Sorted By Test Name - Mayo Medical Laboratories

BAKDM
89609
Detecting all known forms of the Philadelphia (Ph) chromosome Identifying and monitoring of the Ph
chromosome in patients with CML, acute lymphocytic leukemia (ALL), or acute myeloid leukemia
(AML) It is recommended that conventional chromosome analysis (BM/8506 Chromosome Analysis, for
Hematologic Disorders, Bone Marrow) also be performed at initial diagnosis. Subsequently, D-FISH
alone can be used to monitor the effectiveness of therapy.
Interpretation: Specimens that contain > or =1% neoplastic nuclei with BCR and ABL1 fusion have a
high likelihood of having a clone with t(9; 22) (q34; q11.2) or a variant of this anomaly. Specimens with
1% disease when 500 interphase nuclei are scored and >0.079% disease when 6,000 nuclei are
scored. To monitor the effectiveness of therapy, it is useful to divide the percentage of neoplastic cells
after therapy by the percentage of neoplastic cells before treatment. Many clinicians use this calculation to
classify the patient's response to therapy according to the table below. Cytogenetic Response to Therapy
Percent Neoplastic Nuclei Post-treatment Relative to Pretreatment Absent 100% Minimal 67%-99%
Minor 33%-66% Major 1%-32% Complete 0%
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Dewald GW, Wyatt WA, Silver RT: Atypical BCR and ABL D-FISH
patterns in chronic myeloid leukemia and their possible role in therapy. Leuk Lymphoma
1999;34(5-6):481-491 2. Dewald GW, Juneau AL, Schad CR, Tefferi A: Cytogenetic and molecular
genetic methods for diagnosis and treatment response in chronic granulocytic leukemia. Cancer Genet
Cytogenet 1997;94:59-66 3. The Italian Cooperative Study Group on Chronic Myeloid Leukemia:
Interferon alpha-2a as compared with conventional chemotherapy for the treatment of chronic myeloid
leukemia. N Engl J Med 1994;330:820-825 4. Dewald GW: Interphase FISH studies for chronic myeloid
leukemia. In Methods in Molecular Biology. Vol 204. Molecular Cytogenetics: Protocols and
Applications. Edited by YS Fan. Totowa, NJ, Humana Press, USA, 2002 pp 311-342
BCR/ABL, Tyrosine Kinase Inhibitor Resistance, Kinase Domain
Mutation Screen
Clinical Information: Chronic myeloid leukemia (CML) is characterized by the presence of the
t(9:22) BCR-ABL abnormality, resulting in formation of a fusion BCR-ABL mRNA and protein. The
ABL component of this oncoprotein contains tyrosine kinase activity and is thought to play a central role
in the proliferative phenotype of this leukemia. Recent advances have resulted in a number of therapeutic
drugs that inhibit the ABL tyrosine kinase, as well as other protein tyrosine kinases. Imatinib mesylate
(Gleevec, Novartis) is the prototype of these tyrosine kinase inhibitors (TKIs), which are capable of
inducing durable hematologic and (in most patients) cytogenetic remissions. Unfortunately, a significant
subset of patients can develop functional resistance to TKIs, due in a large number of tumors to the
acquisition of point mutations in the kinase domain (KD) of the chmeric ABL gene. To date, over 50
distinct mutations have been described, although 15 of these account for more than 80% of the mutations
encountered and have well documented in vitro or clinical resistance to TKIs. Recognition of TKI
resistance is important in CML, as the effect of some mutations can be overcome by increasing imatinib
dosage, whereas others require switching to either a different (second-generation) TKI, or alternative
therapy. The common T315I KD mutation is particularly important, given that this alteration confers
pan-resistance to all currently employed TKIs. Typically, TKI resistance is suspected in a CML patient
who shows loss of initial therapeutic response (eg, cytogenetic relapse), or a significant and sustained
increase in molecular BCR-ABL quantitative levels. Similar considerations are also present in patients
with Philadelphia chromosome positive (Ph+) B-cell acute lymphoblastic leukemia (ALL), who can also
be treated using TKI therapy. Point mutations in ABL are typically detected by direct sequencing of PCR
products, following RT-PCR amplification of the BCR-ABL mRNA transcript from a peripheral blood
specimen. However, direct sequencing has limited analytic sensitivity (approximately 20-30% mutant
alleles). In contrast, this test utilizes a novel strategy to detect 15 of the most common ABL KD mutations
accounting for > 80% of the most common and clinically important mutations. The sensitivity of this
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