Correspondence

Long-Term Survivors of Acute Lymphoblastic Leukemia

N Engl J Med 2003; 349:1973November 13, 2003

Article

To the Editor:

Pui et al. (Aug. 14 issue)1 determined the rates of complications and survival among patients who were event-free for at least 10 years after childhood acute lymphoblastic leukemia. Overall survival among patients who had not undergone irradiation was comparable with that of the general U.S. population. However, neither the development of cardiac disease nor death from cardiac disease was mentioned. Increased frequencies of serious cardiac disease and cardiovascular risk factors have been described among survivors of childhood acute lymphoblastic leukemia.2,3 Because of the young age of the patients they studied and the relatively short follow-up period, Pui et al. probably underestimated the rate of cardiac complications, since death was their main study end point.

In a single-center cohort of 188 survivors of testicular cancer cured with chemotherapy who remained event-free at 10 years, we observed a high frequency of cardiovascular risk factors and 12 major cardiac events (6 percent), 10 of which were nonfatal. Accordingly, normal survival 10 years after treatment for cancer does not rule out the presence of serious cardiovascular complications.

Janine Nuver, M.D.
University Hospital Groningen, 9700 RB Groningen, the Netherlands

Alexandra W. van den Belt-Dusebout
Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands

Jourik A. Gietema, M.D., Ph.D.
University Hospital Groningen, 9700 RB Groningen, the Netherlands
j.a.gietema@int.azg.nl

3 References

1. 1

   Pui C-H, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 2003;349:640-649
   Full Text | Web of Science | Medline

2. 2

   Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 2001;19:3163-3172
   Web of Science | Medline

3. 3

   Oeffinger KC, Buchanan GR, Eshelman DA, et al. Cardiovascular risk factors in young adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2001;23:424-430
   CrossRef | Web of Science | Medline

Author/Editor Response

Nuver et al. raise an important issue. Late cardiotoxicity has indeed been observed in many clinical studies of childhood acute lymphoblastic leukemia in which anthracyclines were administered. Among the various risk factors for this complication, the cumulative dose of anthracyclines is the most important.1-3 Although there is no absolutely safe dose, a cumulative dose of 240 mg per square meter of body-surface area or less is generally associated with normal cardiac function after treatment.1-3

In a previous study we conducted, late cardiotoxic effects occurred in 8 percent of long-term survivors of acute myeloid leukemia who received a median cumulative dose of 335 mg per square meter (range, 100 to 515)4 but were not observed in long-term survivors of acute lymphoblastic leukemia over a median follow-up period of 18.9 years, probably because of the limited use of anthracyclines in our studies of acute lymphoblastic leukemia. Specifically, 50 to 75 mg of daunorubicin was used in studies 11 and 12 (of the series of 13 studies on which we reported); 100 mg of daunorubicin in studies 6, 9, and 13; and 180 mg of doxorubicin in study 10. Anthracyclines were not used in the other studies. Cardiac function has been normal in all 22 long-term survivors of acute lymphoblastic leukemia who have been evaluated with two-dimensional echocardiography, 12-lead electrocardiography, and 24-hour Holter monitoring in an ongoing study (unpublished data).

Ching-Hon Pui, M.D.
William E. Evans, Pharm.D.
Melissa M. Hudson, M.D.
St. Jude Children's Research Hospital, Memphis, TN 38015
ching-hon.pui@stjude.org

4 References

1. 1

   Sorensen K, Levitt G, Bull C, Chessells J, Sullivan I. Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity. J Clin Oncol 1997;15:61-68
   Web of Science | Medline

2. 2

   Nysom K, Holm K, Lipsitz SR, et al. Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 1998;16:545-550
   Web of Science | Medline

3. 3

   Sorensen K, Levitt GA, Bull C, Dorup I, Sullivan ID. Late anthracycline cardiotoxicity after childhood cancer: a prospective longitudinal study. Cancer 2003;97:1991-1998
   CrossRef | Web of Science | Medline

4. 4

   Leung W, Hudson MM, Strickland DK, et al. Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 2000;18:3273-3279
   Web of Science | Medline