrhage (ICH) often have long-term competing risks of ischemic stroke and recurrent ICH. Limited data are available to help quantify these risks in patients taking direct oral anticoagulants (DOACs). In an open-label trial of 319 patients with prior ICH and atrial fibrillation who were randomly assigned to treatment with a DOAC or withholding anticoagulation, the subsequent ischemic stroke rate was lower in those assigned to a DOAC (0.8 versus 8.6 per 100 patient-years), but this benefit was partially offset by an increase in ICH recurrence (5 versus 0.8 per 100 patient-years) [31]. All-cause mortality was similar between groups, with wide confidence intervals. These data support the feasibility of resuming anticoagulation with a DOAC in selected patients with ICH but highlight the importance of shared decision-making incorporating these competing risks. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Therapeutic options'.)

Bleeding risk with direct oral anticoagulants (March 2025)

Direct oral anticoagulants (DOACs) are often preferred to warfarin since they do not require routine monitoring, but bleeding risks are uncertain. A new meta-analysis of data from randomized trials involving over 26,000 individuals prescribed a DOAC or low-dose aspirin reported that bleeding risks with DOACs were similar to low-dose aspirin, which carries a small increased risk [32]. However, clinicians should use caution when comparing bleeding risks between DOACs from different trials, as trial populations may differ and data from direct comparisons are limited. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Drug class'.)

Prophylactic tranexamic acid did not reduce postpartum hemorrhage after vaginal birth (February 2025)

Tranexamic acid (TXA) is commonly used for managing postpartum hemorrhage (PPH), whereas its role for preventing PPH is unclear. In a meta-analysis of randomized trials, prophylactic use of oxytocin plus TXA after vaginal birth resulted in little or no reductions in PPH ≥500 mL and 1000 mL, blood transfusion, surgical intervention to control hemorrhage, and severe maternal morbidity or death compared with oxytocin plus placebo [33]. The use of additional uterotonics in patients without anemia was modestly reduced. Further investigation is needed to understand whether administering prophylactic TXA in addition to routine oxytocin administration may be beneficial in specific settings. (See "Prophylactic pharmacotherapy to reduce the risk of postpartum hemorrhage", section on 'After vaginal birth'.)

Concizumab for hemophilia A or B without inhibitors (January 2025)

Concizumab is a non-factor prophylaxis for hemophilia A and B that works by inhibiting tissue factor pathway inhibitor (TFPI). It was previously shown to be effective in individuals with hemophilia and an inhibitor and approved by the US Food and Drug administration (FDA) in late 2024 for this indication. A new randomized trial (explorer8) evaluated the safety and efficacy of concizumab in 148 people with hemophilia A or B without inhibitors and reported that, compared with no prophylaxis controls, individuals assigned to concizumab had reduced annualized bleeding rates [34]. These results suggest that concizumab may be more broadly useful as a form of non-factor prophylaxis for people with hemophilia. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Products that can be used for hemophilia A or B'.)

Safety of antithrombotic therapy in factor XI deficiency (January 2025)

Spontaneous bleeding is rare in factor XI deficiency, suggesting that anticoagulation or antiplatelet therapy may be safer in these individuals than in those with other bleeding disorders. A new database study evaluated bleeding risk in approximately 50 percent of the general population in Israel [35]. While use of an anticoagulant or antiplatelet agent increased bleeding risk, individuals with factor XI deficiency did not have an appreciably higher rate of bleeding with these treatments than individuals without factor XI deficiency. These results suggest that antithrombotic therapy may be used when needed in individuals with factor XI deficiency, using shared decision-making based on the individual's bleeding phenotype and thrombotic risk. (See "Factor XI (eleven) deficiency", section on 'Anticoagulation or antiplatelet therapy'.)

Recombinant factor VIIa in Glanzmann thrombasthenia (January 2025)

Glanzmann thrombasthenia (GT) is a hereditary platelet function disorder that can cause severe bleeding despite a normal platelet count. GT is unique in the risk that platelet transfusions can trigger alloantibodies to platelet antigens, resulting in refractoriness to platelet transfusions. Recombinant factor VIIa (rFVIIa) is approved for treatment or prophylaxis of bleeding in these individuals. A new systematic review of rFVIIa in 100 individuals with GT reported good efficacy in surgical and nonsurgical bleeding, with or without platelet transfusions, regardless of platelet refractoriness [36]. These results support the use of rFVIIa in individuals with GT, especially when attempting to avoid platelet transfusions. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Glanzmann thrombasthenia'.)

Anticoagulation for patients hospitalized with COVID-19 (January 2025)

COVID-19 can cause a hypercoagulable state, especially when the disease is severe enough to require hospitalization, but the extent of hypercoagulability has decreased over time. A new meta-analysis of 20 randomized trials reported that, overall, therapeutic-dose anticoagulation was associated with lower 28-day mortality than prophylactic dosing, along with a lower risk of thromboembolic complications and a higher risk of bleeding [37]. However, the more recent trials did not show a significant benefit of therapeutic-dose anticoagulation relative to prophylactic dosing. These data support the use of prophylactic dosing in the intensive care unit (ICU) and in hospitalized (non-ICU) medical patients. (See "COVID-19: Hypercoagulability", section on 'Supporting evidence'.)

Carrier screening for hemophilia (December 2024)

Hemophilia A and B are X-linked conditions. Daughters of affected males are obligate carriers, and mothers of affected males are often carriers (some cases arise de novo). Carriers are typically asymptomatic, but they may require additional interventions during hemostatic challenges (surgery, delivery of a child), and their children may be affected. A new study illustrated the lack of comprehensive carrier screening in 287 kindreds followed in a single hemophilia treatment center [38]. Of 900 females screened, 454 were obligate or genetically proven carriers, but 328 had yet to undergo genetic testing, and 59 obligate carriers had yet to have their factor activity level measured. This study highlights the importance of testing female first-degree relatives of individuals with hemophilia. (See "Clinical manifestations and diagnosis of hemophilia A and B", section on 'Carrier detection'.)

Timing of anticoagulation after acute ischemic stroke in patients with atrial fibrillation (November 2024)

The timing of anticoagulation after acute ischemic stroke in patients with atrial fibrillation (AF) is controversial. Because of concern for intracranial hemorrhage, the start of anticoagulation is often delayed by one to two weeks for certain patients, such as those with large infarcts. However, recent findings from the OPTIMAS randomized trial and the CATALYST meta-analysis challenge this approach [39-41]. In a meta-analysis of patient-level data on over 6700 patients from trials (including OPTIMAS) evaluating the timing of direct oral anticoagulant (DOAC) initiation in patients with stroke and AF, rates of symptomatic intracranial hemorrhage were similarly low for both early (≤4 days from stroke onset) and late (≥5 days) DOAC administration, and the composite outcome of stroke or hemorrhage with early initiation was marginally lower at 30 but not 90 days [40]. Approximately 15 percent of patients had large or severe infarcts in the three largest trials. These data support the safety of early DOAC administration in patients with AF and ischemic stroke, but whether earlier DOAC treatment reduces the risk of recurrent ischemic stroke remains to be settled. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Timing of anticoagulation after acute ischemic stroke or TIA in patients with atrial fibrillation'.)

Tranexamic acid does not reduce bleeding during hepatectomy (October 2024)

Tranexamic acid (TXA) is used routinely during some types of surgery to prevent excessive bleeding; however, its effect during hepatectomy is unclear. In a randomized trial of over 1200 patients undergoing hepatic resection for cancer, administration of an intravenous bolus of TXA followed by an eight-hour infusion did not reduce blood loss or the need for blood transfusion compared with placebo [42]. Patients receiving TXA had more postoperative complications (44 versus 38 percent), with the largest difference in major complications. Venous thromboembolism was similar in the two groups, though the study may have been too small to detect a large difference. These results support our practice of avoiding routine administration of TXA during hepatic resection. (See "Anesthesia for the patient with liver disease", section on 'Preparing for hemorrhage'.)

TRANSFUSION MEDICINE

Prothrombin complex concentrate versus Fresh Frozen Plasma for coagulopathic bleeding after cardiopulmonary bypass (April 2025)

The optimal treatment for coagulopathic bleeding after cardiac surgery with cardiopulmonary bypass (CPB) is unclear. In a trial that randomly assigned 538 patients with post-CPB bleeding to receive unactivated prothrombin complex concentrate (PCC) or Fresh Frozen Plasma (FFP), those in the PCC group were less likely to require hemostatic intervention within 24 hours of therapy, received fewer transfusions, and had fewer serious adverse events [43]. If available, we use PCC rather than FFP to treat bleeding after CPB. (See "Achieving hemostasis after cardiac surgery with cardiopulmonary bypass".)

Inappropriate use of plasma in the intensive care unit (January 2025)

Plasma is thought to be over-used, often without a compelling indication. A new multicenter study supports this impression and illustrates the magnitude of misuse [44]. Among 3643 individuals in the intensive care unit (ICU), 10 percent received one or more plasma transfusions; of these, 37 percent did not have a strong indication and might have been avoided, such as mild elevations of the international normalized ratio (INR) in nonbleeding patients. Plasma transfusion should be limited to situations with a strong clinical rationale and/or demonstrated efficacy. (See "Use of blood products in the critically ill", section on 'Plasma indications'.)

Transfusion threshold for patients with aneurysmal subarachnoid hemorrhage (December 2024)

Anemia in aneurysmal subarachnoid hemorrhage (SAH) has been associated with cerebral infarctions and poor outcomes, but the benefit of a liberal transfusion strategy in this setting is uncertain. In a clinical trial of 742 patients with acute SAH that compared strategies of transfusion thresholds at hemoglobin ≤10 g/dL (liberal) versus ≤8 g/dL, functional outcomes were similar between groups (34 versus 38 percent with an unfavorable outcome at 12 months) [45]. Nearly all patients in the liberal threshold group received transfusions compared with 35 percent in the lower threshold group, and adverse event rates were similar. These results support our practice of using a restrictive transfusion threshold for patients with SAH and anemia. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Anemia'.)

Updated multidisciplinary guidelines for perioperative blood management during cardiac surgery (November 2024)

European multidisciplinary perioperative guidelines to minimize blood loss and the need for transfusion during adult cardiac surgery have been updated [46]. Given that cardiopulmonary bypass (CPB) affects hemostasis, preoperative strategies now emphasize timely management of preoperative anemia and medications affecting hemostasis. Before and during CPB, anticoagulation management, administration of antifibrinolytics, and strategies to avoid excessive hemodilution and unnecessary transfusion are addressed. The approach to achieving hemostasis after CPB has been revised to include updates on procoagulant interventions and utilization of blood products. New guidance on postoperative management covers chest tubes, re-exploration, and transfusion triggers. We generally agree with this guidance. (See "Anticoagulation and blood management strategies during cardiac surgery with cardiopulmonary bypass", section on 'Effects of cardiopulmonary bypass on hemostasis' and "Achieving hemostasis after cardiac surgery with cardiopulmonary bypass".)

OTHER HEMATOLOGY

Add-on danicopan in paroxysmal nocturnal hemoglobinuria (March 2025)

Complement C5 inhibitors (C5i) effectively treat hemolytic paroxysmal hemoglobinuria, but some patients have continued symptoms and ongoing transfusion needs because of breakthrough extravascular hemolysis (EVH). Extended follow-up of a trial that added danicopan to a C5i for breakthrough EVH in 86 patients now reports continued efficacy and safety after two years of therapy [47]. Like all complement inhibitors, danicopan is associated with risk for severe infections with encapsulated bacteria. For symptomatic breakthrough EVH, we suggest adding danicopan to the C5i, rather than continuing the C5i alone or monotherapy with another alternative pathway complement inhibitor (eg, iptacopan or pegcetacoplan). (See "Paroxysmal nocturnal hemoglobinuria: Treatment and prognosis", section on 'Management of breakthrough hemolysis'.)

Investigational flow cytometry assay for splenic function (February 2025)

Functional hyposplenia or asplenia carries an increased risk of serious infection, but a reliable assay for splenic function is not available. A new study describes an investigational assay that uses flow cytometry to detect the amount of red blood cell high mannose glycans (HMGs, which are normally removed by the spleen) as a measure of splenic function [48]. When tested on 527 blood samples from individuals with various causes of hyposplenia or asplenia and 189 controls, the assay performed extremely well (sensitivity 93 percent, specificity 100 percent). Further development of this assay is awaited. (See "Splenomegaly and other splenic disorders in adults", section on 'Asplenia or hyposplenia'.)

Remestemcel (mesenchymal stromal cells) approved for acute graft-versus-host disease in children (January 2025)

Systemic glucocorticoids effectively treat grade ≥2 acute graft-versus-host disease (aGVHD) in more than one-half of patients undergoing allogeneic hematopoietic cell transplantation, but there is no consensus on the preferred treatment for steroid-refractory (SR) aGVHD. Remestemcel-L, the first commercially available mesenchymal stromal cell (MSC) product, was associated with day-100 response in more than two-thirds of 54 children with SR aGVHD, including 44 percent complete responses [49]. No infusion-related or other adverse effects were reported. Remestemcel-L was recently approved by the US Food and Drug Administration for SR aGVHD in children ≥2 months, and we consider it an acceptable option for treating pediatric SR aGVHD. (See "Treatment of acute graft-versus-host disease", section on 'Mesenchymal stromal cells (MSCs)'.)

Neutropenia/agranulocytosis from deferiprone (November 2024)

Deferiprone is an oral iron-chelating agent used to treat iron overload when phlebotomy cannot be tolerated. The most concerning adverse effect is neutropenia/agranulocytosis. A recent review of data from 15 clinical studies (977 patients) found 22 cases of agranulocytosis and 3 serious infections, 1 of which was fatal [50]. Review of post-marketing reports identified 176 cases of agranulocytosis, 19 serious infections, and 11 deaths, mostly from sepsis. Lower neutrophil counts (<200/microL) conferred the greatest risk, and the mean time to onset of agranulocytosis was approximately two years. These data emphasize the need to closely monitor neutrophil counts throughout deferiprone therapy. (See "Iron chelation: Choice of agent, dosing, and adverse effects", section on 'Deferiprone dosing + AEs (Ferriprox)'.)