2  Integrating Approved Immunotherapies into Treatment Approaches for Adult B-Precursor ALL

2.1 Session Overview

Session Details
Session Integrating Approved Immunotherapies into Treatment Approaches for Adult B-Precursor Acute Lymphoblastic Leukemia
Speaker Adele Fielding, MBBS, PhD
Affiliation Centre for Blood Research, Hull York Medical School, University of York, UK
Off-label discussion Inotuzumab, chimeric antigen receptor T cells (CAR-T), Blinatumomab [slide p.2]
Time Day 1, 9:30–10:00 a.m.

Built around a single recurring case—a 38-year-old woman with low-hypodiploid B-ALL, obesity, diabetes, a matched sibling, and MRD negativity by Ig/TCR after a toxic induction [slides p.4, 21, 35]—Dr. Fielding uses ASH 2025 data to answer three questions she says blinatumomab has destabilised: who still has “high-risk” ALL, who still needs an allogeneic transplant, and how much chemotherapy (or which backbone) we can now omit [slide p.9]. The arc moves from prognostic/predictive factors in adult Ph-negative ALL, through the three regulatory settings for blinatumomab CIV, to frontline allo-sparing strategies in Ph-negative (GRAALL-2014/B-QUEST) and Ph-positive (GIMEMA ALL2820) disease, and ends with a glimpse at CAR-T as frontline consolidation [slides p.5–34].

2.2 Speaker Spotlight

Adele K Fielding, MBBS, PhD is Professor of Haematology at Hull York Medical School. She serves as chief investigator for the UKALL14 and UKALL60+ trials, two major UK cooperative group studies defining the treatment landscape for younger and older adults with ALL. Her research centers on MRD-directed therapy optimization and the integration of novel agents into frontline protocols.

2.3 What’s New in 2025–2026

2.3.1 The Case That Frames the Talk

Dr. Fielding anchors the entire session to a 38-year-old woman with B-precursor ALL, presenting WCC 70 × 109/L, low hypodiploidy, CNS-negative, with diabetes and obesity that made marrow aspirates difficult. Induction produced morphologic CR but was complicated by asparaginase-related liver toxicity, VTE, and sepsis; she has a fully matched sibling donor, and MRD by Ig/TCR is negative at 10-4 sensitivity [slides p.4, 21]. Three audience-response questions progressively broaden the consolidation options from “alloSCT vs. await MRD” to “blinatumomab then alloSCT” to—given unrestricted access—“blinatumomab then CAR-T” [slides p.4, 21, 35].

2.3.2 Who Still Has High-Risk Ph-Negative ALL?

Traditional adverse features in Ph-negative adult ALL remain older age, MRD positivity (including pre-RIC alloSCT), and high-risk genetics. UKALL14 data in patients 25–65 show clear event-free survival separation between standard-risk (ZNF384r, high hyperdiploidy), high-risk (KMT2Ar), and very-high-risk groups (low hypodiploidy, complex karyotype, JAK-STAT lesions), while Patel et al. (Hemasphere 2024) confirm age drives outcome regardless of chemotherapy intensity and Marks et al. (Lancet Haematology 2022) show MRD positivity predicts relapse even after reduced-intensity conditioning [slide p.5].

Blinatumomab’s regulatory footprint in BCR::ABL1-negative ALL now spans three dosing scenarios: frank relapse (1-week run-in dose, 5 cycles); MRD positive, either de novo or re-emergent (no run-in, 4 cycles); and MRD-negative de novo disease in consolidation (no run-in, 4 cycles plus chemotherapy) [slide p.8]. Two recent randomised trials underpin frontline use: the pediatric COG AALL1731 study (Gupta, NEJM 2025) and the adult ECOG-ACRIN E1910 trial (Litzow, NEJM 2024), which showed a hazard ratio for death of 0.41 (95% CI 0.23–0.73, p=0.002) favouring blinatumomab consolidation in MRD-negative adults [slide p.7].

Practice-Changing: “Now, ‘everyone’ can receive blinatumomab”

Dr. Fielding’s own slide title captures the shift: CIV blinatumomab has regulatory cover across essentially every frontline Ph-negative scenario, and the open questions have moved on to subcutaneous vs. CIV delivery, starting earlier, how much chemotherapy can be safely omitted without a second targeted agent, optimal CNS prophylaxis, and who still needs an allograft—questions trials such as Golden Gate, Audax, and UKALL15 will address [slide p.9].

2.3.3 Does Blinatumomab Rewrite Prognostic and Predictive Factors?

Dr. Fielding highlights three ASH 2025 abstracts addressing this [slide p.10]:

Arora (Abstract 25-11927) reviewed 213 Ph-negative B-ALL patients in CR1 after frontline blinatumomab (29% in induction, 71% in consolidation/maintenance). With a median 37-month follow-up, 24 (11%) relapsed and 29 (14%) died in CR1; 16 of the 24 relapsers subsequently died. Univariate competing-risk regression flagged BMI >30 kg/m², WBC >50 × 109/L, TP53 mutation, and high hypertriploidy/KMT2Ar signals; on multivariable analysis BMI >30 (sHR 2.98, p=0.027), WBC >50 (sHR 3.64, p=0.007), and TP53 mutation (sHR 2.71, p=0.029) remained independent predictors [slides p.11–13].

Zhong (Abstract 25-7266) performed genomic profiling on 569 B-ALL cases from E1910. Low hypodiploidy (n=80), KMT2A-R (n=66), Ph+ (n=113), and Ph-like CRLF2 (n=68) were the dominant high-risk subtypes. Genomic subtype was significantly associated with induction response (p=0.002): Ph-like CRLF2, Ph-like non-CRLF2, and KMT2A-R were enriched among induction failures and MRD-positive patients, whereas PAX5alt, PAX5 P80R, PAX5::ETV6, and TCF3::PBX1 dominated the MRD-negative group. Critically, among MRD-negative cases, blinatumomab consolidation improved relapse-free survival overall (p=0.0096) and within hyperdiploid (p=0.01) and numerically within every high-risk subtype examined (Ph-like CRLF2, PAX5alt, PAX5 P80R, KMT2A-R) [slides p.14–16].

Gupta (Abstract 25-9139) is the AALL1731 deep-dive in standard-risk pediatric B-ALL. Adding blinatumomab to chemotherapy narrowed or erased the prognostic gap across unfavourable cytogenetics (77.1% → 91.7% 4-year DFS), ETV6::RUNX1, iAMP21, KMT2A-R, and hypodiploidy, and notably rescued end-of-consolidation MRD-positive patients (4-year DFS 30.8% → 81.8%; HR for MRD+ vs. MRD– dropped from 5.9 to 2.6, no longer significant). The hazard ratio for unfavourable cytogenetics fell from 3.49 (p=0.002) on chemotherapy to 4.09 (p=0.04) with blinatumomab, and day-29 MRD positivity lost statistical significance (HR 1.87, p=0.08) once blinatumomab was added [slides p.17–19].

2.3.4 Does Blinatumomab Change Who Needs an AlloSCT? The GRAALL-2014/B-QUEST Data

Boissel (Abstract 25-2780) reported the final GRAALL-2014/B-QUEST substudy: 94 high-risk Ph-negative B-ALL patients (EOI MRD ≥10-4, KMT2A-r, or IKZF1del, CNS-negative) treated after July 2018 with frontline blinatumomab consolidation compared with 90 contemporaneous high-risk controls treated before July 2018 on the same backbone without blinatumomab [slide p.23].

  • 3-year disease-free survival: 70% (95% CI 60–78) with blinatumomab vs. 48% (95% CI 38–58) with chemotherapy alone; HR 0.48 (95% CI 0.31–0.75), p=0.001 [slide p.23].
  • Cumulative incidence of relapse: SHR 0.41 (95% CI 0.25–0.68), p=0.001—a 59% reduction [slide p.23].
  • Overall survival: HR 0.54 (95% CI 0.32–0.93), p=0.03; 52% reduction in DFS events [slide p.23].
  • Benefit was consistent across age, sex, WBC, Ph-like ALL, and MRD ≥10-4, IKZF1del, and KMT2A-r subgroups [slide p.24].
  • AlloSCT interaction (very-high-risk patients): In VHR patients who proceeded to alloHSCT, prior blinatumomab added little (HR 0.76, 95% CI 0.39–1.50). In VHR patients who did not reach alloHSCT, blinatumomab produced a striking benefit (HR 0.18, 95% CI 0.04–0.80)—arguing that blinatumomab can substitute for, not just bridge to, transplant in selected high-risk adults [slide p.25].

2.3.5 Ph-Positive ALL: GIMEMA ALL2820 Randomised Against Imatinib + Chemotherapy

Chiaretti (Abstract 25-7887) presented the first results of the GIMEMA ALL2820 phase III trial, which randomised (2:1) 236 adults ≥18 years with newly diagnosed Ph+ ALL (no upper age limit; 28% >65 years) to experimental ponatinib + blinatumomab (after a steroid prephase, with ponatinib 45 mg/day tapering to 30 mg for 18–65 y and 30 mg/day for >65 y, plus 2 mandatory blinatumomab cycles) or to control imatinib + chemotherapy [slides p.26–27].

  • Patient population (n=236): median age 56.5 (exp) vs. 55 (control) years; ~10% CNS+ at diagnosis; p190 predominant [slide p.27].
  • End-of-induction (day 70) CHR: 94.3% experimental vs. 79.4% control (p=0.004). Induction deaths were markedly lower with ponatinib + blinatumomab (2.5% vs. 10.2%) [slide p.28].
  • Event-free survival at median 23.4 months follow-up: 90% (86–95) experimental vs. 74% (65–85) control, p=0.0015. AlloSCT was used in only 15 experimental vs. 30 control patients [slide p.29].
  • CNS prophylaxis was deliberately strengthened (15 triple intrathecal injections, 18 if CNS+) and cross-over was allowed for patients failing to achieve CHR or remaining MRD+ [slide p.26].
Clinical Pearl: Chemotherapy-Free Ph+ ALL Matures

GIMEMA ALL2820 is the first phase III demonstration that a ponatinib + blinatumomab backbone—no systemic chemotherapy in induction—beats imatinib + chemotherapy on CHR, early mortality, and EFS in adult Ph+ ALL. Combined with Dr. Fielding’s take-home message, de novo Ph+ adults can often avoid both chemotherapy and alloSCT if blinatumomab is combined with a 2nd/3rd-generation TKI, provided CNS prophylaxis is robust [slides p.29, 36].

2.3.6 A Glimpse of the Future: Frontline CAR-T as Consolidation

Two ASH 2025 abstracts push CAR-T from R/R into CR1 [slide p.30]:

Aldoss (Abstract 25-13587) reported a single-arm phase 2 of CD19-CAR T-cells as definitive consolidation in older adults (≥55 y, ECOG <2, CR1, no immediate HCT plans) who had received ≥4 prior intrathecal chemotherapies and were MRD-negative pre-lymphodepletion. 18 patients enrolled (median age 64, range 55–79); 83% had prior blinatumomab, 11% prior inotuzumab; genetics included Ph+, hypodiploid/TP53m, Ph-like, KMT2Ar, ZNF384::EP300, TCF3::PBX1. No DLTs; grade 1 CRS 72%; no grade ≥2 CRS; no ICANS. OS was 100% across follow-up; EFS approximately 75% beyond ~20 months [slides p.31–32].

Gu (Abstract 25-3841) prospectively treated 35 newly diagnosed adult Ph+ B-ALL patients (median age 39, range 20–60; 88.6% p190; 22.8% IKZF1plus) with a VOVP induction (venetoclax–olverembatinib–VCR–prednisone), then a single murine-derived 2nd-generation CD19 CAR-T infusion (4-1BB, 1–2 × 106 cells/kg) during first CR as consolidation, followed by olverembatinib-based maintenance (alternating MM/VPV) and 11 triple intrathecal injections. At median 10.9 months follow-up, 1-year leukemia-free survival was 100%, with no CRS >grade 2 and no ICANS [slides p.33–34].

Dr. Fielding explicitly frames both approaches as not yet within licensed indications and with very short follow-up, but as promising signals that immunotherapy can take over the consolidation role traditionally held by intensive chemotherapy and, in some cases, transplant [slide p.36].

2.4 Clinical Pearls

Five Key Takeaways
  1. Blinatumomab has broad regulatory approval in de novo Ph-negative adult ALL—across frank relapse, MRD+, and MRD– consolidation—and has the potential to revolutionise treatment [slides p.8, 36].
  2. High-risk genetics and even persistent MRD can now achieve vastly improved outcomes with frontline blinatumomab; AALL1731 collapses the EOC MRD+ disadvantage (DFS 30.8% → 81.8%) and GRAALL-QUEST cuts 3-year relapse in very-high-risk adults by 59% [slides p.19, 23, 36].
  3. Deciding how much chemotherapy to omit and who still needs an alloSCT has become harder, not easier. In VHR GRAALL-QUEST patients who did not reach alloHSCT, blinatumomab itself was protective (HR 0.18), suggesting alloSCT can be spared in selected adults [slides p.25, 36].
  4. In de novo Ph-positive ALL, systemic chemotherapy can be omitted if blinatumomab is combined with a 2nd/3rd-generation TKI. GIMEMA ALL2820 shows ponatinib + blinatumomab beats imatinib + chemotherapy on CHR (94.3% vs. 79.4%), induction deaths (2.5% vs. 10.2%), and 2-year EFS (90% vs. 74%) [slides p.28–29, 36].
  5. Adequate CNS-directed prophylaxis remains critical in every chemotherapy-sparing scenario, and CAR-T / inotuzumab in chemo-free frontline approaches appear promising but with very short follow-up and outside licensed indication [slides p.32, 34, 36].
Asia-Pacific Perspective

Access to blinatumomab and inotuzumab ozogamicin has expanded across major Asia-Pacific markets but remains limited in some countries. CAR-T cell therapy availability is concentrated in a few specialized centers. Standardizing MRD assessment methodology across the region is an important quality initiative.

2.5 Key References

  1. Litzow MR, et al. Blinatumomab for MRD-negative B-ALL in adults (ECOG-ACRIN E1910). N Engl J Med. 2024 [slide p.7].
  2. Gupta S, Rau RE, et al. Blinatumomab added to chemotherapy in children with standard-risk B-ALL (COG AALL1731). N Engl J Med. 2025 [slides p.7, 18].
  3. Patel B, et al. Outcomes in older adults with ALL on UKALL14 vs. UKALL60+. HemaSphere. 2024 [slide p.5].
  4. Moorman AV, et al. Genetic classification and outcome in adult ALL (UKALL14). Leukaemia. 2021 [slide p.5].
  5. Marks DI, et al. MRD and outcome after reduced-intensity allogeneic transplantation in adult ALL. Lancet Haematol. 2022 [slide p.5].
  6. Arora S, et al. Predictors of relapse and post-relapse outcomes after frontline blinatumomab-based therapy in Ph-negative B-ALL. ASH 2025 Abstract 25-11927 [slides p.11–13].
  7. Zhong X, et al. Genomic determinants of treatment outcome and identification of a new genomic subset of adult ALL from the ECOG-ACRIN E1910 trial. ASH 2025 Abstract 25-7266 [slides p.14–16].
  8. Gupta S, et al. Blinatumomab mitigates the impact of traditional adverse prognosticators in SR B-ALL (COG AALL1731). ASH 2025 Abstract 25-9139 [slides p.17–19].
  9. Boissel N, et al. Blinatumomab consolidation in high-risk Ph-negative adult B-ALL: final report of the GRAALL-2014/B-QUEST study. ASH 2025 Abstract 25-2780 [slides p.23–25].
  10. Chiaretti S, et al. First results of the Phase III GIMEMA ALL2820 trial comparing ponatinib + blinatumomab to imatinib + chemotherapy for newly diagnosed adult Ph+ ALL. ASH 2025 Abstract 25-7887 [slides p.26–29].
  11. Aldoss I, et al. CD19-CAR T-cell therapy as definitive consolidation in older adults with B-ALL in CR1. ASH 2025 Abstract 25-13587 [slides p.31–32].
  12. Gu R, et al. Single CAR-T infusion during frontline consolidation induces deep and sustained remission in newly diagnosed adult Ph+ B-ALL: a prospective phase 2 study. ASH 2025 Abstract 25-3841 [slides p.33–34].