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AML, sickle cell disease research among highlights of ASH abstracts

Cancer Center experts present at national meeting

headshot of Tim Tedeschi By Tim Tedeschi 513-556-5694
12 minute read December 10, 2024

University of Cincinnati Cancer Center experts presented abstracts at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition Dec. 7-10 in San Diego.

Trial finds AML drug is safe in healthy volunteers

A randomized Phase 1 trial in healthy volunteers found a new drug targeting treatment-resistant acute myeloid leukemia (AML) is safe and attains drug levels that would predict response in this disease.

Up to 30% of patients with AML have a specific mutation called FLT-3, and a standard FLT-3 treatment called gilteritinib was approved by the Food and Drug Administration in 2018. But as the cancer has evolved, patients have developed both intolerance and resistance to gilteritinib.

Members of the Cancer Center’s Leukemia and Drug Development Lab (LDDL) — including John Byrd, MD; Erin Hertlein, PhD; and Ola Elgamal, PhD — partnered with pharmaceutical company Eilean Therapeutics to identify a new drug from initial chemical matter in the laboratory to trials in the clinic to treat the treatment-resistant AML with FLT-3 mutation. 

After testing more than 60 compounds developed together with the company, researchers found one of them, lomonitinib, appears to be the most effective in preclinical testing of novel animal models created by the LDDL.  

Extending from the preclinical work, Eilean, working with members of the LDDL, sought to de-risk what appeared to be a very safe and effective drug targeting resistant FLT-3-positive AML. A total of 24 healthy volunteers were enrolled on the reported trial, which included dose-proportional increases in exposure similar to the dosage a patient with AML would likely need for the drug to be effective. No adverse events were reported.  

“The use of healthy volunteer studies to both de-risk new cancer therapies and also minimize patients exposed to ineffective doses was made possible with the preclinical safety profile of lomonitinib,” said Byrd, Cancer Center member and Gordon and Helen Hughes Taylor Professor and Chair of the Department of Internal Medicine at the UC College of Medicine. “The Eilean and University of Cincinnati LDDL team are excited to see if lomonitinib improves outcome in patients with hard-to-treat, resistant, FLT-3-positive AML.”  

Lomonitinib is now being tested in Phase 1B trials in Australia and in the United States as part of the Beat AML master trial. It is expected that the lomonitinib trial will open at the University of Cincinnati Cancer Center in early 2025.

Byrd presented “A Randomized Placebo-Controlled Phase 1 Trial in Healthy Volunteers Investigating the Safety, Pharmacokinetics and Pharmacodynamics of a Novel FLT3/IRAK4 Inhibitor, Lomonitinib (ZE46-0134)” Saturday, Dec. 7 at 5:30 p.m.

Researchers develop novel compound to target MALT1 protein in CLL

Headshot photo of Sara Elgamal

Sara Elgamal, PhD. Photo/University of Cincinnati.

The LDDL team additionally partnered with Eilean Therapeutics to identify and develop a novel compound that targets a protein called MALT1, a key component of a signaling pathway that chronic lymphocytic leukemia (CLL) and other B-cell cancers depend on to grow and thrive.  

“Developing drug combinations that can target more than one signaling pathway will offer better control of the disease,” said Sara Elgamal, PhD, Cancer Center member and research scientist at UC’s College of Medicine. 

Elgamal said the compound is a degrader that can inhibit both the scaffolding and enzyme function of MALT1.  

“Inhibiting both roles makes it superior to other drugs that can only inhibit its enzyme function,” Elgamal said. “Using cell line models and human leukemia cells, we have demonstrated potent degradation of MALT1.” 

The compound also showed a survival benefit in an animal model of B-cell leukemia. 

“We are currently studying how our novel compound influences the immune system and exploring drug combinations to support the clinical translation,” Elgamal said. “Ultimately our goal is to provide a novel treatment strategy for patients with blood cancers.” 

Elgamal presented the poster “Development of ZE66-0205, a Novel MALT1 Degrader for Treatment of B-Cell Malignancies,” Dec. 8 from 6-8 p.m.

Study: Different RAS mutations each have unique impact on AML, drug response

Headshot photo of Annabelle Anandappa

Annabelle Anandappa, MD. Photo/University of Cincinnati.

Approximately 10% to 20% of patients with acute myeloid leukemia (AML) have a mutation in the RAS genetic pathway at diagnosis. The Cancer Center’s Annabelle Anandappa, MD, said these mutations are increasingly recognized as important factors in resistance to targeted AML treatments. 

The most common RAS mutations in AML are located in the NRAS gene, and the researchers looked more specifically at three codons — a sequence of three consecutive building blocks within DNA — where the mutations most commonly occur. 

Along with their colleagues, co-lead authors Anandappa and Vidushi Trivedi used a novel animal model to assess how specifically located RAS mutations influenced important characteristics of the leukemia. They also tested the mutations’ response to treatment with drugs that specifically inhibit RAS. 

The team found that AML with NRAS mutations located at codon Q61 was more aggressive and led to shorter survival. Additionally, each specific RAS mutation has a unique impact on responsiveness to RAS-targeting drugs. 

“These findings indicate that there is variability in how NRAS mutations affect leukemia development and highlights the need to pay attention to the specific NRAS mutation present as therapies targeting the RAS pathway are developed,” said Anandappa, the abstract’s presenting author and a hematology/oncology fellow in UC’s Department of Internal Medicine. 

Moving forward, Anandappa said the team plans to use differences in gene expression profiles to identify therapeutic targets that may have different activity in AML with specific RAS codon mutations. Additionally, the team will test RAS inhibitors in animal models to further identify differences based on which codon mutation is present. 

“We are hopeful these studies will eventually lead to improved therapies for patients with AML, particularly those who develop relapse after targeted therapies,” she said. 

Anandappa presented the poster “Codon-Specific Differences in RAS Mutations in AML and Differential Response to Therapeutic Agents” Dec. 8, 6-8 p.m. 

The research was funded by the Leukemia & Lymphoma Society. Linde Miles, PhD, a member of the Cancer Center and Cincinnati Children’s Hospital’s Division of Experimental Hematology & Cancer Biology and assistant professor in UC’s Department of Pediatrics, served as Anandappa’s mentor on the project and is corresponding author on the study. Co-lead authors Anandappa and Trivedi, a UC undergraduate student researcher, contributed equally to the research.

Researchers compare point-of-care sickle cell disease screening devices

Headshot photo of Fatou Ka

Fatou Ka, MD. Photo/University of Cincinnati.

Many low-income countries do not have access or resources to perform sickle cell disease newborn screenings with the most robust methods used in high-resource settings.

New methods known as point-of-care screenings have emerged that increase access and lower the cost of newborn screening by reducing the complexity of equipment needed for testing.

Abstract presenting author Fatou Ka, MD, and Kristina Prus, MD, tested 52 blood samples of pediatric patients using a combination of three point-of-care tests.

Ka, abstract presenting author, said the researchers wanted to know if a semi-quantitative test (Gazelle) would perform equally or better than existing qualitative tests (Sickle SCAN and Hemotype SC) and allow for more precise testing of variant hemoglobins.

Additionally, the team tested samples at different times between 24 and 164 hours and mimicked higher temperatures often found in low-resource laboratory environments where “electricity and enclosed testing environments may not be available,” said Ka, a resident in UC’s Department of Pathology and Laboratory Medicine in UC’s College of Medicine.

The qualitative tests were unable to consistently identify hemoglobin C and unable to identify hemoglobin E, but both were identified by the Gazelle test.

“All three methods showed that sample storage in warmer temperatures resulted in changes to the identified hemoglobin in the same sample,” Ka said. “The Gazelle also was able to consistently identify hemoglobin F, which can be useful in situations such as monitoring hydroxyurea treatment.” Hydroxyurea is a medication used to treat sickle cell disease that works by increasing hemoglobin F and making red blood cells larger.

Ka and Prus; director of Transfusion Services, director of Coagulation and Hematology in Cincinnati Children’s Hospital Medical Center’s Division of Pathology and Laboratory Medicine and an assistant professor in UC’s Department of Pathology and Laboratory Medicine; plan to expand the project for capacity-building research in the future.

“We will continue testing more samples to obtain a greater number of variant hemoglobins to further support our findings,” Ka said. “We also plan to look at options for quality control on this device in a low-resource setting.”

Ka presented the poster “Comparison of Utility and Reliability in Low-Resource Laboratory Settings of Low Cost Hemoglobinopathy Point-of-Care Screening Devices” Dec. 8 from 6-8 p.m.

Study: Bone mass declines with age for patients with sickle cell disease

Headshot photo of Jahnavi Gollamudi

Jahnavi Gollamudi, MD. Photo/UC Health.

Sickle cell disease (SCD), a blood disorder that disproportionately affects Black Americans and Latinos, can cause symptoms that include severe pain and organ damage. Another known complication of SCD is low bone mass or density, but researchers did not previously have data on how bone mass or density changes over time, explained UC’s Jahnavi Gollamudi, MD.

“The purpose of this study was to document how bone density changes with time in children and adults with sickle cell disease,” said Gollamudi, assistant professor in the Department of Internal Medicine in UC’s College of Medicine and a UC Health physician.

Using data from the longitudinal Sickle Cell Clinical Research and Intervention Program, Gollamudi and her colleagues analyzed areal bone mineral density and other variables from nearly 450 study participants between 6 and 25 years old.

“We found that a great number of children with sickle cell disease had low bone mass compared to their peers of the same age without the disease,” Gollamudi said. “We also found that the bone mass continues to decline as these kids grow up to become adults. This means that adults with sickle cell disease are at high risk for fractures and other bone complications which might cause pain.”

Moving forward, the team next aims to find clinical risk factors that can predict which individuals with sickle cell disease may develop low bone density and other complications.

“We hope that by identifying individuals who are at risk for bone disease and pain, we can intervene earlier with treatments such as bisphosphonates, which are already Food and Drug Administration-approved to treat bone pain and low bone mass,” she said.

Gollamudi will present the poster “Low Bone Density Associates with Severe Outcomes in Young Adults with Sickle Cell Disease” Dec. 9, 6-8 p.m.

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Other UC research at ASH includes:

Featured photo at top of Erin Hertlein, PhD, left, and John Byrd, MD, working in the lab. Photo/UC Foundation.

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