Myelodysplastic Syndromes and Myeloid Neoplasms

Myelodysplastic syndromes (MDS) are clonal haematological disorders characterized by haematopoietic cell dysplasia, peripheral blood cytopenias, and a predisposition for developing acute myeloid leukaemia (AML). Genetic investigations for detection of chromosomal rearrangements (karyotyping and FISH) and somatic variants (NGS) are valuable for improving the diagnosis and management of patients with unexplained cytopenias. Somatic variants detected by NGS may further distinguish previously defined morphological MDS subtypes. Multiple pathogenic variants have been suggested to have independent prognostic value and may predict duration of response to current therapies.

BCR-ABL

The BCR-ABL1 gene fusion is commonly seen in chronic myeloid leukaemia and acute lymphoblastic leukaemia. The detection and quantitation of transcript levels is important in the diagnosis, treatment, and monitoring of the patients with these disorders.

Test Name	BCR-ABL
Clinical Indication	Used in the differential diagnosis, monitoring, and for treatment selection in patients with laboratory evidence of certain types of leukaemia.
Gene(s)	BCR/ABL1 fusion
Method	Real-time PCR
Turn around time	2 – 4 days
Medicare Eligibility	73314 – criteria apply
Sample Type/ Collection Type	Blood 10mL EDTA tube or Bone Marrow 4mL EDTA tube
Special Instructions	Bone marrow and diagnostic specimens must be received by the laboratory within 48 hours of collection. No collections Friday. Specimens for monitoring purposes must be received in the laboratory within 72hrs from collection. Collection can occur any day.

FLT3/NPM1

Mutations in the FLT3 and NPM1 genes are seen in acute myeloid leukaemia (particularly in cases with a normal cytogenetic karyotype) and are of prognostic significance.

Test Name	Nucleophosmin & FLT3
Clinical Indication	For diagnosis, prognosis, and classification in acute myeloid leukaemia
Gene(s)	NPM1, FLT3
Method	Real-time PCR analysis; Conventional PCR and capillary electrophoresis
Turn around time	14 days
Medicare Eligibility	73314
Sample Type/ Collection Type	6mL Blood EDTA tube or 1 mL bone marrow EDTA tube
Special Instructions	Test is performed on either peripheral blood or bone marrow aspirate. Peripheral blood can be collected by a collector, bone marrow aspirate (doctor collect only) must be placed into EDTA.

Chromosome Studies

Non-random chromosomal rearrangements are associated with different types of haematology-oncology neoplasms. Cytogenetic investigation using a combination of technologies may assist in the diagnosis, prognosis and staging of the haematological malignancy. Conventional cytogenetic analysis Conventional chromosome analysis and targeted FISH are the premier tests for the investigation of haematological malignancies. The conventional chromosome study involves microscopic examination and screening of the whole genome at the cellular level to detect large genomic changes and chromosomal rearrangements that may be prognostic or diagnostic indicators in malignant disease.

Test Name	Chromosomes Bone Marrow	Chromosomes Lymph Nodes	Chromosomes Unstimulated Blood
Clinical Indication	For diagnosis, classification, and prognosis in haem-oncology
Gene(s)	All chromosomes
Method	Conventional chromosome analysis
Turn Around Time	Urgent 2 days; Routine 22 days	10 – 12 days	18 days
Medicare Eligibility	73290	73287	73290
Sample Type	Bone marrow aspirate	Lymph node	Blood
Collection Type	1mL in 1x lithium heparin tube	Sterile container of Antibiotic Transport Media.	6mL in 1x lithium heparin tube and 6mL in 1x tube
Special Instructions	Doctor collect only. Add aspirate to a 2mL lithium heparin tube and mix gently. Transport cooled or at room temperature.	See important notes below*.	None

*Doctor collect. Sample must be kept sterile and moist. DO NOT USE FORMALIN. USE ANTIBIOTIC TRANSPORT MEDIA available from the Histology Department of your local laboratory. For overnight transport cover large specimens with ANTIBIOTIC TRANSPORT MEDIA OR STERILE NORMAL SALINE and sent to your local laboratory IMMEDIATELY. Please indicate if specimen is to be shared with Histology.

Chromosome Microarray

Chromosome microarray (also known as molecular karyotyping) is an advanced genome-wide investigation used to detect sub-microscopic DNA changes that are not detectable by conventional karyotype and/or fluorescence in-situ hybridisation (FISH). This technique can be used in the diagnostic investigation of haematological malignancies such as chronic lymphocytic leukemia, to detect regions of loss and/or gain of DNA and copy neutral loss of heterozygosity (CNLOH). This test will provide information about the genes involved in regions of copy number alteration. The information provided will assist in diagnosis, prognosis and staging of the malignancy and patient management. Microarray and targeted FISH analysis has recently been established as the gold standard cytogenomic investigation of CLL.

Test Name	Chromosomes Unstimulated Blood
Clinical Indication	For diagnosis, classification, and prognosis in haem-oncology
Gene(s)	All chromosomes
Method	Microarray analysis
Turn around time	18 days
Medicare Eligibility	73290
Sample Type	Blood
Collection Type	6mL 1x lithium heparin tube and 6mL 1x EDTA tube
Special Instructions	None

Targeted Testing (FISH)

Fluorescence in-situ hybridisation (FISH) is a targeted molecular cytogenetic technique used for the investigation of precise chromosome regions, particularly relevant when a specific condition is suspected. The technique binds a colour labelled DNA probe to a specific region on the patient chromosomes. As this is a targeted test it is important when requesting a FISH test to indicate the clinical condition that is being tested for. A broad range of FISH is available for the detection of non-random rearrangements, deletions and chromosome aneuploidy that are associated with a haematological malignancy. FISH is a targeted investigation and has the benefit of screening large numbers of cells to detect clonal abnormalities.

Test Name	FISH Haem-Oncology
Clinical Indication	For diagnosis, classification, and prognosis in haem-oncology
Gene(s)	See list of panels and individual targets below
Method	FISH
Turn around time	2 – 14 days
Medicare Eligibility	73314 – Criteria applies
Sample Type	Bone marrow Aspirate
Collection Type	Lithium heparin tube
Special Instructions	Doctor Collect. No additional sample required. Test is performed with Chromosome analysis.

Panel Testing

AML Panel	PML/RARA; CBFB; Del5q; MLL; Del7q; IGH/MYC; Del 20q
Myelodysplastic syndrome	Del5q; del7q; IGH/MYC; MLL; ETV6; del 20q
ALL	IGH/MYC; BCR/ABL1; MLL; ETV6; IGH/FGFR3; CEP9; CEP 10; TP53; E2A/PBX1
Chronic Lymphocytic Leukemia	IGH/CCND1; ATM; CEP12; del 13q14; TP53; MYB; RB1
Multiple Myeloma	1pq; IGH/CCND1; IGH BA; del 13q14; TP53; IGH/FGFR3; IGH/MAF; IGH/MAFB; IGH/CCND3
Lymphoma	BCL6; IGH/MYC; IGH/CCND1; BIRC3/MALT1; RB1; del 13q14

Individual Probes

Syndrome/Indication		Chromosome location
Acute myeloid leukemia	AML/ETO	t(8;21)(q22,q22)
Acute myeloid leukemia	CBFB	inv(16)(p12;q22)
Acute promyelocytic leukemia	PML/RARA	(15;17)(q22;q21.1)
B lymphocytic leukemia/lymphoma	1:19 rearrangements	1:19 rearrangements
B-cell disorders	IGH	14q32
B-cell leukemias	MLL	11q23
B-Cell lymphomas	MYC	8q24
B-Cell lymphomas	BIRC3/MALT	t(11:18)(q21;q21)
B-Cell lymphomas	IGK	2p11.2
B-Cell lymphomas	IGL	22p11.2
Burkitt’s Lymphoma/ -like Leukemia	IGH/MYC/CEP8	t(8;14)(q23;q32)
Chronic lymphocytic leukemia	ATM	11q23
Chronic lymphocytic leukemia	BCL3	19q13.32
Chronic lymphocytic leukemia	Trisomy 12	centromere
Chronic lymphocytic leukemia	MYB	6q23
Chronic lymphocytic leukemia/Myeloma	13q deletion	13q14.3
Chronic lymphocytic leukemia/Myeloma	TP53 deletion	17p13
Chronic lymphocytic leukemia/Myeloma	RB1	13q14.3
Chronic myelomonocytic leukemia	PDGFRB BA	5q32
Follicular lymphoma	IGH/BCL2	t(14;18)(q32;21)
Leukemia	BCR/ABL	t(9;22)(q34;q11.2)
Leukemias including treatment related	Trisomy/monosomy 7	centromere
Mantle cell lymphoma/CLL	IGH/CCND1-XT	t(11;14)(q13;q32)
Multiple myeloma	1pq (CKS1B/CDKN2) amplification/deletion	1q21/1p32.3
Multiple myeloma	IGH/CCND3	t(6;14)(p21;q32.2)
Multiple myeloma	IGH/FGFR3	t(4;14)(p16.3;q32)
Multiple myeloma	IGH/MAF translocation	t(14;16)
Multiple myeloma	IGH/MAFB translocation	t(14;20)
Multiple myeloma	IRF4	6p25.3
Myelodysplastic syndromes	ETV6	12p13
Myeloid and lymphatic leukemias	1pq	1p36/1q25
Myeloid and lymphatic leukemias	Trisomy 9	centromere
Myeloid and lymphoid neoplasms	FIP1L1/PDGFRA: CHIC2- deletion	4q12
Myeloid leukemias	EVI1	3q26.2
Myeloid neoplasms	5q deletion (5q- syndrome)	5q31.2
Myeloid neoplasms	7q deletion	7q22/7q31
Myeloproliferative disorders	FGFR1	8p12
Myeloproliferative disorders/Myeloid neoplasms	20q deletion	20q12
Non-Hodgkin lymphomas	BCL6	3q26
Non-Hodgkin lymphomas	IGH/MALT1	t(14;18)(q32;q21)
Non-Hodgkin lymphomas	PAX 5	9p12
T cell leukemias	TCL1 breakapart	14q32.13

Myeloid Gene Panel

This panel offers comprehensive testing for genomic variants that can provide diagnostic and prognostic information for patients with myeloid neoplasms and myelodysplastic syndromes. It is based on international guidelines and best practices. If required, customisation to suit individual patient needs can be offered.

Test Name	Myeloid 63 gene panel
Clinical Indication	For diagnostic/prognostic work-up of AML/MDS.
Genes (63)	ABL1, ANKRD26, ARID1A, ASXL1, BCOR, BCORL1, BRAF, CALR, CBL, CEBPA, CREBBP, CSF3R, CUX1, CXCR4, DDX41, DNMT3A, ETNK1, ETV6, EZH2, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, MPL, MYD88, NF1, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PIM1, PPM1D, PTEN, PTPN11, RAD21, RHOA, RUNX1, SETBP1, SF3B1, SH2B3, SMC1A, SMC3, SRSF2, STAG2, STAT3, STAT5B, STAT6, TET2, TP53, U2AF1, WT1 and ZRSR2
Method	Next generation sequencing
Turn around time	4 weeks
Medicare Eligibility	73447
Sample Type/ Collection Type	Blood 4mL EDTA tube or Bone Marrow 4mL EDTA tube
Special Instructions	Specialist/consultant physician request only

PAN Haem panel

This panel combines genes from both Myeloid and Lymphoid Gene Panels, recognising that some haematological disorders require additional genes for their workup, classification and prognostication.

Test Name	PAN Haem 96 gene panel
Clinical Indication	For extended assessment of myeloid/lymphoid disorders.
Genes (96)	ABL1, ANKRD26, ARID1A, ASXL1, ATM, B2M, BCL2, BCOR, BCORL1, BIRC3, BRAF, BTK, CALR, CARD11, CBL, CCND1, CD79B, CEBPA, CREBBP, CRLF2, CSF3R, CUX1, CXCR4, DDX41, DNMT3A, EP300, ETNK1, ETV6, EZH2, FBXW7, FLT3, FOXO1, GATA1, GATA2, GNA13, GNAS, HRAS, ID3, IDH1, IDH2, IKZF1, IL7R, JAK1, JAK2, JAK3, KDM6A, KIT, KLF2, KMT2A, KMT2D, KRAS, MAP2K1, MEF2B, MPL, MYC, MYD88, NF1, NFKBIE, NOTCH1, NOTCH2, NPM1, NRAS, PAX5, PDGFRA, PHF6, PIM1, PLCG2, POT1, PPM1D, PRDM1, PTEN, PTPN11, RAD21, RHOA, RUNX1, SETBP1, SETD2, SF3B1, SH2B3, SMC1A, SMC3, SOCS1, SRSF2, STAG2, STAT3, STAT5B, STAT6, TCF3, TET2, TNFAIP3, TNFRSF14, TP53, U2AF1, WT1, XPO1 and ZRSR2
Method	Next generation sequencing
Turn around time	3 – 4 weeks
Medicare Eligibility	73447 (Myeloid) or 73448 (Lymphoid)
Sample Type/ Collection Type	Blood 4mL EDTA tube of Bone Marrow 4mL EDTA tube
Special Instructions	Specialist/consultant physician request only

Regions-of-interest (ROI) in the panel genes

All coding exons	ARID1A, ATM, B2M, BCL2, BCOR, BCORL1, CARD11, CEBPA, CREBBP, CSF3R, CUX1, CXCR4, DDX41, DNMT3A, EP300, ETV6, EZH2, FBXW7, FOXO1, GATA2, GNA13, ID3, IDH1, IDH2, IKZF1, IL7R, JAK1, JAK2, JAK3, KDM6A, KLF2, KMT2A, KMT2D, KRAS, MAP2K1, MPL, MYC, NF1, NFKBIE, NOTCH2, NRAS, PAX5, PDGFRA, PHF6, PIM1, POT1, PPM1D, PRDM1, PTEN, RAD21, RUNX1, SETD2, SH2B3, SMC1A, SOCS1, STAG2, STAT3, TCF3, TET2, TNFAIP3, TNFRSF14, TP53, ZRSR2.
Targeted coverage	ABL1 (exons 4-10), ANKRD26 (exons 1-4), ASXL1 (exons 10,12-13), BIRC3 (exons 6-9), BRAF (exon 15), BTK (exons 10-19), CALR (exon 9), CBL (exons 8-9), CCDN1 (exon 1), CD79B (exons 5-6), CRLF2 (exon 6), ETNK1 (exon 3), FLT3 (exons 11,13-17,20), GATA1 (exons 2-4), GNAS (exons 8-9), HRAS (exons 2-3), KIT (exons 2,8-11,13,17-18), MEF2B (exons 2-3), MYD88 (exons 3-5), NOTCH1 (exons 26-28, 34), NPM1 (exons 10-11), PLCG2 (exons 18-33), PTPN11 (exons 3,7-13), RHOA (exon 2), SETBP1 (exon 4), SF3B1 (exons 10-16), SMC3 (exons 10,13,19,23,25,28), SRSF2 (exon 1), STAT5B (exons 14-17), STAT6 (exons 8-18), U2AF1 (exons 2,6), WT1 (exons 7,9), XPO1 (exons 15-16).
Exons described as per the MANE select reference transcript.
All ROI include 5 bases into flanking introns.

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