LOS ANGELES — Researchers from City of Hope®, one of the largest and most advanced cancer research and treatment organizations in the United States with its National Medical Center ranked among the nation's top cancer centers by U.S. News & World Report, presented scientific results on novel therapies, treatment strategies, and approaches to managing side effects and complications for blood cancer patients at the 2025 American Society of Hematology (ASH) conference in Orlando, Florida, held Dec. 6 to 9.
City of Hope was involved in one ASH plenary . In addition, its scientists and physicians discussed the outcomes of clinical trials and studies investigating novel cellular and immunotherapies, the expansion of therapies to new patient groups, treatment strategies that could give new options to patients with hard-to-treat blood cancers, a first-in-human trial of a new approach to treating GVHD, and more.
"The breadth of studies City of Hope experts are presenting this year reflects our unwavering dedication to advancing innovative, patient-centered care across the full spectrum of blood cancers," said Marcel van den Brink , M.D., Ph.D., City of Hope chief physician executive and president of City of Hope National Medical Center. "From novel therapeutics to new approaches to managing complications, this research underscores our mission to deliver lifesaving breakthroughs for patients."
City of Hope physicians and scientists will present 105 sessions, spotlighting its leadership in the treatment and research of blood cancers and related diseases. Highlights include the following:
LEUKEMIA
PLENARY: Combination Therapy Aza-Ven Outperforms Intensive Chemotherapy for Fit AML Patients
A combination of two therapies, azacitidine and venetoclax, or aza-ven, outperformed intensive chemotherapy for acute myeloid leukemia in patients healthy enough to receive aggressive treatment, according to a phase 2 clinical trial co-led by City of Hope .
Intensive chemotherapy has long been the standard first-line treatment for AML in people who were healthy enough to tolerate it. However, this approach causes severe side effects and long-term outcomes remain poor. Aza-ven has previously shown promise in patients who were not strong enough for chemotherapy. The new trial sought to determine if it could be a more effective first-line option for fit patients as well.
Researchers reported significantly higher event-free survival (EFS) with the combined therapy. One-year EFS was 53% with aza-ven, compared to 39% with intensive chemotherapy, corresponding to a 39% reduction in risk of progression, relapse or death. Aza-ven patients also had a higher overall response (88% vs. 62%), and better composite remission rate (81% vs. 55%). A higher number of patients on aza-ven (61%) was able to proceed to stem cell transplant than those on chemotherapy (40%).
Aza-ven did not just outperform intensive chemotherapy, it also had fewer side effects and complications. At two weeks, aza-ven patients reported significantly better quality of life, with fewer symptoms and less depression. Aza-ven patients were also less likely to need ICU care and had much shorter initial hospital stays (15 days) compared to chemotherapy patients (36 days).
Researchers continue to follow patients to gather data on overall survival, but senior author Ibrahim Aldoss , M.D., City of Hope associate professor, Division of Leukemia, called the results encouraging.
"AML treatment is incredibly demanding for patients and their families," he said. "A therapy that reduces time in the hospitals and makes treatment an easier experience while still delivering good results has the potential to change the patient journey in tangible, meaningful ways."
Study Supports Starting CAR T Therapy Earlier for Older Adults with B-cell Acute Lymphoblastic Leukemia
Older adults with B-cell acute lymphoblastic leukemia (B-ALL) may benefit from receiving CAR T cell therapy sooner rather than later, according to a pilot study by City of Hope researchers . The approach could offer a safer alternative to stem cell transplant, which many older patients are unable to tolerate.
Scientists already know that CAR T therapy is more effective and causes fewer side effects when patients have low levels of leukemia before treatment. Researchers wanted to know if starting the treatment when patients were in their first remission — earlier than it's typically given — would improve outcomes and shorten the treatment duration in older patients.
The new study followed 20 patients aged 55 and older who had entered remission with standard frontline therapies and did not plan to undergo transplant. Eighteen patients ultimately received CAR T cells after undergoing standard lymphodepletion chemotherapy. All were in deep remission, meaning they had no detectable levels of leukemia.
Researchers reported a one-year progression-free survival rate of 90%. Only one patient experienced a molecular relapse, which was successfully treated. All other patients remained in deep remission at subsequent follow-ups, including the first patient treated, who has remained leukemia-free for more than two years without additional therapy. There were no deaths.
Toxicity was also low, with 72% of patients experiencing cytokine release syndrome, which was mild and easily managed with medication. Patients' walking speed, cognition and frailty scores were unchanged, suggesting the treatment did not impair daily functioning in older adults.
The study also suggested good durability showing that CAR T cells expanded strongly in the body after infusion, were detected in the spinal fluid of almost all patients and persisted in patients for up to a year. Most patients' normal B-cells recovered by six months, suggested limited long-term immune suppression.
"The combination of safety and durability we're seeing is very encouraging, could reduce risk of relapse and avoid complications from prolonged courses of consolidation therapy," said first author Ibrahim Aldoss , M.D., City of Hope associate professor in the Division of Leukemia. "We believe using CAR T earlier in this patient population warrants further study."
LYMPHOMA
Benefits of N-AVD in Hodgkin Lymphoma Are Long-Lasting, According to Study Update
Adding the immunotherapy drug nivolumab to standard chemotherapy provides longer-lasting protection against relapse than the current regimen for adolescents and adults with advanced-stage classic Hodgkin lymphoma. The new findings build on earlier results to show that the combination therapy, called N-AVD, not only outperforms standard-of-care, but that those benefits remain strong after more than three years.
"We're now seeing that the advantage isn't just early, it lasts," said first author Alex Herrera *, M.D., chief of the Division of Lymphoma at City of Hope. "At three years, patients treated with N-AVD continue to have better outcomes across every age group and risk category."
Almost 1,000 patients between the ages of 12 and 83 were enrolled in the randomized phase 3 clinical trial , which compared nivolumab combined with doxorubicin, vinblastine and dacarbazine (N-AVD) with the standard of care: a targeted therapy called brentuximab vedotin combined with AVD (BV-AVD).
After three years, 91% of those treated with N-AVD were still in remission, compared with 82% of those treated with BV-AVD. This benefit was seen across every age group studied, as well as in people with more advanced disease and in people who were higher risk. And while overall survival was high with both treatments, there were fewer deaths in the N-AVD group, and second cancers were also slightly less common.
No new safety concerns were raised after the three-year follow-up, researchers noted.
"These results support recommending N-AVD as a frontline treatment for patients with advanced-stage classic Hodgkin lymphoma, including in high-risk patients," Dr. Herrera said.
* Dr. Herrera is a paid consultant with Bristol Myers Squibb.
New Therapy for Relapsed/Refractory B-Cell Lymphomas Shows Promise
A new type of CAR T cell therapy designed to overcome a major cause of relapse in B-cell lymphoma patients shows promising early results, according to findings from an ongoing phase 1 clinical trial .
Current CAR T therapies for B-cell cancers typically target CD19, a protein found on malignant cells. But many patients relapse when their cancer stops expressing CD19, leaving them with few treatment options.
A new therapy City of Hope invented, called PMB-CT01*, takes a different approach by targeting a receptor called BAFF-R. Because this receptor is critical for B-cell survival, cancer cells are less likely to eliminate it to escape treatment. Importantly, BAFF-R is still present in cancers that have already lost CD19, so it can still work in patients who have failed CD19 therapy.
In the dose-escalation study sponsored by Pepromene Bio Inc., which licensed City of Hope's technology, seven patients with relapsed or refractory B-cell non-Hodgkin lymphomas received PMB-CT01 at one of two dose levels. Participants had aggressive disease and had undergone multiple prior treatments, including CD19 CAR T therapy and CD20-targeted bispecific antibodies.
Researchers reported an extremely favorable safety profile for the new therapy, with no dose-limiting toxicities and mild side effects. The drug's effectiveness was also striking; all patients achieved complete remission within three months, with no relapses. Remissions have lasted up to 32 months, with a median follow-up of 17 months.
In addition to the favorable safety results and encouraging outcomes, investigators observed robust CAR T cell expansion in the bloodstream, supporting the therapy's biological activity. Based on safety and response findings, the higher dose of 200 million cells is expected to advance as the recommended phase 2 dose.
The trial is now expanding to multiple U.S. sites and will include additional patients with follicular lymphoma, mantle cell lymphoma and large B-cell lymphoma, researchers said.
"Our goal is to develop therapies that address unmet needs for patients with relapsed or refractory B-cell lymphomas," said first author Elizabeth Budde , M.D., Ph.D., City of Hope associate professor, Division of Lymphoma. "BAFF-R represents a promising target, and we look forward to building on these initial results."
*This technology was invented at City of Hope, who has equity in the developer Pepromene Bio Inc. and receives royalties from the company.
Combination Therapy GLOVe Shows Promise Against Mantle Cell Lymphoma
A three-drug combination shows promise in patients with high-risk, newly diagnosed mantle cell lymphoma (MCL), a group for whom no standard first-line treatment currently exists.
Early results from the phase 1/2 clinical trial are encouraging. The first stage of the study included 20 patients. Among those who were "response evaluable" at the time of abstract submission, 100% achieved a complete response, and 96% became MRD-negative, meaning there was no detectable cancer DNA noted in the blood. At a six-month follow up, progression-free survival was 90%.
This is the first study to test glofitamab in this patient group. The combination therapy, called GLOVe, combines glofitamab, a bispecific antibody that helps the immune system attack cancer cells, with venetoclax, an inhibitor that helps cancer cells self-destruct, and the immunomodulator lenalidomide, which boosts cancer-fighting immune cells.
The trial has enrolled 28 patients who were newly diagnosed with MCL and considered high-risk due to genetic mutations or aggressive features of the disease. Side effects were common but mostly manageable. Mild to moderate cytokine release syndrome occurred in 55% of patients, with one severe case. One patient died from a treatment-related infection during the study.
"This is an important first step in exploring how bispecific antibodies can be incorporated into first-line therapy for patients with mantle cell lymphoma," said first author Tycel Phillips , M.D., City of Hope associate professor, Division of Lymphoma. "We're encouraged by the responses we're seeing so far in what can be a difficult-to-treat patient population."
The study is ongoing, and researchers will continue to track patients to determine how long responses last.
* Dr. Phillips is a paid consultant to AbbVie and Genentech, the manufacturers of venetoclax. Genentech is also the manufacturer of glofitamab. He is also a consultant to Bristol-Myers Squibb, the manufacturer of lenalidomide.
CAR T Therapy Effective in Younger Patients with Treatment Resistant Non-Hodgkin Lymphoma
CAR T cell therapy is known to be an effective treatment for older patients with relapsed or refractory non-Hodgkin lymphoma, but there is less data on how it works in younger patients. Now a new study shows that this treatment is just as effective in adolescents and young adults, with fewer side effects.
City of Hope researchers conducted a retrospective study comparing outcomes for patients aged 15-39 with those over age 40. They found that the two groups had almost identical outcomes for both progression-free survival (37% for younger patients vs. 34% for older) and two-year overall survival (55% for younger vs. 47% for older).
Cytokine release syndrome was the most common side effect of CAR T cell therapy, with similar rates and severity in both groups. However, adolescents and young adults were 70% less likely to develop neurotoxicity, one of the most serious potential complications of CAR T cell therapy. They also had a faster platelet recovery than their older counterparts, with fewer patients showing a very low platelet count at 30 days after treatment.
Importantly, younger patients were almost three times more likely to go on to receive a stem cell transplant after CAR T.
Researchers noted that the younger patients were less likely to have advanced-stage disease at the time they received CAR T therapy but more likely to have primary refractory disease, or cancer that was resistant to treatment from the outset.
First author Lindsey Murphy , M.D., M.S., assistant professor at City of Hope Children's Cancer Center, noted that most clinical trials have focused on older adults, leaving an absence of data on younger patients.
"This study fills a critical gap in our knowledge of how younger patients respond to CAR T cell therapy," she said. "The results offer reassurance that this therapy is both safe and effective for them."
MYELOMA
Cilta-Cel Therapy Offers Benefits for Multiple Myeloma Even When it Fails FDA Criteria
Cilta-cel therapy is a type of CAR T cell therapy that is manufactured from the patient's own immune cells to treat relapsed and resistant multiple myeloma. Now new research finds that it's common for these products to fall short of FDA criteria but that many patients still benefit from using them, and they appear just as safe and effective as those that meet criteria.
The study found that these "manufacturing problems" are not rare , especially in heavily pretreated patients or those who received bispecific antibodies. But outcomes for patients who received these products were as good as the standard criteria products, with high rates for both initial treatment response and progression-free survival.
Although the FDA has allowed cilta-cel therapy to be given to patients even when products fall short of release criteria, little was known about how common these "out-of-specification" products are and how they actually perform in the real world.
Researchers reviewed 212 patients who underwent cell collection for cilta-cel therapy. They found that 16% of the therapies produced were out-of-specification, meaning they fell short of FDA criteria but were still usable, while 2.9% were considered a "manufacturing failure" or unusable.
The most common reasons cilta-cel products were deemed out-of-specification included having too few total cells, lower levels of CAR expression and lower cytokine release, meaning the cells weren't as active. Patients who received prior treatments that affect T cell health had higher rates of manufacturing problems.
Of the 23 patients who ultimately received an infusion with out-of-specification products, 89% achieved an objective response within three months, and the number experiencing progression-free survival at 6 months was also 89%. Side effects were manageable and similar to those seen with standard products.
"Our study shows that even when a cilta-cel product doesn't meet every FDA release standard, many patients can still achieve meaningful, durable responses," said first author Azra Borogovac *, M.D., M.S., a City of Hope assistant professor, Department of Hematology & Hematopoietic Cell Transplantation.
The researchers will continue tracking patient outcomes.
* Dr. Borogovac had previously done paid consultancy and speaking events for Johnson & Johnson, the manufacturer of ciltacabtagene autoleucel.
TRANSPLANTATION
Targeted Radiation Therapy Could Prepare High-Risk Leukemia Patients for Stem Cell Transplant
Older adults with relapsed or hard-to-treat acute leukemia or myelodysplastic syndromes (MDS) generally have poor outcomes and many cannot tolerate the high-dose treatments required before a stem cell transplant. Now a new study finds that a targeted form of radiation therapy combined with chemotherapy can be used safely as a preparation for stem cell transplant in these patients.
The phase 1 clinical trial involved a form of radiation therapy called total marrow and lymphoid irradiation, or TMLI. This therapy delivers higher radiation doses to areas with cancer while exposing the rest of the body to lower levels.
For the study, patients were treated with TMLI and two forms of chemotherapy, fludarabine and melphalan, before undergoing a stem cell transplant. The goal was to find the highest dose of TMLI that patients could safely tolerate. Thirty patients between the ages of 53 and 73 participated in the study.
Researchers found that side effects were common but that patients were able to safely tolerate the therapy, making it a feasible option in this high-risk population. The most common side effects were gastrointestinal, and some patients also had mouth and throat soreness, fatigue, bone pain and fevers.
Importantly, even at higher radiation doses, rates of graft-versus-host disease, a serious transplant complication, did not increase, and patients' immune systems recovered well after transplant.
Results of the treatment were encouraging: All the patients successfully grew the transplanted stem cells, and all evaluable patients were in complete remission one month after transplant. At two years, 55% were still alive, and non-relapse deaths were 28%, which is considered acceptable in this very high-risk group.
"These results suggest that TMLI-based regimens could open the door to curative transplants for older adults who previously might not have been candidates," said first author Monzr Al Malki , M.D., a City of Hope professor, Department of Hematology & Hematopoietic Cell Transplantation.
First-in-Human Trial Finds Novel Cell Therapy Safe, Effective for Refractory, Chronic GVHD
An engineered immune regulatory T cell therapy has shown encouraging early results for patients with chronic graft-versus-host disease that no longer responds to standard treatments. In a first-in-human study, researchers reported that the therapy appeared safe, with no major toxicities, and led to clinical improvement in all six patients treated .
Chronic graft-versus-host disease, or GVHD, is a common long-term complication that can occur after stem cell transplant. It is an inflammatory condition that occurs when the transplanted immune cells attack the patient's body. It's the leading cause of long-term illness and death after transplant; can cause debilitating, multiorgan dysfunction; and is associated with poor quality of life. While there are FDA-approved medications that help control GVHD, they can increase risk of life-threatening infections, incomplete responses and, in most cases, patients' GVHD symptoms eventually return. Thus, there is a need for safer and longer-lasting therapies.
To fill the gap, City of Hope researchers at the Arthur Riggs Diabetes & Metabolism Research Institute led by Enrique Montero , M.D., Ph.D., created a new type of cell therapy using regulatory T cells, or Tregs, taken from the original stem cell donor. This type of immune cell naturally helps calm down immune inflammatory reactions. The team then engineered these Tregs to carry a receptor that targets a protein, CD6, which is expressed on T cells that cause GVHD-related inflammation, and added a special signal inside the cell to make it even better at controlling inflammation. Previous lab and animal tests showed that these cells could reduce harmful immune activity and prevent GVHD-like disease.
For the phase 1 clinical trial , six patients with chronic GVHD that didn't improve with steroids and other FDA-approved drugs received the new therapy, called CD6-CAR Tregs, at escalating dose levels. Most had been living with GVHD for many years and had failed previous treatments.
None of the patients experienced a severe immune reaction like cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome — complications that are sometimes seen with regular CAR T cell therapies. This novel intervention did not compromise the protective immunity against infections. Side effects were manageable and not dose-limiting.
All patients had reached a partial clinical response, and three of them, with an extended twelve-month follow-up, reported improved symptoms and quality of life. None of the patients needed additional rescue therapy for their GVHD.
"This is an entirely new approach to treating chronic GVHD in these patients, and to see clinical responses without major safety concerns in this early trial is tremendously encouraging," said first author Amandeep Salhotra , M.D., a City of Hope associate professor, Division of Leukemia.
City of Hope is at the forefront of translating the fundamental scientific discovery of regulatory T cells (a discovery recently recognized with the 2025 Nobel Prize in Physiology or Medicine) into clinical applications for the unmet medical needs in inflammatory and autoimmune diseases, including type 1 Diabetes. This research was partially funded by a $50 million partnership with The Wanek Family Project for Type 1 Diabetes .
Study Reveals Key Pathway for Thymus Regeneration
Researchers have identified a key molecular pathway that helps the thymus regenerate after damage, a discovery that could lead to new therapies to restore immune function after stem cell transplantation and chemotherapy.
The thymus plays a central role in rebuilding the immune system after hematopoietic cell transplantation. Unfortunately, many patients experience "thymic failure" in which the organ doesn't recover properly, leaving them vulnerable to infections. The new study by City of Hope scientists helps explain the biological reasons why this occurs.
Researchers found that the thymus has a natural repair mechanism: a pathway through which dying cells release a protein that triggers a gene called TLR4 on macrophages, immune cells that support healing by cleaning up dead or dying cells. In healthy macrophages, TLR4 activated a clean-up program that helped them digest dead cells. But in mice that lacked the TLR4 gene, the macrophages could not do this job efficiently, causing dead cells to accumulate in the thymus, leading to inflammation and making it harder for the organ to regenerate.
The team then confirmed similar patterns in human thymus tissue, finding that human thymus macrophages have high levels of TLR4 and cluster around areas where dying thymus cells are being cleared. They also showed that human thymus cells release TLR4-activating proteins when they die.
TLR4 was previously known to help macrophages detect and remove bacteria, but the new study shows that it is also triggered internally by cells dying inside the body.
Importantly, the pathway appears to be targetable. Researchers tested monophosphoryl lipid A (MPLA), a drug that activates TLR4 and that is already being used in humans as a vaccine booster. They found the drug improved macrophages' ability to clear dead cells, boosted thymus regeneration and increased production of new T cells.
First author Andri Lemarquis, M.D., Ph.D., City of Hope staff scientist, said the discovery could lay the groundwork for new therapies.
"By identifying the role of TLR4 and how macrophages help the thymus heal, we've uncovered a promising target to improve immune recovery for patients undergoing stem cell transplantation," he said.
AWARD RECIPIENT
Jenny Paredes, Ph.D., City of Hope staff scientist, received a 2025 ASH Abstract Achievement Award for her abstract titled "Dietary fiber intake improves survival in allogeneic HCT patients and exhibits synergistic effects with taurine supplementation in preclinical models." Dr. Paredes is a member of the Marcel van den Brink Lab .
