Module - Haematological Malignancies 2 (SLS431)

STP

Aim of this module

This module provides trainees with an in-depth knowledge of the diagnosis, prognosis and molecular monitoring of patients with a range of complex haematological malignancies. It builds on the concepts and approaches identified in the haematological malignancies 1 module by investigating more complex and heterogeneous haematological neoplasms including myeloid (AML, MDS) and lymphoid malignancies (CLL, large B cell lymphomas). Trainees will appreciate the importance of the role of molecular genetics approaches for the correct classification of heterogeneous disorders such as AML and Diffuse large B-cell lymphoma (DLBCL). The trainee will acquire the skills required to diagnose and monitor patients with AML, MDS and certain lymphoid malignancies. These skills will also be applicable for other haematological malignancies such as acute lymphoblastic leukaemia, myeloma and less common lymphoid malignancies. At the end of this module the trainee will be able to understand and appreciate the interaction between the laboratory and the clinic for the management of these disorders.

Work-based learning outcomes


  1. Interact with relevant disciplines and apply appropriate approaches for the diagnosis and treatment of heterogeneous myeloid and lymphoid malignancies
  2. Recognise the main clinical features and morphological characteristics of AML, MDS, CLL and large B cell lymphomas
  3. Apply the appropriate testing strategy for a range of complex myeloid malignancies including AML, MDS, considering the approach for subclassification and prognosis of disease
  4. Implement the appropriate strategy for monitoring residual disease in patients with acute myeloid leukaemia
  5. Implement the appropriate testing strategy for a range of lymphoid malignancies including CLL and large B cell lymphomas, including assessment of lymphoid clonality 
  6. Appreciate the role of stem cell transplantation and monitor the presence of donor material by ‘chimerism analysis’
  7. Interpret and report on the relevant laboratory procedures for the diagnosis of a range of myeloid and lymphoid malignancies

Work-based Competencies


Learning outcome Title Knowledge
1 1,2,3

Receive samples and decide on the appropriate diagnostic pathway for patients with a suspected diagnosis of the following conditions : 

  • AML
  • MDS
  • CLL
  • Large B cell lymphoma
  • WHO classification of the relevant disorders
  • Usual clinical features of the relevant disorders
  • Morphological features of the peripheral blood
  • film,bone marrow aspirate, bone marrow trephine or lymph node biopsy (as appropriate) for the relevant disorders
  • Immunophenotypic features, where relevant, of the disorders
  • Interaction between different laboratory and clinical approaches for diagnosis
  • National and international guidelines for laboratory diagnosis of haematological malignancies
  • Identification of samples and documentation
  • Factors affecting sample quality and suitability for examinations
  • Appropriate choice of assays according to clinical details and results of other laboratory findings
  • Application of cytogenetic analysis to guide treatment choice
  • Significance of array CGH (SNP array) Storage of samples
2 3,5

Assist with the preparation of samples for analysis, selecting the correct sample processing pathway(s) :

  • AML
  • MDS
  • CLL
  • Large B cell lymphoma
  • Health and safety requirements for processing of fresh peripheral blood or bone marrow samples and cell culture
  • Cell culture and preparation of G-banded chromosomes
  • Factors affecting quality of samples for G-banding of leukaemia samples
  • Preparation of slides for analysis from paraffin embedded blocks
  • Selection of the appropriate area for analysis (eg morphological assessment of H&E stained slide)
  • Principles of relevant technologies
  • Health and safety requirements for use of appropriate equipment (eg fluorescence microscope)
  • Chromosomal changes in the relevant disorders
  • Role of molecular cytogenetics for diagnosis and prognosis
  • Application of molecular cytogenetic analysis to guide treatment choice
3 3,7

Analyse samples for clinically significant gene fusions

  • Basic chromosome identification
  • Karyotype analysis
  • Numerical and structural abnormalities
  • Correct ISCN nomenclature
  • Chromosomal changes in relevant disorders that are detectable by G-banding
  • Principles of relevant technologies g. FISH, RT-PCR, RNA-Seq 
  • Internal quality control for assays
  • Importance of external quality assurance
  • Role of validation and verification of procedures and equipment
  • Understanding of ISO 15189 or equivalent
  • National guidelines for pathways and procedures
4 3,7

Analyse samples for genomic rearrangements and or copy number variation (CNV) using standard laboratory methodology for patients referred at diagnosis

  • Requirements of the sample for successful nucleic acid extraction
  • Health and safety requirements for processing of fresh peripheral blood, bone marrow or paraffin embedded samples
  • Principles of molecular genetic approaches for identification of oncogene fusions
  • Choice of appropriate tests according to the suspected diagnosis eg G-band analysis, FISH, microarray, RNA-Seq
  • Limitations of each procedure including limit of detection, sensitivity and specificity
  • Factors affecting the quality of molecular results Interpretation of results
  • Integration of results with molecular cytogenetic data
  • Importance of knowledge of the transcript type or breakpoint for fusion genes
  • Consideration of rare and unusual transcript type or breakpoints
  • Internal quality control for assays Importance of external quality assurance
  • Role of validation and verification of procedures and equipment
  • Understanding of ISO 15189 or equivalent
  • National guidelines for pathways and procedures
5 3,7

Perform the appropriate genetic investigations for patients referred with CLL

  • Requirements of the sample for successful nucleic acid extraction
  • Health and safety requirements for processing of fresh peripheral blood, bone marrow or paraffin embedded samples
  • Principles of molecular genetic approaches for identification of acquired mutations
  • Choice of appropriate tests according to suspected diagnosis to include single nucleotide variation (SNV) and copy number variation (CNV)
  • Limitations of each procedure including limit of detection, sensitivity and specificity
  • Factors affecting quality of molecular results Interpretation of results
  • Common artefacts
  • Correct nomenclature for reporting of acquired mutations (ISCN or HGVS)
  • Internal quality control for assays Importance of external quality assurance
  • Role of validation and verification of procedures and equipment
  • Understanding of ISO 15189 or equivalent
  • National guidelines for pathways and procedures
6 3,5,7

 Perform the appropriate genetic investigations for patients referred with large B-cell lymphoma

  • Requirements of the sample for successful nucleic acid extraction
  • Health and safety requirements for processing of fresh peripheral blood, bone marrow or paraffin embedded samples
  • Principles of molecular genetic approaches for identification of acquired mutations
  • Choice of appropriate tests according to suspected diagnosis to include analysis of commonly observed gene rearrangements
  • Limitations of each procedure including limit of detection, sensitivity and specificity
  • Factors affecting quality of molecular results Interpretation of results
  • Common artefacts
  • Correct nomenclature for reporting of acquired mutations (ISCN or HGVS)
  • Internal quality control for assays Importance of external quality assurance
  • Role of validation and verification of procedures and equipment
  • Understanding of ISO 15189 or equivalent National guidelines for pathways and procedures
7 5,7

Analyse and interpret the result of Lymphoid clonality assessment (IG gene rearrangement) to aid the diagnosis of mature lymphoid malignancies

  • Requirements of the sample for successful nucleic acid extraction
  • Health and safety requirements for processing of fresh peripheral blood, bone marrow or paraffin embedded samples
  • Principles of molecular genetic approaches for identification clonal IG gene rearrangement
  • Choice of appropriate tests according to suspected diagnosis
  • Limitations of the procedure including limit of detection, sensitivity and specificity
  • Factors affecting quality of molecular results Interpretation of results
  • Common artefacts
  • International guidelines for the interpretation of gene rearrangement / clonality assays
8 3,4,5,7

Analyse samples for a range of sequence variants to aid diagnosis and prognosis.

  •  Quality analysis of samples for NGS and at each stage of the procedure
  • Different types of approach and panel relevant for the disease
  • Principles of the assays performed
  • Use of bioinformatic tools for the analysis of results Use of various databases to assess and classify variants (pathogenic vs variants of uncertain significance vs benign polymorphisms)
  • Tools to identify relevance of the variant detected Correct nomenclature for reporting of acquired variants (HGVS)
  • Considerations concerning inherited variants
  • Age related clonal haematopoiesis
  • Consent and ethical considerations for the use of next generation sequencing
  • Role of next generation sequencing as a “one size fits all test”
  • Role of large sequencing projects eg100K genomes project
  • National and international guidelines for interpretation of next generation sequencing
9 6,7

Prepare clinical reports for patients being investigated for a range of examples including :

  • AML
  • MDS
  • CLL
  • Large B cell lymphoma
  • Requirements for information to be provided on the report
  • Integration of all laboratory results for a final conclusion
  • Recommendations for future testing
  • National and international guidelines for diagnosis of relevant conditions
  • Factors affecting the interpretation of results
  • Role of multidisciplinary team meetings
  • Correct scientific and clinical nomenclature
  • Confidentiality and clinical governance
10 3,4

Analyse and interpret appropriate genetic investigations for the monitoring of patients (eg AML)

  • Requirements of the sample for successful monitoring of residual disease
  • Health and safety requirements for processing fresh samples
  • Principles of the techniques for monitoring residual disease
  • Choice of appropriate monitoring approaches for different patients
  • Limitations of each procedure including limit of detection, sensitivity and specificity
  • Factors affecting quality of molecular results Interpretation of results
  • National and international guidelines for monitoring of residual disease
  • Clinical and therapy relevance of monitoring results
11 3,6

Perform and interpret appropriate genetic investigations for the monitoring of patients after bone marrow transplantation

  • Principles of the techniques for post transplant chimerism analysis
  • Requirements of the sample for successful chimerism analysis
  • Limitations of the procedure including limit of detection, sensitivity and specificity
  • Factors affecting quality of molecular results Interpretation of results
  • Clinical implications of the results obtained
  • National and international guidelines for post transplant chimerism analysis
12 1,7

Assist with the preparation of cases to be discussed and reviewed in an MDT meeting with other healthcare professionals

  • Integration of laboratory and clinical findings for a final diagnosis
  • Identification of the most appropriate treatment Monitoring of residual disease
  • Role of NICE and clinical trials
  • National and international studies and projects
13 1

Observe a clinic where a patient is being given results of laboratory tests that include genetic analysis. Reflect on this experience and present to colleagues

  • Information regarding potential outcomes of a genetic test
  • Implications of the genetic results for diagnosis/prognosis
  • The role of the Healthcare professional providing the information to the patient
  • Principlas of patient centred careInteraction with patient
  • Consent issues (for patient testing and for observation by a trainee)
  • Professional behaviour
  • Role and process of active listening

Work-based assessment


Complete 3 Case-Based Discussion(s)
Complete 3 of the following DOPS and/or OCEs
Type Title
DOPS Perform and interpret FISH in a case of AML or MDS.
DOPS Perform and interpret FISH in a case of CLL or large B cell lymphoma
DOPS Interpret the results of a molecular genetic assay for the detection of acquired mutations.
DOPS Use bioinformatics tools to analyse the results of a next generation sequencing
DOPS Analyse the results of post transplant chimerism testing
DOPS Prepare a report for a patient diagnosed with AML, MDS, CLL or large B cell lymphoma
DOPS Carry out morphological assessment for a patient with AML, MDS, CLL or large B cell lymphoma
DOPS Prepare a draft report for an inappropriate referral
OCE Discuss patient results with a healthcare professional telephone or in person
OCE Discuss implications of receiving an unlabeled sample with a healthcare professional.
OCE Discuss an inapparopriate referral with a healthcare professaional
OCE Participate in an MDT meeting with other healthcare professionals

Module authors and contributors


Authors: Anthony Bench, Sheila O'Connor

Contributors: Jennie Bell, Anthony Bench, Michelle Bishop, Rachel Butler, Rosalind Ganderton, Victoria Hewitt, Emma Jenkinson, Sheila O’Connor, Anneke Seller