Clinical Impact of Pretransplant Blinatumomab in Predominantly Hispanic Adults with B-Cell Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Ginosyan Anush Aram , Ashouri Karam , Hom Brian , Ann Brandon , Ireland Robert , Chu Mollee I. , Rahimi Yekta , Bragasin Eljie Isaak , Ford Lauren , Humayun Lucas , Baya Mihir , Hong Danielle , Huang Elaine , Chaudhary Preet M. , Ali Amir , Siddiqi Imran , Woan Karrune , Tam Eric L. , Ladha Abdullah , Yaghmour George 
Published: December 2024

Introduction:
Adult B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging disease, particularly in Hispanic patients who often present with unfavorable cytogenetics. Allogeneic hematopoietic stem cell transplantation (HSCT) serves as a potentially curative treatment. Blinatumomab, a bispecific T-cell engager targeting CD19, has shown promise in improving B-ALL outcomes. Our aim is to evaluate the clinical impact of pretransplant blinatumomab.
Methods:
This is a retrospective study includes 145 B-ALL adults who received allogeneic HSCT at Norris Comprehensive Cancer Center from 2014 to 2024. Incidence of severe chronic graft versus host disease (cGVHD), grade 3-4 acute GVHD (aGVHD), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) were evaluated using competing risk regression (Fine-Gray method), with death as a competing outcome. Overall survival (OS), disease-free survival (DFS), and GVHD-free relapse-free survival (GRFS) were analyzed with Cox proportional hazards model.
Results:
Demographics
Our cohort was predominantly male (n=85, 58.6%), Hispanic (n =111, 76.6%) with a median age of 42 years (range 20-69) and underwent a pediatric-based regimen (USC ALL 61.1%, Hyper-CVAD 20.8%, Other 18.1%). Most were Philadelphia (Ph) neg (Ph-negative 40.4%, Ph-positive 35.3%, Ph-like 24.8%) and had unfavorable (51.4%) or intermediate (40.0%) risk cytogenetics according to CALGB criteria.
Patients most often received haploidentical (haplo) HSCT (haplo 36.4%, MSD 32.9%, MUD 25.9%, MMUD 4.9%) with myeloablative conditioning (93.6%) while in CR1 (CR1 68.3%, CR2/CR3 31.7%) and achieved measurable residual disease (MRD) negativity (89.7%). GVHD prophylaxis consisted of posttransplant cyclophosphamide (PTCy) with tacrolimus (tac) and mycophenolate mofetil (58.2%), methotrexate (MTX)/tac(37.6%), or PTCy alone (4.3%). Within six months pretransplant, 36 patients (24.8%) received blinatumomab (median cycles = 2, range 1-5) for positive MRD (75.0%) or relapse/refractory disease (25.0%). When comparing patients by pretransplant blinatumomab, age, sex, cytogenetics, induction regimen, donor type, stage, donor age, and transplant risk index (TRI) did not differ between groups. The blinatumomab group more frequent Ph-like status(38.9% v. 20.2%; p=0.041), and trended towards having fewer MRD-positive patients pretransplant (2.9% v. 12.9%; p=0.115).
Survival/Relapse:
At 3 years post-transplant, our OS, DFS, CIR, and NRM were 83.3% (76.2-91.0), 69.1% (61.1-78.1), 22.8% (15.6-30.8), and 8.15% (4.09-14.0), respectively. Patients who received blinatumomab had improved DFS (93.7% v. 61.5%, HR 0.24, 95%CI 0.07-0.76, p=0.016) and CIR (3.3% v. 29%, HR 0.22, 95%CI 0.05-092, p=0.038), but similar OS (93.5% v. 80.0%, p=0.16) and NRM (2.9% v. 9.7%, p=0.31). Relative to CR1, patients transplant in CR2/3 had worse OS(HR 3.47, 95% CI 1.43=8.42, p=0.006), DFS(HR 2.19, 95% CI 1.16-4.15, p=0.016) and CIR(HR 2.26, 95% CI 1.09-4.67, p=0.028), while pretransplant MRD positivity predicted worse OS(HR 3.63, 95% CI 1.32-10.0, p=0.013) and DFS (HR 2.35, 95% CI 1.04-5.34, p=0.041) on univariate analysis. Higher TRI, absence of radiation, and MTX/tac GVHD regimen were univariate predictors of worse OS, DFS or CIR (data not shown). When controlling for disease status and MRD status at transplant, the blinatumomab group continued to have improved CIR (HR 0.22, 95% CI 0.05-0.92, p=0.039) and DFS (HR 0.24, 95% CI 0.07-0.80, p=0.019) on multivariate analysis. Subgroup analysis of Hispanic patients demonstrated improved DFS with blinatumomab (HR 0.22, 95% CI 0.05-0.94, p=0.041).
GRFS/GVHD:
Our 6-month incidence of grade 3/4 aGVHD was 9.90% (5.67-15.5) while 3-year GRFS and moderate/severe cGVHD was 44.7% (35.8-55.9) and 39.5% (29.9-48.9) respectively. There were no differences in grade 3/4 aGVHD (17.3% v. 7.49%, p=0.1), moderate/severe chronic GVHD (43.0% v. 38.0%, p=0.440), or GRFS (43.3% v. 45.1%, p=0.488) by blinatumomab administration.
Conclusion:
This study demonstrates that pretransplant blinatumomab therapy in adult B-ALL patients undergoing allogeneic HSCT is associated with improved DFS and reduced CIR despite having higher-risk cytogenetics without increasing the risk of GVHD. These findings suggest incorporating blinatumomab into pretransplant treatment strategies may enhance outcomes for adult B-ALL patients undergoing allogeneic HSCT.