Protocol Amendment 1: The description of induction treatment failure for purposes of event-free survival estimation was modified to “failure to achieve morphologic CR after completion of the last cycle of induction chemotherapy (no later than day 42 of the last cycle of induction).” -Revisions were made to clarify the requirements for bone marrow examination. -Amendment 1.0 changed the requirement for all subjects to receive 2 cycles of induction to administration of a second induction cycle contingent upon response to the initial induction cycle. A schematic depiction of study treatment from Cycle 1 Day 1 through completion of Chemotherapy Cycle 2 was added. -“Failure to achieve (or maintain) CR, CRh, or complete remission with incomplete blood count recovery (CRi) post-Chemotherapy Cycle 2” was added as a reason for study treatment discontinuation. -It was clarified that response assessments would be in accordance with the European LeukemiaNet (ELN) criteria but with minor modification for neutrophil and platelet count thresholds for a response of CR, as defined by International Working Group (IWG) criteria. -A statement of estimand for the primary endpoint was added. -Updates and clarifications were included for analyses of the secondary endpoints, event-free survival, relapse-free survival, and overall survival. -Additional explanatory details regarding the function of the DMC with implications for its role to oversee both safety and efficacy (or futility) for this trial were provided.

Protocol Amendment 1.1: -The benefit/risk section was revised to include Leukemia & Lymphoma Society Study BAML-16-001-S6 data collected through 01 October 2021. -A section on COVID-19 considerations was added. Reference to the FDA guidance regarding risk mitigation efforts in clinical trial conduct during the COVID-19 pandemic era was removed in response to request from the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM – Federal Institute for Drugs and Medical Devices). This was replaced with reference to European Union (EU) specific-guidances. -Screening for HIV was added to the study procedures. -Clarification regarding the timeframe for serious adverse event (SAE) reporting was added. -Pregnancy was added as a discontinuation criterion.

Protocol Amendment 2: -Changes introduced in country-specific Amendment 1.1 were incorporated into this global amendment. -Modifications to allow for bone marrow examination up to Day 42 of Induction Cycle 1 in order to allow for recovery of peripheral blood counts before assigning remission status were included. -Requirements were added for ANC and platelet count to recover to > 1 × 109/L and > 100 × 109/L, respectively, prior to initiation of Consolidation Cycle 1 to allow for identification of subjects who achieved morphologic CR post-Induction Cycle 1 (based both on bone marrow and peripheral blood criteria) and for consistency with post-Chemotherapy Cycle 2. -A blanket exclusion was added for subjects with concurrent fms-like tyrosine kinase 3 (FLT3) mutation (including those without prior access to midostaurin). -Language was added allowing subjects who were HIV positive to enroll provided they met specific entry criteria. -Contraceptive guidance was revised to emphasize the lack of a known potential drug-drug interaction between ENTO and hormonal contraceptives that could potentially reduce their efficacy. Language was added to require the use of a barrier method (eg, male condom) in addition to one of the highly effective methods of contraception listed. -Appendix 9: Guidance on the Management of Clinical Trials During COVID-19 Pandemic was updated to include both US and EU guidances.

Protocol Amendment 3: Clarification regarding the timeframe and procedures for SAE reporting was added.