Comparison of Diagnostic Yield Among M-FISH, FISH Probe Panel and Conventional Cytogenetic Analysis in AML

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Brief Title

Comparison of Diagnostic Yield Among M-FISH, FISH Probe Panel and Conventional Cytogenetic Analysis in AML

Official Title

Comparison of Diagnostic Yield Among Multiplex Fluorescent in Situ Hybridization, Fluorescent in Situ Hybridization Probe Panel and Conventional Cytogenetic Studies in Acute Myeloid Leukemia

Brief Summary

      Conventional cytogenetic studies have been the gold standard for more than five decades for
      detecting genetic alterations that are greater than 10 Mb (mega base pairs) in size.
      Conventional cytogenetic studies have paved the way in identifying specific chromosomal
      aberrations associated with clinically and morphologically definitive subsets of
      hematological neoplasms.

      Fluorescence in situ hybridization (FISH) has become a reliable and rapid complementary test
      in targeting critical genetic events associated with diagnostics and prognosis in
      hematological neoplasms.

      With the lack of an evidence-based standardized algorithmic approach, misuse and
      overutilization of laboratory tests are common and result in increased health care costs and
      patient care complexity. In the current health care environment, which increasingly focuses
      on value and efficiency, it is critical for pathologists and clinicians to effectively
      navigate this environment and judiciously incorporate these high-complexity and expensive
      techniques into routine patient care. Going forward, cost-effective integration and
      appropriate test utilization will be a top priority across all medical disciplines. While
      conventional karyotyping provides a comprehensive view of the genome, FISH can detect cryptic
      or submicro¬scopic genetic abnormalities and identify recurrent genetic abnormalities in
      nondividing cells. As a consequence, it is commonly extrapolated that FISH will improve the
      sensitivity of detecting all genetic abnormalities compared with conventional karyotyping
      analysis. This assumption has then been translated in clinical practice to having clinicians
      and pathologists routinely ordering both conventional karyotyp¬ing and FISH studies in
      patients with hematological neoplasms. Depending on how comprehensive the FISH panel is, the
      cost for this testing may be quite expensive, and its additive value remains questionable.

      It is common practice for laboratories to use FISH panels in conjunction with karyotyping
      both in diagnostic specimens and during follow-up to monitor response to therapy.

      Multiplex FISH (M-FISH) represents one of the most significant developments in molecular
      cytogenetics of the past decade. In tumor and leukemia cytogenetics, two groups have been
      targeted by M-FISH to identify cryptic chromosome rearrangements not detectable by
      conventional cytogenetic studies: those with an apparently normal karyotype (suspected of
      harboring small rearrangements not detectable by conventional cytogenetics) and those with a
      complex aberrant karyotype (which are difficult to karyotype accurately due to the sheer
      number of aberrations).
    

Detailed Description

      Neoplastic hematology is at the forefront of personal¬ized medicine. The World Health
      Organization (WHO) classification incorporates genetic data with microscopic,
      immunophenotypic, and clini¬cal findings and categorizes hematologic neoplasms into
      clinically and biologically distinct categories. This system guides diagnosis, prognosis and
      therapeutic choices, which has become increasingly important with emerging targeted therapies
      for lymphoma and leukemia. However, laboratory tests for hematologic neoplasms are of high
      complexity and are generally quite costly.

      The initial assessment of many hematologic neoplasms includes morphological, histological,
      immunophenotypic (flow cytometric and/or immunohistochemical), and conventional cytogenetic
      studies. Data obtained from cytogenetic analysis can be pathognomonic for specific leukemias
      in the WHO classification (for example, acute myeloid leukemia (AML) with recurrent
      cytogenetic abnormalities and chronic myelogenous leukemia (CML)) and are likely to assume a
      greater role in defining specific categories in further classifications.

      Conventional cytogenetic studies have been the gold standard for more than five decades for
      detecting genetic alterations that are greater than 10 Mb (mega base pairs) in size. They
      have paved the way in identifying specific chromosomal aberrations associated with clinically
      and morphologically definitive subsets of hematological neoplasms.

      Fluorescent in situ hybridization (FISH) has become a reliable and rapid complementary test
      in targeting critical genetic events associated with diagnostics and prognosis in
      hematological neoplasms. FISH has addressed the issues with conventional cytogenetic studies
      by targeting interphase cells in addition to metaphases. It has become clear that FISH
      studies may also be an integral component of the diagnostic evaluation, particularly where
      the abnormality is "cryptic" i.e. not evident by conventional cytogenetic studies.

      Although complementary FISH testing increases the overall detection of aberrations, its
      benefit is not uniform across all types of hematological neoplasms. This is because FISH
      probes are restricted to the detection of only specific abnormalities and genetic alterations
      beyond the scope of the FISH probes would therefore be completely missed.

      It is common practice for laboratories to use FISH probe panels in conjunction with
      karyotyping both in diagnostic specimens and during follow-up to monitor response to therapy.
      FISH is targeted toward specific abnormalities, and results can be evaluated in an automated
      fashion on interphase nuclei, allowing for examination of more cells than conventional
      cytogenetic studies. FISH has higher analytic and, in certain circumstances, higher clinical
      sensitivity compared with conventional cytogenetic studies. The usage of FISH probe panels in
      aiding diagnosis or in monitoring follow-up samples of hematologic neoplasms is critical.

      The Eastern Collaborative Oncology Group (ECOG) compared conventional cytogenetic studies and
      FISH in AML patients and found that a probe panel to detect monosomy 5/deletion 5q, monosomy
      7/deletion 7q, trisomy 8, t(8;21), t(9;22), MLL rearrangements with various partners,
      t(15;17), and inv(16)/t(16;16), had a concordance between 98% and 100%. On the other hand, He
      et al study demonstrates the limited value of FISH testing in adult AML in the setting of an
      adequate karyotyping study.

      Despite of many significant technological advances made in recent years in the area of
      clinical genetic testing, conventional cytogenetic studies and routine FISH studies remain
      important laboratory testing tools available for evaluating hematologic neoplasms. Usually
      these two testing methods complement each other and often FISH serves to clarify and better
      define cytogenetic results. Therefore, there is a very strong expectation that cytogenetic
      and FISH results should confirm each other in spite of cases that appear to be exceptions.
      When conflicting results occur by these two testing methods on the same specimen, clinical
      laboratories are challenged to offer explanations based on empirical data beyond simply
      stating that it was or was not due to laboratory error.

      Multiplex FISH (M-FISH) represents one of the most significant developments in molecular
      cytogenetics of the past decade. In tumor and leukemia cytogenetics, two groups have been
      targeted by M-FISH to identify cryptic chromosome rearrangements not detectable by
      conventional cytogenetic studies: those with an apparently normal karyotype (suspected of
      harboring small rearrangements not detectable by conventional cytogenetics) and those with a
      complex aberrant karyotype (which are difficult to karyotype accurately due to the sheer
      number of aberrations).

      Zhang et al. used spectral karyotype (SKY) to re-evaluate the karyotypes of AML cases
      reported as normal by G-banding. This resulted in the identification of one case of
      t(11;19)(q23;p13), a subtle but recognized cytogenetic abnormality, and a minor clone
      containing monosomy for chromosome 7 in another case. In a similar study, Mohr et al.
      compared SKY to conventional karyotyping in patients with AML or MDS with normal karyotypes.
      No abnormalities were identified.

      With the lack of an evidence-based standardized algorithmic approach, misuse and
      overutilization of laboratory tests are common and result in increased health care costs and
      patient care complexity. In the current health care environment, which increasingly focuses
      on value and efficiency, it is critical for pathologists and clinicians to incorporate
      high-complexity and expensive techniques into routine patient care. While conventional
      cytogenetic studies provide a comprehensive view of the genome, FISH probe panel can detect
      cryptic or submicroscopic genetic abnormalities and identify recurrent genetic abnormalities
      in nondividing cells. M-FISH can identify cryptic chromosome rearrangements that are not
      detected by conventional cytogenetic studies. As a consequence, it is commonly extrapolated
      that FISH will improve the sensitivity of detecting all genetic abnormalities compared with
      conventional cytogenetic studies. This assumption has then been translated in clinical
      practice to having clinicians and pathologists routinely ordering both conventional
      cytogenetic studies and FISH studies in patients with hematological neoplasms. Depending on
      how comprehensive the FISH probe panel is, the cost for this testing may be quite expensive,
      and its additive value remains questionable.
    


Study Type

Observational


Primary Outcome

Comparing Diagnostic Yield among Multiplex Fluorescent in situ hybridization, fluorescent in situ hybridization probe panel and conventional cytogenetic analysis in newly diagnosed patients with AML.


Condition

Acute Myeloid Leukemia

Intervention

Conventional Cytogenetics Studies

Study Arms / Comparison Groups

 Acute Myeloid Leukemia (AML) group
Description:  Patients who are diagnosed as Acute Myeloid Leukemia based on peripheral blood, bone marrow aspiration and immunophenotyping and fulfill WHO criteria for diagnosis.
Fluorescent in Situ Hybridization (FISH) Panels for AML, Multiplex FISH (M-FISH) and Conventional Cytogenetics Studies will be performed for AML patients.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

50

Start Date

July 1, 2020

Completion Date

January 31, 2021

Primary Completion Date

December 31, 2020

Eligibility Criteria

        Inclusion criteria:

          1. Patients with newly diagnosed acute myeloid leukemia.

          2. Age group: patients more than 18 years old.

        Exclusion criteria:

          1. Patients less than 18 years old.

          2. Patients with other types of hematologic neoplasms.

          3. Relapsed patients.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Eman Mosaad, MD, , 

Location Countries

Egypt

Location Countries

Egypt

Administrative Informations


NCT ID

NCT03719183

Organization ID

AssiutU-SECI-Cytogenetic 100


Responsible Party

Principal Investigator

Study Sponsor

Assiut University

Collaborators

 South Egypt Cancer Institute

Study Sponsor

Eman Mosaad, MD, Study Director, South Egypt Cancer Institute


Verification Date

February 2020