EHA 2025 Late-Breakers Reflect Diversity of Hematology Topics, From RedirecTT-1 Combo to Frailty Scales

In abstracts presented at the late-breaking oral session of the 2025 European Hematology Association (EHA) Congress in Milan, Italy, researchers delivered exciting updates from trials of combination therapies and novel agents, findings on the cellular level, and implementation of assessments for predicting outcomes—all spanning an array of diseases both oncological and nonmalignant.

RedirecTT-1: Talquetamab and Teclistamab in a Challenging MM Setting

First, Shaji Kumar, MD, of Mayo Clinic in Minnesota, presented findings from the phase 2 RedirecTT-1 trial (NCT04586426) of talquetamab and teclistamab in patients with relapsed or refractory multiple myeloma (MM) and extramedullary disease,¹ which he noted is associated with poor outcomes including an 87% lower likelihood of responding to treatment.² Talquetamab and teclistamab have been approved as single agents, but Kumar and colleagues wanted to test them in combination in this challenging disease setting after preliminary data from the phase 1 trial showed a response rate of 61.1% in this subgroup.

Indeed, the results presented today showed a high overall response rate of 78.9% and deep responses, with over half (54.4%) achieving at least complete response, in these patients with extramedullary disease. Kumar noted a near tripling of complete response rate compared with monotherapy, and he shared that the majority of responders still on therapy as of the data cutoff were switched to monthly dosing with no reduction in response. Although 79% of patients experienced infection, there were no new safety signals with the combination.

“This regimen represents an off-the-shelf dual-targeting bispecific combination that has produced results that we had not seen previously in the context of extramedullary disease,” Kumar said, which is “a big step forward and will hopefully change the natural history of the disease.”

In response to an audience question about which regimen he would choose in clinic, Kumar said he prefers this combination over chimeric antigen receptor T-cell therapy because these responses appear more durable, although this choice could change if the investigational trispecific antibody discussed in yesterday’s plenary session eventually becomes available—given its eye-catching 86% response rate.³

Investigational Monoclonal Antibodies for ET and ITP

Findings presented by John Mascarenhas, MD, of Mount Sinai, showed the promise of INCA33989, an investigational monoclonal antibody for treating essential thrombocythemia (ET) with CALR mutations, which raise risk and are associated with lower response.⁴ In the phase 1 INCA33989-101 and -102 trials (outside US and US only, respectively; NCT05936359 and NCT06034002), 49 patients received the first-in-class agent intravenously every 2 weeks. No dose-limiting toxicities were observed, and patients largely experienced rapid platelet count normalization and profound molecular responses.

“These findings support the potential of INCA33989, a mutation-specific targeted therapy, to provide durable hematological responses and modify the disease of patients with mutated-CALR ET,” Mascarenhas concluded.

Another abstract looked at a novel monoclonal antibody in a nonmalignant setting: immune thrombocytopenia (ITP). As explained by presenter Yanmei Xu, MD, of China’s National Clinical Research Center for Blood Diseases, these findings represent the first randomized controlled trial for the agent, CM313, in adult ITP, which is known to lead to bleeding, fatigue, and poor quality of life.⁵ Trial results revealed an improvement in platelet counts in a median of 1 week and fewer bleeding events in the investigational arm; there were 2 serious adverse events seen.

“Anti-CD38 targeted therapy rapidly boosted platelet levels by inhibiting antibody-dependent cell-mediated cytotoxicity on platelets, and maintained long-term efficacy by clearing plasma cells,” Xu said.

Understanding Cell Markers in Venetoclax-Resistant CLL

Shifting gears, an abstract presented by Daisy Diaz Rohena, a PhD student at MD Anderson Cancer Center in Texas, focused on the transcriptional reprogramming of chronic lymphocytic leukemia (CLL) that is resistant to venetoclax.⁶ While venetoclax and Bruton tyrosine kinase (BTK) inhibitors have transformed the CLL treatment landscape, the emergence of resistance is linked with poor outcomes, so Diaz Rohena and colleagues aimed to identify potential markers in relapsed cells via whole-exon sequencing and single-cell RNA sequencing. Among their findings was that NF-κB signaling is upregulated at the time of relapsing on BTK inhibitors and venetoclax, as well as that CLL that progresses on venetoclax shows resistance to BAK/BAX protein activation.

Diaz Rohena suggested that it may be worthwhile to perform this sequencing before enrollment in clinical trials, “to identify the patients who perhaps can be sensitive to this kind of targeted therapy vs others that are under development like MCL-1 inhibitors.”

Predicting Transplant Outcomes With a Feasible Frailty Scale

The final late-breaker revealed the potential of a frailty scale to be cost-effectively implemented into transplant clinics, yielding important prognostic information for patients who will receive an allogeneic hematopoietic stem cell transplant (alloHCT). Frailty is known to be associated with overall survival and mortality after alloHCT, but current screening methods vary in their methodology and administrative burden, so Maria Queralt Salas, MD, of Hospital Clinic Barcelona, and colleagues developed the HCT Frailty Scale, designed to be administered quickly at the time of HCT consult.⁷

Designed in Princess Margaret Cancer Center in Toronto and then implemented in clinics of the Grupo Español de Transplante Hematopoyético y Terapia Celular in Spain, the assessment was performed by hematologists and nurse teams for 1077 consecutive patients—importantly, using existing resources, without additional funding, and in a median time of 10 minutes with no need for additional appointments. Confirming the prognostic value, Queralt Salas and team found that frail patients had higher median days hospitalized, readmissions, and intensive care unit stays after their transplant, as well as significantly lower overall survival and nonrelapse mortality.

In response to a question from a transplant physician in the audience about how to make the frailty status information more actionable, Queralt Salas noted that “not everything can be fixed with medication” and so her team has implemented a prehabilitation program emphasizing physical activity that starts after the first consultation, then a rehabilitation program starting when they are admitted for transplant and continued after discharge.

This variety of abstracts, in their disease focus and methodologies, “tells us what a vibrant clinical specialty we’re in,” Huntly concluded.

References

1. Kumar S, Mateos MV, Ye JC, et al. Phase 2 study of talquetamab + teclistamab in patients with relapsed/refractory multiple myeloma and extramedullary disease: RedirecTT-1. Presented at: EHA 2025 Congress; June 15, 2025; Milan, Italy. Accessed June 15, 2025. https://library.ehaweb.org/eha/2025/eha2025-congress/4173809/shaji.kumar.phase.2.study.of.talquetamab.2B.teclistamab.in.patients.with.html

2. Voorhees P, Kumar S, Usmani SZ, et al. Clinical outcomes of patients with relapsed or refractory multiple myeloma with and without extramedullary disease. Presented at: EHA 2025 Congress; June 12-15, 2025; Milan, Italy. Accessed June 15, 2025. https://library.ehaweb.org/eha/2025/eha2025-congress/4160175/peter.voorhees.clinical.outcomes.of.patients.with.relapsed.or.refractory.html

3. Mattina C. EHA plenary abstracts zoom in from investigational drugs to molecular signatures. AJMC^®. June 14, 2025. Accessed June 15, 2025. https://www.ajmc.com/view/eha-plenary-abstracts-zoom-in-from-investigational-drugs-to-molecular-signatures

4. Mascarenhas J, Ali H, Yacoub A, et al. INCA33989 is a novel, first in class, mutant calreticulin-specific monoclonal antibody that demonstrates safety and efficacy in patients with essential thrombocythemia (ET). Presented at: EHA 2025 Congress; June 15, 2025; Milan, Italy. Accessed June 15, 2025. https://library.ehaweb.org/eha/2025/eha2025-congress/4173810/john.mascarenhas.inca33989.is.a.novel.first.in.class.mutant.html

5. Xu Y, Chen Y, Dai J, et al. Safety and efficacy of CM313 in adults with immune thrombocytopenia: a randomized, placebo-controlled trial. Presented at: EHA 2025 Congress; June 15, 2025; Milan, Italy. Accessed June 15, 2025. https://library.ehaweb.org/eha/2025/eha2025-congress/4173812/yanmei.xu.safety.and.efficacy.of.cm313.in.adults.with.immune.thrombocytopenia.html

6. Diaz Rohena D, Zhou Y, Ravikrishnan J, et al. Transcriptional reprogramming and survival co-dependencies of chronic lymphocytic leukemia resistant to venetoclax. Presented at: EHA 2025 Congress; June 15, 2025; Milan, Italy. Accessed June 15, 2025. https://library.ehaweb.org/eha/2025/eha2025-congress/4173811/daisy.diaz.rohena.transcriptional.reprogramming.and.survival.co-dependencies.html

7. Queralt Salas M, Alfaro-Moya T, Pasic I, et al. HCT frailty scale (HCT-FS) for assessing frailty in allogeneic hematopoietic cell transplant patients. results from a multicenter and prospective Canadian and Spanish initiative. Presented at: EHA 2025 Congress; June 15, 2025; Milan, Italy. Accessed June 15, 2025. https://library.ehaweb.org/eha/2025/eha2025-congress/4173813/maria.queralt.salas.hct.frailty.scale.28hct-fs29.for.assessing.frailty.in.html