Report of the cancer therapy evaluation program monitoring plan for secondary acute myeloid leukemia following treatment with epipodophyllotoxins

Malcolm A. Smith, Lawrence Rubinstein, Lorraine Cazenave, Richard S. Ungerleider, Harold Maurice Maurer, Ruth Heyn, Farced M. Khan, Edmund Gehan

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Abstract

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 epipo-dophyllotoxin and risk of treatment-related AML has not been determined. Purpose: 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 epipodophyl-lotoxin 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 teni-poside (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 (≥4000 mg/m2). Cases of treatment-related AML and treatment-related myelo-dysplastic 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. Implications: 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 leuke-mogenic risk for the moderate- and high-cumulative-dose groups when four cases of treatment-related AML/MDS have been identified within each group.

Original languageEnglish (US)
Pages (from-to)554-558
Number of pages5
JournalJournal of the National Cancer Institute
Volume85
Issue number7
DOIs
StatePublished - Apr 7 1993

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Podophyllotoxin
Program Evaluation
Leukemia
Acute Myeloid Leukemia
Acute
Therapy
Cancer
Monitoring
Dose
Tumors
Neoplasms
Pediatrics
Therapeutics
Program evaluation
National Cancer Institute (U.S.)
Alkylating Agents
Etoposide
Tumor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Report of the cancer therapy evaluation program monitoring plan for secondary acute myeloid leukemia following treatment with epipodophyllotoxins. / Smith, Malcolm A.; Rubinstein, Lawrence; Cazenave, Lorraine; Ungerleider, Richard S.; Maurer, Harold Maurice; Heyn, Ruth; Khan, Farced M.; Gehan, Edmund.

In: Journal of the National Cancer Institute, Vol. 85, No. 7, 07.04.1993, p. 554-558.

Research output: Contribution to journalArticle

Smith, Malcolm A. ; Rubinstein, Lawrence ; Cazenave, Lorraine ; Ungerleider, Richard S. ; Maurer, Harold Maurice ; Heyn, Ruth ; Khan, Farced M. ; Gehan, Edmund. / Report of the cancer therapy evaluation program monitoring plan for secondary acute myeloid leukemia following treatment with epipodophyllotoxins. In: Journal of the National Cancer Institute. 1993 ; Vol. 85, No. 7. pp. 554-558.
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abstract = "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 epipo-dophyllotoxin and risk of treatment-related AML has not been determined. Purpose: 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 epipodophyl-lotoxin 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 teni-poside (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 (≥4000 mg/m2). Cases of treatment-related AML and treatment-related myelo-dysplastic 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. Implications: 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 leuke-mogenic risk for the moderate- and high-cumulative-dose groups when four cases of treatment-related AML/MDS have been identified within each group.",
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AU - Rubinstein, Lawrence

AU - Cazenave, Lorraine

AU - Ungerleider, Richard S.

AU - Maurer, Harold Maurice

AU - Heyn, Ruth

AU - Khan, Farced M.

AU - Gehan, Edmund

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N2 - 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 epipo-dophyllotoxin and risk of treatment-related AML has not been determined. Purpose: 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 epipodophyl-lotoxin 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 teni-poside (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 (≥4000 mg/m2). Cases of treatment-related AML and treatment-related myelo-dysplastic 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. Implications: 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 leuke-mogenic risk for the moderate- and high-cumulative-dose groups when four cases of treatment-related AML/MDS have been identified within each group.

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