AUTHORS
Tamara P. Miller, MD, MSCE, John A. Kairalla, PhD2, Emily Hibbitts3, Joel Thompson, MD4, Caitlin W. Elgarten, MD, MSCE5, Karen R. Rabin, MD, PhD6, Susan Conway, BA7, Kira Bona, MD, MPH8, Lia Gore, MD9, Olga Militano, PharmD10, Naomi J. Winick, MD11, Faraz Zaman, MD12, Gerhard Zugmaier, MD, PhD13, Meenakshi Devidas, PhD14, Stephen P. Hunger, MD15, David Teachey, MD16, Elizabeth A. Raetz, MD17, Mignon L. Loh, MD18, Rachel E. Rau, MD19, Sumit Gupta, MD, PhD, FRCPC20, Sarah Alexander, MD21
AFFILIATIONS
1 Children's Healthcare of Atlanta, Atlanta, Georgia, United States, Emory University, Atlanta, Georgia, United States
2 Children's Oncology Group, Gainesville, Florida, United States
3 Children's Oncology Group, Gainesville, Florida, United States
4 Children's Mercy Hospital, Kansas City, Missouri, United States
5 Children's Hospital of Philaldephia, Philadelphia, Pennsylvania, United States
6 University of California, San Francisco, San Francisco, California, United States
7 Children's Oncology Group, Gainesville, Florida, United States
8 Dana-Farber Cancer Institute, Boston, Massachusetts, United States
9 University of Colorado, Aurora, Colorado, United States
10 Children's Oncology Group, Arcadia, California, United States
11 University of Texas Southwestern, Dallas, Texas, United States
12 Amgen, Thousand Oaks, California, United States
13 Philipps University of Marburg, Marbug, Germany
14 St. Jude Children's Research Hospital, Memphis, Tennessee, United States
15 Children's Hospital of Philaldephia, Philadelphia, Pennsylvania, United States
16 Children's Hospital of Philaldephia, Philadelphia, Pennsylvania, United States
17 Laura and Isaac Perlmutter Cancer Center at NYU Langone, New York, New York, United States
18 Seattle Children's Hospital, Seattle, Washington, United States
19 Seattle Children's Hospital, Seattle, Washington, United States
20 Hospital for Sick Children, Toronto, Canada
21 British Columbia Children's Hospital, Vancouver, Canada
ABSTRACT
Introduction: The Children’s Oncology Group study AALL1731 demonstrated that the addition of two courses of blinatumomab (blina) to chemotherapy improved 3-year disease-free survival (DFS) for children with NCI standard risk (SR) B-ALL. Consequently, blina has become a standard component of therapy for most children and adolescents with B-ALL. However, the impact of the addition of blina on measures of immune function is unknown. Minimal data exists on the depth and duration of B-cell aplasia or secondary hypogammaglobulinemia (SHG). In addition, though AALL1731 showed that blina was associated with an increased risk of infectious adverse events (AEs), whether this risk is associated with specific infectious pathogens is unknown. Herein we compare these measures in those randomized to receive chemotherapy plus blinatumomab (chemo+blina) vs. chemotherapy (chemo) only.
Methods: AALL1731 was a phase 3 international, open-label, randomized trial in children (age 1 to 9.9 years) with SR B-ALL. All enrolled and randomized patients without Down syndrome were included in this analysis. Measures of immune function, including absolute lymphocyte counts (ALC), CD19+ lymphocyte (CD19+) counts, and immunoglobulin (IgG/IgM) concentrations were obtained at 4 timepoints: Timepoint (TP) 1 (post induction/consolidation; i.e. prior to blina), TP2 (start of delayed intensification; i.e. after two cycles of blina), TP3 (start of maintenance), and TP4 (end of therapy). Measurements were classified as normal or mild, moderate or severely low based on previously used predefined age-based cutoffs. IVIG administration and grade 3+ infectious AEs per Common Terminology Criteria for Adverse Events (CTCAE) v5 were captured within each chemotherapy course. Measurements of immune status, use of IVIG (recommended but not required to be given per protocol for IgG <400 mg/dL), and incidence/type of AEs were compared between randomized treatment groups, both overall and stratified by SR-average (standard intensity chemotherapy backbone) vs. SR-high (high intensity backbone) arms. Risk factors for prolonged SHG were also examined. Data are current to March 2026.
Results: There were 1412 patients who met inclusion criteria for this analysis [758 (52.5%) males; mean age 4.7 years (standard deviation 2.3 years)]. At TP1, immune measures were similar across groups with 118/1239 (9.6%) and 281/1239 (22.7 %) of all patients having moderate or severely low ALC and IgG levels, respectively. At TP2, patients randomized to receive chemo+blina were more likely than those who received chemo alone to have severely low CD19+ counts [134/193 (89.7%) versus 81/186 (53.2%), P<0.0001] and moderate or severely low IgG [118/193 (61%) versus 13/186 (7%), P<0.0001]. Differences in IgG levels remained significant at TP3 [211/488 (43.2 %) versus 63/529 (11.9%), P<0.0001]. Notably, at TP4, greater than one year post the last blinatumomab exposure, nearly 20% of patients randomized to receive chemo+blina still had moderate to severe SHG [60/305 (19.7%)] compared to only 2.4% of those randomized to chemo alone (7/297) (P<0.0001). Other measures of immunity (listed above) were not significantly different between groups at TP3 or TP4.
Patients in the chemo+blina group were more likely than those in the chemo group to receive IVIG during therapy. For example, patients randomized to receive chemo+blina were more likely to receive IVIG in the reporting period both immediately before TP3 [140/488 (28.7%) vs. 31/531 (5.8%), p<0.0001] and immediately before TP4 [56/308 (18.2%) vs. 16/301 (5.3%), p<0.0001]. The above IgG results thus likely underestimate the true differences in moderate or severe SHG.
Among those treated with blina, neither age, sex, nor SHG at TP1 was associated with prolonged moderate or severe SHG at TP4, though SR-High patients were at greater risk (adjusted odds ratio 5.7, 95th confidence interval 2.7-11.8, p<0.0001).
The proportion of grade 3+ sepsis caused by an encapsulated bacterial pathogen was similar between the chemo+blina vs. chemo arms [52/145 (35.8%) versus 36/90 (40.0%), p=0.52]. Fungal infections were extremely rare in all arms.
Conclusion: Though the addition of blina improves DFS, it is associated with a greater risk of prolonged SHG, which persists at least to the end of therapy, despite CD19+ lymphocyte recovery. Further characterization of the total duration of SHG, its consequences, and identification of patients at greatest risk is warranted.
DISCLOSURES
Tamara P. Miller, MD, MSCE: No relevant conflicts of interest to declare.