Erfassung der Anzahl der Transplantationen, der Diagnosen, der Konditionierung sowie des Datensatzes Stammzelltransplantation. Weitergabe der Daten an das EBMT

Bedarfsplanung der Stammzelltransplantationen im Kindesalter Standardauswertungen zur Qualitätskontrolle der Transplantationen Bereitstellung der Daten für wissenschaftliche Auswertungen.

Patient ≤ 18 Jahre Stammzelltransplantation in einem deutschen Stammzelltransplantationszentrum Vorliegende Einwilligungserklärung zur Datenweitergabe

entfällt

To evaluate the efficacy of ONC201 administered following radiotherapy in participants with H3 K27M-mutant diffuse glioma

To evaluate the safety and tolerability of ONC201 versus placebo To evaluate the efficacy of ONC201 administered following radiotherapy using RANO-HGG criteria in participants with H3 K27M-mutant diffuse glioma To evaluate clinical benefits of treatment with ONC201 To evaluate the impact of ONC201 on health-related QoL and neurological function

1. Able to understand the study procedures and agree to participate in the study by providing written informed consent (by participant or legally authorized representative), and assent when applicable. 2. Body weight ≥ 10 kg at time of randomization. 3. Histologically diagnosed H3 K27M-mutant diffuse glioma (new diagnosis). Detection of a missense K27M mutation in any histone H3-encoding gene detected by testing of tumor tissue (immunohistochemistry [IHC] or NGS in a CLIA-certified or equivalent laboratory). [Site to provide (as available): ≥ 10 unstained formalin-fixed paraffin-embedded (FFPE) slides from tumor tissue.] 4. At least one, high-quality, contrast-enhanced MRI of the brain obtained prior to starting radiotherapy for submission to sponsor's imaging vendor for central read. For participants who had a surgical resection, this scan must be post-resection; for participants who did not have a resection, this scan may be pre- or post-biopsy. 5. At least one, high-quality, contrast-enhanced MRI of the brain obtained 2 to 6 weeks after completion of frontline radiotherapy. [Site to also provide all available MRIs completed prior to initiating treatment with study intervention.] 6. Completed standard frontline radiotherapy within 2 to 6 weeks prior to randomization. Standard frontline radiotherapy is defined as a dose of 54 to 60 Gy at 1.8 to 2.2 Gy/fraction. Radiotherapy must be initiated within 12 weeks from initial diagnosis of H3 K27M-mutant diffuse glioma and within 8 weeks of most recent surgical resection/biopsy. 7. Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time of randomization (refer to Appendix 6 for KPS/LPS scoring). 8. Stable or decreasing dose of corticosteroids and anti-seizure medications for 7 days prior to randomization, if applicable. Stable steroid dose is defined as ≤ 2 mg/day increase (based on dexamethasone dose or equivalent dose of alternative steroid).

1. Primary spinal tumor. Protocol ONC201-108 Amendment 1: 12 September 2022 36 2. Diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons. 3. Evidence of leptomeningeal spread of disease or cerebrospinal fluid dissemination. 4. Any known concurrent malignancy. 5. New lesion(s) outside of the radiation field. 6. Received whole-brain radiotherapy. 7. Received proton therapy for glioma. 8. Use of any of the following treatments within the specified time periods prior to randomization: a. ONC201 or ONC206 at any time. b. Bevacizumab (includes biosimilars) at any time. c. Temozolomide within past 3 weeks. d. Tumor treating fields at any time. e. DRD2 antagonist within past 2 weeks. f. Any investigational therapy within past 4 weeks. g. Strong CYP3A4/5 inhibitors (see Appendix 8) within 3 days. h. Strong CYP3A4/5 inducers (includes enzyme-inducing antiepileptic drugs; see Appendix 8) within 2 weeks. [Note: Refer to Section 6.10 for additional information on concomitant therapy.] 9. Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization: a. Absolute neutrophil count < 1.0 × 109/L or platelets < 75 × 109/L. b. Total bilirubin > 1.5 × ULN (participants with Gilbert's syndrome may be included with total bilirubin > 1.5 × ULN if direct bilirubin is ≤ 1.5 × ULN). c. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN. d. Creatinine clearance ≤ 60 mL/min as calculated by the Cockcroft Gault equation (or estimated glomerular filtration rate < 60 mL/min/1.73 m2). 10. QTc > 480 msec (based on mean from triplicate electrocardiograms [ECGs]) during screening (see Section 8.3.3 for details about QTc correction formulas). 11. Known hypersensitivity to any excipients used in the study intervention formulation. 12. Pregnant, breastfeeding, or planning to become pregnant while receiving study intervention or within 3 months after the last dose. Participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study intervention. 13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy or psychiatric illness/social situations that would limit compliance with study requirements. 14. Any other condition (eg, medical, psychiatric, or social) that, in the opinion of the investigator, may interfere with participant safety or the ability to complete the study according to the protocol.

Validierung Immunscore "SysT48" und modifizierter Glasgow Prognostic Score (mGPS) in einer prospektiven Patientenkohorte

Identifikation von Biomarkern für das Ansprechen auf eine Therapie mit ICIs vor Therapiestart (prädiktiv) sowie während der Therapie (longitudinal) -Identifikation von prädiktiven und longitudinalen immunologischen Biomarkern für das Auftreten von immunvermittelten Nebenwirkungen

Nachweis der Nichtunterlegenheit beim Gesamtüberleben (OS) von Patienten mit Ph+ ALL und molekularer CR, die mit Tyrosinkinase-Inhibitor (TKI), Chemotherapie (Chemo) im Wechsel mit Blinatumomab (Blina) (TKI-Chemo-Blina) im Vergleich zur sofortigen Stammzelltransplantation (SZT) behandelt werden

Haupt-Sekundärziel: Vergleich der Rate der molekularen Komplettremissionen (MolCR) nach Induktion und erster Konsolidierung mit Chemotherapie und Ponatinib (Pona) gegenüber Imatinib (Ima)

Auswahl: De novo Ph+ ALL Alter 18 - 65 Jahre Keine Vorbehandlung mit Ausnahme von Kortikosteroiden ≤ 7 Tage, Standard-GMALL-Vorphase mit Dexamethason und Cyclophosphamid einschließlich intrathekaler Therapie, Hydroxyurea, einer Einzeldosis Vincristin oder anderen Zytostatika und Beginn der Standardinduktion bei Ph-positiver ALL (1 Dosis Vincristin, 1 Dosis von Rituximab, 2 Dosen Dexamethason und bis zu 5 Tage Imatinib) ECOG-Performance Status ≤2

Auswahl: Anamnestisch andere bösartige Erkrankungen als ALL, die innerhalb von 5 Jahren (Jahren) vor Beginn der protokollspezifischen Therapie diagnostiziert wurden, mit definierten Ausnahmen: o Angemessen behandelter nicht-melanozytärer Hautkrebs oder Lentigo maligna ohne Anzeichen einer Erkrankung o Angemessen behandeltes Zervixkarzinom in situ ohne Anzeichen einer Erkrankung o Angemessen behandeltes duktales Mammakarzinom in situ ohne Anzeichen einer Erkrankung o Prostata intraepitheliale Neoplasie ohne Anzeichen von Prostatakrebs Kontraindikationen gegen die Anwendung von Imatinib, Ponatinib, Chemotherapie oder Blinatumomab Patient, der zuvor mit Tyrosinkinase-Inhibitoren behandelt wurde

To compare the efficacy of MaaT033 with its placebo on OS at 12 months after alloHCT

To evaluate MaaT033 efficacy in gut microbiota diversity restoration using alpha-diversity (Richness index) To evaluate the cumulative incidence of grade 2-4 acute GvHD within 6 months after alloHCT To evaluate the cumulative incidence of non-relapse mortality within 12 months after alloHCT

Age ≥ 50 years old Presence of a hematologic malignancy for which an alloHCT is indicated with a reduced toxicity or reduced intensity conditioning regimen Patients with polynuclear neutrophils > 0.5 G/L Patients having received wide spectrum antibiotics within the last 90 days prior to inclusion Karnofsky index ≥ 70%

Patients planned to receive a non-myeloablative conditioning regimen (2 Gray total body irradiation (TBI) +/- purine analog, fludarabine + cyclophosphamide or equivalent) Patients planned to receive a conventional myeloablative conditioning regimen (e.g. high dose cyclophosphamide and high dose TBI (≥10Gy); high dose busulfan (12.8 mg/kg IV) + high dose cyclophosphamide) Patients receiving a manipulated graft (in-vitro T-cell depletion) Patients planned to receive a conditioning regimen with alemtuzumab Patients planned to receive alloHCT with cord blood cells Patients planned to receive alloHCT from unrelated donor with >= 3/10 HLA-mismatches Patients receiving a large spectrum antibiotic at time of randomization

To assess the maximum tolerable dose and safety of intrathecal (IT) PD1 antibody administration

Overall survival

1. Must be ≥ 18 years at the time of signing the informed consent. 2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures. 3. Patients with a "good risk" status as defined by the NCCN guidelines (version 1.2021) 4. Tumor board protocol confirming: - a clinical recommendation for intrathecal therapy and evaluation of trial enrollment - a statement on the potential necessity of additional systemic treatment of metastatic tumor outside the CNS 5. Able to adhere to the study visit schedule and other protocol requirements. 6. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment. 7. Patients with Karnofsky performance score > 50% 8. Diagnosis of LMD by CSF and/or MRI a. A thorough CSF evaluation must be performed in every patient prior to the inclusion in this trial. The reason is that a positive CSF cytology is consideredthe gold standard for LMD diagnosis. Furthermore, a thorough CSF evaluation will allow the thorough assessment of potential differential diagnosis (for example, viral meningitis, bacterial meningitis, aseptic meningitis, sarcoidosis etc.) b. Presence of malignant cells on CSF cytology. The frequency of CSF evaluation is based on guideline of the German Society of Neurology: Please note that the first lumbar puncture is only 50-60% sensitive. Repeat collection increases sensitivity up to approximately 80%. Thus, a negative first CSF evaluation should at least be repeated once. According to guidelines from the German Society for Neurology each CSF collection should draw enough, i.e. at least 5- 10 ml CSF and should be processed within one hour of collection. c. MRI diagnosis of LMD: pial enhancement, pial nodular manifestations (as defined per LANO criteria, see appendix). d. A positive CSF cytology and an MRI evidence is enough to determine the LMD diagnosis. e. Please note that approximately 20% of patients with symptomatic LMD might lack positive CSF cytology even upon repeated puncture. In these cases, the LMD diagnosis can also be performed based on cerebral/spinal MRI manifestations and by exclusion of differential diagnosis f. In the absence of diagnostic findings for LMD in the CSF: patients must present with typical clinical and MRI signs of LMD (Le Rhun et al., 2017). If the CSF has signs of pleocytosis (BUT NOT any malignant, atypical or suspicious cells) the differential diagnoses for CSF pleocytosis (aseptic meningitis, viral meningitis, bacterial meningitis) must be excluded. g. Some centers perform biopsies of leptomeninges for obtaining a LMD diagnosis. The LMD diagnosis will be based on histology and should be documented accordingly. Yet, a histological diagnosis of LMD is NOT required for the inclusion in this trial. 9. If radiation therapy had occurred: Please make sure that a documentation of the past radiation therapy is available (including applied dosage and radiation therapy fields): a. Participants eligible for IT-PD1 should have completed their radiation therapy due to clinical indication > 2 weeks prior to enrollment into the trial b. All LMD patients without an indication for radiation therapy (per investigator`s choice) can be enrolled immediately 10. Neurological examination (NANO scale) (Nayak et al., 2017)11. MRI: the assessment at baseline and for subsequent time points should be based on the LANO scorecard (see appendix) according to (Le Rhun et al., 2019) 12. Ability to undergo intrathecal therapy via an intraventricular catheter (e.g. Ommaya reservoir) 13. Primary tumor tissue for the assessment of PD1 and PD-L1 should be available but does not need to be shipped before enrollment of patient into the trial. 14. Female Patient of childbearing potential1 and male patients with female partner of childbearing potential1 is willing to use highly effective contraceptive methods during treatment and for 150 days (male or female, see SmPC) after the last dose. Recommendations highly effective contraceptive methods are: a. combined hormonal contraception associated with inhibition of ovulation (oral-, intravaginal, -transdermal) b. progestogen-only hormonal contraception associated with inhibition of ovulation (pral injectable, implantable), c. intrauterine device (IUD), d. intrauterine hormone - releasing system (IUS), e. bilateral tubal occlusion, f. vasectomized partner2, g. sexual abstinence3

1. Women during pregnancy and lactation. 2. Previous intrathecal nivolumab application. 3. Patient at "poor risk" (NCCN guidelines version 1.2021) 4. The following differential diagnoses to LMD are exclusion criteria a. Aseptic meningitis b. Viral meningitis c. Bacterial meningitis 5. History of hypersensitivity to monoclonal antibodies 6. Participation in other clinical trials or observation period of competing trials. 7. A clinical condition that in the opinion of the investigator would interfere with the evaluation or interpretation of patient safety or trial results or that would prohibit the understanding of informed consent and compliance with the requirements of the protocol 8. Any treatment-related toxicities from prior systemic anti-tumor or immune therapy not having resolved to CTCAE version 5.0 grade 1, with the exception of alopecia 9. Patient with confirmed history of current autoimmune disease 10. Patients with any disease resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy 11. Clinically significant active infection, for example: a. Presence of human immunodeficiency virus b. Active hepatitis B virus/hepatitis C virus. HIV infection or active Hepatitis B or C infection, PCR-based detection of SARS-Cov2 or active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients' blood or tissue (e.g. rabies) *. 12. Inability to undergo MRI with contrast agent 13. The underlying primary tumor has not a registered and authorized indication in the European Union for intravenous treatment with nivolumab, pembrolizumab or atezolizumab. The solide tumor registered are, i.e. melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck region,urrothelial carcinoma, squamous cell carcinoma of the oesophagus tumours, triplenegative breast carcinoma 14. Abnormal laboratory values for the following values in haematology, coagulation parameters, liver and renal function: a. Haemoglobin < 8 g/dl b. White blood cell count < 2.0 x 109/L) c. Platelet count decrease < 50 x 109/L d. Bilirubin > 2.5 x upper limit of normal (ULN) according to the performing laboratory`s reference range. Note that benign hereditary hyperbilirubinemia e.g. Gilbert`s syndrome is permitted. e. Alanine aminotransferase > 3 x ULN f. Aspartate aminotransferase > 3 x ULN g. Serum creatinine increase > 1.5 x ULN 15. Patients who have received live or attenuated vaccine therapy used for prevention of infectious disease within 4 weeks of the first IT application of nivolumab 16. Patients requiring chronic systemic corticosteroid therapy (> 10 mg prednisone or equivalent per day) or any other immunosuppressive therapies (including anti-TNF-a therapies).

The primary objective is to assess the 5-year distant recurrence-free interval (dRFI, according to STEEP criteria version 2.0) [9] in all patients treated by (intensified) endocrine therapy alone (and with ovarian suppression in cases with enhanced clinical risk according to current AGO-recommendations)

to assess 10-year dRFI, according to STEEP 2.0 criteria, in all patients treated by (intensified) endocrine therapy alone (and with ovarian suppression in cases with enhanced clinical risk according to current AGO-recommendations)  to assess 5- and 10-year dRFI, according to STEEP 2.0 criteria, in all patients treated by SOC chemotherapy treatment followed by ET+/-OFS  to assess 5- and 10-year distant disease-free survival (dDFS, according to STEEP 2.0) in all patients and all treatment groups (i.e., patients treated by ET alone, ET + GnRH, chemotherapy followed by ET, chemotherapy followed by ET + GnRH, OFS-treated patients)  to assess 5- and 10-year overall survival (OS) in all patients and all treatment groups  to assess 5- and 10-year breast cancer-free interval (BCFI, according to STEEP 2.0) in all patients and all treatment groups  to describe and compare the quality of life (QLQ BR23 and QLQ-C30) at baseline, 3 months, 6 months, 12 months, 18 months, 2 years, 3 years 4 years and after 5 years between all treatment groups  to capture adherence to OFS and endocrine treatment in all patients  to assess concordance between BluePrint®/MammaPrint® molecular subtyping results vs. pathological immune-histochemistry results  to assess endocrine response measured by post-endocrine Ki-67 (≤10% and/or relative change vs. baseline) in patients treated by preoperative ET according to MammaPrint® result  to perform sub analyses of all endpoints using the MINDACT clinical high-risk clientele definition (i.e., G1, N0, tumor size >3cm and N+, tumor size >2-5cm; G2, N0, tumor size >2cm and N+, any tumor size; G3, N0, tumor size >1cm and N+, any tumor size)  to assess the prognostic value of ultralow versus low MammaPrint® assessment for dRFI and OS  to assess the additional prognostic value of ultralow / low MammaPrint® assessment adjusted for clinicopathological markers (histology, grade, expression levels of ER, PR, HER2 and Ki-67 at baseline and after preoperative endocrine therapy) for dRFI and OS  5 and 10-year iDFS in node-negative patients with ultralow MammaPrint® treated by shorter duration of ET (2-3 years at investigator decision) Endpoints Primary endpoint: 5-year distant recurrence-free interval (dRFI, according to STEEP criteria version 2.0) [9] in all patients treated by (intensified) endocrine therapy alone (and with ovarian suppression in cases with enhanced clinical risk according to current AGO-recommendations).

Female breast cancer patients  Pre- or perimenopausal at registry entry (age <60 years and state after hysterectomy or amenorrhea for <12 months: confirmation by blood hormone levels (FSH and estradiol in premenopausal range as per local normal range) recommended)  Primary tumor diagnosis not older than three months prior to inclusion (primary diagnosis defined as date of initial tumor biopsy)  Estrogen- and/or progesterone-receptor-positive/HER2 negative early breast cancer without any clinical signs of metastases Adequate risk for recurrence:  intermediate clinical risk for recurrence, defined as (clinical in case of neoadjuvant treatment):  c/pT1 and  c/pN0 and  Ki-67 15-24% or  G2 or patients, who do not meet these criteria but are at intermediate clinical risk for recurrence at investigator decision (e.g., very young age, low expression of hormone receptors etc.) can be included on individual decision basis or  high clinical risk for recurrence, defined as either (clinical in case of neoadjuvant treatment):  c/pT2-4 or  c/pN1 or  Ki-67 ≥25% or  G3  Low genomic risk of recurrence by MammaPrint® (tested on treatment naïve tumor specimen)  Luminal-type by BluePrint®  Treatment according to standard-of-care (e.g., AGO Guidelines) planned or started (until completion of local therapy the latest, including started or completed endocrine induction therapy, started, or planned adjuvant or neoadjuvant treatment)  Availability of untreated tumor material (core biopsy if preoperative endocrine therapy performed or neoadjuvant treatment intended or surgery specimen)  Capability to give written informed consent  Nodal positive patients will be accepted to the registry up to 25% of the genomic low/ultralow-risk population (n=441).

Any other genomic testing, besides MammaPrint®/BluePrint®, has been performed on the tumor material  Medical or psychological conditions that would not permit the patient to sign informed consent  Legal incapacity or limited legal capacity  Current participation in any interventional clinical trial with medicinal products  Non-compliance of the patient

Ja

The primary aim of the trial is to demonstrate the efficacy of pre-surgical perampanel compared to placebo treatment with respect to A) the shift of mRNA expression patterns to a lower connectivity score in tumour tissue, and B) the presurgical tumour growth rate as assessed by tumour volume [cm³] per a central blinded independent review committee (BIRC) based on AI-quantified MRI parameters (T2/FLAIR-weighted images) in patients with recurrent/progressive glioblastoma willing to adhere to the randomised treatment and who will undergo surgery.

Efficacy: To explore the efficacy of perampanel compared to placebo as regards  kinetics in contrast-enhancing (T1CE images) tumour volume by central AI-based MRI assessment per BIRC [pre-surgical; postsurgical ]  kinetics in tumour volume (T2/FLAIR) by central AI-based MRI assessment per the BIRC [post-surgical]  health-related quality of life (HRQoL) and symptoms as assessed by the EORTC QLQ-C30 and QLQ-BN20 patient questionnaires,  severity of cognitive impairment as assessed by the mini-mental state examination (MMSE)  overall survival (OS)  progression-free survival (PFS) (from randomisation until progression according to RANO criteria)  epileptic seizure activity Safety:  To check for the occurrence of the adverse effects reported in the summary of the medical product characteristics (SmPC) of the drug and to compare between both treatments

1. Histologically confirmed glioblastoma, progressive or recurrent after 1 or 2 lines of prior treatment, involving one radiotherapy and drug treatments (temozolomide, lomustine and/or other) according to institutional standards or prior trial participation, >3 months after end of radiotherapy, and therapy for relapse not yet started. 2. Indication for surgical resection of progressive or recurrent tumour tissue 3. A sufficient amount of resected tumour tissue (minimum 0.5 cm3) is expected to be available for the trial-specific molecular, morphological, functional and perampanel level analysis. 4. Tumour progression according to RANO criteria 5. Age ≥18 years 6. Karnofsky Performance status score (KPS) ≥ 60% 7. Life expectancy > 3 months 8. Willing and able to comply with regular neurocognitive and health-related quality of life tests/questionnaires. 9. Written informed consent. 10. Cognitive state to understand rationale, necessity and individual consequences of study therapy and procedures. 11. Female patients with reproductive potentiala must use an approved contraceptive method during and for 4 weeks after the end of trial medication (Pearl Index <1%) 12. Female patients with reproductive potential: a negative serum pregnancy test (beta-HCG) must be obtained prior to treatment start.

1. Participation in other ongoing interventional clinical trials. 2. Inability to undergo contrast-enhanced MRI. 3. Inability to undergo surgery (e.g. because of need for continuous anticoagulation, known bleeding disorders, thrombocytopenia <50/nl, pre-existing wound healing problems). 4. According to the assessment of the local investigator, a safe waiting interval of 4-5 weeks for surgical resection is not possible because the growth dynamics, configuration, or location of the brain tumour, or any complication, require immediate or earlier surgical intervention to save the patient from harm (e.g. by herniation or other emergency situations, or brain damage due to tumour mass effects) 5. Any continued or planned standard or experimental treatment for the tumour other than resection, including antiangiogenic therapy (such as Bevacizumab), and local therapy in addition to the planned resection, including BCNU wafers, loco-regional hyperthermia, tumour bed irradiation, and photodynamic therapy. 6. Tumour carries a known mutation in the IDH1 or IDH2 gene 7. Severe or significant abnormal (≥ Grade 3 CTCAE v5.0) laboratory values for haematology (Hb, WBC, neutrophils, or platelets), liver (serum bilirubin, ALT, or AST) or renal function (serum creatinine). 8. Known active tuberculosis; HIV infection or active Hepatitis B (HBV) or Hepatitis C (HCV infection, or active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients' blood or tissue (e.g. rabies). 9. Any prior treatment with perampanel 10. Pre-existing conditions like psychosis, aggression or suicidal thoughts that are considered as not allowing Perampanel treatment according to the assessment of the local investigator. 11. Concomitant intake of enzyme-inducing antiepileptic drugs (EIAEDs: carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidon, rufinamid) 12. Steroid intake of more than 4 mg dexamethasone (or equivalence dose) in the last week, or expected indication for it in the foreseeable future 13. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within the last 2 years unless the patient has been disease-free for 2 years. 14. Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study. 15. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry. 16. Pregnancy or breastfeeding. 17. History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product. 18. The presence of any other concomitant severe, progressive, or uncontrolled renal, hepatic, haematological, endocrine, pulmonary, cardiac, or psychiatric disease, or signs or symptoms thereof, that may affect the subject's participation in the study, according to investigators judgement.

Vergleich der Wirksamkeit von all-trans-Retinsäure (ATRA) versus Placebo als Zusatztherapie zu Decitabine (DAC) und Venetoclax (VEN) hinsichtlich der Gesamtüberlebenszeit (OS) der Patienten.

Vergleich von all-trans-Retinsäure (ATRA) versus Placebo als Zusatztherapie zu Decitabine und Venetoclax hinsichtlich des objektiven besten Ansprechens (komplette Remission mit (CR) oder ohne (CRi) kompletter hämatopoietischer Regeneration, morphologisch leukämiefreier Zustand (MLFS) oder partielle Remission (PR)), CR ohne messbare Resterkrankung (CRMRD), Überlebenszeit mit bestem objektivem Ansprechen, Lebensqualität, Sicherheit.

1. Alter ≥ 18 Jahre 2. Bislang unbehandelte AML (WHO 2016) 3. ECOG ≤ 2 4. Anzahl der weißen Blutkörperchen < 25 × 109/L (Zytoreduktion mit Hydroxyharnstoff oder Cytosinarabinosid (Ara-C) sind erlaubt um dieses Kriterium zu erfüllen) 5. Standard-Induktion-Chemotherapie nicht durchführbar; die folgenden Kriterien sind allgemein anerkannt:  Alter ≥ 75 Jahre  ECOG ≥ 1  HCT-CI ≥ 3  Patient lehnt eine aggressive Standard-Chemotherapie ab  fehlendes soziales Unterstützungssystem 6. Voraussichtliche Lebenserwartung von mindestens 8 Wochen 7. Schriftliche Einwilligungserklärung nach Aufklärung gemäß internationalen Richtlinien und lokalen Gesetzen 8. Fähigkeit, die Bedeutung und die Konsequenzen der Studienprozeduren zu verstehen und ihnen zuzustimmen

Auswahl: 1. Akute promyelozytäre Leukämie (APL, FAB M3) 2. Vorherige Behandlung mit DAC, Azacitidin oder anderen DNAhypomethylierenden Wirkstoffen, all-trans-Retinsäure (ATRA), Venetoclax und anderen Bcl-2-Hemmern 3. Frühere allogene Stammzelltransplantation oder Organtransplantation 4. Vorherige Induktionschemotherapie 5. Frühere niedrig dosierte Chemotherapie (z. B. Hydroxyharnstoff, Ara-C, Melphalan etc.) innerhalb von 4 Wochen vor der ersten Gabe der Studienbehandlung. Ausnahme: Zytoreduktion der Leukozytose ≥ 25.000/μl mit Hydroxyharnstoff oder Ara-C gemäß Studienprotokoll; der Patient muss sich von allen klinisch relevanten reversiblen nichthämatologischen Toxizitäten erholt haben 6. Leukämie des zentralen Nervensystems (ZNS)