ASH 2024 press briefing rundown: treating not-so-benign hematology conditions

ASH 2024 Press Briefing Rundown: Treating Not-So-Benign Hematology Conditions

VJHemOnc is thrilled to bring you a feature covering the latest updates from the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, which was held in San Diego, CA, from 7-10 December, 2024.

Fertility Preservation outcomes for people with ovaries and sickle cell anemia

Sickle cell anemia (SCA) presents significant reproductive challenges in patients with ovaries, with an accelerated decline in ovarian reserve starting in early adulthood. This may be driven by direct end-organ injury to the ovaries because of ovarian sickling and further exacerbated by exposure to gonadotoxic preparative regimens prior to receiving curative therapeutic strategies, such as stem cell transplantation (SCT) or gene therapy.¹Fertility preservation (FP) measures, namely ovarian tissue and oocyte/embryo cryopreservation, offer patients hope that pregnancy may be a possibility in the future. However, there is inadequate data on FP outcomes in patients with SCA, including on the potential complications and barriers to access.

At ASH 2024, Marti Goldenberg, DO, Department of Pediatric Hematology at Johns Hopkins Hospital, Baltimore, MD, presented the data from a multicenter study investigating FP outcomes for patients with ovaries and SCA in five large academic centers. The study aimed to assess clinical factors associated with oocyte recovery and the incidence of complications related to controlled ovarian hyperstimulation (COH) with oocyte cryopreservation (OC). The median age of the 46 patients included in the analysis was 23.7 (IQR: 18, 28), with the majority (n=44) undergoing FP measures prior to receiving a curative therapeutic regimen.

The results indicated that a proportion of patients (13%) required more than one cycle of COH as a result of low oocyte yield (n=5) or cycle cancellation (n=1). COH complications were common, occurring in 45% of the 55 cycles included in the analysis, and almost a quarter of subjects (n=11) experienced more than one complication. An association was found between the incidence of any complication of COH and the occurrence of three or more vaso-occlusive episodes (VOE) in the year prior to COH (mean: 3 VOE per patient without a complication versus 6 per patient with a complication; p = 0.036). This highlights the need for personalized care strategies and the implementation of individualized pain plans long before FP measures are considered to improve outcomes for patients with SCA and ovaries.²

LUNA 3: investigating rilzabrutinib in previously treated immune thrombocytopenia

Despite the availability of treatments such as corticosteroids, intravenous immunoglobulin (IVIg), and anti-D immunoglobulin (anti-D) for the treatment of primary immune thrombocytopenia (ITP), a significant number of patients do not achieve adequate platelet counts with these therapies.³ This results in increased morbidity and mortality rates and impaired quality of life, highlighting a need for novel agents to improve clinical outcomes in this autoimmune disease. In recent years, bruton tyrosine kinase inhibitors (BTKis) have emerged as a promising new class of agents for the treatment of ITP. Rilzabrutinib is an oral, covalent, reversible BTKi, which may increase platelet counts in ITP by reducing the destruction of platelets and the production of autoantibodies. The agent has shown promising safety and efficacy in a previous Phase II trial (NCT03395210).⁴

The Phase III placebo-controlled, multicenter LUNA 3 trial (NCT04562766), presented at ASH 2024 by David Kuter, MD, DPhil, Massachusetts General Hospital, Boston, MA, is evaluating the efficacy and safety of rilzabrutinib in patients with previously treated ITP who demonstrated intolerance or insufficient response to standard-of-care ITP therapy.

The first analysis of data from the adult population included 202 patients (n=133 rilzabrutinib, n=69 placebo) and found that rilzabrutinib significantly improved platelet counts compared with placebo, with 65% of patients in the treatment arm achieving a platelet response compared with 33% for placebo. Rilzabrutinib also resulted in significant and clinically meaningful improvements in all secondary endpoints, reducing the need for rescue therapy by 52% compared with placebo, reducing bleeding, and improving physical fatigue and quality of life measures. The safety and tolerability profile of the agent was favorable, with a similar rate of all-cause, any-grade adverse events (AEs) and serious AEs (SAEs) between groups. Commonly observed treatment-related AEs for rilzabrutinib were all low-grade (Grade 1 or 2) and included diarrhea, nausea, headache, and abdominal pain.⁵

This study supports rilzabrutinib as a potential treatment option for patients with ITP who are not adequately managed by traditional therapies, marking a significant step forward in ITP management.

Etavopivat reduces incidence of vaso-occlusive crises in sickle cell disease

Sickle cell disease (SCD) is characterized by recurrent painful vaso-occlusive crises (VOCs), which are a major cause of morbidity and hospitalization.⁶ Current treatment strategies have shown effectiveness in reducing VOCs, but alternative therapies are needed for patients who do not respond adequately. Etavopivat, an activator of erythrocyte pyruvate kinase (PKR), has been shown to increase hemoglobin (Hb) oxygen affinity and reduce the sickling of red blood cells, providing a potential avenue for decreasing VOCs in patients with SCD.⁷

The multicenter, Phase II/III, randomized, double-blind, placebo-controlled HIBISCUS trial (NCT04624659) is investigating the safety and efficacy of etavopivat in SCD, and the 52-week data from the Phase II portion of the trial were presented at ASH 2024 by Julie Kanter, MD, University of Alabama at Birmingham, Birmingham, AL. In the study, 60 participants were randomized to receive etavopivat 200 mg (n=21), etavopivat 400 mg (n=20), or placebo (n=19) once daily for 52 weeks.

Findings from the intent-to-treat (ITT) population demonstrate that etavopivat reduced the incidence of VOCs in patients with SCD over 52 weeks, with an annualized VOC rate of 1.07 for the etavopivat 200 mg group, 1.06 for the 400 mg group, and 1.97 for the placebo arm. Etavopivat also improved hemolysis biomarkers from baseline at week 24, with a decrease in lactate dehydrogenase (LDH) being sustained through week 52. Furthermore, increased hemoglobin levels at week 24 and improved patient-reported fatigue as measured by the PROMIS Fatigue Scale were observed in both treatment arms.⁸

These results are consistent with an earlier Phase I study (NCT03815695) investigating etavopivat in SCD,⁹and thereby help to establish proof of concept for the agent in this indication. Etavopivat’s ability to reduce VOCs could offer a new therapeutic option for patients, improving quality of life and reducing hospitalizations.

Hydroxyurea for HbSC disease: results of the PIVOT trial

Hemoglobin SC (HbSC) disease, a variant of sickle cell disease (SCD), has historically been less studied than the more severe HbSS form of the disease, despite patients also suffering from significant clinical complications, such as vaso-occlusive crises, and negative impacts on quality of life. Hydroxyurea was approved by the FDA for adult and pediatric patients with HbSS disease in 1997 and 2017, respectively, and demonstrated significant clinical benefits in this patient population. However, the drug is not approved for the HbSC sub-type, due to a lack of prospective studies and high-quality evidence regarding its safety and efficacy in these individuals.¹⁰

At ASH 2024, Yvonne Dei-Adomakoh, MBBS, FWACP, MWACP, University of Ghana Medical School, Accra, Ghana, presented the primary study results of the Prospective Identification of Variables As Outcomes for Treatment (PIVOT) trial (PACTR 202108893981080), a Phase II, double-blind, placebo-controlled trial investigating hydroxyurea treatment in pediatric and adult patients with HbSC disease. In this study, 212 patients were randomized to receive hydroxyurea (n=107) or placebo (n=105) for 12 months, with participants in the treatment arm receiving an average starting dose of 20.0 ± 0.4 mg/kg/day.

The primary endpoint analysis revealed a significantly higher rate of dose-limiting toxicities (DLT) in the hydroxyurea arm (32.7% vs 10.5%, p<0.001); however, almost all observed cytopenias were transient Grade 2 thrombocytopenia or neutropenia. In addition to this, elevated hemoglobin occurred in 12 participants (20 events) receiving hydroxyurea and 10 participants (11 events) receiving placebo. Regarding secondary outcomes, hydroxyurea administration led to some laboratory benefits, including an increase in mean corpuscular volume (MCV; +17 fL) and fetal hemoglobin (HbF; +7.6%). Both pediatric and adult patients in the treatment arm also experienced significantly fewer VOCs (p<0.0001) and hospitalizations (p=0.012).¹¹

The findings of the PIVOT trial suggest that treatment with hydroxyurea at a dose of 20 mg/kg/day reduces the incidence of VOCs and hospitalizations, while being well-tolerated by pediatric and adult patients with HbSC disease. Therefore, this agent is likely an important therapeutic option in this subgroup and may improve disease management and patient quality of life. As there is a lack of consensus study endpoints, the study also determined that standard clinical VOCs are an appropriate primary endpoint for future clinical trials in HbSC disease.

Autologous CD34+ base edited hematopoietic stem cells in sickle cell disease: BEAM-101

Gene therapies for sickle cell disease (SCD) have shown promise in early-phase trials, with strategies such as gene editing offering the potential for a long-term cure. Base editing, a technique that allows precise genetic modifications without causing double-stranded breaks, is one such promising approach. Base editing of the HBG1/2 genes, which regulate fetal hemoglobin (HbF) production, has been shown to reduce sickle hemoglobin (HbS) and alleviate symptoms of SCD.¹²

The ongoing BEACON study (NCT05456880) is investigating the safety and efficacy of BEAM-101, a gene therapy that uses autologous CD34+base-edited hematopoietic stem and progenitor cells (HSPCs) to increase HbF production, in patients with SCD. Initial results of the study, presented at ASH 2024 by Matthew Heeney, MD, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, demonstrate that, in the patients dosed (n=4), rapid platelet engraftment occurred (20 [11–34] days), anemia improved markedly, and hemolysis markers (lactate dehydrogenase, indirect bilirubin, haptoglobin, and reticulocyte counts) normalized or improved. Both HbF and HbS levels improved in all patients, with >60% HbF and ≤36% HbS in non-transfused Hb/blood being observed at Month 1 and sustained to the last time point (LTP) available. Following treatment, there was an absence of VOCs in all patients. Regarding safety, the safety profile of BEAM-101 was comparable to that of busulfan conditioning and autologous stem cell transplantation (autoSCT). In patients with safety data available (n=6), no ≥Grade 3 adverse events (AEs) related to the investigational product have been reported.¹³

The initial data from the BEACON study demonstrate that BEAM-101 is well-tolerated and shows promising signs of early efficacy in SCD and solidifies base editing of the HBG1/2 promoters as a potential therapeutic modality for the treatment of the disease. The trial is ongoing and will now assess BEAM-101 in a larger sample of patients in order to confirm these findings.