Report from the 2022 American Society of Hematology Annual Meeting — Benign Hematology

Presenters at the 2022 American Society of Hematology (ASH) annual meeting, held December 10–13 in New Orleans, reported the latest research in hematology. NEJM Group was on hand to cover the meeting. Here, NEJM Journal Watch Oncology and Hematology reports on some of the key findings in benign hematology, and Associate Editor Dr. Anjali A. Sharathkumar provides her clinical perspective. Abstracts can be found on the ASH meeting site.

Among hospitalized adults with pulmonary embolism (PE), nonwhite patients and those of lower socioeconomic status are less likely to receive advanced treatments — and are more likely to die in the hospital — according to a retrospective analysis.

Using 2016–2018 data from the Nationwide Inpatient Sample, U.S. researchers identified more than 1 million hospitalizations with a discharge diagnosis of acute PE. Advanced PE therapy (thrombolysis, catheter-directed treatment, surgical embolectomy, or extracorporeal membrane oxygenation) was used in 6% of cases. Among the findings, after multivariable adjustment:

• Compared with white patients, Black patients were 13% less likely to receive advanced PE therapy and Asian/Pacific Islander patients were 24% less likely.
• Compared with privately insured patients, Medicare patients were 27% less likely to receive advanced therapy and Medicaid patients were 32% less likely.

Patterns of therapy intervention were similar among the 6% of patients with high-risk PE.

The overall in-hospital case-fatality rate was 6% and for high-risk cases, 50%. Nonwhite patients had increased risks. For example, Asian/Pacific Islander patients had a 50% greater likelihood of dying than white patients — both overall and in the high-risk population. Additionally, among overall cases, those with the lowest incomes faced greater mortality risk.

Summary by Amy Herman, Staff Writer

COMMENT — DR. ANJALI A. SHARATHKUMAR

This study underscores the racial and socioeconomic disparities in outcomes of PE in the United States. Clinicians should be aware about adverse outcomes of PE in underserved populations and aim to eliminate treatment disparities so as to improve these outcomes.

Read more about the study.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) with residual anemia despite standard-of-care treatment with intravenous anti-C5 monoclonal antibodies (eculizumab or ravulizumab) derive significant benefits from switching to oral iptacopan — an investigational, first-in-class, selective complement factor B inhibitor — rather than continuing the standard of care, according to an industry-supported, phase 3, randomized trial.

Ninety-seven patients with mean hemoglobin below 10 g/dL on eculizumab or ravulizumab for at least 6 months were assigned 8:5 either to receive iptacopan (200 mg twice daily) or to continue standard-of-care treatment for 24 weeks. Iptacopan bested the standard of care for both primary outcomes — the proportion of patients with at least a 2-mg/dL increase in hemoglobin without a red blood cell transfusion (marginal proportion, 82% vs. 2%) and the proportion achieving a hemoglobin level of at least 12 mg/dL without a transfusion (marginal proportion, 69% vs. 2%).

Secondary outcomes also favored iptacopan, including transfusion avoidance, fatigue scores, and rates of breakthrough hemolysis. Overall, just one major adverse vascular event occurred: An iptacopan recipient experienced a transient ischemic attack, which was considered unrelated to treatment.

Summary by Amy Herman, Staff Writer

COMMENT — DR. ANJALI A. SHARATHKUMAR

PNH is a rare but life-threatening condition with limited therapy options. This phase 3 study showed clear benefit of single-agent iptacopan over standard of care by laboratory parameters. The study will affect clinical care substantially as the therapy is outpatient and oral — and, most importantly, was superior to standard of care.

Read more about the study.

Treatment with low-molecular-weight heparin (LMWH) during pregnancy does not improve live birth rates or reduce adverse outcomes in women with recurrent pregnancy loss and inherited thrombophilia, according to an open-label, randomized, controlled, phase 3 trial.

In the international study, investigators assigned 326 women within 7 weeks of a positive pregnancy test to receive standard pregnancy surveillance or subcutaneous LMWH injections once daily until the end of pregnancy. The women had experienced a median of three miscarriages before enrollment. Factor V Leiden heterozygosity was the most common type of thrombophilia.

Rates of live birth were similar in the LMWH and surveillance groups (71.6% and 70.9%, respectively). Adverse events occurred in nearly one quarter of women in both groups.

The authors conclude, “We do not advise routine use of LMWH in women with recurrent pregnancy loss and confirmed inherited thrombophilia, and we advise against routine testing for inherited thrombophilia in women with recurrent pregnancy loss.”

Summary by Cara Adler, Staff Writer

COMMENT — DR. ANJALI A. SHARATHKUMAR

The benefits of LMWH to prevent miscarriages are unclear. This randomized controlled trial shows lack of benefit of LMWH over close surveillance for prevention of pregnancy loss in women with inherited thrombophilia and previous history of two or more pregnancy losses; therefore, clinicians will have to reassess their practice and avoid using LMWH for prevention of pregnancy loss.

Read more about the study.

The safety profile of the bispecific monoclonal antibody emicizumab “is favorable” in patients with hemophilia A, according to a postmarketing, industry-supported analysis of data from the European Haemophilia Safety Surveillance (EUHASS) database.

The analysis included 1000 patients who took emicizumab from 2017 to 2020 either alone (84%) or with other hemophilia treatments (factor VIII in 10%, activated recombinant factor VII in 6%, activated prothrombin complex concentrate in 0.1%). Most patients were treated in 2020.

Adverse events reported to EUHASS for these patients during the 4-year period were as follows:

• Four thrombotic events: two myocardial infarctions (MIs), one thrombus in a port-a-cath, and one superior mesenteric artery thrombus
• One factor VIII inhibitor recurrence, occurring after more than 50 emicizumab exposures
• Four allergic or other acute reactions: one case each of rash, headache, visual impairment, and dizziness

There were no reports of thrombotic microangiopathy (TMA).

Summary by Cara Adler, Staff Writer

COMMENT — DR. ANJALI A. SHARATHKUMAR

Emicizumab has revolutionized the treatment of hemophilia A in patients with and without factor VIII inhibitors. However, safety concerns remain, specifically TMA and thromboembolism. While it is reassuring that this postmarketing study shows emicizumab is safe, it is important to note that thromboembolic events (venous thromboembolism [VTE] and MI) continue to occur at low frequency, both with emicizumab used alone and with other hemostatic concentrates. Clinicians should closely monitor patients for TMA/VTE events while on this therapy.

Read more about the study.

The thrombopoietin receptor agonist eltrombopag may offer an additional treatment option for children with refractory/relapsed severe aplastic anemia after immunosuppressive therapy (IST), according to an industry-supported, multicenter, phase 2, dose-escalation trial.

Fifty-one pediatric patients were enrolled. Those with refractory/relapsed severe aplastic anemia after IST received either oral eltrombopag plus IST (horse antithymocyte globulin and cyclosporin A), or eltrombopag plus cyclosporin A. Those who were previously untreated received eltrombopag plus IST. Eltrombopag was given for 26 weeks (maximum daily dose, 150 mg) and could be continued during an additional 52 weeks' follow-up.

Among the findings for the primary outcome, pharmacokinetics: For patients who stayed on their highest tolerated dose for at least 14 days, the geometric mean total area under the curve plasma concentration (AUC_tau) was 1230 μg∙h/mL for patients aged 1 through 5 years, and 733 μg∙h/mL for those aged 6 through 17 years. Corresponding peak serum concentration (C_max) values were 71.6 μg/mL and 36.2 μg/mL, respectively. Both findings suggest age-dependent variations in drug metabolism.

The overall response rate (ORR) at week 26 was 71% for those with refractory/relapsed disease and 46% for those with previously untreated disease. ORRs at week 52 were 57% and 51%, respectively. The most common adverse events were increased bilirubin, alanine transaminase, creatinine, and aspartate aminotransferase levels. Half of patients discontinued treatment, most often due to physician decision or adverse events.

Summary by Amy Herman, Staff Editor

COMMENT — DR. ANJALI A. SHARATHKUMAR

Eltrombopag has been approved for the treatment of severe aplastic anemia in children as an upfront therapy along with standard-of-care IST. Its benefit in children with relapsed or refractory disease is unclear. It is reassuring that no untoward safety signal was noted during 26 weeks of therapy in this study. Although the study was designed to assess the pharmacokinetics of eltrombopag along with other standard therapeutics for severe aplastic anemia, the careful assessment of data suggests that the addition of eltrombopag to standard of care could offer beneficial effects in refractory/relapsed disease.

Read more about the study.

A nationwide blood bank alloantibody data exchange could reduce mortality and be cost-effective in patients with sickle cell disease, according to a computer simulation.

Red blood cell alloimmunization can occur when patients are exposed to other people's red blood cell antigens (i.e., allogeneic antigens) during transfusion or pregnancy. When pretransfusion screening tests fail to detect previously formed alloantibodies, recipients can experience delayed hemolytic transfusion reactions (DHTRs). Rates of alloimmunization and DHTR mortality are “particularly high” in patients with sickle cell disease. Researchers have proposed a registry for blood banks to easily share data on patients' alloimmunization histories.

In this simulation, which utilized data from over 500 prospective and retrospective studies of DHTR incidence in people with sickle cell disease, the researchers estimated that implementing alloantibody data sharing would lead to a cumulative lifetime DHTR mortality of 2.4%, as compared with 5.7% if an exchange were not implemented.

Based on this DHTR-specific mortality benefit, nearly 16,000 quality-adjusted life years would be gained across the alloimmunized population with sickle cell disease. An estimated $34,000 would be saved per alloimmunized patient in the exchange, with $1.5 billion saved overall.

The authors say that the benefit may also extend to alloimmunized patients with myelodysplastic syndrome, thalassemia, autoimmune conditions, and pregnancy.

Summary by Kelly Young, Staff Writer

COMMENT — DR. ANJALI A. SHARATHKUMAR

There is an effort towards integration and exchange of medical health information across various healthcare systems that will impact clinical care in the near future. This study underscores the importance of this technology for reducing DHTRs among multiply transfused sickle cell patients with a history of alloantibody development, as getting appropriately matched donor red cell units can take days.

Read more about the study.