MD Anderson at ASH

The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention. These advances are made possible through seamless collaboration between MD Anderson’s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.

This special edition features upcoming oral presentations by MD Anderson researchers at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, providing new insights and advances in hematological malignancies and diseases. All ASH content from MD Anderson can be found at MDAnderson.org/ASH.

Novel drug overcomes anemia in preclinical models of MDS-RS and sickle cell disease (Abstract 153)  
Patients with blood disorders such as myelodysplastic syndromes with ringed sideroblasts (MDS-RS) and sickle cell disease have a stress response mechanism that includes the heme-regulated inhibitor (HRI) pathway. This pathway can be activated when heme, a fundamental part of hemoglobin, is low. In particular, patients with MDS-RS may have a mutation that affects red blood cell production and function, causing anemia and requiring blood transfusions. Research led by Simona Colla, Ph.D., and Vera Adema, Ph.D., used a virtual screening platform to design and create more than 200 diverse HRI inhibitors, including two notably potent and selective inhibitors. In lab models of MDS-RS and sickle cell disease, these compounds improved red blood cell development, reduced anemia and increased hemoglobin production. These findings show the therapeutic potential of targeting the HRI pathway to overcome anemia, reducing the need for blood transfusions in patients with MDS-RS and sickle cell disease. Adema will present the findings Dec. 7.    

Triplet therapy improves survival in older adults with FLT3-mutated AML (Abstract 220) 
Small studies have indicated that combining a FLT3 inhibitor with a hypomethylating agent (HMA) and venetoclax may improve outcomes for older patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), a high-risk subtype of the disease. In a clinical trial led by Nicholas Short, M.D., this triplet therapy achieved promising responses, with 92% of patients reaching complete or incomplete remission. The median overall survival (mOS) was 28.1 months, with a three-year survival rate of 46%, indicating encouraging long-term results. Patients with RAS pathway mutations had poorer survival rates, and new RAS mutations emerged in 20% of relapses. Overall, the triplet regimen demonstrated superior outcomes compared to the standard of care in older adults with FLT3-mutated AML, where the historical mOS was only 10 months. The study highlights this treatment as a viable option for improving survival in this high-risk AML population. Short will present updated findings Dec 7. 

Luspatercept provides long-lasting benefits in lower-risk MDS (Abstract 350)
The COMMANDS trial demonstrated that treatment with luspatercept significantly reduced the need for regular blood transfusions in most patients with lower-risk myelodysplastic syndrome (MDS). In a long-term analysis of the trial, led by Guillermo Garcia-Manero, M.D., researchers reported that 44.5% of patients receiving luspatercept experienced at least one year of transfusion independence, compared to 27.6% of those treated with epoetin alfa. Notably, 30.2% of patients treated with luspatercept maintained transfusion independence for over 18 months. These benefits were consistent across subgroups, including patients with ring sideroblast-negative status and low baseline erythropoietin levels. Progression to high-risk MDS or acute myeloid leukemia remained rare and comparable between treatment groups. These results position luspatercept as a durable and effective option for epoetin alfa-naive, transfusion-dependent patients with lower-risk MDS. Garcia-Manero will present the findings Dec 7. 

Lengthening treatment timeline and adding novel agents may benefit patients with high-risk leukemia (Abstract 506)
Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) generally have poor outcomes, even after stem cell transplantation (SCT). While busulfan-based treatments are effective as conditioning therapy for SCT, patients can still relapse, highlighting a need for more effective strategies. Preclinical studies suggest combining busulfan and fludarabine with additional drugs – cladribine, venetoclax, and thiotepa – can destroy leukemia cells. In a Phase II trial led by Uday Popat, M.D., researchers investigated the effectiveness of this combination and extended its administration from a few days to three weeks. The trial, which included 49 patients with high-risk AML or MDS, met its primary endpoint and revealed an encouraging two-year progression-free survival rate of 61% in very high-risk patients. The findings suggest this protocol merits further investigation. Popat will present the findings Dec. 8.  

Single-cell multi-omic profiling identifies factors associated with BCMA-targeted treatment responses (Abstract 767)
Therapies targeting B cell maturation antigen (BCMA) have changed the landscape for patients with relapsed or refractory myeloma, but further insights are needed to better sequence treatments and predict responses. In a study led by Minghao Dang, Ph.D., and Robert Orlowski, M.D., Ph.D., researchers performed single-cell RNA and T/B cell receptor sequencing on 89 samples from 54 patients, characterizing the cellular and molecular properties of the tumor microenvironment. They found distinct profiles associated with responses to BCMA-targeted therapies. For example, responders had more monocytes and conventional dendritic cells present, while non-responders showed evidence of upregulated interferon-stimulated genes. These observations provide valuable insights into mechanisms of responsiveness and could help better predict patient outcomes. The study also highlighted potential targets to overcome the immunosuppressive microenvironment in patients who did not respond to BCMA-targeted treatments. Dang will present the findings Dec. 9.

Specific FLT3 mutations without NPM1 co-mutations linked to lower survival rates in AML (Abstract 841) 
FLT3 tyrosine kinase domain (FLT3-TKD) mutations occur in 8 to 10% of patients with newly diagnosed acute myeloid leukemia (AML), but the outcomes and prognosis of these patients is unclear. To characterize potential risk factors, researchers led by Sankalp Arora, M.D., and Naval Daver, M.D., compared patients with FLT3-TKD mutated AML with and without co-occurring NPM1 mutations. Patients without co-occurring NPM1 mutations had poorer outcomes, with a median overall survival (mOS) of 13.8 months on intensive chemotherapy and 4.4 months with low-intensity therapy. Patients with co-occurring NPM1 mutations had improved outcomes; the mOS with intensive chemotherapy had not yet been reached (three-year OS 71%), and the mOS was 22.9 months with low-intensity therapy. Allogeneic stem cell transplantation improved mOS for FLT3-TKD mutated AML without NPM1 co-mutation but did not demonstrate a clear survival benefit when NPM1 co-mutations were present.  Arora will present the results Dec 9.

Axi-cel CAR T cell therapy delivers durable five-year outcomes in lymphoma
(Abstract 864)
The ZUMA-5 trial demonstrated that axi-cel, a chimeric antigen receptor (CAR) T cell therapy, provided durable responses after two years in patients with relapsed/refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) who received at least two prior treatments. In long-term follow-up on the Phase II trial, led by Sattva Neelapu, M.D., investigators found the therapy continued to show durable effectiveness after more than five years. The median progression-free survival (PFS) was 62.2 months, and 50% of patients reached a median PFS of 60 months. Among patients achieving complete responses, median PFS had not yet been reached at the time of data cutoff, and 58% of patients remained in remission. Overall survival at 60 months was 69%, and more than half of the patients required no additional therapy. No new safety concerns emerged, and only one late progression event occurred in FL after four years. Neelapu will present the results Dec 9. 

New preclinical model for therapy-related myeloid neoplasms reveals potential targets (Abstract 882) 
Patients treated with certain chemotherapies can sometimes develop a life-threatening complication known as therapy-related myeloid neoplasms (t-MNs). While the causes for this are not completely understood, TP53 mutations are seen in 25 to 40% of cases. Therefore, researchers led by Rasoul Pourebrahim, M.D., Ph.D., developed a novel TP53-mutant model that consistently replicates the biology of t-MNs. This model addresses a critical gap in understanding the progression from clonal expansion to malignant transformation in hematopoietic stem cells harboring TP53 mutations. Key findings include recurrent chromosomal deletions, mutations in RAS pathway genes, and upregulation of DNA repair and cell cycle regulation pathways. The model provides a critical tool for exploring the mechanisms driving t-MNs, providing insights into potential targets to treat or prevent the disease. Pourebrahim will present the findings Dec. 9. 

Vibecotamab shows promise in high-risk leukemia and myeloid diseases (Abstract 1007)
Many patients with leukemia and other blood cancers involving blast cells – abnormal blood stem cells in the bone marrow – relapse after initial responses to standard therapies. Previous studies have identified CD123 as a marker on these blast cells, leading researchers Daniel Nguyen, M.D., Ph.D., Nicholas Short, M.D., and colleagues to evaluate vibecotamab, a novel CD123-targeting immunotherapy. The Phase II study treated 37 patients with low-blast myeloid diseases from two groups: one with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), and the other with measurable residual disease (MRD)-positive acute myeloid leukemia (AML). In the MDS/CMML group, 68% of patients responded to vibecotamab. Among patients with MRD-positive AML, 28% achieved MRD negativity, with some responses ongoing for over two years. All responses were observed after the first cycle of therapy. These findings highlight the effectiveness of vibecotamab and show its potential for combination treatments in this setting. Nguyen will present the results Dec. 9. 

ABSTRACT: 805

SAN DIEGO – Adult patients with newly diagnosed malignancy-associated hemophagocytic lymphohistiocytosis (mHLH) – a rare, aggressive hyperinflammatory condition – who were treated with the first-in-class monoclonal antibody, ELA026, experienced a 100% response rate and an improved survival rate at two months, according to researchers from The University of Texas MD Anderson Cancer Center.

Data from the Phase Ib trial were presented today at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition by Abhishek Maiti, M.D., assistant professor of Leukemia and the trial’s principal investigator. The findings suggest that early intervention with ELA026 may provide meaningful clinical benefits for patients with few options.

“It is common for patients with mHLH and cancer to be treated with chemotherapy, but this can often cause challenges towards treating their primary cancer diagnosis at the same time due to the side effects and poor organ function due to HLH,” Maiti said. “This therapy was well tolerated as a frontline treatment for mHLH and helped us to gently control the disease using a precise approach, which enabled us to deliver treatment for the underlying cancer simultaneously.”

Triggered by malignancies, infections, autoimmune diseases or treatment with immunotherapy or CAR T cell therapy, mHLH is caused by the body’s inability to inactivate T cells and macrophages after an initial immune response. The condition can cause organ failure and has a mortality rate of approximately 50% at two months. There are no current approved therapies for mHLH. 

ELA026 works by targeting the SIRPα/b proteins found on myeloid cells and SIRPγ on T lymphocytes, leading to their depletion. In the global, open-label, single-arm trial, patients were treated with ELA026 for 12 weeks either intravenously or subcutaneously.

The study enrolled a total of 22 sHLH patients, including 7 with relapsed or refractory sHLH and 15 being treated with ELA026 as frontline therapy. Earlier cohorts suggested patients with relapsed or refractory sHLH had worse outcomes compared to those who were treated in the frontline settings, so the study was refined to focus on those patients predicted to benefit the most from treatment with ELA026.

Of the 12 mHLH patients, treated in frontline settings, 58% had T-cell Lymphoma, 17% had B-cell lymphoma, 17% had leukemia and 8% had Hodgkin lymphoma. The median age of participants was 47.

By week four, the response rate with ELA026 was 100% in the frontline setting, with two patients having a modified complete response and ten having a partial response. In mHLH patients treated in frontline settings, survival was 92% at two months, and the median overall survival had not yet been met at data cutoff.

Although patients with relapsed/refractory hemophagocytic lymphohistiocytosis achieved response with therapy, they did not appear to derive survival benefit. Researchers recommend early intervention to provide meaningful clinical benefits.

Side effects included treatment-related infusion reactions and cytopenias, which were manageable with supportive care and dosing modifications.

“These early results are encouraging and reinforce the need for early intervention with mHLH in order to provide better outcomes for patients,” Maiti said. “We look forward to the next phase of this study so that we may evaluate the potential of ELA026 as an effective treatment for patients with this rare but aggressive condition.”

Additional MD Anderson collaborators on this trial include Naval Daver, M.D., professor of Leukemia, Swaminathan Iyer, M.D., professor of Lymphoma/Myeloma, and David McCall, M.D., assistant professor of Pediatrics. The trial was funded by Electra Therapeutics. Maiti receives research support from Electra. A full list of co-authors and their disclosures may be found here. 

ABSTRACTS: 216, 219, 1011  

SAN DIEGO ― Three clinical trials led by researchers from The University of Texas MD Anderson Cancer Center demonstrated significant positive results from novel triplet therapies in the treatment of relapsed or refractory and newly diagnosed leukemias. The results were presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition. More information on all ASH Annual Meeting content from MD Anderson can be found at MDAnderson.org/ASH.   

Study demonstrates strong overall responses with triplet regimen that includes novel menin inhibitor (Abstract 216)  
Combining the menin inhibitor, revumenib, plus the hypothemylating agent, ASTX727, and venetoclax achieved an overall response rate of 82% in 33 adult and pediatric patients with relapsed or refractory advanced acute myeloid leukemia (AML) with KMT2A or NUP98 rearrangements, according to results from the Phase I/II SAVE trial led by Ghayas Issa, M.D., associate professor of Leukemia.   

Forty-eight percent of patients achieved a complete remission or a complete remission with a partial hematologic recovery with these all-oral agents. Two patients completed the maintenance therapy after receiving a stem cell transplant and remain in remission. The measurable residual disease (MRD) negativity rate was the lowest in patients with NUP98r rearrangements. With a median follow-up was 9.3 months, the six-month overall survival was 68% and the median duration of response was not reached.   

"We demonstrated significant clinical benefits and efficacy from this therapy combination, which provides patients with an improved option for treatment,” Issa said. “This is a major step forward for treating acute leukemias with these genetic rearrangements.”   

Revumenib is a potent, oral selective inhibitor of the menin-KMT2A interaction. In November, the Food and Drug Administration approved revumenib as a single-agent therapy for the treatment of adults and pediatric patients with relapsed or refractory advanced acute leukemia with KMT2A rearrangement based on results from the AUGMENT-101 clinical trial lead by Issa.

To date, 33 patients have been enrolled in the SAVE trial, with a median age of 35 years. The trial also included five pediatric patients. Trial participants had three previous lines of therapy on average. Of the total patients, 16 had KMT2A rearrangements, 12 had NPM1 mutations, five had NUP98 rearrangements, and five had extramedullary disease.   

Side effects were manageable and consistent with previous studies. The most common side effects patients experienced were prolongation of the QT interval on electrocardiogram monitoring and an elevation in liver enzymes.   

Issa presented updated findings Dec. 7. The investigator-initiated trial is on-going and continues to enroll patients. This study was supported by Astex and Syndax. A complete list of collaborating authors and their disclosures can be found with the abstract.    

Triplet regimen targeting IDH-1 mutant AML demonstrates strong response with long term follow-up (Abstract 219)  
In a Phase Ib/II trial, the triplet regimen of ivosidenib, venetoclax and azacitidine demonstrated an overall response rate of 94% and a composite complete remission rate of 93% in 56 patients with newly diagnosed or relapsed/refractory IDH1-mutant hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndromes and myeloproliferative neoplasms.  

The trial was led by Courtney DiNardo, M.D., professor of Leukemia, and presented by Jennifer Marvin-Peek, M.D., clinical hematology/oncology fellow.   

The three-year overall survival rate was 70.5%, and patients who went on to receive a stem cell transplant had a three-year overall survival rate of 94.7%. Of the trial participants who did not undergo a stem cell transplant, 47% still are receiving trial therapy. Measurable residual disease (MRD) negativity by flow cytometry was achieved in 77% of patients. With a median follow-up of 36 months, the median overall survival has not been reached at the time of data cutoff.  

“This triplet regimen is safe, well tolerated and provided impressive response rates for those enrolled in the trial,” Marvin-Peek said. “Thus far, the results we are seeing really position this triplet regimen as a potential standard-of-care option for treating this subtype of AML.”   

Previous research identified ivosidenib combined with azacitidine as an effective and well-tolerated treatment of IDH1-mutant AML. An additional clinical trial found venetoclax and azacitidine effective in treating this disease. Thus, researchers sought to explore the triplet combination treatment to further improve long-term patient outcomes. 

The multi-center trial included 56 adult patients with newly diagnosed AML (31), relapsed/refractory AML (13), or myelodysplastic syndromes and myeloproliferative neoplasms (12). The median age of participants was 69 years. Patients received a median of four treatment cycles, though several patients received more than 40 cycles of the triplet regimen.  

Side effects were consistent with what was observed in previous studies with these medications and were manageable with supportive care. The most common adverse events were low blood counts and gastrointestinal side effects. Four patients also experienced differentiation syndrome.    

Marvin-Peek presented updated findings Dec. 7. The trial was supported by both Servier and Abbvie/Genentech. A complete list of collaborating authors and their disclosures can be found with the  abstract.    

First-line triplet regimen for CLL yields high rates of undetectable measurable residual disease (Abstract 1011)   
A triplet regimen combining the noncovalent BTK-inhibitor, pirtobrutinib, with the CD20 monoclonal antibody, obinutuzumab, and BCL2 inhibitor, venetoclax, demonstrated high rates of undetectable measurable residual disease (MRD) in patients with previously untreated chronic lymphocytic leukemia (CLL), according to Phase II trial results presented by Nitin Jain, M.D., professor of Leukemia.   

After 13 cycles, the undetectable MRD rate was 98% in bone marrow and 100% in blood at 10^-4 sensitivity – indicating less than one CLL cell per 10,000 lymphocytes – among 41 evaluable patients. The corresponding MRD rates at a more sensitive threshold of 10^-6 were 80% and 85% in bone marrow and blood, respectively.   

“We were extremely impressed by the results of this frontline triplet regimen for our patients, as we observed some of the highest depths of remission, we have ever seen in patients with CLL,” Jain said. “Today, we have several patients who are no longer on the therapy and are monitored by regular blood MRD testing.”   

The trial enrolled 80 adult patients with a median age was 63 years. Of trial participants, 79% had immunoglobulin heavy chain unmutated CLL, and 13% had del(17p)/TP53 mutation. As part of the trial, responses were monitored by imaging and bone marrow assessment. MRD was assessed by next generation sequencing in both blood and bone marrow following cycles 7 and 13. After completing therapy, all patients are monitored by blood MRD every three months for one year, followed by every six months.  

The most common grade 3-4 side effects were neutropenia and thrombocytopenia, which were consistent with previous trials.   

Jain presented updated findings Dec. 9. The trial was funded by Eli Lilly. A complete list of collaborating authors and their disclosures can be found with the abstract.