ACUTE MYELOID LEUKEMIA: EXPLORING THE FEASIBILITY OF MULTIMODAL-OMICS BASED GENOMIC CHARACTERIZATION, MRD EVALUATION AND COMPUTATIONAL DRUG MODELLING TO INFORM DISEASE MANAGEMENT

Aim

To Establish a Precision Oncology Work platform at Tata Medical Center in patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome with Excess Blasts (MDS-EB).

Hypothesis

a. Multimodal Omics based Comprehensive Genomic Characterization of a uniformly treated cohort of AML patients, accompanied by computational modeling POP model and MRD assessments will potentially enable the following

i) Refining and Personalizing the Selection of therapy

ii) Unbiased analysis of predictive and prognostic factors, both clinical and molecular.

b. In the Induction and Consolidation phase of AML therapy, it will be feasible to add biomarker guided approved therapy concurrently with standard consolidation therapy

Objectives

a. Primary Objectives

a. To describe the Comprehensive Genomic Characteristics of Acute Myeloid Leukemia/ MDS-EB patients using a Multi-modal Omics based strategy

b. To Develop and evaluate feasibility of Measurable Residual Disease (MRD) detection in patients undergoing therapy for Acute Myeloid Leukemia/ MDS-EB.

c. To develop a patient specific computational drug modelling platform.

b. Secondary Objectives

a. To describe Clinical outcomes of a uniform group of patients undergoing therapy using approved agents.

b. To determine characteristics of the Faecal and Oral Microbiome, and surveillance cultures of the patient cohort.

c. To correlate Clinical outcomes with genomic information, MRD status and Microbiome information.

c. Exploratory Objectives

a. To explore the immune cell profile at defined time points in patients undergoing therapy.

b. To explore the molecular pathways within the immunological tumour microenvironment

c. In patients undergoing hematopoietic cell transplant, explore the immunological interactions, specifically KIR related, between the donor cells and host environment.

Materials and Methods

Treatment Plan: Standard of Care Practise as per established guideline, with

Induction Therapy: Intensive Chemotherapy or modified, as per standard of care

Consolidation Therapy: Consolidation Chemotherapy with or without Consolidation Hematopoietic Cell transplant (HCT) as indicated, based on standard of care practise

Bio-marker Informed Concurrent Targeted/Precision Therapy with FDA approved agents

Maintenance Therapy

Samples: Bone marrow, Peripheral blood, Saliva, Faeces, and buccal swab collected at study pre-defined time points; and Bio-Banking

Study Methods:

NGS (and Data storage): Whole exome Sequencing, Targeted Sequencing and Methylation assay

Integration of genomic signatures for characterization and identifying new bio-markers in adult AML

Developing and evaluating the role of minimal residual disease in adult AML: MRD assessment by flowcytometry: Standardising methodology and Reporting; and MRD assessment by Next generation Sequencing

Cytoscan HD

Microbiome analysis: Exploring the clinical impact of longitudinal (oral and stool) microbiome composition in adult AML patients

Statistical Analysis

Training and capacity building

Study population

Inclusion criteria

Adult subjects ≥ 18-60 years of age who are able to understand study procedures, comply with them, and provide written informed consent before any study-specific procedure. Cytologically or histologically confirmed diagnosis of AML & MDS-EB2 (except acute promyelocytic leukemia and therapy related AML/MDS) according to the 2008 World Health Organization (WHO) classification (bone marrow [BM] or peripheral blood [PB] blast counts ≥20%).

Exclusion criteria

Known clinically active central nervous system (CNS) or extramedullary AML, except leukemia cutis, Relapsed or Refractory AML, BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).

End points/outcome measures

Primary endpoints

To describe proportion of patients with adequate ‘individual’ Comprehensive Genomic profiling (genome, methylome, etc.). To describe MRD information of patients undergoing therapy for AML/MDS-EB by Standardized and validated MRD assays. To establish and report patient specific Computational drug modelsusing individual patient derived comprehensive genomic information.

Secondary endpoints

 Describe the Alpha and beta diversity of microbiome within patients at different time points and between patients, 30-day all-cause mortality, Composite Response Rates including MRD, duration of CR, 2y OS, 2y PFS, incidence and severity of adverse events. [Subject and investigator-observed AEs], MDRO colonization rate of patients, to correlate patient clinical outcomes with background Genomics, MRD and Microbiome Information.

Tertiary endpoints

To describe the ‘potential’ impact of Individual patient Computational Drug Model with their clinical outcomes, to establish a Drug Screening Platform for patient derived Cell lines, to describe the changes in immune cell profile in the peripheral blood of patients during therapy and Cost-effectiveness.