Report from the 2023 American Society of Hematology Annual Meeting — Benign Hematology

Presenters at the 2023 American Society of Hematology (ASH) annual meeting, held December 9–12 in San Diego, 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.

In adults with sickle cell disease (SCD), the next-generation sickle hemoglobin polymerization inhibitor known as GBT021601 is associated with large increases in mean hemoglobin (Hb) levels and is well tolerated, according to the preliminary results of an industry-supported, multicenter, phase 2/3 trial.

In the open-label part A of the three-part study, 35 patients (18 to 65 years of age) with SCD (HbSS/HbSβ⁰ genotype) and Hb 5.5–10.5 g/dL were randomized to receive a loading dose of 100 mg or 150 mg GBT021601, twice daily for 4 days, followed by once-daily maintenance doses for 12 weeks.

From baseline to week 12, hemoglobin increased by a mean of 2.67 g/dL in the 100-mg group (n=12) and 3.17 g/dL in the 150-mg group (n=11). Improvements were also seen in biomarkers for hemolysis and vaso-occlusive crisis risk.

Adverse events were predominantly grade 1 and 2.

Summary by Renée Ruthel, Staff Writer

COMMENT — Dr. Anjali Sharathkumar

GBT021601, a next-generation HbS polymerization inhibitor, is showing promise in achieving higher hemoglobin levels and improving hemolysis in patients with SCD. The major advantage will be reduction of pill burden and potentially improving therapy adherence and clinical outcomes. It would be of great interest to carefully evaluate efficacy data, specifically the type and severity of vaso-occlusive crisis.

Read more about the study and a related abstract.

A single infusion of a novel gene therapy, lovo-cel, in patients with sickle cell disease and recurrent severe vaso-occlusive events (VOEs) or history of overt stroke led to long-term sustained production of anti-sickling HbA^T87Q and almost complete resolution of VOEs, according to an industry-sponsored follow-up study. On December 18, 2023, the FDA approved lovo-cel and another gene therapy, exa-cel, for the treatment of patients 12 years of age and older with sickle cell disease.

Lovo-cel gene therapy involves autologous transplantation of hematopoietic stem and progenitor cells transduced with a lentiviral vector encoding a modified β-globin gene. Patients in the follow-up study were enrolled from phase 1/2 and phase 3 studies of lovo-cel therapy in patients aged 12 to 50 years.

Among 47 patients who were followed for up to 61 months (median, 36 months) after lovo-cel therapy, the median HbA^T87Q level was maintained at or above 4.5 g/dL from 6 months onward. The median total Hb increased from 8.7 g/dL at baseline to 11.8 g/dL at last follow-up. Among 33 patients with 4 or more VOEs in the 2 years before therapy, VOEs resolved in 91% and severe VOEs resolved in 97% within 6 to 18 months after therapy.

Most patients (94%) had at least one grade 3 or higher adverse event, most commonly stomatitis and thrombocytopenia. On quality-of-life measures, patients reported improvements in pain intensity, pain interference, and fatigue over 48 months.

Summary by Cara Adler, Staff Writer

COMMENT — Dr. Anjali Sharathkumar

These longitudinal data on a single infusion of lovo-cel gene therapy show sustained production of HbA^T87Q and near-complete resolution of severe VOEs at a median of 3 years. The long-term toxicity profile will be carefully monitored.

Read more about the lovo-cel study here and find out more about the exa-cel study also presented at ASH here.

Emicizumab is efficacious among infants with severe hemophilia A without factor VIII inhibitors, according to the industry-sponsored, phase 3b HAVEN 7 study.

Fifty-five infants aged 12 months and under received subcutaneous emicizumab at a dose of 3 mg/kg weekly for 4 weeks, then every 2 weeks for 52 weeks. They could then either continue with this regimen or switch to 1.5 mg/kg weekly or 6 mg/kg every 4 weeks during a 7-year follow-up period.

After a median treatment duration of 100 weeks, the model-based annualized bleeding rate for treated bleeds was 0.4. Just over half of patients had no treated bleeds. The annualized bleeding rate for all bleeds was 2.0.

Nearly 30% of patients experienced serious adverse events, but none were considered to be related to the treatment.

Summary by Kelly Young, Staff Writer

COMMENT — Dr. Anjali Sharathkumar

The HAVEN 7 study endorses the safety and efficacy of emicizumab in infants with severe hemophilia A, with a similar pharmacokinetics profile as that of adults. These promising results may imply that emicizumab could become the standard of care for infants with hemophilia A.

Read more about the study and a related abstract.

For patients with hereditary hemorrhagic telangiectasia (HHT), treatment with pomalidomide was associated with a clinically relevant reduction in epistaxis and improvement in an HHT-specific quality-of-life score, according to a multicenter, phase 2, U.S. trial. Pomalidomide is a thalidomide analogue and is used as an anticancer therapy (multiple myeloma).

Roughly 140 patients with moderate to severe epistaxis (mean Epistaxis Severity Score [ESS] at baseline, 5.0) were randomly assigned in a 2:1 ratio to receive 4 mg of pomalidomide or placebo daily for 6 months. The primary end point was the change in the ESS from baseline to the end of the 6-month treatment period. A key secondary end point was the change in an HHT-specific quality-of-life score.

At 6 months, the ESS, which ranges from 0 to 10, decreased by a mean of −1.84 among pomalidomide recipients as compared with −0.89 among placebo recipients.

The HHT-specific quality-of-life score, which ranges from 0 to 16 with higher scores indicating more limitation, also favored the treatment group, decreasing by a mean of −2.6 as compared with −1.2 with placebo.

Mild-to-moderate neutropenia, constipation/diarrhea, and rash occurred more frequently in the pomalidomide group. The incidence of venous thrombosis was the same in both groups (2%).

Summary by Renée Ruthel, Staff Writer

COMMENT — Dr. Anjali Sharathkumar

This randomized clinical trial in patients with HHT showed that treatment with pomalidomide improved nose bleeding severity and improved quality of life. It remains to be seen if the toxicity profile interferes with adherence and efficacy of the drug.

Read more about the study.

Adding danicopan to a complement component 5 inhibitor increases hemoglobin while reducing the need for transfusion in patients with paroxysmal nocturnal hemoglobinuria (PNH) and clinically significant extravascular hemolysis, according to an industry-sponsored, phase 3 trial. Danicopan is an investigational oral factor D inhibitor.

Investigators randomized 86 adults to add danicopan or placebo to their existing treatment with ravulizumab or eculizumab for 12 weeks, after which placebo recipients switched over to danicopan. The researchers previously reported that the change in mean hemoglobin level from baseline to 12 weeks — the primary outcome — was greater with danicopan than with placebo (increases of 2.94 vs. 0.50 g/dL).

From week 12 to 24, mean hemoglobin levels increased in patients who switched to danicopan (by 2.26 g/dL) and were maintained in those who had remained on danicopan. Key secondary outcomes also improved in the placebo–danicopan group from weeks 12 to 24 and were maintained in the danicopan–danicopan group, including change in absolute reticulocyte count, proportion of patients who avoided transfusion, and proportion with a hemoglobin increase ≥2 g/dL without transfusion.

While on danicopan, 90% of patients had one or more treatment-emergent adverse events. No deaths, meningococcal infections, or treatment discontinuations due to hemolysis were reported.

Summary by Cara Adler, Staff Writer

COMMENT — Dr. Anjali Sharathkumar

This pivotal phase 3 trial confirms that the addition of danicopan, an oral factor D inhibitor, to a standard-of-care complement C5 inhibitor (ravulizumab or eculizumab) improves hemoglobin levels and reduces extravascular hemolysis in patients with PNH with clinically significant extravascular hemolysis, without increasing risk of infection. It needs to be seen if post-marketing surveillance studies replicate this finding.

Read more about the study.