Short-course blinatumomab as a bridge-to-transplantation improves the survival of Ph-negative MRD-positive B-ALL

Abstract

Post-transplant relapse remains the chief therapeutic challenge in Ph-negative B cell acute lymphoblastic leukemia (Ph^- B-ALL). This retrospective study evaluated whether short-course blinatumomab for measurable resident disease (MRD) eradication could improve transplant outcomes. We compared 23 patients receiving pre-transplant short-course blinatumomab (2-week) for MRD eradication with 46 chemotherapy-only controls. All achieved MRD-negative before allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Only two patients developed grade 2 cytokine release syndrome with blinatumomab. The neutrophil and platelet engraftment times were similar between the two groups. The blinatumomab cohort had a significantly lower 18-month cumulative incidence (CI) of relapse (p = 0.05) and chronic graft-versus-host disease (GVHD) (14.8% vs. 41.8%; p = 0.05), with comparable non-relapse mortality (NRM) (p = 0.98) and 180-day grade II-IV acute GVHD rates (p = 0.93). Consequently, this cohort showed superior 18-month relapse-free survival (RFS) (90.9% vs. 65.2%; HR 0.30, 95% CI 0.09-1.04; p = 0.04), improved 18-month overall survival (OS) (95.7% vs. 81.9%; HR 0.20, 95% CI 0.03-1.71), and a trend toward better GVHD-free and relapse-free survival (GRFS) (74.71% vs. 63.71%; HR 0.64, 95% CI 0.23-1.78). Multivariate analysis confirmed blinatumomab as an independent favorable factor for RFS. In conclusion, short-course blinatumomab as a bridge-to-transplantation could reduce the risk of relapse and improve survival for Ph^- B-ALL patients undergoing allo-PBSCT.

Graphical Abstract

Keywords

short-course blinatumomab B-cell acute lymphoblastic leukemia (B-ALL)philadelphia chromosome-negative (Ph-)allogeneic peripheral blood stem cell transplantation (allo-PBSCT)

Introduction

Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-negative B-ALL) is the most common type of adult ALL. Although nearly 90% of patients could achieve complete remission (CR) with chemotherapy, relapse rates remain high (40-50%), and the 5-year overall survival (OS) rate is only ranging from 30% to 50%.^1,2 Even in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) era, post-transplant relapse rates remain substantial (20-30%).^1,3

Pre-transplant measurable residual disease (MRD) status is one of the most important risk factors for post-transplant relapse. Clinical evidence has demonstrated that the patients with positive MRD prior to transplantation significantly increased the risk of relapse and reduced the survival after allo-HSCT.⁴ Achieving deeper MRD clearance at earlier treatment before allo-HSCT is associated with superior long-term survival and lower relapse rates.^5,6Blinatumomab—a bispecific antibody engaging CD3 on T cells and CD19 on leukemic B cells—induces cytotoxic T-cell effector activation by physically bridging these cell populations.⁷ Growing clinical data have indicated that blinatumomab-facilitated bridging to allo-HSCT expands transplant eligibility and enhances durable survival.^8–11 Furthermore, blinatumomab has also been shown to enhance overall survival even in MRD-negative B-ALL patients.¹² However, it is not clear whether short-course (2 weeks) blinatumomab as a bridge to allo-HSCT could reduce the relapse risk and improve survival for MRD-positive (MRD⁺) B-ALL patients.

Here, we present the single-center results of short-course blinatumomab for MRD⁺ B-ALL patients undergoing allogeneic peripheral blood stem cell transplantation (Allo-PBSCT). The results showed that the short-course blinatumomab could decrease the relapse risk and improve the relapse-free survival for MRD⁺ B-ALL patients.

Methods

Patients

Total 69 patients diagnosed with Ph-negative B-ALL undergoing allo-PBSCT in our center from November 2021 to June 2024 were enrolled into the retrospective single-center observational study. All patients received VDLP regimen for induction therapy. The dosage of anthracycline was adjusted based on patient’s age and ECOG. All patients who achieved CR after one cycle of induction then received two cycles of consolidation therapy, including at least one cycle of high-dose methotrexate. Among these patients, those who remained MRD-positive after consolidation were managed differently. Twenty-three patients MRD-positive prior to transplantation received a short course of blinatumomab to eradicate MRD (Blina group) and were hospitalized for the entire 14-day infusion period, with no toxicity-related admissions during or after the course. Concurrently, the other 46 patients, who were also MRD-positive after consolidation, continued conventional chemotherapy for one to two cycles with VDCP (vincristine, daunorubicin, cyclophosphamide, prednisone) and CAM (cyclophosphamide, cytosine arabinoside, 6-mercaptopurine) regimens in sequence, and achieved MRD-negative status before transplantation (Control group). The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Medical Ethics Committee of Shanghai General Hospital (Ethical approval number: 2025009). Written informed consent was obtained from all participants or their authorized guardians.

Treatment selection and financial considerations

During the study period (November 2021 – June 2024), blinatumomab was not covered by China’s National Reimbursement Drug List. The 14-day short-course blinatumomab regimen cost approximately $ 1595–2215 per patient with no insurance reimbursement, while conventional chemotherapy was covered by basic medical insurance (70-90% reimbursement), with estimated out-of-pocket costs of $ 295–1329 per patient. Financial constraints were the primary reason the 46 control group patients continued with conventional chemotherapy rather than receiving blinatumomab. Patients in the blinatumomab group had financial support enabling them to afford the drug.

MRD eradication with short-course blinatumomab

The short course was defined as 14-day blinatumomab treatment as compared with routine 28-day course.^13,14 Blinatumomab was administered with 24-h continuous intravenous infusion (9 μg/day on days 1-2 and 28 μg/day on days 3–14). Pretreatment with corticosteroids was mandatory to prevent neurological events and cytokine release syndrome (CRS). After one week of finishing the blinatumomab with MRD eradication, the transplantation course was initiated.

Transplantation procedures

Donors were from haploidentical, matched sibling and unrelated donors based on high-resolution HLA typing.¹⁵ Reduced intensity conditioning (RIC) was used for patients with age ≥55 years or hematopoietic stem cell transplantation-comorbidity index (HCT-CI) > 2, which was based on busulfan (3.2 mg/m²/d for 2 days) and fludarabine (30 mg/m²/d for 5 days),^16,17 while myeloablative conditioning (MAC) was prescribed to patients with age < 55 years or HCT-CI ≤2, which was based on busulfan (3.2 mg/m²/d for 4 days) or total body irradiation (TBI 10 Gy).¹⁸Graft-versus-host disease (GVHD) prophylaxis regimens included low-dose anti-thymocyte globulin (ATG)/post-transplant cyclophosphamide (PTCy)-based for haplo- and unrelated donor transplantation, and cyclosporine A-based for HLA matched sibling donor transplantation.^19–21 All patients received granulocyte-stimulating colony factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) as grafts.

Supportive care

G-CSF was given from day +5 until neutrophil recovery. Chimerism was assessed by short tandem repeat (STR) PCR analysis on bone marrow (BM) CD3⁺ T cells. Full donor chimerism was defined as ≥ 95% donor-derived T cells in BM samples.²² Quantitative PCR assays for cytomegalovirus (CMV)-DNA and Epstein-Barr Virus (EBV)-DNA levels in peripheral blood were monitored weekly or biweekly until day +100 or beyond. Viral reactivation was defined as two consecutive detections of viral DNA exceeding 1000 copies/mL.^23,24 Letermovir was prescribed to prevent CMV re-activation from day +1 to 3 months post-transplant. Acyclovir was administered from the time of engraftment until 1-year post-transplant. Additionally, posaconazole (300 mg orally daily) was started on the first day of conditioning regimen and continued for at least 3 months after transplantation.

Definitions

Remission was subclassified depending on peripheral blood count recovery into CR with full hematologic recovery (CR: Bone marrow blasts < 5%; absence of circulating blasts; absence of extramedullary disease; Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L; platelet count ≥ 100 × 10⁹/L)‌. MRD evaluation was performed with multiparameter flow-cytometry (MFC) and MRD negativity was defined as < 0.01% (<10⁻⁴) of leukemia-associated immunophenotype (LAIP) cells in bone marrow samples. Relapse was defined by the reappearance of over 5% blasts in the bone marrow or by the presence of extramedullary disease post‐CR, including central nervous system (CNS) involvement. Neutrophil engraftment was achieved when the absolute neutrophil count (ANC) reached ≥ 0.5 × 10⁹/L for 3 consecutive days post-transplantation without G-CSF support. Platelet engraftment was defined as the first of 7 consecutive days with platelet count > 20 × 10⁹/L in the absence of platelet transfusion. Acute GVHD (aGVHD) was diagnosed and graded according to the modified Glucksberg criteria.²⁵ Chronic GVHD (cGVHD) was assessed and classified as mild, moderate, or severe based on the 2014 National Institutes of Health (NIH) consensus criteria.²⁶

Statistical analysis

OS was defined as the time from the date of HSCT to death from any cause or the last follow-up. RFS was defined as the time interval from HSCT until the first occurrence of relapse or death from any cause. GVHD-free and relapse-free survival (GRFS) was calculated as a composite endpoint that without grade III-IV aGVHD, cGVHD requiring systemic immunosuppressive treatment, relapse, or death from any cause. To better evaluate the effect of post-transplant remission, the 18-month rates of OS, RFS, and GRFS were analyzed concurrently. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were measured from the date of transplant, with CIR defined by relapse and NRM by death from any cause other than relapse.²⁷ Cumulative incidence of aGVHD and cGVHD was calculated at 180 day and 18 months post-transplantation, respectively. Data are presented as descriptive values, including percentages, medians, and ranges, as appropriate. Nonparametric tests were performed for comparisons among groups (χ 2 and Fisher exact tests for categorical variables and Mann-Whitney and Kruskal-Wallis tests for continuous variables). OS, RFS, and GRFS, with 95% confidence intervals, were estimated using the Kaplan-Meier product limit estimator and compared using the log-rank test. The cumulative incidence method was applied to analyze aGVHD and cGVHD, NRM, and CIR. Multivariate analysis was performed using Cox proportional hazards models for variables with p value < 0.15 in univariate analysis. All Statistical analyses were conducted using R software (version 4.5.1). All tests were two-sided, with a P value <0.05 considered statistically significant.

Results

Patients characteristics

This study enrolled 69 patients with Ph-negative B-ALL who underwent allo-PBSCT. All patients achieved MRD negativity before transplantation. The median age of the entire cohort was 37 years (range, 15 – 65), while the median age in Blina group was higher than that in the control group (p = 0.07). A majority of patients in both groups received haploidentical PBSCT (haplo-PBSCT), specifically 70% and 67% in the Blina and control groups, respectively. Despite comparable molecular risk categories (Supplementary Table), lower number of patients in Blina group were observed in CR1 than in the control group (78% vs. 98%, p = 0.02). Baseline characteristics of all the patients are summarized in Table 1.

Table 1.

Clinical characteristics of patients.

Characteristics	Control (N = 46)	Blina (N = 23)	P
Age, median (range), years	31 (15, 65)	38, (16, 68)	0.07
≥35, n (%)	26 (57)	7 (30)
<35	20 (43)	16 (70)
Gender, n (%)			0.59
Male	23 (50)	13 (56)
Famle	23 (50)	10 (44)
WBC at initial diagnosis, median (range), ×10⁹/L			0.52
0-30, n (%)	37 (80)	20 (87)
>30	9 (20)	3 (13)
Immunophenotype, n (%)			0.71
Pro-B	2 (4)	2 (9)
Common B	41 (89)	19 (83)
Pre-B	3 (7)	2 (8)
Molecular/Cytogenetic Risk Stratification, n (%)			0.55
Standard-risk	30 (65)	13 (57)
High-risk	16 (35)	10 (43)
Median Cycle Number of chemotherapy, n (range)	3 (1, 14)	4 (1, 8)	0.32
Pre-allo-HSCT disease status (morphology), n (%)			0.02
CR1	45 (98)	18 (78)
CR2	1 (2)	5 (22)
Donor type, n (%)			0.14
Haploidentical	31 (67)	16 (69)
Matched sibling	11 (24)	2 (9)
Matched unrelated	4 (9)	5 (22)
ECOG performance status score of 0-1, n (%)	46 (100)	23 (100)	0.99
HCT-CI, n (%)			0.11
0-2	46 (100)	21 (91)
≥3	0 (0)	2 (8)
Pretransplant Conditioning Regimen, n (%)			0.59
MAC	44 (96)	21 (91)
RIC	2 (4)	2 (9)
Donor age, year, n (%)	40 (17, 59)	36 (11, 54)	0.22
<40	30 (65)	18 (78)
≥40	16 (35)	5 (22)
Donor/recipient gender, n (%)			0.89
Female to Male	8 (17) 4 (15)
Others	38 (83) 19 (85)
ABO blood type, n (%)			0.12
Matched	22 (47)	6 (26)
Unmatched	24 (53)	17 (74)
PBSC graft, median (range)
Mononuclear cells, ×10⁸/kg	16.52 (9.9, 39.47)	13.72 (8.03, 29.83)	0.53
CD3⁺ cells, ×10⁸/kg	2.96 (1, 6.13)	2.4 (1.67, 6.44)	0.29
CD34⁺ cells, ×10⁶/kg	9.47 (5.96, 23.62)	8.56 (1.31, 19.13)	0.33

Blina: Blinatumomab; CR: Complete response; ECOG: Eastern Cooperative Oncology Group; HCT-CI: Hematopoietic Cell Transplantation-Specific Comorbidity Index; MAC: Myeloablative Conditioning; PBSC: peripheral blood stem cells; RIC: Reduced Intensity Conditioning; WBC: White blood cell.

MRD response and treatment-related toxicity of short-course blinatumomab

All 23 patients achieved MRD negativity after short-course blinatumomab. The most common associated toxicities were pyrexia (occurring in 20 cases, 77%). Only two patients developed grade 2 cytokine release syndrome (CRS; fever with hypotension), which resolved rapidly following tocilizumab intervention. No grade 3 or more CRS, neurologic toxicity, pneumonia, or sepsis was observed.

Engraftment

All patients achieved full-donor chimerism by day 28 post-transplantation, with a median donor chimerism level of 98.59% (range, 96.25%–100%). The time to neutrophil engraftment and platelet engraftment did not differ significantly between the blinatumomab and control groups. The median time to neutrophil engraftment was 12 days (range, 10–20) and 13 days (range, 9–17) in the blinatumomab and control groups (p = 0.173), and to platelet engraftment was 13 days (range, 11 – 30) and 14 days (range, 10 – 28) (p = 0.321), respectively.

Graft-verus-host disease

The 180-day cumulative incidence (CI) of grade II-IV aGVHD in the entire cohort was 8.7% (95% CI, 3.5%-16.8%). Bridging therapy with short-course blinatumomab had no impact on the incidence of grade II-IV aGVHD (8.5% vs. 9.0%; p = 0.93) (Figure 1(a)). The 18-month CI of cGVHD in the overall cohort was 34.3% (95% CI, 20.5%-48.6%). However, the short-course blinatumomab significantly reduced the overall incidence of cGVHD (14.8% vs. 41.8%; p = 0.05) (Figure 1(b)). This benefit was specifically observed for mild cGVHD (8.3% vs. 38.7%; p = 0.04, Supplementary Fig. A). In contrast, no significant difference was observed in moderate-to-severe cGVHD (7.1% vs. 4.7%; p = 0.85, Supplementary Fig. B).

Figure 1.

Cumulative incidence of grade Ⅱ-Ⅳ acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD), non-relapse mortality (NRM), and cumulative incidence of relapse (CIR). (a) The cumulative incidence of grade Ⅱ-Ⅳ acute GVHD (aGVHD); (b) cGVHD; (c) NRM; (d) CIR.

Non-relapse mortality, relapse, and infection

The 18-month NRM for the entire cohort was 5.7 % (95% CI: 1.4%-14.6%), and the CIR was 20.3 % (95% CI: 13.8%-34.7%). No significant difference in NRM was observed between the two groups (5.0% vs. 6.0%; p= 0.98) (Figure 1(c)). In the blinatumomab group, one (4%, 1/23) patient experienced NRM due to multi-organ failure (MOF). In the control group, NRM occurred in 2 (4%, 2/46) patients, including one with MOF and one with infection (Table 2). Blinatumomab bridging significantly reduced the 18-month CIR (9.8% vs. 23.5%; p= 0.05) (Figure 1(d)). Interestingly, short-course blinatumomab regimen did not increase the incidence of CMV reactivation within one year (30% vs. 22% for CMV infection, p= 0.55; 4% vs. 4% for CMV disease, p= 1.00). Nevertheless, numerical increases in EBV infection (21% vs. 13%; p= 0.48) and EBV-related posttransplant lymphoproliferative disorder (PTLD) (8% vs. 4%; p= 0.59) were observed in the blinatumomab group, albeit without statistical significance (Table 2).

Table 2.

Causes of non-relapse mortality and viral infection.

Characteristics	Control (N = 46)	Blina (N = 23)	P
Cause of NRM
Infection	1 (2%)	0	1.00
MOF	1 (2%)	1 (4%)	1.00
Viaral infection
CMV viremia	10 (22%)	7 (30%)	0.55
CMV disease	2 (4%)	1 (4%)	1.00
EBV viremia	6 (13%)	5 (21%)	0.48
EBV-related PTLD	2 (4%)	2 (8%)	0.59

aGVHD: acute graft-versus-host disease, Blina: Blinatumomab, CMV: cytomegalovirus, MOF: multiple organ failure, NRM: non-relapse mortality, PTLD: post-transplant lymphoproliferative disorder.

Survival analysis

In the entire cohort, the median OS (Figure 2(a)) and RFS (Figure 2(b)) were not reached, while the median GRFS was 15 months (Figure 2(c)). Landmark analysis at 18 months revealed that although the difference was not statistically significant, the short-course blinatumomab cohort showed a trend toward improved OS (95.65% vs. 81.92%; HR = 0.21, 95% CI: 0.03-1.71; p= 0.15) (Figure 2(d)). A significant improvement in 18-month RFS rates was observed (90.87% vs. 65.19%; HR = 0.30, 95 % CI 0.09-1.04; p= 0.04) (Figure 2(e)). The 18-month GRFS rate was also numerical higher in the blinatumomab cohort (74.71% vs. 63.71%; HR 0.64, 95% CI 0.23-1.78; p = 0.38), but this difference did not reach statistical significance (Figure 2(f)).

Figure 2.

Survival outcomes. (a–c) For all patients. (a) Overall survival (OS); (b) Relapse-free survival (RFS); (c) GVHD-free, relapse-free survival (GRFS). (d)–(f) For patients in different groups. (d) OS; (e) RFS; (f) GRFS.

OS was adversely affected by high-risk molecular/cytogenetic status, which remained a significant independent poor prognostic factor in the multivariate analysis (Figure 3(a)). Concerning RFS, the high-risk status predicted worse outcomes, whereas pre-transplant short-course blinatumomab therapy was identified as a favorable prognostic factor in univariate analysis. Both factors retained independent significance in multivariate analysis (Figure 3(b)). Similarly, high-risk molecular/cytogenetic status was associated with a higher CIR and remained an independent prognostic factor in the multivariate model (Figure 3(c)). Upon evaluating prognostic interactions, standard-risk Ph-negative B-ALL patients exhibited particularly favorable outcomes, especially those who received short-course blinatumomab prior to HSCT.

Figure 3.

Univariate and multivariate analysis for Overall survival (OS), relapse-free survival (RFS) and cumulative incidence of relapse (CIR). (a) OS; (b) RFS, and (c) CIR.

Discussion

In the present study, the results showed that the short-course blinatumomab for MRD eradication could significantly reduce the CIR post-transplant and improve the survival, especially RFS for Ph^- B-ALL. The short-course blinatumomab didn’t have impact on acute GVHD, while significantly lowered the CI of total cGVHD. It also did not increase the infection risk and NRM. This approach thus represents a favorable clinical intervention to improve the efficacy of allo-HSCT for B-ALL patients.

The study rationale incorporated multiple elements. First, in relapsed/refractory ALL (R/R ALL), blinatumomab demonstrated greater efficacy during the first salvage attempt compared to subsequent ones.⁷ Additionally, MRD positivity was associated with a substantially elevated risk of relapse and death.^4,28,29 Most patients achieved MRD negativity after blinatumomab treatment and experienced improved survival relative to historical data.^12,30 Our findings demonstrated that short-course blinatumomab achieved a 100 % MRD clearance rate, positioning it as a highly effective bridging strategy for achieving this critical state. Moreover, despite achieving MRD negativity before allo-HSCT in the conventional chemotherapy group, the short-course blinatumomab cohort still demonstrated superior long-term survival. This may be attributable to blinatumomab inducing deeper molecular remission beyond conventional detection thresholds, which warrants further investigation using next-generation sequencing (NGS-MRD).

Building upon existing evidence, a full-course blinatumomab regimen bridging to HSCT for Ph-negative B-ALL demonstrated significant long-term survival benefits in a Phase III trial (NCT02013167),³¹ where 405 R/R B-ALL patients achieved 100 % 12-month OS. Real-world data from 106 patients further confirmed blinatumomab’s efficacy and safety profile, with 2-year PFS and OS rates of 48% and 58%, respectively.³² Considering the potent anti-leukemia effect of blinatumomab in B-ALL, integrating it into pre-transplant bridging therapy shows clinical promise.⁹ Despite its efficacy, blinatumomab’s short half-life necessitates 24-hour continuous infusion (typically 4-week cycles with 2-week intervals), and its prohibitive cost limits broad clinical adoption. This has prompted the exploration of abbreviated, or short-course, blinatumomab protocols. Using a 14-day course of blinatumomab could facilitate rapid bridging to transplantation, and shortening the duration may improve tolerability and reduce financial burden while preserving efficacy, as suggested by emerging literature.¹³ In line with this rationale, no severe adverse events were observed in the present study, which may be potentially attributable to the shortened treatment duration and prophylactic use of dexamethasone.

Previous studies on short-course blinatumomab before HSCT have shown variable outcomes. A retrospective single-center study reported that 82.62% 2-year OS and 78.35% 2-year PFS were achieved with the short-course blinatumomab bridging to HSCT among adult R/R B-ALL patients,¹³ while pediatric R/R cases (n = 33) showed enhanced tolerability but no short-term survival gains.³³ In the present study, we evaluated short-course blinatumomab in non-R/R B-ALL patients and observed compelling outcomes even in a group with a higher prevalence of adverse cytogenetic and molecular features. Following blinatumomab bridging, all achieved MRD negativity with significantly reduced relapse rates, with 18-month OS of 95.65% and 18-month RFS of 90.87% (p = 0.05), the latter demonstrating a statistically significant difference versus controls. A borderline significant trend towards superior OS (p = 0.15) may reflect limited sample size and follow-up duration, which may attain statistical significance with extended follow-up and larger patient cohorts. The superior outcomes (the longer RFS, lower relapse, lower incidence rate of cGVHD) were achieved despite the higher baseline risk profile of the blinatumomab group.

Multiple observations support the potential of abbreviated blinatumomab regimens. First, pharmacodynamically, blinatumomab achieves steady-state T-cell activation within days,⁹ and in patients with low tumor burden (MRD-positive but in morphologic CR), as shown by the 100% MRD negativity rate in our cohort. Second, published studies using abbreviated (14-day) blinatumomab have reported post-transplant outcomes comparable to historical 28-day data.^13,33 Third, our 18-month RFS of 90.9% is numerically similar to that reported in trials employing full-course blinatumomab. Nonetheless, we acknowledge that lack of a direct 28-day comparator is a major limitation, and prospective randomized trials are urgently needed to establish non-inferiority of the short-course regimen. Short-course blinatumomab demonstrated improved survival without increasing risk of infection versus standard extended regimens in Ph-negative ALL. Collectively, short-course blinatumomab represents a viable, well-tolerated, and cost-effective bridging strategy that significantly reduces relapse and improves survival outcomes in Ph-negative B-ALL patients.

In our study, short-course blinatumomab significantly reduced the incidence of cGVHD (p = 0.05). Substantial preclinical evidence indicates that blinatumomab ameliorates cGVHD through: (1) B-cell depletion-mediated reduction of BAFF levels; (2) inhibition of Th17/TFH cell differentiation; and (3) promotion of Treg expansion and functional enhancement—collectively suppressing autoantibody production and decreasing profibrotic cytokines IL-17.^34,35 Our findings provide clinical validation for these mechanisms. In contrast, aGVHD pathogenesis primarily involves CD8⁺ T cells and Th1 cells mediating tissue necrosis via massive inflammatory cytokine release.³⁶ These molecular mechanisms potentially underlie blinatumomab’s significant reduction in cGVHD incidence, for which our study provides empirical support. Further investigation into blinatumomab’s precise mechanisms in GVHD modulation remains warranted. Although our study did not include a full-course blinatumomab cohort, published data indicate that patients who received ≥ two cycles of blinatumomab had a trend towards increased cumulative incidence of cGVHD versus single-cycle recipients.⁹

Conclusion

This single-center retrospective observational study confirms the feasibility of short-course blinatumomab bridging to HSCT in patients with Ph-negative B-ALL, achieving not only MRD negativity but also demonstrating potential for long-term survival with reduced treatment-related toxicities. Although our study presented limitations, including the limited sample size, relatively short follow-up duration, and absence of a full-course blinatumomab comparator group, these results provide a foundation for future prospective investigations.

Supplemental material

Supplemental material -Short-course blinatumomab as a bridge-to-transplantation improves the survival of Ph-negative MRD-positive B-ALL

Supplemental material for Short-course blinatumomab as a bridge-to-transplantation improves the survival of Ph-negative MRD-positive B-ALL by Xia Shao, Miao Zhang, Huiying Qiu, Jun Yang, Xinxin Xia, Yu Cai, Yin Tong, Chongmei Huang, Baoxia Dong, Kun Zhou, Liping Wan, Yuhu Feng, and Xianmin Song in Cell Transplantation.

Footnotes

Acknowledgements

This study was conducted at the Department of Hematology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine. The authors sincerely thank all the staff and participants for their important contributions.

ORCID iDs

Liping Wan

Xianmin Song

Ethical considerations

This study was approved by the Ethics Committee of Shanghai General Hospital on January 23, 2025 (Ethical approval number: 2025009).

Consent to participate

Written informed consent was obtained from all participants or their authorized guardians.

Author contributions

This study was conceived and designed by Song X and Feng Y; Shao X and Zhang M was responsible for data acquisition, analysis, and interpretation, and drafted the manuscript; Qiu H, Yang J and Xia X acquired data and played an important role in interpreting the results; Cai Y, Tong Y, Huang C, Dong B, Zhou K and Wan L took care of patients in clinical practice. All authors read and approved the final manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (82270226 for Xianmin Song); the three-year development project from Shanghai Shen Kang Hospital Development Center (SHDC2020CR1012B for Xianmin Song).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.*

Supplemental material

Supplemental material for this article is available online.

References

Haddad

Kantarjian

Short

, et al. Incorporation of Immunotherapy Into Adult B-Cell Acute Lymphoblastic Leukemia Therapy. J Natl Compr Canc Netw 2025; 23(8): e257050. https://doi.org/10.6004/jnccn.2025.7050, e-pub ahead of print 2025/07/15.

Rowe

Buck

Burnett

, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; 106(12): 3760–3767. https://doi.org/10.1182/blood-2005-04-1623, e-pub ahead of print 2005/08/18.

Kurosawa

Fukuda

Ichinohe

, et al. Center effect on allogeneic hematopoietic stem cell transplantation outcomes for B-cell acute lymphoblastic leukemia. Cytotherapy 2024; 26(10): 1185–1192. https://doi.org/10.1016/j.jcyt.2024.05.004, e-pub ahead of print 2024/05/28.

Bruggemann

Schrauder

Raff

, et al. Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. Leukemia 2010; 24(3): 521–535. https://doi.org/10.1038/leu.2009.268, e-pub ahead of print 2009/12/25.

Short

Kantarjian

Ravandi

, et al. High-sensitivity next-generation sequencing MRD assessment in ALL identifies patients at very low risk of relapse. Blood Adv 2022; 6(13): 4006–4014. https://doi.org/10.1182/bloodadvances.2022007378, e-pub ahead of print 2022/05/10.

Yilmaz

Kantarjian

Wang

, et al. The early achievement of measurable residual disease negativity in the treatment of adults with Philadelphia-negative B-cell acute lymphoblastic leukemia is a strong predictor for survival. Am J Hematol 2020; 95(2): 144–150. https://doi.org/10.1002/ajh.25671, e-pub ahead of print 2019/11/05.

Kantarjian

Stein

Gokbuget

, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med 2017; 376(9): 836–847. https://doi.org/10.1056/NEJMoa1609783, e-pub ahead of print 2017/03/02.

Gokbuget

Dombret

Bonifacio

, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood 2018; 131(14): 1522–1531. https://doi.org/10.1182/blood-2017-08-798322, e-pub ahead of print 2018/01/24.

Algeri

Massa

Pagliara

, et al. Outcomes of children and young adults with B-cell acute lymphoblastic leukemia given blinatumomab as last consolidation treatment before allogeneic hematopoietic stem cell transplantation. Haematologica 2025; 110(3): 596–607. https://doi.org/10.3324/haematol.2024.286350, e-pub ahead of print 2024/10/31.

10.

Hogan

Brown

, et al. Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. J Clin Oncol 2023; 41(25): 4118–4129. https://doi.org/10.1200/JCO.22.02200, e-pub ahead of print 2023/05/31.

11.

Topp

Gokbuget

Stein

, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 2015; 16(1): 57–66. https://doi.org/10.1016/S1470-2045(14)71170-2, e-pub ahead of print 2014/12/20.

12.

Litzow

Sun

Mattison

, et al. Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults. N Engl J Med 2024; 391(4): 320–333. https://doi.org/10.1056/NEJMoa2312948, e-pub ahead of print 2024/07/26.

13.

Yin

Cai

Qian

, et al. Short-Course Blinatumomab Treatment as a Bridge to Further Salvage Therapy for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia: A Retrospective Single-Center Study. Cancer Med 2024; 13(24): e70515. https://doi.org/10.1002/cam4.70515, e-pub ahead of print 2024/12/18.

14.

Zhao

, et al. Blinatumomab added to conditioning regimen of allogeneic hematopoietic stem cell transplantation for adult MRD-positive acute lymphoblastic leukemia: a single-center case series. Hematology 2025; 30(1): 2439605. https://doi.org/10.1080/16078454.2024.2439605, e-pub ahead of print 2025/01/09.

15.

Shike

Zhang

. HLA and Non-HLA Factors for Donor Selection in Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide GvHD Prophylaxis. Cells 2024; 13(24): 2067. https://doi.org/10.3390/cells13242067, e-pub ahead of print 2025/01/08.

16.

Lee

Jung

, et al. Reduced-Intensity Conditioning with Busulfan and Fludarabine for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Lymphoblastic Leukemia. Yonsei Med J 2020; 61(6): 452–459. https://doi.org/10.3349/ymj.2020.61.6.452, e-pub ahead of print 2020/05/30.

17.

Jia

Xia

Yang

, et al. Improved survival in older patients with myeloid malignancies undergoing haploidentical peripheral blood stem cell transplantation with low-dose anti-thymocyte globin (ATG)/post-cyclophosphamide (PTCy)-based regimen for graft-versus-host disease prophylaxis. Ann Hematol 2025; 104(3): 1857–1866. https://doi.org/10.1007/s00277-025-06305-1, e-pub ahead of print 2025/03/17.

18.

Gao

Qiu

, et al. Age- and comorbidity-adjusted busulfan, fludarabine, cytarabine, and low-dose TBI-based conditioning regimen is effective for myelodysplastic syndromes with excess blasts undergoing allogeneic peripheral blood stem cell transplantation. Cell Transplant 2025; 34: 9636897251380928. https://doi.org/10.1177/09636897251380928, e-pub ahead of print 2025/10/18.

19.

Desai

Altareb

Remberger

, et al. PTCy-based graft-versus-host disease prophylaxis for matched sibling donor allogeneic hematopoietic cell transplantation. Blood Adv 2025; 9(3): 660–669. https://doi.org/10.1182/bloodadvances.2024014781, e-pub ahead of print 2024/11/20.

20.

Sun

Yang

Cai

, et al. Low-dose antithymocyte globulin plus low-dose posttransplant cyclophosphamide combined with cyclosporine and mycophenolate mofetil for prevention of graft-versus-host disease after HLA-matched unrelated donor peripheral blood stem cell transplantation. Bone Marrow Transplant 2021; 56(10): 2423–2431. https://doi.org/10.1038/s41409-021-01358-y, e-pub ahead of print 2021/05/27.

21.

Zhou

Cai

Yang

, et al. Lower Absolute Lymphocyte Count Before Conditioning Predicts High Relapse Risk in Patients After Haploidentical Peripheral Blood Stem Cell Transplantation With Low Dose Anti-Thymocyte Globulin/Post-Transplant Cyclophosphamide for GvHD Prophylaxis. Cell Transplant 2022; 31: 9636897221079739. https://doi.org/10.1177/09636897221079739, e-pub ahead of print 2022/03/01.

22.

Clark

Scott

Jack

, et al. Monitoring of chimerism following allogeneic haematopoietic stem cell transplantation (HSCT): technical recommendations for the use of short tandem repeat (STR) based techniques, on behalf of the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping Chimerism Working Group. Br J Haematol 2015; 168(1): 26–37. https://doi.org/10.1111/bjh.13073, e-pub ahead of print 2014/08/26.

23.

Ljungman

Griffiths

Paya

. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002; 34(8): 1094–1097. https://doi.org/10.1086/339329, e-pub ahead of print 2002/03/27.

24.

Ratiu

Dufresne

Thiant

, et al. Epstein-Barr Virus Monitoring after an Allogeneic Hematopoietic Stem Cell Transplant: Review of the Recent Data and Current Practices in Canada. Curr Oncol 2024; 31(5): 2780–2795. https://doi.org/10.3390/curroncol31050211, e-pub ahead of print 2024/05/24.

25.

Przepiorka

Weisdorf

Martin

, et al. Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15(6): 825–828, e-pub ahead of print 1995/06/01.

26.

Jagasia

Greinix

Arora

, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015; 21(3): 389–401. https://doi.org/10.1016/j.bbmt.2014.12.001, e381. e-pub ahead of print 2014/12/23.

27.

Pasquini

Logan

Jones

, et al. Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials. Biol Blood Marrow Transplant 2018; 24(6): 1274–1280. https://doi.org/10.1016/j.bbmt.2018.01.002, e-pub ahead of print 2018/01/13.

28.

Bar

Wood

Radich

, et al. Impact of minimal residual disease, detected by flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia. Leuk Res Treatment 2014; 2014: 421723. https://doi.org/10.1155/2014/421723, e-pub ahead of print 2014/04/30.

29.

van der Linde

Gatt

Smith

, et al. Measurable Residual Disease (MRD) by Flow Cytometry in Adult B-Acute Lymphoblastic Leukaemia (B-ALL) and Acute Myeloid Leukaemia (AML): Correlation with Molecular MRD Testing and Clinical Outcome at One Year. Cancers (Basel) 2023; 15(20): 5064. https://doi.org/10.3390/cancers15205064, e-pub ahead of print 2023/10/28.

30.

Bassan

Chiaretti

Della Starza

, et al. Up-front blinatumomab improves MRD clearance and outcome in adult Ph-B-lineage ALL: the GIMEMA LAL2317 phase 2 study. Blood 2025; 145(21): 2447–2459. https://doi.org/10.1182/blood.2024027500, e-pub ahead of print 2025/02/26.

31.

Jabbour

Gokbuget

Kantarjian

, et al. Transplantation in adults with relapsed/refractory acute lymphoblastic leukemia who are treated with blinatumomab from a phase 3 study. Cancer 2019; 125(23): 4181–4192. https://doi.org/10.1002/cncr.32335, e-pub ahead of print 2019/08/23.

32.

Badar

Szabo

Litzow

, et al. Multi-institutional study evaluating clinical outcome with allogeneic hematopoietic stem cell transplantation after blinatumomab in patients with B-cell acute lymphoblastic leukemia: real-world data. Bone Marrow Transplant 2021; 56(8): 1998–2004. https://doi.org/10.1038/s41409-021-01279-w, e-pub ahead of print 2021/04/08.

33.

Xie

Liu

Zhou

, et al. Short-course blinatumomab for refractory/relapse precursor B acute lymphoblastic leukemia in children. Front Pediatr 2023; 11: 1187607. https://doi.org/10.3389/fped.2023.1187607, e-pub ahead of print 2023/08/21.

34.

McManigle

Youssef

Sarantopoulos

. B cells in chronic graft-versus-host disease. Hum Immunol 2019; 80(6): 393–399. https://doi.org/10.1016/j.humimm.2019.03.003, e-pub ahead of print 2019/03/09.

35.

Vincent

Saulep-Easton

Figgett

, et al. The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev 2013; 24(3): 203–215. https://doi.org/10.1016/j.cytogfr.2013.04.003, e-pub ahead of print 2013/05/21.

36.

Jamy

Zeiser

Chen

. Novel developments in the prophylaxis and treatment of acute GVHD. Blood 2023; 142(12): 1037–1046. https://doi.org/10.1182/blood.2023020073, e-pub ahead of print 2023/07/20.

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