THERAPY-RELATED MYELODYSPLASIA AND ACUTE MYELOID-LEUKEMIA - CYTOGENETIC CHARACTERISTICS OF 115 CONSECUTIVE CASES AND RISK IN 7 COHORTS OF PATIENTS TREATED INTENSIVELY FOR MALIGNANT DISEASES IN THE COPENHAGEN SERIES
J. Pedersenbjergaard et al., THERAPY-RELATED MYELODYSPLASIA AND ACUTE MYELOID-LEUKEMIA - CYTOGENETIC CHARACTERISTICS OF 115 CONSECUTIVE CASES AND RISK IN 7 COHORTS OF PATIENTS TREATED INTENSIVELY FOR MALIGNANT DISEASES IN THE COPENHAGEN SERIES, Leukemia, 7(12), 1993, pp. 1975-1986
Therapy-related acute myeloid leukemia (t-AML), often presenting as my
elodysplasia (t-MDS), has become the most serious longterm complicatio
n of cancer therapy and offers a unique opportunity to study chemical
leukemogenesis. Seven cohorts of patients treated for six different ty
pes of primary tumor have been followed closely for leukemic complicat
ions, and 115 consecutive patients with t-MDS or t-AML, including 45 c
ases from the cohorts, have been investigated cytogenetically at our i
nstitutions during the past 16 years. In patients primarily treated wi
th alkylating agents, the risk of t-MDS and t-AML increased by approxi
mately 1% per year from 2 to at least 8 years after start of treatment
. In most cases, the disease presented as t-MDS with loss of a whole c
hromosome 5 or 7, or various parts of their long arms, and the leukemi
as were of FAB-subtypes M1, M2, or M4. In patients treated with drugs
targeting at DNA-topoisomerase II, such as etoposide, doxorubicin, 4-e
pidoxorubicin, or mitoxantrone combined with drugs reacting directly w
ith DNA, such as cisplatin or alkylating agents, the risk of leukemia
increased much more steeply from only one year after start of therapy.
These early onset cases often presented as overt leukemia of FAB-subt
ypes M4 or M5 with balanced translocations to chromosome bands 11q23 a
nd 21q22, whereas later onset cases often shared characteristics with
cases observed after therapy with alkylating agents alone. Both alkyla
tion of DNA and poisoning of DNA-topoisomerase II may result in develo
pment of t-AML with different clinical and cytogenetic characteristics
. There may be a synergistic leukemogenic effect between the two types
of drug, and in patients with germ cell tumors treated with etoposide
, cisplatin and bleomycin, reassessment suggested the risk of leukemia
to increase exponentially with increasing doses of cisplatin and etop
oside.