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Report from the 2024 American Society of Hematology Annual Meeting — Benign Hematology
NEJM Group was on hand to cover the 2024 American Society of Hematology (ASH) annual meeting, held December 7 to 10 in San Diego. Here, NEJM Journal Watch Oncology and Hematology Associate Editor Dr. Anjali Sharathkumar reports some of the key findings in benign hematology.
Pulmonary hypertension is common among patients hospitalized for sickle cell crisis and is associated with significant increases in mortality and complication risks, according to an observational study presented at the conference.
Using the National Inpatient Sample database (2018–2020), researchers identified roughly 250,000 adults hospitalized with a primary diagnosis of sickle cell crisis, 70% of whom also had pulmonary hypertension.
After multivariate adjustment, concomitant pulmonary hypertension was associated with increased mortality risk (adjusted odds ratio, 2.14) and complications like right heart failure (aOR, 21.45). Patients with pulmonary hypertension also had longer mean hospital stays than patients without pulmonary hypertension (7 vs. 5 days) and higher mean hospital costs (roughly $65,000 vs. $42,000).
The authors conclude: “Overall, the study highlights the critical relationship between pulmonary hypertension and [sickle cell crisis] in hospitalized patients and the need for careful management and monitoring of these patients to improve their clinical outcomes.”
Summary by Kelly Young, Staff Editor
COMMENT — Dr. Anjali Sharathkumar
Analyses of the National Inpatient Sample database reveal that pulmonary hypertension is highly prevalent in hospitalized patients with sickle cell crisis, significantly increasing mortality risk, complications, length of stay, and healthcare costs, underscoring the need for vigilant management to improve outcomes.
Read more about the study and watch a 6-minute interview with the lead author.
Among children with sickle cell anemia, allogeneic stem cell transplantation (alloSCT) is associated with better primary prevention of silent cerebral infarcts and better cognitive performance measures after 10 years, compared with standard care, suggests the industry-funded, nonrandomized DREPAGREFFE-2 study.
In DREPAGREFFE-1, 67 children under age 15 years with sickle cell anemia (SS/Sb0) either underwent matched-sibling donor alloSCT or — for those without a matched donor — were maintained on chronic transfusion for at least 1 year and then potentially switched to hydroxyurea (standard care). Researchers now report long-term follow-up of these patients from the DREPAGREFFE-2 study.
Among those with silent cerebral infarcts detected at baseline, the infarcts were either no longer visible or were less than 3 mm in one standard-care patient and in four alloSCT patients at 10 years' follow-up. New silent cerebral infarcts were detected in five patients in the standard-care arm and none in the alloSCT arm.
In cognitive tests, the mean working memory index and the processing speed index were higher in the alloSCT patients. Mean quality-of-life scores were also higher for physical, school, and social functioning in the alloSCT group.
Summary by Kelly Young, Staff Editor
COMMENT — Dr. Anjali Sharathkumar
The DREPAGREFFE-2 study shows that allogeneic stem cell transplantation in children with sickle cell anemia offers superior long-term outcomes, including better prevention of silent cerebral infarcts, improved cognitive function, and enhanced quality of life, potentially transforming the treatment paradigm for this disease.
In patients with transfusion-dependent β-thalassemia, gene addition therapy with betibeglogene autotemcel (beti-cel) shows benefits and a favorable safety profile over the long term, according to a follow-up analysis of several industry-funded studies.
The analysis included 63 patients who received beti-cel; 80% were followed for 5 years or more, with two patients followed for 10 years. Among the findings, after a median follow-up of roughly 6 years:
- Peripheral blood vector copy number (PB VCN) and levels of adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) were stable by month 6 after treatment and sustained for up to 10 years.
- At last follow-up, median PB VCN ranged from 0.4 to 1.6 c/dg across studies.
- Among the 68% of participants who achieved transfusion independence in phase 1/2 studies, median HbAT87Q was 7.6 g/dL, and weighted average hemoglobin during transfusion independence was 10.24 g/dL. In the 90% who achieved transfusion independence in phase 3 studies, median HbAT87Q was 9.8 g/dL, and weighted average hemoglobin was 11.24 g/dL.
- Reductions in serum ferritin and liver iron concentration at month 60 indicated improvement in iron overload.
No serious adverse events related to beti-cel were reported after 2 years of follow-up.
Summary by Amy Herman, Staff Editor
COMMENT — Dr. Anjali Sharathkumar
This long-term analysis of beti-cel gene therapy for transfusion-dependent β-thalassemia, with up to 10 years of follow-up, shows stable peripheral blood vector copy numbers and adult hemoglobin levels by month 6 posttreatment. Notably, the majority of participants achieved transfusion independence, with significant improvements in hemoglobin levels and reductions in iron overload. Additionally, the findings indicate a promising long-term safety profile for this therapy.
A novel approach using lentiviral vector–transduced hematopoietic stem cell (HSC)–based gene therapy shows promise in patients with severe hemophilia A, according to a small, first-in-human trial published in the New England Journal of Medicine and presented at the conference.
This phase 1, single-center trial in India enrolled five participants, aged 22 to 41, with severe hemophilia A without factor VIII inhibitors. Patients underwent gene therapy by transplantation of autologous CD34+ HSCs that were transduced with the CD68-ET3-LV vector, which included a novel F8 transgene. Two patients received double exposure to the vector (group 1), and three received a single exposure with a transduction enhancer (group 2).
Among the efficacy and safety findings over a median 14 months of follow-up:
- The median plasma factor VIII activity after day 28 until last follow-up was 5.2 and 1.7 IU/dL in group 1 participants and 37.1, 19.3, and 39.9 IU/dL in group 2 participants.
- No patients experienced spontaneous bleeding during HSC transplantation or after gene therapy. Prior to gene therapy, all patients had reported an annualized bleeding rate above 20 events.
- There were no unexpected safety concerns. All patients developed cytopenia, as expected.
- All patients experienced engraftment by day 30.
- Two patients experienced trauma (a minor motor vehicle accident and a cat bite) during follow-up. Neither patient required additional factor VIII replacement.
Summary by Kelly Young, Staff Editor
COMMENT — Dr. Anjali Sharathkumar
This innovative gene therapy approach for hemophilia A represents a significant departure from previous trials, potentially transforming the landscape of gene therapy treatment for this condition by offering several potential advantages:
- Long-term efficacy through stable engraftment of gene-modified HSCs
- Possibility of re-treatment if needed
- Avoidance of preexisting immunity to adeno-associated viral (AAV) vectors
- Potential for higher and more-consistent factor VIII expression
While long-term follow-up is needed to fully assess its efficacy and safety, this novel approach represents an exciting step forward in the field of gene therapy for hemophilia A.
Empfohlen von
Anjali A. Sharathkumar, MBBS, MD, MS