Category: 3. Business

Eliminating total body irradiation (TBI) from conditioning regimens yielded efficacy outcomes comparable with established benchmarks for pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL), according to results from the phase 2 EndRAD trial (NCT03509961). The findings, presented at the 2025 ASH Annual Meeting and Exposition showed that TBI-free conditioning maintained disease control without compromising treatment response.

The 2-year event-free survival (EFS) rate in the treatment arm was 76.3% (95% CI, 61.1%-86.1%), and the 2-year overall survival (OS) rate was 82.0% (95% CI, 67.1%-90.6%). These results showed that the primary end point of the trial of EFS was met.

“Based upon this data, pediatric and young adult patients who are bone marrow next-generation sequencing (NGS)-minimal residual disease (MRD)-negative may consider non-TBI approaches as they choose therapy,” Hisham Abdel-Azim, MD, chief of Transplant and Cellular Therapy at Loma Linda University Health, said during the presentation.

A total of 202 patients were enrolled in the trial. The treatment arm (n = 51) was designed to estimate survival after non-TBI myeloablative conditioning prior to allogeneic hematopoietic cell transplant (HCT) for NGS-MRD-negative B-ALL. A total of 86% of patients were given busulfan, fludarabine, and thiopeta. Other comparable therapies included fludarabine, melphalan, and thiopeta (6%), and fludarabine, melphalan, clofarabine, and thiopeta (6%). In the observational arm (n = 151), patients were given myeloablative HCT and were not eligible for the treatment arm.

Abdel-Azim stated he and his colleagues hypothesized that the 2-year EFS and OS rates in patients who are NGS MRD negative and receiving a non-TBI-based regimen would be around 75% and 80%, respectively. The study was conducted in 45 centers in North America between 2018 and 2025.

Infants were not allowed in the treatment arm, and young children who were not eligible and received non-TBI treatment were included in the observational arm. Additionally, the observational arm included those who were flow-negative but NGS-positive who received TBI.

In the treatment arm, patients were eligible for treatment if they were between 1 and 31 years old and had high-risk complete remission 1 (CR1) or CR2 status. Receipt of prior CAR T-cell therapy and blinatumomab (Blincyto) was allowed. Patients were excluded from the treatment arm but were eligible to enroll on the observational arm if they were less than 1 year old, CR2 with a history of central nervous system relapse, had T-cell ALL and mixed-phenotype acute leukemia, and had active CNS/extramedullary disease at HCT.

In the treatment arm, the median age was 13.5 years (range, 2.3-30.5), and 51% of patients were male. Additionally, 37% had HLA-matched sibling donors, 35% had mismatched/unrelated haploidentical donors, 20% had matched unrelated donors, and 8% had unrelated cord blood donors. Bone marrow graft was given in 71% of patients, peripheral blood stem cell graft was given to 21% of patients, and 8% received an unrelated cord blood graft. Additionally, at HCT, 49% of patients had CR1 and 51% had CR2.

“OS and EFS in our phase 2 non-TBI treatment arm for NGS MRD-negative B-ALL matched our hypothesis and were comparable with outcomes of patients who are MRD-negative receiving TBI in previous studies,” Abdel-Azim concluded.

Abdel-Azim disclosures: Kite, consultancy; Novartis, consultancy; Adaptive, consultancy and research funding; Vertex, consultancy; and Johnson and Johnson, consultancy.

Reference

Abdel-Azim H, Quigg T, Kapoor N, et al. High event-free (EFS) and overall survival (OS) after non-total body irradiation (TBI) conditioning and allogeneic hematopoietic cell transplantation (HCT) in next-generation-sequencing minimal residual disease (NGS-MRD) negative B-acute lymphoblastic leukemia (B-ALL): Results from the EndRAD trial (PTCTC ONC1701). Blood. 2025;146(suppl 1):163. doi:10.1182/blood-2025-163

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

Treatment with adjuvant atezolizumab (Tecentriq) provided disease-free survival (DFS) and overall survival (OS) benefits over placebo regardless of tumor stage, nodal status, or prior receipt of neoadjuvant chemotherapy (NAC) in patients with circulating tumor DNA (ctDNA)–positive muscle-invasive bladder cancer (MIBC) by serial testing, according to data from an exploratory subgroup analysis of the phase 3 IMvigor11 trial (NCT04660344) presented at the 26th Annual Meeting of the Society of Urologic Oncology.¹

Of note, the rates of ctDNA positivity were higher in patients with higher tumor stage or a positive nodal status at the time of cystectomy, though investigators noted that surgical staging alone was not sufficient for predicting ctDNA status.

Among patients with persistent ctDNA negativity, the risk of recurrence or death was low across all tumor stages, nodal statuses, and receipt of prior NAC following cystectomy.

“These results support the use of serial ctDNA testing after cystectomy to enhance risk determination beyond classical surgical pathological staging and identify patients with ctDNA-positive status who benefit from adjuvant atezolizumab while sparing patients who persistently test ctDNA-negative from unnecessary treatment,” Juergen E. Gschwend, MD, PhD, a professor of urology at the Technical University of Munich’s School of Medicine and Health in Germany, stated in a presentation of the data.

What did previously reported data from IMvigor011 indicate about the potential role of adjuvant atezolizumab in ctDNA-positive MIBC?

Radical cystectomy with or without neoadjuvant therapy represents a potential curative option for patients with MIBC, but patients often experience variable outcomes. Accordingly, improving the identification of patients with MIBC at a higher risk of disease recurrence is a priority. There is an increasing body of evidence supporting the prognostic value of ctDNA-based minimal residual disease (MRD) detection following cystectomy.

IMvigor011 was designed to evaluate the use of adjuvant atezolizumab in ctDNA-positive MIBC by way of serial ctDNA monitoring. Findings from the study were previously presented at the 2025 ESMO Congress and simultaneously published in the New England Journal of Medicine.² At a median follow-up of 16.1 months, patients who tested positive for ctDNA and were treated with atezolizumab (n = 167) achieved a median DFS of 9.9 months (95% CI, 7.2-12.7) vs 4.8 months (95% CI, 4.1-8.3) with placebo (n = 83), per investigator assessment (HR, 0.64; 95% CI, 0.47-0.87; P = .0047). The HR for DFS was 0.69 (95% CI, 0.48-0.91). The median OS was 32.8 months (95% CI, 27.7-not evaluable [NE]) with atezolizumab vs 21.1 months (95% CI, 14.7-NE) in the placebo arm (HR, 0.59; 95% CI, 0.39-0.90; P = .0131).

How was the IMvigor11 trial designed?

IMvigor011 enrolled patients with MIBC who underwent radical cystectomy within 6 to 24 weeks of screening and had histologically confirmed (y)pT2-T4aN0M0 or (y)pT0-T4aN+M0 urothelial cancer with no evidence of radiographic disease progression.¹ Prior neoadjuvant therapy was permitted, and an ECOG performance status of 0 to 2 was required.

Following enrollment, patients underwent serial ctDNA testing every 6 weeks and radiographic imaging every 12 weeks until 1 year post-cystectomy. If patients tested ctDNA negative, serial ctDNA testing was repeated; those who remained ctDNA negative for up to 1 year did not receive any treatment, and surveillance continued with follow-up. Patients who tested positive for ctDNA at any point without evidence of radiographic disease were randomly assigned 2:1 to receive either 1680 mg of atezolizumab or placebo once every 4 weeks for up to 1 year.

The trial’s primary end point was Investigator-assessed DFS; OS was a key secondary end point.

Of the 761 patients enrolled during the surveillance monitoring period, 379 tested positive for ctDNA at any point, and 377 patients remained in persistent ctDNA negativity. Five patients had no ctDNA results. Assessment of pathologic staging at cystectomy showed that patients had (y)pT2N0 disease, (ctDNA+, n = 48; ctDNA-negative, n = 129), including pT2N0 (n = 17; n = 66) and (y)pT2N0 (n = 31; n = 63) staging; (y)pT3-4N0 disease (n = 123; n = 171),(y)pT≤2M+ disease (n = 66; n = 45), or (y)pT3–4N+ disease (n = 141; n = 30). Corresponding ctDNA positivity rates for patients with pT2N0, (y)pT2N0, (y)pT3-4N0, (y)pT≤2M+ and (y)pT3–4N+ disease were 20.5%, 33.0%, 41.8%, 59.5% and 82.5%, respectively .The data cutoff for the current analysis was June 15, 2025, and the median follow-up from random assignment was 16.1 months.

How did DFS and OS differ according to tumor stage, nodal status, and prior NAC in the ctDNA-positive patient population?

Tumor Stage

In those with (y)p≤T2 disease:

• The median DFS was 14.8 months (95% CI, 6.6-25.1) with atezolizumab (n = 53) vs 8.4 months (95% CI, 4.2-14.6) with placebo (n = 27; unstratified HR, 0.56; 95% CI, 0.31-1.01).
• The 12- and 24-month DFS rates with atezolizumab were 54.9% and 36.2%, respectively; corresponding rates with placebo were 37.1% and NE.
• The median OS was NE (95% CI, 29.1-NE) with atezolizumab vs 27.4 months (95% CI, 20.1-NE) with placebo (unstratified HR, 0.77; 95% CI, 0.32-1.90).
• The 12- and 24-month OS rates were 91.9% and 74.0% with atezolizumab. Corresponding rates in the placebo arm were 91.8% and 60.6%.

In the (y)pT3–4 group:

• The median DFS with atezolizumab (n = 114) was 8.3 months (95% CI, 6.5-10.6) vs 4.2 months (95% CI, 3.0-6.3) with placebo (n = 56; unstratified HR, 0.64; 95% CI, 0.45-0.92).
• The 12- and 24-month DFS rates with atezolizumabwere 39.8% and 24.1%, respectively; corresponding DFS rates with placebo were 25.7% and 18.4%.
• The median OS was 29.9 (95% CI, 21.1-NE) with atezolizumab vs 13.1 months (95% CI, 10.5-NE) with placebo (unstratified HR, 0.58; 95% CI, 0.37-0.93).
• The 12- and 24-month OS rates were 81.9% and 57.4% with atezolizumab. Corresponding rates in the placebo arm were 58.3% and 40.0%.

Nodal Status

In patients with (y)pN0 disease:

• The median DFS was 8.3 months (95% CI, 4.5-13.2) with atezolizumab (n = 71) vs 6.2 months (95% CI, 2.3-10.6) with placebo (n = 35; unstratified HR, 0.74; 95% CI, 0.45-1.12).
• The 12- and 24-month DFS rates in the atezolizumab arm were 42.5% and 25.2%, respectively; corresponding DFS rates with placebo were 30.6% and 10.2%.
• The median OS was 29.9 months (95% CI, 21.1-NE) with atezolizumab vs 18.1 (95% CI, 12.1-NE) with placebo (unstratified HR, 0.72; 95% CI, 0.38-1.39).
• The 12- and 24-month OS rates in the atezolizumab arm were 81.2% and 55.4%, respectively. Corresponding OS rates with placebo were 69.2% and 43.9%.

In the (y)pN+ population:

• The median DFS was 10.4 months (95% CI, 7.1-19.5) with atezolizumab (n = 96) and 4.8 months (95% CI, 4.1-8.3) with placebo (n = 48; unstratified HR, 0.58; 95% CI, 0.39-0.86).
• The 12- and 24-month DFS rates in the atezolizumab arm were 46.4% and 30.0%, respectively; corresponding DFS rates with placebo were 28.6% and 13.4%.
• The median OS was 34.4 months (95% CI, 29.1-NE) with atezolizumab vs 22.2 months (95% CI, 17.4-NE) with placebo (unstratified HR, 0.61; 95% CI, 0.36-1.05).
• The 12- and 24-month OS rates in the atezolizumab arm were 87.8% and 67.8%, respectively. Corresponding OS rates with placebo were 70.9% and 48.4%.

Prior NAC

In patients with no prior exposure to NAC:

• The median DFS was 10.5 months (95% CI, 6.6-14.5) with atezolizumab (n = 87) and 5.3 months (95% CI, 2.3-9.7) with placebo (n = 50; unstratified HR, 0.66; 95% CI, 0.44-1.00).
• The 12- and 24-month DFS rates in the atezolizumab arm were 45.1% and 28.1%, respectively; corresponding DFS rates with placebo were 34.9% and 16.4%.
• The median OS was 35.9 months (95% CI, 24.4-NE) with atezolizumab vs 18.2 months (95% CI, 13.1-NE) with placebo (unstratified HR, 0.52; 95% CI, 0.31-0.89).
• The 12- and 24-month OS rates in the atezolizumab arm were 89.0% and 65.5%, respectively. Corresponding OS rates with placebo were 66.5% and 43.9%.

In patients who had received prior NAC:

• The median DFS was 8.2 months (95% CI, 6.1-12.8) with atezolizumab (n = 80) and 4.4 months (95% CI, 3.7-10.4) with placebo (n = 33; unstratified HR, 0.59; 95% CI, 0.37-0.95).
• The 12- and 24-month DFS rates in the atezolizumab arm were 44.5% and 28.1%, respectively; corresponding DFS rates with placebo were 20.1% and 5.0%.
• The median OS was 30.8 months (95% CI, 22.0-NE) with atezolizumab vs NE (95% CI, 14.7-NE) with placebo (unstratified HR, 1.00; 95% CI, 0.50-1.99).
• The 12- and 24-month OS rates in the atezolizumab arm were 80.5% and 69.9%, respectively. Corresponding OS rates with placebo were 75.7% and 53.3%.

What were the DFS and OS outcomes with adjuvant atezolizumab according to tumor stage, nodal status, and prior NAC in patients with persistent ctDNA negativity?

Efficacy outcomes according to tumor stage were as follows:

• In the (y)p≤T2 population (n = 166), 12- and 24-month DFS rates were 96.3% and 89.1%, respectively; the 12- and 24-month OS rates were 100% and 97.3%
• In the (y)pT3–4 population (n = 189), corresponding DFS rates were 94.6% and 87.5%; corresponding OS rates were 100% and 96.9%.

When assessed by nodal status:

• In the (y)pN0 population (n = 285), 12- and 24-month DFS rates were 96.4% and 89.3%, respectively; the 12- and 24-month OS rates were 100% and 96.7%.
• In the (y)pN+ population (n = 72), corresponding DFS rates were 91.5% and 84.5%; corresponding OS rates were 100% and 98.4%

DFS and OS rates according to receipt of prior NAC were as follows:

• Among patients with no prior receipt of NAC (n = 189), 12- and 24-month DFS rates were 96.2% and 86.2%, respectively; the 12- and 24-month OS rates were 100% and 95.7%, respectively.
• For those who previously received NAC (n = 168), corresponding DFS rates were 94.6% and 90.8%; corresponding OS rates were 100% and 98.6%, respectively.

References

1. Gschwend JE, Bellmunt J, Arslan C, et al. Circulating tumor DNA-guided adjuvant atezolizumab vs placebo in patients with muscle-invasive bladder cancer after radical cystectomy: exploratory subgroup analysis of the phase 3 IMvigor011 trial. Presented at: 26th Annual Meeting of the Society of Urologic Oncology. December 2-5, 2025; Phoenix, Arizona.
2. Powles T, Kann AG, Castellano D, et al. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med. Published online October 20, 2025. doi:10.1056/NEJMoa2511885