Allogeneic hematopoietic stem cell transplantation (allo-HSCT) stays a healing remedy for sufferers with high-risk B-cell acute lymphoblastic leukemia/lymphoma (B-ALL/LBL) [1]. Nevertheless, in response to the EBMT database, the relapse fee of allo-HSCT recipients throughout their first full remission (CR) can attain 22% [2], and submit allo-HSCT relapse is related to a disappointing remission fee and dismal outcomes [3, 4]. Due to this fact, it’s essential to implement methods to mitigate the danger of relapse after allo-HSCT. Tyrosine kinase inhibitors are extensively used as efficient upkeep therapies for Philadelphia (Ph)-positive B-ALL [1, 5]. Nevertheless, there are few studies on appropriate upkeep therapies for Ph-negative B-ALL following allo-HSCT. A single-center retrospective research advised these with Ph-negative B-ALL might profit from decitabine upkeep following allo-HSCT, as decitabine greater than halved the 3-year relapse fee (19.5% vs. 42.2%, P = 0.068) [6]. Prophylactic donor-derived CD19 CAR-T cell infusion after allo-HSCT was reported to considerably decrease the 2-year cumulative incidence of relapse in high-risk B-ALL to five.6% [7]. Not too long ago, a section 1 scientific trial was carried out to analyze the protection and efficacy of low-dose inotuzumab ozogamicin (INO) as a posttransplant upkeep [8]. INO demonstrated a positive security profile and 1-year progression-free survival (PFS) of 89%.
Blinatumomab is a bispecific T-cell engager (BITE) molecule that directs CD3+ T cells to have interaction and lyse goal CD19+ cells [9]. The drug was initially authorised for relapsed/refractory (R/R) Ph-negative B-cell precursor (BCP)-ALL based mostly on section 3 of the TOWER research, and was demonstrated to lead to the next total response fee and longer median total survival (OS) in comparison with commonplace care. Blinatumomab was additional authorised for sufferers with BCP-ALL with persistent or reappearing measurable residual illness (MRD) following section 2 of the BLAST research [10, 11], and several other publications have reported the efficacy of blinatumomab as a salvage remedy for B-ALL sufferers after allo-HSCT [12]. Nevertheless, there are few studies describing the efficacy and security of blinatumomab as a upkeep technique following allo-HSCT. Moreover, the potential impression of blinatumomab on transplantation-related problems, reminiscent of acute graft-versus-host illness (aGvHD), has not been completely documented. On this real-world research, we aimed to explain the feasibility and scientific advantages of blinatumomab upkeep in high-risk B-ALL/LBL sufferers after allo-HSCT.
This retrospective, multicenter research was designed based mostly on the transplant databases of Shanghai Ruijin Hospital, Wuhan Tongji Hospital, the First Affiliated Hospital of Soochow College, Shanghai Renji Hospital, Shanghai Zhaxin Hospital, and the First Affiliated Hospital of Zhengzhou College. B-ALL/LBL sufferers transplanted between January 2022 and October 2023 have been screened utilizing the next eligibility standards: those that (1) had a excessive danger of relapse following allo-HSCT; (2) achieved CR with undetectable MRD post-HSCT, as assessed by movement cytometry with a sensitivity of 0.01% throughout the first three months, and acquired at the least one cycle (at the least consecutive 7 days) of blinatumomab upkeep; (3) had B-ALL/LBL with CD19 expression; (4) had full medical info. The final follow-up was on March 10, 2024. All procedures used on this research have been in accordance with Declaration of Helsinki and have been authorised by the institutional evaluate board [Ethical approval number: TJ-IRB202402092]. Written knowledgeable consent was waived as a result of retrospective nature of the research.
The protocols used for the preconditioning routine, GvHD prophylaxis, an infection prophylaxis, and MRD methodology and detection frequency are described within the Supplementary Strategies. Knowledge assortment ended on the time of dying or final follow-up. The first endpoint was relapse fee. Secondary endpoints included OS, event-free survival (EFS), GvHD-free and relapse-free survival (GRFS), non-relapse mortality (NRM), and antagonistic occasions (AEs). All endpoints have been measured from the date of transplantation. Remedy interruption was outlined as a interval exceeding 8 days with out the therapy being administered. Statistical analyses have been carried out utilizing R 4.2.0 software program. Steady and categorical variables have been introduced as medians and vary variables, and counts and percentages, respectively. The Kaplan–Meier technique was used to estimate survival chances, whereas the High-quality–Grey mannequin was used to calculate the cumulative incidences of relapse fee and NRM. The 95% confidential intervals have been calculated, and a p-worth of < 0.05 was thought-about statistically vital.
Twenty-one B-ALL sufferers who acquired at the least one cycle of blinatumomab remedy after allo-HSCT have been included on this research. Of the 21 sufferers, one affected person was recognized with Ph-positive B-ALL (P16), and the opposite 20 sufferers had Ph-negative B-ALL/LBL (Desk 1). Supplementary Desk 1 summarizes the baseline traits of the research cohort. 9 sufferers (42.9%) have been recognized as having refractory/relapsed B-ALL/LBL. Throughout the B-ALL group, one affected person had extramedullary involvement at prognosis (P14, central nervous system) that resolved earlier than transplantation, and one affected person had extramedullary relapse throughout therapy and didn’t go into remission previous to transplantation (P17, central nervous system and testicles). Affected person therapy histories earlier than allo-HSCT are detailed in Supplementary Desk 2.
The median time from transplantation to the beginning of blinatumomab remedy was 102 (vary: 42–227) days. Sufferers accomplished a median of two (vary: 1–6) programs (1 cycle: n = 10, 2 cycles: n = 6, 3 cycles: n = 2, ≥ 4 cycles: n = 3). The median interval between cycles of blinatumomab was 82 (vary: 31–202) days. A complete of 42 programs of blinatumomab have been administered, with one therapy course interrupted on account of COVID-19 an infection. Causes for discontinuation of therapy are described in Supplementary Desk 3. Particulars relating to blinatumomab therapy are proven in Supplementary Desk 4. One Ph-positive B-ALL affected person acquired olverembatinib plus with blinatumomab as upkeep remedy. The therapy schedule for every affected person is illustrated in Supplementary Fig. 1.
Essentially the most regularly AEs noticed have been cytopenias (Supplementary Desk 5). Infections, together with bloodstream and respiratory infections, have been noticed in 8 sufferers (38.1%). One affected person (P5) skilled Epstein–Barr virus reactivation 10 days after finishing the earlier cycle of blinatumomab. Grade I cytokine launch syndrome (CRS) occurred in three sufferers however was resolved with symptomatic therapy. No neurologic toxicities have been reported.
Previous to upkeep remedy, 11 sufferers had discontinued their programs of immunosuppressants, whereas the remaining 10 sufferers have been taking calcineurin inhibitors in the course of the first upkeep cycle. The cumulative incidences of grades I-II and III-IV aGvHD have been 28.6% (n = 6) and 4.8% (n = 1), respectively, and circumstances occurred at a median of 31 (vary:13–52) days after the initiation of blinatumomab. 5 sufferers have been recognized with cGvHD (delicate/average cGvHD: n = 4; extreme cGvHD: n = 1, Supplementary Desk 6) at a median of 78 (35–143) days after the initiation of blinatumomab upkeep. Following anti-GvHD therapies, the whole response fee was 100% in sufferers with aGvHD and 80% in sufferers with cGvHD.
There was a median follow-up time of 325 (vary: 156–775) days for all sufferers, and 18 sufferers (85.7%) have been alive on the finish of the research. Causes of dying included relapsed/progressive illness (n = 1) and NRM (transplant-associated thrombotic microangiopathy: n = 1; an infection: n = 1). The relapse fee was 6.3%, representing a refractory/relapsed B-ALL affected person (P13) who was in second CR with detectable MRD at allo-HSCT. No NRM occasions have been attributable to blinatumomab. The scientific outcomes of all sufferers are displayed in Supplementary Desk 7. The 1-year OS, EFS, and GRFS for your entire cohort have been 81.6% (95% CI 64.7–100%), 82.1% (95% CI 65.6–100%) and 82.5% (95% CI 66.2–100%), respectively (Fig. 1). Of the 15 sufferers of their first CR with undetectable MRD at allo-HSCT, one died from NRM (an infection), and no relapses have been reported. The 1-year OS, EFS, and GRFS for these sufferers have been 92.9% (95% CI 80.3–100%), 92.9% (95% CI 80.3–100%), and 93.3% (95% CI 81.5–100%), respectively. For non-refractory/relapsed B-LBL/ALL sufferers, the one-year OS and EFS have been 100% and 100%, respectively.
Stein et al. [12] reported that blinatumomab produced a forty five% CR fee for B-ALL sufferers who relapsed following allo-HSCT. Nevertheless, regardless of this salvage therapy, roughly 80% of sufferers skilled relapse inside one yr, resulting in a poor long-term OS fee of 36% at 1 yr and 18% at 3 years. The usage of prophylactic blinatumomab for high-risk sufferers who’ve achieved hematological CR after allo-HSCT is predicted to boost the anti-leukemic impact of engrafted donor-derived CD3-positive T cells. In a section 2b trial, the MD Anderson group investigated the efficacy and security of blinatumomab following allo-HSCT in 21 sufferers. They reported that the 81% of sufferers (n = 17) who acquired grafts from HLA-matched donors had 1-year OS and PFS charges of 85% and 71%, respectively [13]. In our research, all sufferers achieved CR with undetectable MRD earlier than the initiation of blinatumomab therapy; moreover, 81% of the sufferers (n = 17) acquired grafts from haploidentical donors, distinguishing our research from the expertise of the MD Anderson group. A section Ib/II trial that enrolled high-risk CD19-positive B-ALL and non-Hodgkin lymphoma sufferers who had attained MRD-negative CR after allo-HSCT recorded a 3-year RFS of 73% [14]. Within the Campus ALL research, blinatumomab led to a transient redistribution of effector T-cell subsets and Treg cells, together with a persistent improve in cytotoxic NK cells within the peripheral blood [15].
A decrease leukemia burden is a optimistic indicator for efficient immunotherapy. All alive sufferers of their first CR with undetectable MRD on the time of allo-HSCT achieved sustained MRD remission after receiving blinatumomab upkeep (P3 died of NRM). 9 sufferers have been in refractory/relapsed B-ALL/LBL earlier than allo-HSCT, and 6 sufferers achieved sustained MRD remission after allo-HSCT and blinatumomab upkeep (P13 died of relapse, and P3 and P15 died of NRM).
Considerations relating to the potential dangers of blinatumomab-associated immune-mediated toxicities following allo-HSCT haven’t been adequately addressed within the literature. These embody the exacerbation of GvHD, delayed engraftment, and graft failure or rejection. Within the current research, no improve in NRM incidences was noticed inside our cohort. CRS and encephalopathy syndrome have been recognized as AEs of curiosity, and the incidences of grade I CRS and grade III-IV aGvHD have been 14.3% and 4.8%, respectively. Blinatumomab was effectively tolerated by sufferers, and there was a low incidence of myelosuppression. Notably, three sufferers in our cohort have been aged ≤ 18 years, and no further AEs have been noticed in these sufferers.
The findings of the current research recommend that blinatumomab upkeep remedy following allo-HSCT is possible, efficacious, and secure. You will need to observe that our research had sure limitations, together with its retrospective design, small cohort measurement, and comparatively brief follow-up interval. Due to this fact, additional potential, randomized research are wanted to determine sufferers who would profit most from blinatumomab upkeep remedy after allo-HSCT.
