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Therapy-related Myelodysplasia (T-MDS/T-AML) Following Treatment Of Children With Osteosarcoma

Diana Stripp, MD

University of Pennsylvania Cancer
Last Modified: May 15, 2001

Presenter: Smita Bhatia
Affiliation: City of Hope Comprehensive Cancer Center, Duarte, CA

Background:

1. T-MDS/T-AML is known to be associated with anti-neoplastic treatment.
2. With alkylating agents, T-MDS/T-AML is associated with deletion of chromosome 5 and/or 7, with a long latency (4-7 yrs) and MDS.
3. With Topoisomerase II, abnormality of 11q23, shorter latency period (2-3 yrs) and lack MDS feature.
4. This trial is designed to study T-MDS/T-AML in children treated for osteosarcoma, to identify risk factors and evaluate the effect of ifosfomide.

Materials and Methods:

1. 778 children and adolescents diagnosed with osteosarcoma between 1992 and 1997 (and treated according to a therapeutic protocol: CCG-7921/POG- 9351) were entered to this phase III, prospective, randomized trial of two chemotherapy regimens:
2. A - high-dose methotrexate (cumulative dose: 144 g/m2), doxorubicin (450 mg/m2) and cisplatin (480 mg/m2).
3. B - called for the administration of these agents plus ifosfamide (45 g/m2).

Results:

1. Median age at diagnosis (dx) was 14.0 yr. (range: 6.2-26.2), and median follow up was 2.6 years (yrs) (range: 0-6.1).
2. Thirteen patients (pts.) developed T-MDS/T- AML, and 11 had cytogenetic abnormalities.
3. 3 pts suffered a relapse of the primary disease prior to developement of T-MDS/T-AML and only those pts developed T-MDS/T-AML were subsequently analysed.
4. The cumulative incidence of T-MDS/T-AML, was 3.3±1.2% at 6 yr. The median time to development of T-MDS/T-AML was 3.1 yr. (range 1.7-4.7 yr.)
5. Relative risk of developing T-MDS/T-AML was no different between age of diagnosis, genders, treatment regimens, or between cytogenetic abnormalities.

Authors' Conclusions

1. Overall, the risk was similar for patients in both regimens.
2. The addition of ifosfamide at a cumulative dose of 45 g/m2 (Regimen B) did not increase the risk of T-MDS/T-AML.
3. Continued follow-up of this cohort is necessary to determine the incidence of late occurance of T-MDS/T-AML in this cohort.

Clinical/Scientific Implications:

1. Even though this trial showed the addition of ifosfamide did not increased the risk of developing T-MDS/T-AML, the follow-up period of this study is short.
2. The findings of this study are similar to other studies that showed a cummulative risk of developing a secondary malignancy is 2-3% at 4 yrs.