TO THE EDITOR:

Acute lymphoblastic leukemia (ALL) is a malignant clonal disease of bone marrow lymphoid stem progenitor cells. Traditional chemotherapy era, ALL patients have a much poorer prognosis. With the recent advent of targeted therapy and immunotherapy, the rates of morphologic complete remission (CR) of B-cell ALL (B-ALL) patients have reached 90% and the prognosis in adults has also markedly improved. However, persistent leukemia cells can be detected by reverse transcriptase-polymerase chain reaction (RT-PCR) or multiparameter flow cytometry (MFC) in approximately 30% to 50% of patients who achieve morphologic CR, which are referred to as minimal residual disease (MRD) [1]. MRD negativity at time of transplantation is associated with a significant benefit in terms of risk of relapse [2]. Summing up, it is important to reduce the tumor load and achieve MRD negativity before allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Blinatumomab (BITE), a CD19-CD3 bispecific T-cell engager, exerts antitumor effects by inducing cytotoxic T lymphocytes to lyse CD19-expressing lymphocytes, which is effective in treating resistant B-cell ALL and achieving MRD negativity of 78%-80% [3, 4]. It is less clear whether the administration of BITE prior to transplantation cloud result in deeper remission in MRD negative patients and then improve prognosis. Herein, we first summarized the safety and efficacy of B-ALL in first CR (CR1) with MRD negativity who were treated with BITE as bridge therapy to allo-HSCT.

In this retrospective study, 34 B-ALL patients who received a short term of BITE bridging transplantation (9 μg/day D1-3 and 28 μg/day D4-14) were defined as the BITE group, while others who did not receive BITE bridging therapy were classified as the non-BITE group (n = 68) from August 2021 to December 2023. All patients received modified busulfan/cyclophosphamide (BU/CY) as myeloablative conditioning regimen. The details for conditioning regimen, graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) prophylaxis, relative definitions and statistical methods could be found in the supplementary materials.

Table 1 showed that clinical characteristics were similar between BITE and non-BITE group (P > 0.05). Within 180 days post-HSCT, the BITE group had a notable lower incidence of hemorrhagic cystitis (14.7% versus 35.3%, P = 0.030), while other transplant-related complications were also similar between these two groups in different time-points post-transplantation (Table S1). No Epstein-Barr virus (EBV) associated post-transplantation lymphoproliferative disorder (PTLD) and sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were observed in this study.

Table 1 Patient demographic and clinical characteristics.
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The rates of acute GVHD (aGVHD) at day 100 were similar between the BITE and non-BITE group: grades II-IV, 20.6% versus 36.8% (P = 0.102, Fig. 1A), and grades III-IV, 5.9% versus 10.6% (P = 0.445, Fig. 1B). A notable lower of 2-year cumulative incidence of chronic GVHD (cGVHD) was presented in the BITE group (26.9% versus 52.4%, P = 0.007, Fig. 1C). Moreover, the moderate-severe cGVHD was also significantly lowered in BITE group (6.3% versus 27.4%, P = 0.021, Fig. 1D). Non-BITE bridging HSCT, Karnofsky score (KPS) score < 90 and hematopoietic cell transplant comorbidity index (HCT-CI) score ≥ 3 had adverse impacts on the cGVHD (P < 0.05, Table S3).

Fig. 1: Transplant outcomes according to use of pretransplant blinatumomab.
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A II-IV aGVHD, (B) III-IV aGVHD, (C) cGVHD, (D) Moderate-severe cGVHD, (E) Overall survival (OS), (F) graft-versus-host disease- and relapse-free survival (GRFS), (G) Cumulative incidence of relapse (CIR), (H) Non-relapse mortality (NRM).

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At a median follow-up of 17.5 months, the 2-year OS in the whole cohort was 64.9%, and 25 cases died due to different causes (Table S4). The BITE group had better 2-year OS (89.1% versus 58.2%, P = 0.043, Fig. 1E) and 2-year GVHD-free and relapse-free survival (GRFS) (75.7% versus 43.4%, P = 0.003, Fig. 1F) compared to the control. Multivariable analysis indicated that BITE bridging HSCT had favorable impacts on OS and GRFS (P < 0.05, Table S3). Additionally, patients with a time from diagnosis to HSCT ≥ 6 months and grades III-IV aGVHD had a worse OS (P < 0.05, Table S3).

As of March 1, 2024, 16 patients relapsed with a median of 6.6 months (range, 1.8–17.0) post-transplantation, while a total of 16 cases died but without disease recurrence. The BITE group had a lower 2-year relapse rate than non-BITE group (9.9% versus 25.3%, P = 0.029, Fig. 1G). BITE bridging therapy and Philadelphia chromosome-positive (Ph+) ALL were further confirmed as protective factors of relapse (P < 0.05, Table S3). Besides, the 2-year non-relapse mortality (NRM) in BITE group was similar with non-BITE group (10.9% versus 24.5%, P = 0.343, Fig. 1H). Grades III-IV aGVHD and moderate-severe cGVHD had adverse impacts on NRM in multivariable model (P < 0.05, Table S3).

All patients received BITE bridging therapy had different grades of adverse events (AEs) (Table S5). Overall, 50% and 29.4% of patients had grade 3 and 4 AEs, respectively. The most common hematologic AE was lymphocytopenia, while the most common non-hematologic AEs were CRS (26.5%, 9/34) and prolonged activated partial thromboplastin time (APTT) (26.5%, 9/34). CRS occurred in 9 patients, of which 8 (23.5%) had grade 1 CRS with fever, and 1 (2.9%) had grade 2 CRS with fever and transient blood pressure drop. One patient (2.9%, 1/34) had grade 1 nervous system symptoms of headache. No grade 3 and 4 non-hematologic and fatal AEs were observed in any patients.

Despite improvements in survival for adult newly-diagnosed ALL, approximately 30% of patients relapse [5]. About 30% to 50% of ALL patients with CR still have positive MRD, which is associated with the high recurrence rate [1, 6]. Many studies have shown that blinatumomab is effective in eliminating MRD and improving the prognosis in B-ALL [3, 4]. Additionally, recent study indicates that patients with MRD-negative B-ALL can also benefit from BITE immunotherapy, even in the absence of a subsequent transplant [7].

In this study, we first evaluated the impact of a short-course blinatumomab bridging transplantation on the outcomes after transplantation in MRD-negative B-ALL patients. Various early and late complications post-transplantation were similar and acceptable between BITE group and non-BITE group, such as pulmonary infection, bloodstream infection, and etc, which is consistent with the previous report [8]. In the previous report [9], blinatumomab group experienced a lower incidence of grades III-IV aGVHD due to more cases in the blinatumomab group received T cell depletion or post-transplant cyclophosphamide. Different from which, our baseline characteristics were balanced, and the incidence of grades III-IV aGVHD was similar in BITE and non-BITE group.

Interestingly, our results suggested a lower rate of cGVHD in BITE group. Multiple antibodies produced by activated B cells are detected elevated in patients with cGVHD, and the efficacy of anti-B-cell therapy using the monoclonal anti-CD20 antibody for cGVHD has also been previously reported [10]. The depletion of the B cells by blinatumomab may contribute to the lower incidence of cGVHD in our blinatumomab-treated patients. Further kinetics of immune reconstitution post-transplantation, including B/T cell subsets, may help to explain this phenomenon. The lack of these data is also a major limitation of our results.

Besides, OS and GRFS at 2-year in our cohort were higher than the previous report [9], which may due to the enrolled patients were all CR1 and MRD negative pre-transplantation. All Ph+ B-ALL patients in our cohort were treated with tyrosine kinase inhibitors (TKIs) after allo-HSCT, which may contribute to lower recurrence, as in previous study [11]. The lower incidence of relapse and cGVHD may contribute to the superior OS and GRFS of B-ALL patients in the BITE group. In our results, relapse rate in the BITE group was 9.9%, which was notably lowered to the previous report of 17.6% among standard-risk, CR1 and MRD-negative allo-HSCT patients and 18.9% among high-risk, CR1 and MRD-negative allo-HSCT patients [12].

Although MRD monitor using by MFC has also been shown to discriminate patients with different risks of relapse [13], which is sensitive to 10−4. However, in a cohort of 455 B-ALL patients with negative MRD (MRD < 10−4), the 5-year relapse rate of patients with MRD < 10−5 or without MRD detection was notably lower than that of patients with MRD from 10−5 to 10−4 (P < 0.047) [14]. Moreover, nearly 68% of children ALL patients who were MRD-negative by MFC (sensitivity of <10−4) achieved further MRD clearance (sensitivity of < 10−6) by Next-generation Sequencing (NGS) after blinatumomab consolidation therapy, achieving deeper disease remission [15], which meant that patients who benefited from blinatumomab had MRD values between 10−4 and 10−6. Hence, NGS-MRD, which is sensitive to 10−6, may be more suitable for assessing those treated by blinatumomab. In our results, MFC was used to monitor MRD of Ph- ALL, while MFC combined with RT-PCR (10−5 to 10−4) was performed for Ph+ ALL, these resulted in less sensitivity and those limitations could prevent us from classifying who really benefitted from a short course of blinatumomab prior to allo-HSCT.

Furthermore, BITE bridging therapy presented a high safety profile and did not increase NRM, and only 29.4% of patients had grade 4 hematologic AEs but none of patients experienced grade 3/4 non-hematologic AEs, which were less frequent than previous studies [3, 4]. Better pretransplant disease status (CR1 and MRD negativity) and a short course of blinatumomab may contribute to these lower AEs in our study.

In conclusion, well-designed prospective multicenter trials are needed to confirm the superiority of this approach. Higher precision MRD monitor (NGS-MRD) might be more suitable for assessing patients following blinatumomab treatment, and evolution of immune sub-populations will help to further understand the effects of blinatumomab treatment on post-transplantation. However, our research still highlighted the feasibility and safety of blinatumomab bridging to transplantation in B-ALL and demonstrated its beneficial effect on reducing relapse and improving prognosis. Thus, a short course of blinatumomab bridging to transplantation may be a good potential option for CR1 and MRD negative B-ALL patients.