Paper Details

ABSTRACT

Background: Advances in outcomes for childhood acute lymphoblastic leukemia (ALL) have been made by incorporating leukemia biology and minimal residual disease (MRD) assessment to inform risk-adapted treatment. Novel features of DFCI 16-001 included: Low Risk (LR) patients (pts) received no anthracycline, pts 10-14.99 years (yrs) of age without other High Risk (HR) features were treated as LR, IKZF1 deletion was incorporated as a very high risk (VHR) feature, and intensity of therapy was adjusted during Induction based on biology results.

Methods: Pts aged 1 to < 22 yrs with newly diagnosed ALL were eligible for DFCI 16-001. Pts with B-ALL were assigned a Provisional (Prov) Risk Group at diagnosis. Prov LR was defined as age <15 yrs, WBC <50,000/μL, and not CNS-3; Prov HR included all others. Centrally reviewed biology results from diagnostic marrow established Initial Risk Group during Induction. Pts with any of the following were assigned to Initial VHR: IKZF1 deletion, KMT2A-rearrangement (KMT2A-r), low hypodiploidy, or TCF3::HLF fusion. Pts with iAMP21 and Prov HR pts without VHR biology were assigned to Initial HR; all others were assigned to Initial LR. Pts with BCR::ABL1 were removed from protocol by day 15. Intensity of Induction therapy was stratified by Initial Risk Group (3-drug for Initial LR, 4-drug for Initial HR/VHR). Induction Failure (IF) was defined as M3 marrow at end of the first month of therapy (TP1), or M2/M3 marrow after 10 weeks (TP2). For pts achieving complete remission (CR), Final Risk Group was assigned: 1) Final LR: Initial LR with low TP1 MRD (<10^-4); 2) Final Intermediate Risk (IR): Initial HR and low TP1 MRD; 3) Final HR: Initial LR or HR with high TP1 MRD but low TP2 MRD (<10^-3), 4) Final VHR: adverse biology regardless of MRD or high TP2 MRD (≥10^-3). Final LR pts received no anthracycline. Final VHR pts received 2 intensified chemotherapy cycles added to HR backbone. Total duration of treatment was 24 months from CR. Overall survival (OS) and event-free survival (EFS) were estimated with the Kaplan-Meier method. EFS was modeled univariately and adjusted in multivariable models with the Cox proportional hazards model.

Results: Between 2017-2022, 462 eligible Ph-negative B-ALL pts enrolled. Of these, 343 were classified as Prov LR and 119 Prov HR. After biology results became available (Day 11 of induction), 285 (60.5%) were classified as Initial LR, 96 (21.7%) as Initial HR, and 81 (17.8%) as Initial VHR. Of 455 pts evaluable for Induction events, 452 (99.3%) achieved CR; 1 Initial LR and 2 Initial VHR pts experienced IF. There were no deaths in Induction. 442 pts were assigned a Final Risk Group, 212 (48.0%) Final LR, 74 (16.7%) Final IR, 76 (17.2%) Final HR, and 80 (18.1%) Final VHR (57 for IKZF1 deletion, 8 KMT2A-r, 7 hypodiploidy, 1 TCF3::HLF fusion, 7 for high TP2 MRD). Treatment related mortality (TRM) in CR occurred in 2 pts (0.4%). With 5.1-yr median follow-up, 5-yr OS was 95.5% (95% CI 93.0%, 97.1%) and EFS was 89.2% (85.9%, 91.8%). 5-yr EFS was 95.0% for Final LR, 84.4% for IR, 89.2% for HR, and 80.3% for VHR (p=0.002). Among Final LR pts, for those <10 yrs of age, 5-yr EFS was 96.3%, and for 10-14.99 yrs was 89.5%. 5-yr EFS was 91.3% for pts with Low TP1 MRD (N=332), 86.2% for High TP1/Low TP2 (N=97), and 51.9% for High TP2 (N=13) (p<0.0001). LR pts with TP1 MRD <10^-6 had 5-yr EFS 96.3% (vs. 94.2% for LR pts with MRD 10^-6 to <10^-4, p=0.45). LR pts with TP1 MRD <10^-6 and ETV6::RUNX1 or high hyperdiploidy with trisomy 4 and 10 had 5-yr EFS 100%. Pts with IKZF1 deletion had 5-yr EFS of 82.6%; excluding pts with ERG deletion/DUX4-rearrangement, 5-yr EFS was 80.4%. Univariate prognostic factors included age, WBC at diagnosis, MRD at TP1 and TP2, IKZF1 deletion, ETV6::RUNX1, and high hyperdiploidy with trisomy 4 and 10. On multivariable analysis age ≥10 yrs, WBC ≥50,000/μL, and high TP2 MRD were significant predictors for adverse outcome.

Conclusion: Conducted prior to the routine use of blinatumomab in frontline therapy, DFCI 16-001 achieved a favorable EFS and OS for Ph-negative B-ALL pts, with very low TRM. LR pts had 5-yr EFS of 95.0% with an anthracycline-free regimen; VHR pts had EFS of 80.3% with intensified therapy, although those with High TP2 MRD had poorer outcome. Future efforts should explore further de-intensification of therapy for LR pts and incorporation of immunotherapy to improve outcome and decrease toxicity, especially for pts with HR features.