Predictors of Relapse and Post‐Relapse Outcomes After Frontline Blinatumomab in Philadelphia Chromosome‐Negative B‐ <scp>ALL</scp>

The addition of blinatumomab to multiagent chemotherapy regimens has improved outcomes in patients with newly diagnosed Philadelphia chromosome-negative (Ph-negative) CD19+ B-cell acute lymphoblastic leukemia (B-ALL) [1-4]. In a phase 3 trial, the addition of blinatumomab to consolidation chemotherapy in patients who achieved flow cytometry-based measurable residual disease (MRD) negative remission demonstrated a significantly improved 3-year overall survival (OS) and 3-year relapse free survival (RFS) of 85% and 80%, respectively [5]. However, the outcomes of patients with relapsed disease following frontline blinatumomab-based therapy in Ph-negative B-ALL are unknown. In this study, we describe the risk factors for relapse and post-relapse outcomes in a large cohort of patients with newly diagnosed Ph-negative B-ALL receiving blinatumomab-based regimens. This is a retrospective study in patients aged ≥ 18 years with newly diagnosed Ph-negative B-ALL who achieved first remission [complete remission (CR)/CR with inadequate platelet response (CRp)] after treatment with blinatumomab-based chemotherapy regimens from 11/2014–3/2025. Patients who received blinatumomab for MRD positive recurrence were excluded. Frontline regimens (Table S1) were classified as intensive (HCVAD2) or low-intensity (mini-HCVD3). Univariate (UVA) and multivariable analysis (MVA) were conducted using the Fine-Gray competing risk regression model to identify factors associated with increased relapse risk. Thresholds for specific covariates [white blood cell (WBC) count > 50 × 109 /L, TP53 mutation variant allelic frequency (VAF) ≥ 45%] were chosen for analysis based on prior published data [6, 7]. Survival outcomes were estimated using the Kaplan Meier method. Additional details are included in the Supporting Information. A total of 213 consecutive patients were included (Figure S1: Consort diagram). The median age at diagnosis was 42 years (range, 18–88), with 28% of patients (n = 59) aged ≥ 60 years. Blinatumomab was added in the induction phase (i.e., prior to attaining remission) in 61 patients (29%), and in consolidation/maintenance phase (i.e., after remission was attained) in 152 patients (71%). Among the patients who received blinatumomab as consolidation and who had available MRD testing by flow cytometry (n = 151), 27 patients (18%) were MRD-positive prior to blinatumomab initiation. The median time from diagnosis to initiation of blinatumomab was 2.5 months (range, 0.1–13.2 months). A total of 158 patients (74%) also received frontline inotuzumab, and 50 patients (24%) underwent allogeneic stem cell transplantation (allo-SCT) in first remission. After a median follow-up of 36.7 months (95% CI: 31.7–39.2) from blinatumomab initiation, 24 patients (11%) relapsed, 29 (14%) died in first remission, and 160 (75%) remain alive in first remission. The 2-year cumulative incidence of relapse (CIR) was 11.4% (95% CI: 6.8–16.1; Figure S2). The baseline characteristics stratified by relapse are described in Table 1. Patients who relapsed were older (median age 56 years versus 39 years, p = 0.04), and had a higher prevalence of obesity [body mass index (BMI) > 30 Kg/m2; 71% versus 43%, p = 0.02], WBC count > 50 × 109 /L (33% vs. 12%, p = 0.01) and TP53 mutation with VAF ≥ 45% (29% vs. 9%, p = 0.01) compared with patients who did not relapse. On MVA (performed using variables selected from UVA; Table 2), obesity (sHR 2.98, 95% CI: 1.1–7.8, p = 0.03), WBC count > 50 × 109/L (sHR 3.64, 95% CI: 1.4–9.4, p < 0.01), and TP53 mutation with VAF ≥ 45% (sHR 5.34, 95% CI: 2.2–12.8, p < 0.001) were independently associated with increased relapse risk. In the relapsed cohort (n = 24), the median age at relapse was 57 years (range, 25–75). Among these, 9 patients (38%) had age ≥ 60 years. Eleven patients (46%) had a first CR/CRp duration (CR1D) of ≥ 1 year. Relapse sites were medullary in 10 patients (42%), both marrow and extramedullary in 7 (29%), and extramedullary only in 7 (29%). Extramedullary sites included lymph node/soft tissue in 8 patients (33%) and central nervous system (CNS) in 7 (29%). Loss of CD19 expression occurred in 4/22 patients (18%) with available testing at relapse among which one patient each had KMT2A rearrangement and TP53 mutation. All 24 relapsed patients received at least one line of salvage therapy, with 2nd CR/CRp attained in 13 patients (54%). Among these responders, 6 patients received consolidation with allo-SCT or chimeric antigen receptor T-cell (CAR T-cell) therapy, out of which four patients remain alive without relapse (relapse and death in remission occurred in 1 patient each). Among the 7 responders who did not receive allo-SCT or CAR T-cell consolidation in 2nd CR/CRp, only one patient is still alive without relapse (relapse occurred in 4 patients, death in remission in 2 patients). First salvage regimens are described in Table S2. After a median follow-up of 27.5 months (95% CI: 7.6—NR), median OS from the date of relapse was 7 months (95% CI: 2.9–24.6), with a 2-year OS rate of 30% (Figure 1A). Median OS was 5.2 months in patients with CR1D < 1 year and 17.6 months in those with CR1D ≥ 1 year (p = 0.06; Figure 1B). Median OS was 9.5 months and 2.9 months in patients aged < 60 years and aged ≥ 60 years, respectively (p = 0.09; Figure 1C). There was no difference in survival when stratified by the presence of extramedullary disease (6.1 months vs. 9.5 months, p = 0.43; Figure 1D). In this study, the incidence of relapse post frontline blinatumomab-based therapy was low, with a 2-year CIR of 11.4%. This is consistent with prior published data (3-year RFS 70%–80%) [2, 5] and demonstrates the durability of remissions obtained with blinatumomab-based therapy. Previous studies evaluating patterns of relapse following blinatumomab-based therapy have shown high rates of extramedullary relapses (50%–60%) with CNS as the most common site, particularly in the salvage setting [8-10]. This was noted in our frontline cohort as well, with extramedullary involvement noted in 58% of relapses (CNS involvement in 29%). Therefore, it is imperative to monitor patients on blinatumomab-based therapy for extramedullary disease, especially at the time of systemic relapse. Another point to highlight is the loss of CD19 expression, reported to occur in 10%–30% of cases, often secondary to acquired mutations in CD19 [10-13]. In our cohort, only 18% of the relapses were CD19 negative, indicating that this is an infrequent relapse mechanism to frontline blinatumomab-based therapy. On MVA, obesity, WBC > 50 × 109 /L, and TP53 mutation with VAF ≥ 45% were independently associated with increased risk of relapse. While obesity has been associated with higher relapse risk in children and adolescent/young adults with B-ALL treated with pediatric regimens [14], data in adults is limited. In our cohort, obesity was associated with a three-fold higher risk of relapse. These findings highlight the need to optimize the dosing of chemo-immunotherapy in this population to avoid possible undertreatment. Further studies are needed to evaluate the mechanisms associated with relapse in obese patients. A high baseline WBC count (> 50 × 109 /L) is an established risk factor for relapse with conventional chemotherapy in B-ALL [6]. Our findings indicate that this relapse risk persists despite the addition of frontline blinatumomab. Finally, while blinatumomab consolidation has improved outcomes of patients with TP53 mutation to a certain extent compared with standard chemotherapy, patients with TP53 mutated B-ALL continue to have worse RFS and OS [7, 15, 16]. A TP53 VAF threshold of ≥ 45% has been previously shown to correlate with increased relapse risk [7]. In our cohort, TP53 mutation with VAF ≥ 45% was the strongest risk factor, with a five-fold higher risk of relapse. These data suggest that blinatumomab may not sufficiently overcome the adverse disease biology associated with TP53 mutation. The risk factors identified in this study could help define a subset of patients with Ph-negative B-ALL at high risk for treatment failure with frontline blinatumomab-based therapy who may benefit from aggressive consolidation strategies. Although such high-risk patients are currently referred for allo-SCT in first remission, early incorporation of CAR T-cell therapy into the frontline setting may overcome their poor prognosis. Studies evaluating frontline CD19 CAR T-cell consolidation in high-risk B-ALL are ongoing [17, 18]. Outcomes of patients post frontline blinatumomab failure remain dismal, with a median OS of 7 months (2-year OS 30%). This data can serve as a benchmark for comparison in future studies evaluating newer therapies post blinatumomab failure. Survival outcomes were particularly poor among older patients (aged ≥ 60 years) and those with CR1D of < 1 year. A short CR1D may reflect aggressive disease biology and has been associated with inferior post-relapse outcomes in prior studies [19]. Of note, 75% of patients in our relapsed cohort had received frontline inotuzumab, which is a common component of salvage regimens in B-ALL [20]. This may partly explain the dismal outcomes observed even in the first salvage setting in our cohort, as patients with relapsed/refractory B-ALL following failure of both blinatumomab and inotuzumab have been reported to have very poor survival, with a median OS of 3.8 months in one study [19]. In summary, relapse following frontline blinatumomab therapy in Ph-negative B-ALL is relatively uncommon, with obesity, baseline WBC count > 50 × 109 /L and TP53 mutation with VAF ≥ 45% independently associated with relapse risk. Post relapse outcomes are dismal, highlighting the strong need for novel therapies. E.J. and H.K. conceptualized the study; N.J., N.S., F.R., G.B., A.B., F.H., J.S., H.K., and E.J. provided patients; R.G., R.K. and S.A. collected the data; K.S., Z.L., W.Q. and S.A. performed the statistical analysis; S.L. and G.T. provided cytogenetics data, S.A. and E.J. wrote the first manuscript draft; E.J., C.R., and S.A. revised the manuscript draft; All authors reviewed the final manuscript prior to submission. Biorender (biorender.com) was used to make Figure 1 and Figure S1. This research is supported in part by the MD Anderson Cancer Center Leukemia Specialized Programs of Research Excellence (SPORE) Grant CA1100632 and the University of Texas MD Anderson Cancer Center (CA016672). Prior Presentation: ASH 2025 oral abstract #759. This study was approved by the MD Anderson Cancer Center institutional review board. E.J.–Research and consultancy: Amgen, Adaptive biotechnology, Abbvie, Ascentage Pharma, Autolus, Astex pharmaceuticals, Bristol Myers Squibb, Pfizer, Novartis, Takeda, Terns pharmaceuticals, tgrx therapeutics, Kite, AstraZeneca. Other authors- No relevant conflicts of interest. Blinded clinical data can be procured from corresponding author on reasonable request. Figure S1: Study Consort Diagram. Figure S2: Cumulative incidence of relapse for the full cohort. Table S1: Frontline treatment regimens. Table S2: Post relapse salvage 1 treatment regimens. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.