Report from the 63rd American Society of Hematology Annual Meeting — Benign Hematology

Presenters at the 2021 meeting of the American Society of Hematology (ASH; December 11–14, 2021) reported the latest research in hematology. Here, NEJM Journal Watch Oncology and Hematology Associate Editor Dr. Brady L. Stein describes the key findings in benign hematology.

Prophylactic use of fitusiran, an investigational small interfering RNA (siRNA) therapeutic, is associated with a lower bleeding rate than on-demand bypassing agents (BPA) in people with hemophilia A or B with inhibitors, according to the industry-conducted, phase 3 ATLAS-INH study (abstract 4).

Nearly 60 males with hemophilia A or B with inhibitors who were taking on-demand BPA were randomized to receive monthly subcutaneous injections of prophylactic fitusiran (80 mg) or to continue with on-demand BPA.

The estimated annualized bleeding rate was significantly lower in the fitusiran group (1.67 vs. 18.07 for on-demand BPA). Rates of treated spontaneous and joint bleeds were also significantly lower with fitusiran. Roughly 17% of the fitusiran group and 26% of the on-demand BPA group reported treatment-emergent serious adverse events.

Summary by Kelly Young, Staff Writer

COMMENT — DR. BRADY L. STEIN

Management of hemophilia patients with inhibitors can be quite challenging. This study suggests an impressive efficacy and safety profile for an agent with a novel mechanism of action — rebalancing hemostasis by targeting antithrombin. An agent that considerably reduces bleeding events and can be administered subcutaneously, once per month, will be welcomed by this patient population.

Watch our interview with the lead ATLAS-INH author.

Fitusiran helps prevent bleeding episodes in people with severe hemophilia A or B without inhibitors, according to the industry-conducted, open-label, phase 3 ATLAS-A/B trial (abstract LBA-3).

Some 120 male patients aged 12 years or older who were previously treated on demand were randomized to receive either prophylactic fitusiran once monthly (80 mg subcutaneously) or factor concentrates on demand for bleeding episodes, for a total of 9 months' treatment.

During follow-up, the median observed annualized bleeding rate was 0.0 in the fitusiran group versus 21.8 in the on-demand group. Secondary endpoints, including annualized spontaneous bleeding rate and annualized joint bleeding rate, also favored fitusiran, as did health-related quality of life.

Treatment-emergent serious adverse events were reported by 6.3% of the fitusiran group and 12.5% of the on-demand group. In the fitusiran arm, these included cholelithiasis, cholecystitis, lower respiratory tract infection, and asthma. No thromboses or fatalities occurred.

Summary by Amy Herman, Staff Writer

COMMENT — DR. BRADY L. STEIN

This study complements the ATLAS-INH study presented above. Here, the patient population of interest included those with severe hemophilia A or B, but lacking inhibitors. This agent is intended to “rebalance” hemostasis by targeting antithrombin — it is impressive to see an annualized bleeding rate of 0.0 in the treatment group. No serious thrombotic event was reported. From a quality-of-life standpoint, patients would certainly welcome a subcutaneous agent that can be administered monthly, with great efficacy.

Direct-acting oral anticoagulants (DOACs) are more effective than low-molecular-weight heparin (LMWH) for preventing recurrent venous thromboembolism (VTE) in patients with cancer and acute VTE, according to an updated meta-analysis comprising research results available through early August 2021 (abstract 668).

The analysis included six randomized trials in which 3690 patients with cancer and acute VTE were assigned to receive a DOAC or LMWH. During 3 to 6 months' follow-up, recurrent VTE occurred significantly less often in the DOAC group than in the LMWH group (5.3% vs. 8.3% of patients). The risk for major bleeding did not differ significantly between the two groups (4.2% and 3.5%, respectively), although the risk for clinically relevant nonmajor bleeding was significantly higher with DOACs (10.3% vs. 6.3%). All-cause mortality did not differ between the groups.

The researchers conclude, “Our results provide additional evidence for the use of DOAC as a safe and effective first-line option for the treatment of [cancer-associated thrombosis] in patients who are not at high risk of bleeding.”

Summary by Amy Herman, Staff Writer

COMMENT — DR. BRADY L. STEIN

This study adds to prior data supporting use of DOACs (rivaroxaban, apixaban, edoxaban) in patients with cancer-associated thrombosis. Here, reduction in recurrence risk without an increase in major bleeding should add to the hematologist/oncologist's confidence level when choosing such agents. However, we still need to be selective — bleeding risk, thrombocytopenia, organ insult, drug–drug interactions, and cancer site should be considered when deciding between LMWH or a DOAC. Without question, an oral agent is preferable for the patient, provided safety criteria are met. This study suggests an appropriate safety and efficacy profile for the DOAC class.

Myeloproliferative neoplasms (MPN) are associated with higher excess mortality in younger patients — for whom less-intensive treatments are often recommended — than in older patients, suggests a new study (abstract 235).

Researchers used the U.S. Surveillance, Epidemiology, and End Results (SEER) registry to identify roughly 40,000 people diagnosed with MPN between 2001 and 2017.

For patients under age 60, the 10-year all-cause mortality rate was 13% for those with essential thrombocythemia, 18% for polycythemia vera, and 49% for primary myelofibrosis. In comparison, the mortality rate for matched population-based controls was 6%. Excess all-cause mortality relative to controls was higher in patients younger than age 60 compared with those older than 60 who had essential thrombocythemia (relative risk, 2.75 vs. 1.82), polycythemia vera (3.16 vs. 1.92), and primary myelofibrosis (10.6 vs. 5.73).

The authors call the excess mortality in younger patients “unacceptably high.”

Summary by Kelly Young, Staff Writer

COMMENT — DR. BRADY L. STEIN

MPN in the young presents a particular challenge, as these patients, unfortunately, have a lot of time/opportunity to experience progression events, which can include a thrombotic event (patients shift from “low” to “high” risk if this occurs) or transformation to myelofibrosis or acute leukemia. Younger patients are often observed, as by virtue of age, they often distribute into lower risk groupings. In part, observation is often recommended because of the lack of effective treatments proven to delay progression. Interferons have gained traction in academic communities and are considered a drug of choice by some for an “early intervention.” A study like this challenges the current paradigm of watchful waiting, and as the authors state, builds a case for earlier treatments.

Patients with immune thrombocytopenia (ITP) before SARS-CoV-2 vaccination may experience worsening of thrombocytopenia postvaccination, but this responds well to rescue medications, a new study finds.

Researchers studied 117 patients with ITP who underwent SARS-CoV-2 vaccination, most often with an mRNA vaccine. Among the findings for patients with evaluable data:

• After dose 1, roughly one third of patients had an increase in platelet counts, one third had stable platelets, and one third had a decrease in platelets. The same pattern occurred with dose 2.
• 17% of patients had an ITP exacerbation after dose 1, and 20% after dose 2. All patients who received rescue treatments responded.
• Patients who had undergone splenectomy or had received at least five prior lines of medical therapy were most likely to experience ITP exacerbations.
• Age, sex, vaccine type, and autoimmune disease were not associated with postvaccine platelet counts.

The researchers conclude: “These findings should encourage patients with ITP to not only be vaccinated, but to receive the second dose when applicable to ensure optimal immunization.”

Summary by Amy Herman, Staff Writer

COMMENT — DR. BRADY L. STEIN

A well-described and tragic report of fatal ITP following COVID-19 vaccination heightened anxiety among patients and hematologists. That ITP can flare following vaccinations is known to hematologists. However, this study should increase confidence for patients and hematologists caring for ITP patients — the key finding is that the platelet decline could be rescued.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with protection from Alzheimer disease (AD) dementia, according to surprising results of a genetic analysis (abstract 5). In CHIP, hematopoietic stem cells acquire genetic mutations that give them a survival advantage. CHIP is associated with increased risk for blood cancers, as well as atherosclerosis and other inflammatory disorders.

Researchers studied data from two genome sequencing studies on roughly 5700 people. In both cohorts, the presence of CHIP was linked to lower risk for AD dementia and, among those without dementia, a lower burden of brain amyloid plaques and neurofibrillary tangles, compared with noncarriers.

Next, the researchers examined eight occipital cortex samples from deceased patients with CHIP; six were cognitively normal at death. They found that mutant marrow-derived cells infiltrate the brain, where they take on a microglial-like phenotype.

Summary by Kelly Young, Staff Writer

COMMENT — DR. BRADY L. STEIN

This is a very interesting and unexpected finding. Until now, CHIP has had more of a negative association with health outcomes, including coronary heart disease and risk for hematological malignancy. It is possible that this protective effect would be restricted to AD dementia rather than vascular dementia since CHIP associates with inflammation and vascular risk.