Etiology and Management of
Therapy-Related Myeloid Leukemia
Richard A. Larson
Department of Medicine and Cancer Research Center, University of Chicago, Chicago, IL
The diagnosis of therapy-related myeloid leukemia
(t-MDS/t-AML) identifies a group of high-risk patients
with multiple and varied poor prognostic features.
These neoplasms are thought to be the direct conse-
quence of mutational events induced by cytotoxic
therapy. Their outcomes have historically been poor
compared with those of people who develop acute
myeloid leukemia (AML) de novo. The question arises
whether a diagnosis of t-AML per se indicates a poor
prognosis, or whether their bad outcomes result from
other clinical and biologic characteristics. Because of
lingering damage from prior cytotoxic therapy and, in
some cases, the persistence of their primary disorder,
patients with t-AML are often poor candidates for
intensive AML therapy. The spectrum of cytogenetic
abnormalities in t-AML is similar to de novo AML, but
the frequency of unfavorable cytogenetics, such as a
complex karyotype or deletion or loss of chromo-
somes 5 and/or 7, is higher in t-AML. Survival varies
according to cytogenetic risk group, with better
outcomes observed in patients with t-AML with
favorable-risk karyotypes. Treatment recommenda-
tions should be based on performance status and
karyotype. Patients with t-AML should be enrolled on
front-line chemotherapy trials, appropriate for de novo
AML patients with similar disease characteristics.
Allogeneic hematopoietic cell transplantation can cure
some patients with t-AML. Most important , the
molecular and genetic differences that appear to
determine the phenotype and the outcome of these
patients need to be investigated further.
What Further Therapy Would You
Recommend for These Patients?
Patient 1: A 50-year-old woman developed carcinoma of
the ampulla of Vater and underwent surgical resection,
followed by 60 Gy local radiation therapy plus 5-fluorou-
racil. Three years later, she presented with leukocytosis
and peripheral myeloblasts. She was diagnosed with
acute myeloid leukemia. Her karyotype was 46,XX,inv(16).
She achieved a complete remission (CR) after 1 course
of continuous infusion cytarabine plus 3 doses of
daunorubicin. She received 1 course of consolidation
therapy with high-dose cytarabine. She had no siblings.
Several volunteers who were mismatched at one HLA
allele were listed in the National Marrow Donor Program
Patient 2: A 30-year-old man presented with superior
vena cava syndrome and was found to have a large
mediastinal mass. A diagnosis of Hodgkin lymphoma,
nodular sclerosis subtype, stage IIB was made. He
achieved a CR after 6 cycles of ABVD (doxorubicin,
bleomycin, vinblastine, dacarbazine) followed by 30 Gy
radiation to the residual mass. Two years later, the
Hodgkin lymphoma recurred in the mediastinum and
lung. He achieved a second remission after 2 courses of
gemcitabine, navelbine, and Doxil. Stem cells were
mobilized with cyclophosphamide, and he underwent
autologous transplantation after BEAM (carmustine,
etoposide, cytarabine, melphalan) chemotherapy. Three
years later, he became pancytopenic and was diagnosed
with therapy-related myeloid leukemia. His karyotype
was 45,XY,–7. A CR was induced with high-dose cytara-
bine and mitoxantrone. He had no siblings, but several
HLA-matched donors were listed in the NMDP registry.
Therapy-related myeloid leukemia (t-MDS/t-AML) is a
well-recognized clinical syndrome occurring as a late com-
plication following cytotoxic therapy.1-5 The term “therapy-
related” leukemia is descriptive and based on a patient’s
history of exposure to cytotoxic agents. Although a causal
relationship is implied, the mechanism remains to be proven.
These neoplasms are thought to be the direct consequence of
mutational events induced by cytotoxic therapy, or via the
selection of a myeloid clone with a mutator phenotype that
has a markedly elevated risk for a mutational event. Sev-
eral distinct clinical and cytogenetic subtypes of t-AML
are recognized that are closely associated with the nature
of the preceding treatment. The latency between primary
diagnosis and therapy-related disease ranges between a few
months to several years, depending in part on the cumula-
tive dose or dose intensity of the preceding cytotoxic
therapy, as well as the exposure to specific agents. Most
patients have clonal chromosome abnormalities in their
bone marrow cells at diagnosis. A spectrum of morpho-
logic abnormalities is observed.4,5 There is a continuum in
the percentage of marrow blasts from a myelodysplastic
syndrome (t-MDS) to overt acute myeloid leukemia (t-
AML), and rapid progression from the former to the latter.
Thus, it is reasonable to consider this as a single clinical
syndrome. The clinical course is typically progressive and
relatively resistant to conventional therapies used for leu-
kemias arising de novo.
Hematology 2007 459
cytogenetic abnormalities. Patients who have an HLA-
matched donor should be considered for allogeneic HCT,
although patients with favorable karyotypes may do well
with conventional chemotherapy.
Supported in part by grants CA40046 and CA14599 from the
National Cancer Institute, USA.
Richard A. Larson, MD, University of Chicago, MC-2115, 5841
S. Maryland Avenue, Chicago, IL 60637; phone (773) 702-6783;
fax (773) 702-3002; firstname.lastname@example.org
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