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Acute Myeloid Leukemia, Genetics, and Risk Stratification: Data Overload or Ready for a Breakthrough?

  • Simon B. Zeichner
Published/Copyright: July 1, 2012
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Journal of Osteopathic Medicine
From the journal Journal of Osteopathic Medicine Volume 112 Issue 7

To the Editor:

Acute myeloid leukemia (AML) consists of a group of relatively well-defined hematopoietic neoplasms involving precursor cells committed to the myeloid line of cellular development. These neoplasms account for 80% of all adult leukemias, with an incidence of approximately 3 to 5 cases per 100,000.1,2

Until 2010, AML was classified according to the French-American-British classification system.3 This classification scheme, proposed in 1976, divided AML into 8 distinct subtypes (M0-M7) on the basis of type of cell from which the leukemia developed and the condition's degree of maturity. Classification relied heavily on the appearance of the malignant cells as seen with light microscopy.

With advancing technology and increasing insight provided by cytogenetics research, a new AML classification scheme was devised. In 2008, the World Health Organization (WHO) classified AML on the basis of a combination of morphologic, immunophenotypic, genetic, and clinical features.4 The 4 main groups in this WHO system were (1) AML with recurrent genetic abnormalities—inv(3), inv(16), t(1;22), t(6;9), t(8;21), t(9;11), t(15;17), mutated CEBPA, or mutated NPM1; (2) AML with features related to myelodysplastic syndromes; (3) therapy-related AML; and (4) AML not otherwise specified. This landmark WHO classification4 was notable not only because it allowed the incorporation of clinical and immunohistochemistry data with new genetic data, but also because it introduced genetic risk stratification into treatment for patients with AML.

Risk stratification was nothing new in cancer research. Since 1952, when Pierre Denoix of the Institute Gustave-Roussy devised the TNM (tumor, lymph nodes, metastasis) staging system for solid tumors, physicians around the world had been determined to devise improved ways to predict tumor behavior and patient survival.5 During the late 20th century—despite the advances in risk stratification for solid tumors—prognostication in hematologic malignancies, such as AML, remained difficult. Overall survival rates with AML treatment were extremely heterogeneous, and no one could easily predict which patients would do poorly. The only poor prognostic signs that had been identified for AML were advanced age at diagnosis (>55 years), poor performance status (Eastern Cooperative Oncology Group performance score ⩾3), exposure to cytotoxic agents or radiation therapy, and history of previous myelodysplasia.6-15

In the early 21st century, with additional research and increased emphasis on cytogenetics, AML has been further subdivided on the basis of karyotype—favorable, intermediate, and unfavorable.16 Favorable karyotypes (occurring in 16% of patients) consist of inv(16), t(8;21), t(15;17), and t(16;16). Intermediate karyotypes (20% of patients) are those abnormalities not described as favorable or unfavorable. Unfavorable karyotypes (13% of patients) include add(5q), add(7q), del(5q), del(7q), inv(3), t(3;3), t(6;11), t(9;22), t(10;11), 17p abnormalities, monosomies 5 or 7, monosomy 17, and many others. Attesting to the heterogeneity of the disease, 10-year survival rates have been found to be 69%, 38%, 33%, and 12% for patients with favorable risk, normal karyotype, intermediate risk, and unfavorable risk, respectively.16

With the outpouring of genetics research and data in the 2000s, there have been continual questions within the research community regarding whether patient characteristics in the new WHO classification scheme correspond to other genetic abnormalities. Patients with therapy-related AML secondary to DNA topoisomerase inhibitors typically have been found to have abnormalities involving the MLL gene at chromosome locus 11q2317 or the RUNX1 gene at chromosome locus 21q22.18-22 There is a high frequency of the loss of the long arms of chromosomes 5 and 7 among patients with myelodysplasia-associated AML.23,24 In addition, patients with AML not otherwise specified have been found to have mutations in the FLT-3ITD/TKD, NRAS, BAALC, and WTI genes.25-41

Although correlating studies continue to this day, physicians currently have an abundance of prognostic information for their patients with AML. This information allows physicians to accurately risk-stratify patients on the basis of their extensive tumor profiles.

Despite the wealth of information acquired over the past 10 to 15 years, overall patient survival—the gold standard in cancer research—remains unchanged. Current standards of hematologic practice dictate that patients with poor cytogenetic profiles be evaluated for bone marrow transplant. However, no randomized, controlled trials have described benefits from this approach or whether certain chemotherapeutic regimens (excluding treatments for acute promyelocytic leukemia) are more effective for patients with certain cytogenetic abnormalities.

We have entered a new frontier in cancer research—a frontier full of hope and opportunity for improvement. Thousands of dedicated researchers have helped describe a multitude of genetic abnormalities associated with AML. However, this research is only a piece of the puzzle. We must expand our new knowledge and develop innovative approaches and treatment regimens for patients with AML to extend the overall survival rate of these individuals.

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Published Online: 2012-07-01
Published in Print: 2012-07-01

© 2012 The American Osteopathic Association

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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https://doi.org/10.7556/jaoa.2012.112.7.463
Creative Commons
BY-NC-ND 4.0

Articles in the same Issue

  1. AOA Communication (Reprints)
  2. Official Call
  3. Proposed Amendments to the AOA Constitution and Code of Ethics and New “Rules and Guidelines”
  4. Letters
  5. Efficacy of a Physician's Words of Empathy: An Overview of State Apology Laws
  6. Ecthyma Gangrenosum Caused by Pseudomonas aeruginosa
  7. The Somatic Connection
  8. “How much lymph can a lymph pump pump if a lymph pump can pump lymph?”
  9. Myofascial Release Therapy's Effect on Immune System in Breast Cancer Survivors Modulated by Positive Attitude
  10. Myofascial Trigger Point Massage Reduces Pain of Chronic Tension-Type Headache
  11. Massage Shown to Benefit Patients With Chronic Low Back Pain
  12. Oropharyngeal Exercises Improve Sleep Apnea
  13. Adjunctive OMT May Improve Exercise Capacity for Patients With Severe COPD
  14. Special Reports
  15. Joining Forces Initiative: Steps Toward Improved Care for Military Personnel
  16. Military Medicine Content in an Osteopathic Medical School's Curriculum
  17. Original Contributions
  18. Somatic Dysfunction and Its Association With Chronic Low Back Pain, Back-Specific Functioning, and General Health: Results From the OSTEOPATHIC Trial
  19. Cervical Spine Bending: A Factor Confounding Whole Trunk and Lumbar Forward Bending Range of Motion
  20. Use of and Attitudes Toward Complementary and Alternative Medicine Among Osteopathic Medical Students
  21. Special Communication
  22. A New Triadic Paradigm for Osteopathic Research in Real-World Settings
  23. Case Report
  24. Osteopathic Manipulative Treatment to Resolve Head and Neck Pain After Tooth Extraction
  25. Clinical Images
  26. Sister Mary Joseph Nodule From Prostate Cancer
  27. Letters
  28. Acute Myeloid Leukemia, Genetics, and Risk Stratification: Data Overload or Ready for a Breakthrough?
  29. Thinking Osteopathically
  30. Correction
  31. Correction
  32. CME Quiz
  33. CME Quiz
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