Late-Breaking Abstracts at EHA 2024 Span From the Clinic to the Proteome to the Andes Mountains

The abstracts presented at the late-breaking oral session of the European Hematology Association (EHA) 2024 Congress are “hot off the press,” said session cochair Brian Huntly, PhD, of the University of York. These findings were submitted after the abstract deadline, but their timeliness and relevance to clinical practice and scientific knowledge justify their presentation at this hotly anticipated session.

First up, Michael Wang, MD, professor at MD Anderson Cancer Center in Houston, presented findings from the phase 3 ECHO trial (NCT02972840) of acalabrutinib plus bendamustine and rituximab (BR) in patients with untreated mantle cell lymphoma who are 65 years or older.¹ Previous findings have shown that adding the first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib to BR in this setting did not result in improved overall survival (OS) due to toxicity, so he and colleagues tested replacing ibrutinib with the second-generation BTK inhibitor acalabrutinib. Data showed a significant 27% reduction in risk of disease progression or death, but OS again was not significant, although the trend favored the acalabrutinib arm.

To explain this finding, Wang pointed to the impact of the COVID-19 pandemic, which coincided with the study period and resulted in 28 patient deaths from COVID-19 in the acalabrutinib arm. With COVID-19 deaths censored, there was a 36% improvement in progression-free survival (PFS) and a 25% improvement in OS. Wang said he’s confident that if they were to repeat the study “now that the COVID-19 crisis is over, I think the separation would be even wider.” As these are the first evidence of a positive OS trend from adding a BTK inhibitor in this setting, “in my personal opinion, this is a new standard of therapy,” he said.

Meletios Dimopoulos, MD, professor at Athens School of Medicine in Greece, presented results from another phase 3 trial: the DREAMM-8 study of belantamab mafodotin (bela-maf) plus pomalidomide and dexamethasone vs pomalidomide plus bortezomib and dexamethasone in relapsed/refractory multiple myeloma (NCT04484623).² He noted that we need new agents to counteract acquired resistance to triplet therapy in this setting, and the addition of the antibody-drug conjugate bela-maf delivered results. There was a significant PFS benefit with this regimen (HR, 0.52; P < .001), and this was one of the first studies to show a similar HR even among patients with high-risk cytogenetics.

The bela-maf arm also showed deeper responses, with 40% vs 16% achieving at least complete response, and the minimal residual disease negativity rate was 5 times greater in this arm. Dimopoulos said that these data suggest bela-maf treatment combinations can be considered a new standard of care for this setting. In response to an audience question about how this regimen stacks up against the efficacy of chimeric antigen receptor (CAR) T-cell therapy, Dimopoulos replied that it’s important to have different approaches, and “I believe that for the majority of the patients treated in the community in many countries…the more realistic, applicable, and easier combination to administer is a combination of bela-maf with pomalidomide and dexamethasone.”

Switching gears to genetic research, Josef Prchal, MD, professor at the University of Utah, took the podium to deliver the finding that elevated hemoglobin levels in the Aymara people living at high altitudes in the Andes mountains of Argentina and Bolivia are caused by alternatively spliced NFKB1 genes.³ This overexpression increases hypoxia-inducible factor (HIF) transcriptional activity and expression of inflammatory genes, which is the mechanism for the relationship with hemoglobin, he and colleagues determined through their genomic analysis. That HIF pathway increases erythropoiesis to an extent great enough to overcome the general inhibitory effect of inflammation on erythropoiesis, but Prchal noted that we still don’t know the evolutionary benefit of this relationship, so research is ongoing.

Next, Abhishek Maiti, MD, an assistant professor at MD Anderson, presented results from a phase 1b trial of the experimental monoclonal antibody ELA026 in treatment-naive malignancy-associated hemophagocytic lymphohistiocytosis (HLH), a rare and severe hyperinflammatory condition with very high mortality due to cytokine storms.⁴ Focusing on 8 patients with this type of HLH across 3 trial cohorts, investigators found that 7 experienced partial response and 1 had a modified complete response. All were discharged from the hospital, and their 60-day survival rate was 88% compared with the approximately 50% seen in natural history.

“Earlier intervention resulted in high response rates, which translate into clinical benefit such as hospital discharge and improved survival,” Maiti concluded. Again, an audience member inquired about the agent’s place in the context of CAR T-cell therapy. Maiti replied that although this trial excluded patients who had received CAR T, further research should investigate whether ELA026 depletes certain CAR T cells; however, considering the dismal prognosis of HLH, the benefits may outweigh the risks.

Zooming into the proteome, which is the entire set of proteins that can be expressed by an organism, Maria Jassinskaja, PhD, postdoctoral fellow at the University of York in the United Kingdom, presented on proteomic dynamics during hematopoietic stem cell expansion.⁵ By generating a comprehensive map of the proteome, she and colleagues found that high expression of certain proteins is associated with hematopoietic stem cell expansion. Huntly congratulated her on what he called “a very technically elegant study.”

Finally, the research turned back to the interventional realm, as Stine Ulrik Mikkelsen, MD, of Rigshospitalet in Copenhagen, Denmark, delivered findings from the phase 2 EVI-2 trial (NCT03682029) of vitamin C supplementation in patients with low-risk myeloid malignancies including myelodysplastic syndromes or myeloproliferative neoplasms, as well as clonal cytopenia of undetermined significance.⁶ After administering oral vitamin C or placebo for 12 months, investigators noted the surprising finding of significantly better OS in the vitamin C arm (HR, 0.35; P = .0025). Mikkelsen said this “largely untoxic, readily available, and inexpensive treatment could represent an attractive therapeutic approach in this category of patients who currently have limited treatment options,” and further investigation in better-powered phase 3 trials is warranted.

An audience member inquired about the difficulty of recruiting for such a trial, given that patients may hear about this OS benefit and go acquire vitamin C supplements themselves at their local pharmacy. Mikkelsen agreed that this is a valid concern, as all participants will be told of this result during the informed consent process, but investigators will monitor protocol adherence through questionnaires and vitamin C levels. “Feasibility will be an important measure in this phase 3 study, definitely,” she concurred.

References

1. Wang M, Mayer J, Belada D, et al. Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma: results from the phase 3, double-blind, placebo-controlled ECHO trial. Presented at: EHA 2024 Congress; June 16, 2024; Madrid, Spain. Accessed June 16, 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/4136515/michael.wang.acalabrutinib.plus.bendamustine.and.rituximab.in.untreated.mantle.html

2. Dimopoulos MA, Beksac M, Pour L, et al. Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone vs pomalidomide plus bortezomib and dexamethasone in repalpsed/refractory multiple myeloma. Presented at: EHA 2024 Congress; June 16, 2024; Madrid, Spain. Accessed June 16, 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/4136513/meletios.dimopoulos.results.from.the.randomized.phase.3.dreamm-8.study.of.html

3. Song J, Han S, Amaru R, et al. Elevated hemoglobin of Andean Aymaras is caused by alternatively spliced NFKB1. Presented at: EHA 2024 Congress; June 16, 2024; Madrid, Spain. Accessed June 16, 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/4136518/josef.prchal.elevated.hemoglobin.of.andean.aymaras.is.caused.by.alternatively.html

4. Maiti A, Daver N, Johnson W, et al. Targeting of SIRP(+) immune cells results in a high response rate and improved 2-month survival of treatment-naive malignancy-associated hemophagocytic lymphohistiocytosis in a phase 1 study. Presented at: EHA 2024 Congress; June 16, 2024; Madrid, Spain. Accessed June 16, 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/4136517/abhishek.maiti.ela026.targeting.of.sirp282B29.immune.cells.results.in.a.high.html

5. Jassinskaja M, Kooi H, Bode D, et al. Intra- and extracellular proteome dynamics during normal and malignant hematopoietic stem cell expansion. Presented at: EHA 2024 Congress; June 16, 2024; Madrid, Spain. Accessed June 16, 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/4136514/maria.jassinskaja.intra-.and.extracellular.proteome.dynamics.during.normal.and.html

6. Mikkelsen SU, Vallentin A, Nielsen A, et al. Vitamin C supplementation in patients with clonal cytopenia of undetermined significance or low-risk myeloid malignancies: results from EVI-2, a randomized, placebo-controlled phase 2 study. Presented at: EHA 2024 Congress; June 16, 2024; Madrid, Spain. Accessed June 16, 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/4136519/stine.ulrik.mikkelsen.vitamin.c.supplementation.in.patients.with.clonal.html