Amendment No. 1 was applicable in all countries. It mainly concerned: - Removal of non-screening criterion #6 (patients previously treated with HMA) - Modification of DLT definition for isolated AST or ALT elevation - Modification of treatment dose adaptations and readministration criteria based on AST or ALT values - Additional timepoints for monitoring of AST, ALT and total bilirubin - Update of criteria for study discontinuation during the LID period - Update on pharmacokinetic timepoints - Clarification of inclusion criteria 29 - Update of exclusion criteria 43 - Additional recommendations for management of IRR - Update of the reporting of fatal events during inclusion period - Modification of the deadlines for obtaining certain examinations for inclusion (Chest X-Ray and hepatitis markers) - Clarification in case of TLS Grade 3 or 4 in the protocol Table (8.12) 1 - Clarification on cardiac marker samples - Update of the protocol Table (4.4.1) 1 in accordance with the investigational medicinal product dossier-Quality - Modification implemented in Not statistically Significant Amendment n°1 - Typo corrections

Amendment No. 2 was applicable in all countries. It mainly concerned: - Updates following FDA’s recommendations: • Addition of safety stopping rules and dose modification rules in expansion part • Addition of study safety stopping rules for any death suspected to be related to S64315 occurring within 30 days of study treatment administration • Monitoring of DLTs implemented at all cycles of treatment in escalation and expansion parts • Update of DLT definition for haematologic toxicity and troponin increase • Update of eligibility criteria 16 and 43 • Update of management of S64315 dose modifications for QTc interval, creatine phosphokinase elevation and troponin elevation • Update of dose modifications for non-hematologic toxicities • Sub-Arm A3 enrolling patients with newly diagnosed AML removed from the Phase II expansion part • Phase II expansion part primary objective updated to CR rate • Clarifications added on study design for the expansion cohorts • Addition of treatment failure definition - Addition of recommendation in case of coronavirus disease 2019 (COVID-19) infection - Addition of recommendation in case of C1D9 infusion missed - Implementation of non-substantial amendment #2

Amendment No. 3 was applicable in all countries. It mainly concerned: - To allow the possibility to include more than 6 DLT-evaluable patients in a cohort - To remove the collection of blood samples for PK that are considered unnecessary - Update of blood sampling timepoints for PK - Update of blood sampling timepoints for peripheral blood mononuclear cells assessment - Change in instructions that one of the 2 IMPs is permanently discontinued or discontinued for more than 28 days - Update for re-starting of study treatment after COVID-19 infection - Clarification of wording related to treatment discontinuation during LID period (LID2 or C1D2) - Clarification about the investigations to be performed in the case of the need for an additional LID period - Clarification of the definition of DLT - Clarification about any new concomitant medication administration - Clarification in the wording of the one-week safety window between C1D2 of the first patient and C1D2 of subsequent patients in the same cohort - Clarification added in the situation where MTD is not be reached in some situations - Clarification for a secondary objective during expansion Phase II: CRi is defined according to ELN recommendations - Update of statistical analysis sets for the expansion Phase II part - Update for attesting authenticity of the data collected in the eCRF

Amendment No. 4 was applicable in all countries. It mainly concerned: - Update of inclusion criteria #13 due to EU SmPC of azacitidine update (April 2022)