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Measurable residual disease (MRD) following induction chemotherapy may robustly predict overall survival (OS) among patients with acute myeloid leukemia (AML), according to findings from a pooled analysis study presented in a press briefing at the 2025 American Society of Hematology Annual Meeting & Exposition (ASH).

Pooled data on 1858 patients undergoing treatment across 7 randomized trials showed that the achievement of MRD negativity correlated with a risk of death that was twice as low vs patients who had MRD-positive status (P <.0001). This association between MRD and OS occurred regardless of age, genetics, and treatment arm; outcomes were consistent across trials and the use of multiparameter flow cytometry (MFC) or qPCR for NPM1 in the evaluation of MRD. Overall, the data showed a strong patient-level link between survival and MRD status.

Across the evaluable trials, MRD responses showed a strong correlation with OS benefit (R² = 0.91; 95% CI, 0.56-1.00). As far as trial-level surrogacy was concerned, presenting author Jesse Tettero, MD, PhD, noted that the confidence interval for this finding fell below what is typically used in the FDA framework.

“The lower bound of the confidence interval was 0.56. The FDA requires the lower bound to be above 0.60, so there is some caution to be noted when interpreting these data,” Tettero, a postdoctoral associate at Fralin Biomedical Research Institute (FBRI) Cancer Research Center in Washington, DC, and a visiting hematology fellow at Amsterdam University Medical Center in the Netherlands, said in the presentation.

However, findings showed an even stronger relationship between MRD responses and survival among patients who did not undergo a transplant (R² = 0.99; 95% CI, 0.94-1.00). Tettero described how such agreement was rare for oncologic end points.

“We could identify effective therapies [with MRD] earlier than OS; that could be a benefit of 4 to 5 years. It therefore enables potential accelerated approval…only if the FDA truly regards MRD as a surrogate end point,” Tettero said. “When supported, it could lead to smarter and faster trials for [patients with] AML.”

Despite the advent of new treatment modalities such as FLT3 and IDH inhibitors, Tettero stated that AML remains a difficult-to-cure disease, as most patients will relapse following treatment. Additionally, he noted how the longer follow-up associated with OS end points in clinical trials may delay progress for therapeutic advances. Given that MRD is already used as a surrogate marker for approval in other blood cancers like acute lymphoblastic leukemia and multiple myeloma, Tettero and colleagues aimed to determine whether MRD could represent an earlier predictor of survival in AML.

As part of the largest collaboration to evaluate MRD as a surrogate end point in AML, investigators collected patient-level data from 7 randomized trials. These studies included 4 from European cooperative groups: the German-Austrian AML Study Group (AMLSG), the Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK), Study Alliance Leukemia (SAL), and the UK National Cancer Research Institute (UK-NCRI). The study compared MRD status with long-term OS based on FDA expectations.

Eligible studies were those that randomly assigned patients to experimental or placebo treatments in combination with standard intensive induction chemotherapy, with at least 20 patients on each arm and the inclusion of MRD subgroups.

Regarding study limitations, Tettero stated that the analysis only related to trials assessing intensive therapy in the EU, as less intensive regimens such as venetoclax (Venclexta) plus hypomethylating agents (VEN-HMA) were not represented, and the confidence intervals for trial-led surrogacy were wide, as the lower bound was below the 0.6 threshold typically used in regulatory framework. Additionally, the study did not fully standardize the use of MRD assays across clinical trials, which may have correlated with data heterogeneity. According to Tettero, several relevant MRD datasets were also inaccessible for the analysis.

Looking towards the future, Tettero and colleagues aim to expand analyses that account for modern, non-intensive treatment backbones and regimens like VEN-HMA and FLT3 or IDH inhibitors. The investigators also look to achieve global harmonization of MRD testing across these treatment modalities while promoting data sharing on an international level to expand the number of eligible trials.

Disclosures: Tettero had no relevant relationships to disclose.

Reference

Tettero J, Eric S, Freeman S, et al. Validation of measurable residual disease as a surrogate endpoint in acute myeloid leukemia: a HARMONY Alliance study of European randomized trials. Blood. 2025;146(supplement 1):343. doi:10.1182/blood-2025-343

Lisaftoclax, a BCL-2 inhibitor, demonstrated a significant overall response rate (ORR) of 62.5% and a progression-free survival (PFS) of 23.89 months (95% CI, 13.01–not reached [NR]) with a tolerable safety profile in heavily treated patients with relapse/refractory chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), according to findings of a phase 2 pivotal registration study (NCT05147467).¹

At the data cutoff of July 25, 2025, among 72 evaluable patients, the median time to first response was 3.68 months (range, 1.81–11.14) and the median duration of response was 18.53 months (95% CI, 14.75–NR).¹ The median follow-up period was 22.01 months (range, 0.80–38.0).

The 12-month PFS rate was 66.4% (95% CI, 53.1%–76.7%). The 30-month overall survival (OS) rate was 78.0% (95% CI, 66.1%–86.2%) and the median OS was NR.

“Further, minimal residual disease [MRD] negativity in peripheral blood was observed in 21.8% of patients and 54.5% in bone marrow,” Kenshu Zhou, MD, of the Henan Cancer Hospital in Zhengzhou, China, said during a presentation of the data at the 67th American Society of Hematology Annual Meeting and Exposition in Orlando, Florida.¹

Study Design

A total of 77 patients were enrolled if they met the dual criteria of prior refractory, relapsed, or intolerance to both Bruton tyrosine kinase (BTK) inhibitors and immunotherapy or had high-risk factors such as del(17p)/TP53 mutation or chromosomal complex karyotype (CK).

Eligible patients received lisaftoclax on a daily ramp-up schedule to reach the target dose of 600 mg once a day administered every 28 days in a dosing cycle. The primary end point was ORR, and secondary end points were complete response, PFS, time to response, OS, and safety.

Baseline Characteristics

At baseline, patient median age was 63.0 years (range 37–84), 59.7% were male, and had been treated with a median of 3 previous therapies (range, 1–10). Patients had an ECOG status of 0 to 1 (68.8%) or 2 (31.2%).

Eighty-seven percent were refractory to BTK inhibitors and 39% had del(17p)/TP53 mutation, 53.2% had unmutated immunoglobulin heavy chain variable (IGHV), and 42.9% had CK.

Among patients with CK (n = 33), 63.6% had high CK with 5 or more aberrations and 21 (63.6%) also had del(17p) of TP53 mutation.

In patients with del(17p)/TP53 mutation, the median PFS was 11.2 months vs 29.6 months in patients without this mutation or CK (HR, 5.0; P =.018). In patients with high CK, the median PFS was 12.9 months vs 25.7 months in those without high CK (HR, 2.7; P =.001).

“In our study, CK accounted for 42.9% of the total population. Patients with the del(17p)/TP53 mutation accounted for 39.0% of the population, which was higher than that observed in prior studies.^2,3 This represents true BTK inhibitor failure and a refractory population,” Zhou said.

Regarding safety, most treatment-related adverse events (TRAEs) were grade 1 or 2, although there were grade 3/4 instances of neutropenia (27.3%), thrombocytopenia (16.9%), anemia (9.1%), and pneumonia (3.9%) reported. “There were no cases of tumor lysis syndrome [TLS] or drug-related deaths reported,” Zhou continued.

Zhou further compared the agent with another BCL-2 inhibitor, venetoclax (Venclexta), noting significant efficacy in heavily pretreated patients with CLL/SLL, a short half-life, and the absence of drug-drug interactions with BTK inhibitors or CD20 monoclonal antibodies.

“Lisaftoclax monotherapy showed significant efficacy in heavily treated patients with relapsed/refractory CLL/SLL with a favorable safety profile and no TLS observed,” Zhou said. “The agent received a conditional approval in China in July 2025,” Zhou concluded.

REFERENCES

1. Zhou K, Wang T, Niu T, et al. Results of a registrational Phase 2 study of lisaftoclax monotherapy for treatment of patients (pts) with Relapsed/Refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who had failed Bruton’s tyrosine kinase inhibitors (BTKis). Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida. Abstract 88.

2. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol; 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

3. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582