Feasibility of Adjusting Risk Group and Risk Group-Based Therapy during Induction in the Treatment of B-Cell Acute Lymphoblastic Leukemia: Results from DFCI ALL Consortium Protocol 16-001

Background: Advances in treatment of childhood acute lymphoblastic leukemia (ALL) have been made by incorporating leukemia biology into treatment stratification. Historically, biology-based treatment adjustments have been made after completion of the first 4-week treatment phase (Induction). A novel feature of DFCI 16-001 was early incorporation of leukemia biology results, by day 11 of Induction, to adjust treatment within the Induction phase in a risk-stratified manner. We assessed the feasibility of modifying therapy based on biology within the first 2 weeks of Induction. Methods: Patients (pts) aged 1 to < 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts with B-ALL were assigned a Provisional (Prov) Risk Group, Low Risk (LR) or High Risk (HR), at diagnosis. Prov LR was defined as age <15 years, WBC <50,000/µL, and not CNS-3; these pts began a 3-drug induction (no anthracycline). Prov HR included all other pts; they received a 4-drug induction with doxorubicin (DOX) given on days 4 and 5. Centrally reviewed FISH/cytogenetics and testing for IKZF1 deletion (using NGS assay) from diagnostic marrow established Initial Risk Group by Induction day 11 (+/-3 days). Pts were assigned to Initial Very High Risk (VHR) Group if any of the following were present: IKZF1 deletion, KMT2A-rearrangement (KMT2A-r), low hypodiploidy (≤40 chromosomes), or TCF3::HLF fusion. Pts with iAMP21 or BCR::ABL1 were assigned to Initial HR. Pts were considered Indeterminate Initial Risk if results were insufficient by day 11 to establish Initial Risk Group. Prov LR pts assigned to Initial HR or VHR had DOX added on days 11 and 12 (delayed DOX), converting from a 3-to 4-drug induction. All Indeterminate Risk pts who had not received DOX days 4 and 5 (Prov LR pts) also had DOX added on days 11 and 12. Results: Between 3/2017-9/2022, 471 eligible pts with B-ALL enrolled. Of these, 347 were classified as Prov LR and 124 Prov HR. By day 11, 281 (81%) of the Prov LR pts were assigned to Initial LR (continued 3-drug induction), 14 (4%) changed to Initial HR (11 iAMP21, 3 BCR::ABL1), and 44 (13%) to VHR (38 IKZF1 deletion, 5 hypodiploidy, 1 KMT2A-r); of the Prov HR pts, 85 (69%) were assigned to Initial HR, and 34 (27%) to Initial VHR (25 IKZF1 deletion, 7 KMT2A-r, 2 hypodiploidy). At day 11, 13 pts (3%) were Indeterminate, 8 Prov LR pts (all received delayed DOX: 7 ultimately Initial LR, 1 VHR for IKZ1F1 deletion), and 5 Prov HR pts (already received DOX days 4/5: 3 Initial HR and 2 VHR, 1 for IKZF1 deletion and 1 hypodiploidy). Reasons for Indeterminate were inconclusive/delayed FISH (3 pts), delayed karyotype (4 pts), and delayed IKZF1 determination (6 pts). Five pts had Initial Risk Group revised to VHR later in Induction (3 Prov LR who did not receive DOX, and 2 Prov HR pts) based on findings of IKZF1 deletion not identified on initial testing. Thus, 281 (60%) pts received a 3-drug induction, 124 (26%) received a 4-drug induction with DOX days 4/5; 58 (12%) changed from a 3 to 4-drug induction with delayed DOX due to adverse biology and 8 (<2%) for Indeterminate Risk. There were no deaths in Induction. Among the 463 pts who achieved complete remission (excluding 8 pts with M2/M3 marrow at end-induction) there was no significant difference in the percentage of pts with delayed count recovery at day 32 between Prov LR pts who received delayed DOX compared with Prov HR pts receiving DOX on days 4/5 (27.4 vs. 24.6%, p=0.68). Among those with delayed count recovery at day 32, median days to recovery did not differ between those receiving delayed DOX and those receiving DOX on days 4/5 (7 days, range 7-19 days, vs. 7 days range 4-41 days, p=0.42). Conclusion: Adjusting treatment intensity within Induction using early incorporation of leukemia biology results was feasible. By day 11, 97% of pts had interpretable biology results and all Indeterminate Risk pts were ultimately assigned Initial Risk Group based on biology testing. Adverse biology resulting in treatment change was identified in 17% of Prov LR pts (13% of NCI-SR pts). Only 3 pts (<1%) received a 3-drug induction in the setting of adverse biology identified after day 11. Administering delayed DOX (days 11 and 12) in pts with adverse or Indeterminate biology initially receiving a 3-drug induction was not associated with a higher rate of delayed count recovery or longer delay compared with DOX administration days 4 and 5. Further efforts should explore the impact of risk-stratified early intensification of Induction therapy.

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