Report of the Cancer Therapy Evaluation Program monitoring plan for secondary acute myeloid leukemia following treatment with epipodophyllotoxins.
BACKGROUND
Recent reports have documented the occurrence of treatment-related acute myeloid leukemia (AML) following therapy with epipodophyllotoxins. These reports have led to growing concern among oncologists, which could lead to premature abandonment of these agents at a time when the relationship between cumulative dose of epipodophyllotoxin and risk of treatment-related AML has not been determined.


OBJECTIVE
Because of the increasingly important role of epipodophyllotoxins in the treatment of several types of adult and pediatric tumors, the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of treatment-related AML following epipodophyllotoxin treatment.


METHODS
We identified 12 NCI-supported Cooperative Group clinical trials in which patients with solid tumors are being treated with epipodophyllotoxins at different cumulative doses. One trial is using a moderate dose of teniposide (900 mg/m2), and 11 trials are using etoposide at a low dose (< 1500 mg/m2), a moderate dose (1500-3999 mg/m2), or a high dose (> or = 4000 mg/m2). Cases of treatment-related AML and treatment-related myelodysplastic syndrome (MDS) (hereafter referred to as treatment-related AML/MDS) occurring in these trials are reported to CTEP, with initial analysis for each cumulative dose group triggered by the reporting of four cases of treatment-related AML/MDS in that group. For each analysis, total patient follow-up for the group is determined and cumulative 6-year incidence rate is calculated.


RESULTS
Three cases of treatment-related AML and one case of treatment-related MDS (with documented monosomy 7) were reported in a group of 207 patients who received etoposide at a low cumulative dose. The calculated 6-year rate of development of treatment-related AML/MDS was 3.2% (95% upper confidence interval bounded by 7.2%).


CONCLUSIONS
The 6-year cumulative rate of treatment-related AML/MDS (3.2%) is within the range previously reported for alkylator-based regimens that did not include epipodophyllotoxins.


CONCLUSIONS
Previous reports have suggested that higher cumulative doses of alkylators are associated with increased risk of treatment-related AML, and a critical goal of the monitoring plan is to determine whether a similar relationship exists for the epipodophyllotoxins. Estimates will be developed for leukemogenic risk for the moderate- and high-cumulative-dose groups when four cases of treatment-related AML/MDS have been identified within each group.
Smith
M A
MA
Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Rubinstein
L
L
Cazenave
L
L
Ungerleider
R S
RS
Maurer
H M
HM
Heyn
R
R
Khan
F M
FM
Gehan
E
E
D000208:Acute Disease; D000328:Adult; D002648:Child; D002986:Clinical Trials as Topic; D005047:Etoposide / Q000009:adverse effects; D006801:Humans; D015994:Incidence; D007951:Leukemia, Myeloid / Q000139:chemically induced*; D009190:Myelodysplastic Syndromes / Q000139:chemically induced*; D016609:Neoplasms, Second Primary / Q000139:chemically induced*; D011034:Podophyllotoxin / Q000009:adverse effects*
D005047:Etoposide; D011034:Podophyllotoxin