AUTHORS
Haley Newman, MD, MSCE, Ryan Summers, MD2, Petri Polonen, PhD3, Meenakshi Devidas, PhD4, Derek Wong, PhD5, Rawan Shraim, PhD6, Lahari Uppuluri, PhD7, Lingyun Ji8, Michael Borowitz, MD, PhD9, Kara L. Davis, D.O.10, Caroline Diorio, MD11, Sumit Gupta, MD, PhD, FRCPC12, Andrew Hughes, MD, PhD13, Yimei Li, PhD14, Jennifer McNeer, MD, MS15, Ferro Nguyen, MSc16, Karen R. Rabin, MD, PhD17, Rachel E. Rau, MD18, Yansong Wen, PhD19, Brent Wood, MD, PhD20, Stephen P. Hunger, MD21, Mignon L. Loh, MD22, Elizabeth A. Raetz, MD23, Kimberly Dunsmore, MD24, Stuart Winter25, Charles G. Mullighan, MBBS (Hons), MSc, MD26, David T. Teachey, MD27
AFFILIATIONS
1 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
2 Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, United States
3 St. Jude Children's Research Hospital, Memphis, Tennessee, United States
4 St. Jude Children's Research Hospital, Memphis, Tennessee, United States
5 Children's Hospital of Philadelphia, Philadephia, Pennsylvania, United States
6 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
7 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
8 University of Southern California, Keck School of Medicine, Los Angeles, California, United States
9 Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
10 Stanford University, Stanford, California, United States
11 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
12 Hospital for Sick Children, Toronto, Canada
13 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
14 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
15 University of Utah and Primary Children's Hospital, Salt Lake City, Utah, United States
16 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
17 University of California San Francisco, San Francisco, California, United States
18 University of Washington/Seattle Children's Hospital, Seattle, Washington, United States
19 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
20 Children's Hospital Los Angeles, Los Angeles, California, United States
21 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
22 Seattle Children's Research Institute, Seattle, Washington, United States
23 Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, New York, United States
24 University of Virginia School of Medicine, Charlottesville, Virginia, United States
25 Children's Minnesota, Minneapolis, United States
26 St. Jude Children's Research Hospital, Memphis, Tennessee, United States
27 Children's Hospital of Philadelphia, Philadlephia, Pennsylvania, United States
ABSTRACT
Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Median age at diagnosis in B-lineage ALL is 4-5 years (yrs) vs 8-10 yrs in T-lineage (T-ALL). T-ALL is rare in infants and toddlers. In a recent European study, patients <3 yrs with T-ALL had distinct clinical features and genomic drivers, but similar survival outcomes compared with older patients (Delafoy, Hemasphere 2025). Outcomes and molecular profiles of young patients with T-ALL treated on Children’s Oncology Group (COG) clinical trials have not been reported.
Methods: Clinical and disease characteristics of young children (age 1-2.99 yrs) and older children/young adults (age 3 to <31) with T-ALL were compared on COG trials AALL0434 and AALL1231. Infants (< age 1) were not eligible for the trials. We examined the impact of age on major trial endpoints (AALL0434: disease-free survival [DFS], event-free survival [EFS], and overall survival [OS]; AALL1231: EFS and OS), and genomic subtype (AALL0434 only).
Results: Young patients comprised 7% (n=114/1562) of cases on AALL0434 and 8% (n=51/615) on AALL1231. Young patients were more likely to be female than older patients on both trials (37% vs 25%, P<0.01, P=0.05), with similar racial and ethnic distributions. Median presenting WBC was higher in AALL0434 young patients (102x109/L [IQR 38-311] vs 71x109/L [19-219], P<0.01) but not AALL1231 (77x109/L [25-328] vs 66 [16-209], P=0.12), with similar proportions of CNS3 disease. There was no difference by age in Day 29 minimal residual disease (MRD) positivity (>0.01%) on AALL0434 (P=0.19) or AALL1231 (P=0.16). For those with available end consolidation MRD on AALL1231, there was higher rate of MRD positivity (>0.1%) among young vs older: 6/24 (25%) vs. 19/179 (11%), although statistically non-significant P=0.09.
Young patients were significantly more likely than older to harbor NKX2-1 (21% vs 5%, P<0.01), NKX2-5 (4% vs 0.3%, P<0.01), SPI1 (3% vs 1%, P=0.05), and STAG2::LMO2 (7% vs 0.1%, P<0.01) genomic subtypes and less likely to harbor genomically defined ETP-like (8% vs 19%, P<0.01). There were no young patients with the prognostically favorable TLX3 subtype, (18% of older cases, P<0.01).
AALL0434: Young patients had significantly inferior 5yr DFS: 83.0% (74.7-88.8) versus 91.4% (89.8-92.8), P<0.01 and EFS: 76.8% (67.8-83.6) vs 85.0% (82.9-86.7), P<0.01. No statistically significant difference in 5yr OS was observed, although there was a trend toward inferiority: young 86.6% (78.8-91.7) vs older 90.5% (88.8-91.9), P=0.15. AALL1231: Young patients had a trend toward lower 5yr EFS: 71.1% (56.1-81.8) vs 82.5% (79.1-85.4), P=0.06; no significant difference in 5yr OS: 83.6 (69.8-91.4) vs 88.5 (85.5-91.0), P=0.24.
AALL0434: 30 young patients had events (30/114=26%): 23 relapses (77%), 3 deaths (10%), 2 induction failures (IF, M3 marrow), and 2 second malignant neoplasms (SMN). In older patients 244 events (244/1448, 17%): 133 relapses (55%), 48 deaths (20%), 41 IF (17%), 22 SMN (9%). Among 23 young patients who relapsed, 12 died (52%).
AALL1231: 16 young patients had events (16/51=31%): 6 relapses (38%), 7 deaths (44%), 2 refractory disease (persistent MRD post 6 cycles), 1 SMN. Attribution among patients with death as first event: 4 from disease, 2 multiorgan failure, 1 cardiac arrest. Among 6 relapsed patients, 2 died of disease,1 developed SMN. Among older patients 99 (99/564=18%) events: 50 relapses (50%), 31 deaths (30%), 10 refractory/progressive disease, 8 SMN.
Conclusion: Young patients (age 1-2.99 yrs) with T-ALL exhibit a distinct distribution of genomic profiles and have significantly inferior EFS as compared with older patients when treated with COG therapy. OS is similar, suggesting relapses may be salvageable; however, trend is toward inferior survival and lack of significance may be due to small numbers. A shift in first event type from more deaths/fewer relapse was observed from AALL0434 to AALL1231 for the trial overall due to more intensive backbone, yet there may be disproportionate excess toxicity in young patients. Multivariable modeling is in process to elucidate the potential contribution of high-risk genomic features as possible drivers of increased risk for events/toxicity. This is critical as specific subtypes may be amenable to precision medicine and empiric prophylaxis for prevention of toxic complications. CM and DT contributed equally.
DISCLOSURES
Haley Newman, MD, MSCE: No relevant conflicts of interest to declare.