University of Cincinnati researchers will present research at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition Dec. 6 to 9 in Orlando.
Phase 1 data testing new CLL treatment encouraging
A class of drugs called BTK inhibitors have become a standard treatment for chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). However, the prevalence of new resistance mutations has created a need for new treatments in patients with relapsed CLL who progressed through approved standard of care options, said the Cancer Center’s Zulfa Omer, MD.
“This is an area of unmet need, with current options providing limited disease control or requiring very fit patients, which is sometimes difficult to achieve in this population,” said Omer, assistant professor in the Department of Internal Medicine in UC’s College of Medicine.
Omer and colleagues are conducting a Phase 1 trial of a new BTK degrader called Bexobrutideg in patients with relapsed/refractory B-cell malignancies, including CLL, with 129 patients enrolled as of May 2025.
“Bexobrutideg has great efficacy in relapsed CLL patients, with an 83% overall response rate,” Omer said. “Side effects were very tolerable, and there was no dose limiting toxicity. The duration of response and time to next therapy is very encouraging.”
Omer said two patients are in complete remission with use of the drug for more than two years.
“Additionally, we are seeing efficacy in patients with CNS involvement and those with BTK mutations that none of the currently approved BTK inhibitors are effective against,” she said. “Current data is very encouraging and indicates prolonged control in this very difficult-to-treat population is possible, but we will need to wait for further maturation of data and prolonged follow-up.”
As the current trial continues for relapsed patients, Omer said the team plans to advance this therapy as a first-line treatment.
Omer will present “Bexobrutideg (NX-5948), a novel Bruton’s tyrosine kinase (BTK) degrader, demonstrates rapid and durable clinical responses in Relapsed/Refractory chronic lymphocytic leukemia (CLL): New and updated findings from an ongoing Phase 1a/b trial” Dec. 6 at 9:45 a.m. Other coauthors include Alexey Danilov, Francesco Forconi, Talha Munir, Mary Gleeson, Nirav Shah, Graham Collins, Alvaro Alencar, Jane Robertson, Jonathon Cohen , Karan Dixit, Danielle Brander, John Byrd, Allison Winter, Jeffery Smith, Dima El-Sharkawi, Michal Kwiatek, Iwona Hus, Prioty Islam, Sebastian Grosicki, Michael Tees, Thorsten Zenz, Joanna Romejko-Jarosinska, Sarah Injac and Wojciech Jurczak.
JAK2 inhibitor shows promise to target mutation, spare normal function
Myeloproliferative disorders are a group of chronic blood cancers where the body produces too many red blood cells, white blood cells or platelets. Within these disorders, a mutation called JAK2 V617F is most common, and it also occurs less frequently in other blood cancers.
“The central research question was: Can we develop a JAK2 inhibitor that selectively targets the mutant JAK2 V617F form — responsible for driving myeloproliferative neoplasms (MPNs) — while sparing the wild-type JAK2 necessary for normal production of blood cells and platelets (hematopoiesis),” said abstract first author Shailaja Hegde, PhD, a University of Cincinnati Cancer Center research scientist working with Leukemia and Drug Development Lab senior members Erin Hertlein and John C. Byrd.
Using computer modeling and artificial intelligence, research partner Eilean Therapeutics and investigators at the University of Cincinnati identified and characterized a new drug called ZE74-0282 that preferentially binds to the mutated form of JAK2 but not to the regular form in the JH2 domain. They found the drug effectively inhibited mutated JAK2 but spared normal JAK2 activity in cell lines, human patient blood samples and animal models.
In contrast, other commercially approved, nonselective JAK2 inhibitors such as Ruxolitinib inhibit wild type and mutant JAK2 and kill normal and cancer blood cells without selectivity.
“ZE74-0282 shows potential as a disease-modifying therapy for JAK2 V617F-mutated diseases, unlike current drugs that mainly provide symptomatic relief,” Hegde said.
Moving forward, Hegde said the Eilean team will conduct further testing with the hope of translating the drug into clinical trials for JAK2 V617F mutant hematologic malignancies and also in combination with other therapies.
“If ZE74-0282 maintains its selectivity in humans, it could redefine targeted therapy in myeloproliferative diseases by preserving normal hematopoiesis while eradicating mutant clones,” she said. “The combination of AI-driven drug design, mutant-specific biochemistry and translational validation makes this a strong candidate for first-in-human development of a JH2 domain-specific JAK2 inhibitor.”
Hegde will present “ZE74-0282 is a novel JH2 domain JAK2 inhibitor with promising pre-clinical activity in JAK2 V617F mutant diseases” Dec. 6 at 5:30 p.m. Other coauthors include Alexander Khvat, Ruben Karapetian, Brian Ledwith, Fraser Pickersgill, Megan Johnstone, Eric Vick, Emily Curran, Iain Dukes, Amy Burd, Nikolay Savchuk, Vladislav Parchincky, Igor Rezekin, Hertlein and Byrd.
Coaching improves hematologic disease, treatment understanding in veterans
Veterans are diagnosed with hematologic disorders including multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SM) and myelodysplastic syndrome (MDS) at higher rates than the general population, potentially due to environmental exposures encountered during their military service.
While the U.S. Department of Veterans Affairs provides extensive health care services, veterans diagnosed with these conditions often still experience fragmented care and gaps in disease-specific education.
To address these gaps, the University of Cincinnati, Cincinnati VA Medical Center and Blood Cancer United (formerly Leukemia & Lymphoma Society) conducted a pilot project testing a health care coaching program to improve disease understanding and treatment engagement.
In the pilot study, 101 veterans with MM, MGUS, SM or MDS were referred by their providers to a one-on-one health coaching session covering education topics such as diagnosis, treatment pathways, symptom recognition and access to external resources.
“At baseline, less than half of patients had a clear understanding of their diagnosis, treatment plan and red-flag symptoms for their hematological condition,” said abstract first author Mark Rudolph, MD, a fellow in the Department of Internal Medicine in UC’s College of Medicine. “Health care coaching led to significantly improved patient-reported disease and treatment understanding and can allow for integration with the resources available at Blood Cancer United.”
Rudolph said large-scale integration of health coaches into VA hematologic care can be beneficial in this vulnerable population of patients.
“Continued implementation would require additional resources to support a permanent health coach,” he said. “The question of whether health coaches can be beneficial in other complex disease states is something to be considered as well.”
Rudolph will present “A prospective pilot study integrating health care coaching into VA hematologic cancer care: A VA-Leukemia & Lymphoma Society (LLS) collaborative initiative” Dec. 6 at 5:30 p.m. Other coauthors include Aliecia Hochhausler, Catherine Robson, Pamela Leisure-Svaranowic and Jaskirat Randhawa.
Neuroinflammation may play role in sickle cell disease cognitive deficits
Individuals with sickle cell disease (SCD) are at risk for cognitive deficits starting in infancy, with changes to the brain’s network of blood vessels and chronically low oxygen levels known to play roles.
“However, we think that neuroinflammation, and specifically activated microglia (a brain immune cell), are also damaging,” said first author Kristine Karkoska, MD, assistant professor of internal medicine in UC’s College of Medicine.
In a pilot project using time-dependent diffusion-weighted MRI, Karkoska and colleagues mapped activated microglia in the brains of five people with SCD and four healthy controls.
“We provided proof-of-concept and found some differences between the groups, with people with SCD having more inflammation in the anterior hippocampus (responsible for memory) and frontal/parietal lobes (responsible for learning/attention),” Karkoska said.
The pilot data is the basis for a larger National Institutes of Health research grant where Karkoska will enroll 60 subjects starting this spring to learn more about how inflammation and activated microglia affect cognitive deficits.
Karkoska will present “Mapping activated microglial density in individuals with sickle cell disease utilizing time-dependent diffusion-weighted MRI and correlation with cognitive performance” Dec. 6 at 5:30 p.m. Other coauthors include Brady Williamson, Daniel Nader and Hyacinth I. Hyacinth.
Other UC research at ASH includes:
- Julianna Fisher presenting “The somatic hotspot mutation of DDX41 (p.R525H) elicits dominant-negative effects upon non-truncating germline variants, explaining similar disease risk as truncating variants” Dec. 7 at 6 p.m.
- Annabelle Anandappa, MD, presenting “RAS G12 and Q61 codon mutations confer distinct disease characteristics in Acute Myeloid Leukemia and exhibit differential response to RAS(ON) inhibitor RMC-7977” Dec. 7 at 6 p.m.
- Shakyrah Smith presenting “Chromatin remodeler SATB2 thorough Bmi1/PRC1 activity controls transformation and reprogramming of ph+ B-cell progenitors” Dec. 8 at 6 p.m.