Outcomes of Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia Given Blinatumomab As Last Consolidation Treatment before Allogeneic Hematopoietic Cell Transplantation
Authors: Algeri Mattia , Massa Michele , Pagliara Daria , Bertaina Valentina , Galaverna Federica , Pili Ilaria , Li Pira Giuseppina , Carta Roberto , Quagliarella Francesco , Pinto Rita Maria , Rosignoli Chiara , Lucarelli Barbarella , Cefalo Maria Giuseppina , Boccieri Emilia , Benini Francesca , Del Bufalo Francesca , Becilli Marco , Merli Pietro , Zugmaier Gerhard , Locatelli Franco 
Published: December 2024

Introduction:
Blinatumomab has remarkable efficacy in patients with relapsed/refractory or measurable residual disease (MRD)-positive B-cell acute lymphoblastic leukemia (B-ALL). In many patients, blinatumomab treatment is followed by allogeneic hematopoietic cell transplant (HCT). However, the influence of blinatumomab on HCT outcomes in children and young adults (YA) remains to be fully elucidated.
Methods and Patients:
This single-center, retrospective study, conducted at Bambino Gesù Children's Hospital in Rome, Italy, included all consecutive pediatric and YA patients with B-ALL who received blinatumomab as last therapy before undergoing HCT between 2016 and 2023.
Seventy-eight patients met the inclusion criteria, with a median age at HCT of 8 years (range 1-25). Blinatumomab was administered for refractory disease in 3 patients, as an MRD negativization strategy in 23 patients and as a consolidation strategy in 52 MRD-negative patients. At time of HCT, 14 patients were in first (CR1), 59 in second (CR2), and 5 in third complete remission (CR3). Pre-HCT MRD was assessed by either flow-cytometry, PCR or both, within 30 days before transplant and was negative (&lt;1x10-4) in 72 (92.3%) patients. Thirty-one patients exhibited at least one clinical or cytogenetic/molecular very high-risk feature (hypodiploidy; TCF3::HLF; KMT2A::AFF1; IKZF1plus deletion and poor MRD response after induction; absence of CR at Day+33; very early relapse, &lt;18 months from diagnosis, for CR2 patients). Twenty-six relapsed patients received Inotuzumab Ozogamicin (InO) as part of the reinduction strategy prior to blinatumomab.
Except for six cases, all patients received a total body irradiation-based conditioning regimen. Patient transplanted from matched related (n=13) and unrelated donor (UD, n=33) received unmanipulated bone marrow or peripheral blood stem cells (PBSC) grafts with conventional cyclosporin-A and short-term MTX GvHD prophylaxis. Anti-T-lymphocyte globulin was administered to all recipients of UD or haploidentical donor transplants. Subjects transplanted from haploidentical donors (n=32) received αβT- and B-cell-depleted PBSC grafts without post-HCT GvHD prophylaxis.
Results:
All patients but one achieved engraftment. Median time to neutrophil and platelet recovery was 17 (IQR 14-19) and 16 days (IQR 11-20), respectively.
With a median follow-up of 23.23 months (range=3-93), the 2-year disease-free (DFS) and overall survival (OS) probabilities were 72.2% and 89.2%, respectively. No significant differences in DFS and OS were observed depending on the age group, conditioning regimen, MRD status at HCT or presence of high-risk cytogenetic features. A trend toward improved 2-year DFS, but not OS, was noted in CR1 patients compared to those in CR2/3 (92.9 vs. 68.5%, p=0.18) due to a lower cumulative incidence (CI) of relapse (0% vs. 29.9%, p=0.05). Among CR2/3 patients, those receiving the sequential combination of InO and blinatumomab had a significantly lower CI of relapse (9.5% vs. 40.4%, p=0.023) and exhibited a trend toward better DFS (86.7% vs. 59.6%; p=0.07) as compared to those who received only chemotherapy and blinatumomab.
One patient died because of idiopathic pneumonia and one of disseminated adenovirus infection, the CI of non-relapse mortality (NRM) being 2.6%. No cases of sinusoidal obstruction syndrome or unexpected toxicities were observed in the entire cohort. Patients who received 2 cycles (n=23) of blinatumomab had a higher CI of acute GvHD compared to those who received 1 cycle (47.8% vs. 11.0%; p=0.06). Multivariable analysis confirmed a significant association between the number of blinatumomab cycles and the development of acute GVHD (HR=3.5 [95% CI, 1.6-7.64], p=0.001),
Relapse after HCT occurred in 16 patients, all exhibiting CD19-positive blasts; 10 of them received anti-CD19 chimeric antigen receptor T-cells (CAR-T) and 2 InO as salvage therapy, leading to a 2-year post-relapse OS of 52.7%.
Conclusions:
HCT following blinatumomab in children and YA with B-ALL is highly effective, determines low NRM and does not affect the efficacy of subsequent salvage immunotherapies. Results obtained in CR1 support the incorporation of blinatumomab bridging in all subjects with a transplant indication after first-line therapy. For CR2/3 patients, sequential targeting of CD22 and CD19 with InO and blinatumomab before HCT offers excellent DFS probabilities.