This leukemia occurs as a late complication of cytotoxic and/or radiation therapy.
There is a spectrum of disease with three stages of therapy-related panmyelosis (damage to bone marrow from treatment):
- Pancytopenia with associated myelodysplastic changes
- Frank myelodysplastic syndrome (MDS)
- Overt acute myeloid leukemia (AML)
Etiology:
The main commonly implicated agents are the topoisomerase II inhibitors (Etoposide), alkylating agents and large field ionizing radiation including bone marrow.
The majority of patients will have been exposed during therapy for a malignant condition, t-AML can occur following therapy for non-malignant conditions.
Incidence depends on prior therapy and disease. Patients with underlying disorders of DNA repair or drug metabolism may be at increased risk.
Recent studies have shown an increased risk with:
- Dose intensification (high doses of alkylating agents)
- Support with G-CSF (related to high doses)
Alkylating agents and ionizing radiation associated leukemia:
- Risk associated with alkylating agents and radiation increases with age
- Occurs approximately 5-10 years following exposure
- Morphologically there are typically dysplastic features and commonly a myelodysplastic syndrome will proceed to overt leukemia.
- Cytogenetically, there is commonly but not exclusively loss of genetic material, typically from chromosomes 5 or 7.
Topoisomerase II inhibitor associated leukemia:
- Risk associated with topoisomerase inhibitors is similar across age groups
- Less frequent group of t-AML
- Occurs earlier, typically from 1 to 5 years following exposure to topoisomerase II inhibitors.
- These are typically not dysplastic in morphology and present as leukemia.
- Balanced cytogenetic abnormalities rather than loss of genetic material are most often seen, particularly involving 11q23 (see MLL amplification in leukemia) or 21q22 (RUNX1). Lymphoid leukemia can occur also.
Onset:
About 30% of cases presenting in MDS phase evolve to AML in one to 12 months
The myelodysplastic phase, with or without evolution to acute leukemia, is a highly lethal disease with a median survival comparable to that of the patients who present with AML.
Classification:
- Half of AML cases not readily classified according to French-American-British (FAB) criteria because multiple cell lines are involved.
- Among cases that can be classified M2 is the most frequent type.
- Clonal chromosome abnormalities very common (often abnormalities of chromosomes 5 and/or 7).
Prognosis:
The prognosis is generally poor with 5-year survival approximately 10%. However this is influenced by the karyotype and status of the original malignancy for which therapy was given.
Abnormalities of chromosome 5 and 7 have a median survival less than one year whereas t(15;17) or inv(16) may have similar survival to their de novo counterparts.
Differences between t-AML and de novo AML:
Therapy related AML has:
- A high incidence of trilineage involvement
- Difficulty in classification
- Frequent cytogenetic abnormalities
- Poor response to antileukemic therapy
The author and literary critic Susan Sontag died of secondary myelodysplasia/leukemia. Her son wrote a memoir about her initial treatment for breast cancer and then her subsequent illnesses, therapy and death. This book is reviewed in the New York Review of Books.
