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Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 7936-7941
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.01.0033
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Risk of Adverse Events After Completion of Therapy for Childhood Acute Lymphoblastic Leukemia

Ching-Hon Pui, Deqing Pei, John T. Sandlund, Dario Campana, Raul C. Ribeiro, Bassem I. Razzouk, Jeffrey E. Rubnitz, Scott C. Howard, Nobuko Hijiya, Sima Jeha, Cheng Cheng, James R. Downing, William E. Evans, Mary V. Relling, Melissa Hudson

From the Departments of Hematology-Oncology, Pharmaceutical Sciences, Biostatistics, and Pathology, St Jude Children's Research Hospital; and Colleges of Medicine and Pharmacy, University of Tennessee Health Science Center, Memphis, TN

Address reprint requests to Ching-Hon Pui, MD, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: ching-hon.pui{at}stjude.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: We studied the frequency, causes, and predictors of adverse events in children with acute lymphoblastic leukemia (ALL) who had completed treatment on contemporary clinical protocols between 1984 and 1999. Our goal was to use the information to further refine therapy and advance cure rates.

METHODS: Cumulative incidence functions of any post-treatment failure or any post-treatment relapse were estimated by the method of Kalbfleisch and Prentice and compared with Gray's test. The Cox proportional hazards model was used to identify independent prognostic factors.

RESULTS: Of the 827 patients who completed all treatment while in initial complete remission, 134 patients subsequently had major adverse events, including 90 leukemic relapses, 40 second malignancies, and four deaths in remission. The cumulative incidence of any adverse event was 14.0% ± 1.2% (SE) at 5 years and 16.9% ± 1.4% at 10 years. The risk of any leukemic relapse was 10.0% ± 1.1% at 5 years and 11.4% ± 1.2% at 10 years. Male sex was the only independent predictor of relapse (hazard ratio, 1.74; 95% CI, 1.11 to 2.74; P = .02).

CONCLUSION: Further treatment refinements for children with ALL should aim not only to decrease the leukemic relapse rate, but also to reduce the risk of development of second malignancies.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Treatment outcome for children with acute lymphoblastic leukemia (ALL) has improved steadily over the past four decades, to the extent that up to 80% of patients treated in some effective clinical trials in the 1990s are cured of their disease.1-6 Although the adverse events in these studies developed mostly during treatment and consisted mainly of leukemic relapses, there was a substantial frequency of such events after the cessation of therapy that could be attributed to a variety of factors. Identification of the causes and predictors of these adverse events in patients who have completed treatment could be useful in refining clinical protocols, with the aim of decreasing the frequency of these events, thus increasing rates of event-free survival and cure. Our experience with post-treatment sequelae in children with ALL treated in the 1970s and early 1980s had been reported previously.7 Here, we assess the risk and identify the causes of adverse events as well as risk factors in cohorts of patients treated in the mid-1980s and 1990s whose long-term event-free survival rates range from 70% to 80%.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patients and Treatment
From February 1984 to July 1999, 1,011 consecutive children and adolescents 18 years of age or younger with newly diagnosed ALL were enrolled onto five successive clinical trials (Total Therapy studies XI, XII, XIIIA, XIIIB, and XIV) at St Jude Children's Research Hospital. The details of treatment in these five studies can be found in earlier publications.8-12 All patients received etoposide, teniposide, or both, at least during remission induction. Cranial irradiation was administered at 1 year to patients with higher-risk leukemia (18 Gy) or CNS leukemia at diagnosis (24 Gy) in the first four studies. This modality of therapy was given to decreasing proportions of patients in successive clinical trials: 63% in XI, 30% in XII, 22% in XIIIA, 12% in XIIIB, and none in XIV. The treatment protocols were approved by the institutional review board at St Jude, and signed informed consent was obtained from the patients' parents or guardians.

Statistical Analysis
The duration of event-free survival was defined as the time from the date of completion of therapy until the date of treatment failure (relapse, death, or the development of a second malignancy) or until the date of last contact. Event-free and disease-free survival rates were estimated by the method of Kaplan and Meier and compared with the Mantel-Haenszel test.13 Cumulative incidence functions of post-treatment failure from any cause and overall or any type of post-treatment relapse were estimated by the method of Kalbfleisch and Prentice,14 and the functions were compared with Gray's test.15 For the latter analyses, deaths in remission and therapy-related malignancies were considered competing events in the estimation of cumulative incidence function of each specific relapse. The Cox proportional hazards model was used to identify independent risk factors for any type of treatment failure or any type of leukemic relapse, separately. The database last updated on October 26, 2004, was used for analysis. The median follow-up time for patients remaining in continuous remission was 11.9 years (range, 2.4 to 20 years). At the time of analyses, 84.6% of survivors had been seen within 2 years; only 13 patients (1.8%) lacked a documented contact within the previous 5 years.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Of the 1,011 patients enrolled in this series of Total Therapy studies, 827 (81.8%) remained in continuous complete remission on completion of all treatment. Although patients treated in studies XIIIA, XIIIB, and XIV have better overall event-free survival than those in studies XI and XII,16 the cumulative risk of post-treatment relapse did not differ significantly among the five studies (P = .56, Table 1); hence all patients were combined for subsequent analyses. The overall event-free survival rate for the entire cohort of 827 patients was 86.0% ± 1.3% (SE) at 5 years and 83.1% ± 1.9% at 10 years after completion of treatment (Fig 1). The overall survival rate was 91.9% ± 1.1% at 5 years and 90.5% ± 1.5% at 10 years.


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  		Table 1. Post-Treatment Failure Rate According to Initial Features

 


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  		Fig 1. Event-free and overall survival of the entire cohort of 827 patients.

 
Of the 134 major adverse events developed after completion of therapy, 51 events (38%) occurred in the first year, 31 events (23%) occurred in the second year, nine events (7%) occurred in the third year, 14 events (10%) occurred in the fourth year, eight events (6%) occurred in the fifth year, 16 events (12%) occurred between the sixth and tenth years, and five events (4%) occurred beyond the tenth year. The estimated risk per year of any adverse event after completion of therapy is shown in Figure 2.



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  		Fig 2. Risk of any adverse event per year after completion of therapy (adjusting for the number of patients at risk in each year).

 
The cumulative risk of any adverse event was 14.0% ± 1.2% (SE) at 5 years of post-treatment follow-up and 16.9% ± 1.4% at 10 years (Fig 3). Bone marrow relapse was the most common cause of failure (Table 2), followed by the development of a second malignancy (15 cases of acute myeloid leukemia, five cases of myelodysplasia, two cases of secondary acute lymphoid leukemia; 14 brain tumors; and chronic myeloid leukemia, Ewing sarcoma, osteosarcoma, and breast cancer [one each]). The cumulative risks for isolated CNS and testicular relapses at 10 years were only 0.9% ± 0.3% and 0.4% ± 0.2%, respectively (Table 2). The cumulative risk of any type of leukemic relapse was 10.0% ± 1.1% at 5 years and 11.4% ± 1.2% at 10 years (Fig 3). The risk of relapse was highest in the first 3 years after the completion of therapy, becoming almost nil after 10 years (Fig 4). Of the five failures occurring after 10 years, only one was due to relapsed leukemia; the remaining causes were brain tumors (n = 2), carcinoma (n = 1), and death in remission (n = 1). As expected, patients with bone marrow relapse or second malignancy fared poorer than those with extramedullary relapse (Table 2).



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  		Fig 3. Cumulative risk of any adverse event and any leukemic relapse.

 

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  		Table 2. Patterns of Failure After Completion of Therapy

 


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  		Fig 4. Risk of any leukemic relapse (solid bar) or CNS relapse (open bar) per year after completion of therapy (adjusting for the number of patients at risk in each year).

 
Table 1 lists the relation of initial clinical and biologic features to the risk of post-treatment relapse, without adjustment for competing covariates. In a multivariate analysis of relapse, only male sex was an independent adverse prognostic factor (hazard ratio, 1.74; 95% CI, 1.11 to 2.74; P = .02). There was no significant difference in CNS relapse between boys and girls (P = .31). A separate multivariate analysis for any type of treatment failure revealed three high-risk factors: leukocyte count ≥ 100 x 109/L (hazard ratio, 1.92; 92% CI, 1.12 to 3.31; P = .02), the presence of the Philadelphia chromosome (hazard ratio, 2.71; 95% CI, 1.16 to 6.36; P = .02), and male sex (hazard ratio, 1.41; 95% CI, 0.99 to 2.01; P = .06).

Unfavorable age group (< 1 or > 10 years), leukocyte count ≥ 100 x 109/L, and Protocol XII were associated with an increased risk of second malignancy (Table 1). Patients with Philadelphia chromosome also tended to have a higher risk of the development of second malignancy. In a multivariate analysis including all presenting features and the use of cranial irradiation, only cranial irradiation conferred a higher risk of the development of second malignancy (hazard ratio, 3.1; 95% CI, 1.3 to 7.1; P = .008).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
Recent improvements in treatment have clearly reduced the risk of adverse sequelae in children with ALL who have completed treatment. In contrast to the cumulative risk of approximately 25% at 5 years among patients treated in the early treatment era at our center or elsewhere,7,17-24 only 14% of patients developed any adverse event at 5 years (17% at 10 years) in this large cohort receiving treatment in the modern era.

Previous studies indicated that leukemic relapse was the most common cause of off-therapy events, accounting for approximately 90% of failures.7,17-24 The decreased overall risk of an adverse event in more recent patient cohorts was mainly due to a reduced frequency of leukemic relapse. The cumulative risk of any leukemic relapse was 11% at 10 years in this study, and consistent with the findings of previous studies,25-27 it became virtually nil beyond 10 years (Figs 3 and 4). Notably, testicular relapse has become a rare event (three cases among a total of 90 relapses), contrary to the finding of our previous study, in which up to 15% of relapses occurred in the testes.7 With the use of early intensification of triple intrathecal therapy, CNS relapse rate has also been reduced substantially in our recent clinical trials.10,11

Partly because of the reduction in leukemic relapses, second malignancies have become a major cause of treatment failure, accounting for almost a third of the adverse events in patients treated at our center since the mid-1980s. The increased risk of acute myeloid leukemia can be attributed to routine use of epipodophyllotoxins in these clinical trials,28 whereas most of the brain tumors occurred in a single clinical trial (Protocol XII) featuring intensive antimetabolite treatment before and during cranial irradiation.29 Apparently, antimetabolites potentiated the carcinogenic effects of epipodophyllotoxins and irradiation, especially among patients with a deficiency of thiopurine methyltransferase activity.28,29 We expect that additional second malignancies will develop in our irradiated patients with extended follow-up. In a recent study, we showed that the cumulative incidence of second neoplasms among irradiated patients increased sharply 20 years after the diagnosis of ALL (estimated cumulative risk of 21% at 30 years).25 In this regard, virtually all of the irradiated patients in this study have been followed-up for less than 20 years and hence are still at risk of developing a second neoplasm. Nonetheless, the vast majority of the late-onset second neoplasms are expected to be benign tumors or low-grade cancers, such as meningioma and basal cell carcinoma.25

The prognosis for males with ALL has been slightly worse than that for females in a number of studies of childhood ALL, for reasons that are not well understood.30-32 Of the many clinical and biologic factors that were examined in the present study, only male sex was associated with an increased risk of relapse after completion of therapy. By contrast, unfavorable age group, leukocyte count ≥ 100 x 109/L, T-cell immunophenotype, the presence of Philadelphia chromosome, and the presence of minimal residual disease at the end of remission induction were independent predictors for on-therapy relapse or induction failure (data not shown). To improve outcome for male patients, we have extended their treatment duration from 2.5 years to 3 years in our current first-line clinical trial. Whether this approach or some other strategy of intensified treatment will nullify the poor prognosis conferred by male sex remains to be determined. Lower leukemic cell DNA content (DNA index < 1.16) was predictive of late treatment failure in our previous study7 and seemed to be associated with an increased risk of relapse in this study, albeit not attaining statistical significance. Notably, in contrast to some studies,33-35 the presence of the TEL-AML1 fusion gene was not associated with late relapses in this study. In fact, patients with this fusion gene tended to have a lower risk of off-therapy relapse as compared with that for other patients, suggesting that the prognostic impact of this genetic factor is also treatment-dependent.

Early response to remission induction treatment as measured by minimal residual disease assays is strongly associated with overall treatment outcome.36-38 This measure did not achieve statistical significance in this study, partly because a substantial proportion of patients with minimal residual disease after remission induction had experienced relapse during chemotherapy and partly because of the relatively small number of patients studied. Ongoing studies will determine whether the presence of minimal residual disease detected by a very sensitive technique on completion of treatment is predictive of subsequent relapse. The increased risk of any treatment failure among our patients with a leukocyte count ≥ 100 x 109/L and those with the Philadelphia chromosome was related to their uniform use of cranial irradiation and the consequently higher risk of developing a second malignancy.

This analysis suggests that further advances in the cure rate for childhood ALL will depend not only on decreasing the rate of leukemic relapse, but also on curtailing the development of second malignancies. To address this issue, we are attempting to avoid under- or overtreatment by relying on more precise risk classification that incorporates the measurement of minimal residual disease.36 We also apply pharmacokinetic and pharmacogenetic measures (eg, thiopurine methyltransferase genotype and phenotype) to individualize therapy.39 Finally, we are omitting cranial irradiation in all patients by optimizing systemic and intrathecal therapy.40 In our current trial, irradiation is reserved exclusively for treatment of relapse, and the epipodophyllotoxins are used only in patients who undergo hematopoietic stem-cell transplantation for very high-risk leukemia.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   NOTES
 
Supported by National Institutes of Health Grant Nos. R37 CA36401, R01 CA78224, R01 CA51001, R01 CA60419, and U01 GM61393, Cancer Center Support Grant No. CA21765, and American-Lebanese-Syrian Associated Charities.

C.-H.P. is the American Cancer Society F.M. Kirby Clinical Research Professor.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
1. Schrappe M, Reiter A, Ludwig WD, et al: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: Results of trial ALL-BFM 90—German-Austrian-Swiss ALL-BFM Study Group. Blood 95:3310-3322, 2000[Abstract/Free Full Text]

2. Gaynon PS, Trigg ME, Heerema NA, et al: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14:2223-2233, 2000[CrossRef][Medline]

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4. Silverman LB, Gelber RD, Dalton VK, et al: Improved outcome for children with acute lymphoblastic leukemia: Results of Dana-Farber Consortium Protocol 91-01. Blood 97:1211-1218, 2001[Abstract/Free Full Text]

5. Gustafsson G, Schmiegelow K, Forestier E, et al: Improving outcome through two decades in childhood ALL in the Nordic countries: The impact of high-dose methotrexate in the reduction of CNS irradiation—Nordic Society of Pediatric Haematology and Oncology (NOPHO). Leukemia 14:2267-2275, 2000[CrossRef][Medline]

6. Pui C-H, Sandlund JT, Pei D, et al: Results of therapy for acute lymphoblastic leukemia in black and white children. JAMA 290:2001-2007, 2003[Abstract/Free Full Text]

7. Pui C-H, Dodge RK, Look AT, et al: Risk of adverse events in children completing treatment for acute lymphoblastic leukemia: St. Jude Total Therapy Studies VIII, IX, and X. J Clin Oncol 9:1341-1347, 1991[Abstract]

8. Pui C-H, Boyett JM, Rivera GK, et al: Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St. Jude Children's Research Hospital. Leukemia 14:2286-2294, 2000[CrossRef][Medline]

9. Evans WE, Relling MV, Rodman JH, et al: Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 338:499-505, 1998[Abstract/Free Full Text]

10. Pui C-H, Mahmoud HH, Rivera GK, et al: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92:411-415, 1998[Abstract/Free Full Text]

11. Pui C-H, Sandlund JT, Pei D, et al: Improved outcome for children with acute lymphoblastic leukemia: Results of Total Therapy Study XIIIB at St. Jude Children's Research Hospital. Blood 104:2690-2696, 2004[Abstract/Free Full Text]

12. Kishi S, Griener J, Cheng C, et al: Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol 21:3084-3091, 2003[Abstract/Free Full Text]

13. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline]

14. Kalbfleisch JD, Prentice RL: The statistical analysis of failure time data. New York, NY, Wiley, 2002

15. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988

16. Pui C-H: Recent advances in childhood acute lymphoblastic leukemia. J Formos Med Assoc 103:85-95, 2004[Medline]

17. Johansen OJ, Moe PJ: Relapse rate after cessation of therapy in childhood leukemia: A follow-up report on 277 cases from the five Nordic countries. Acta Paediatr Scan 69:663-666, 1980[Medline]

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22. Miller DR, Leikin SL, Albo VC, et al: Three versus five years of maintenance therapy are equivalent in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Study Group. J Clin Oncol 7:316-325, 1989[Abstract]

23. Jankovic M, Fraschini D, Amici A, et al: Outcome after cessation of therapy in childhood acute lymphoblastic leukaemia: The Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP). Eur J Cancer 29A:1839-1843, 1993[CrossRef]

24. Miniero R, Saracco P, Pastore G, et al: Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: A 10-year follow-up study—Italian Association of Pediatric Hematology-Oncology (AIEOP). Med Pediatr Oncol 24:71-76, 1995[Medline]

25. 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 349:640-649, 2003[Abstract/Free Full Text]

26. Rizzari C, Valsecchi MG, Aricò M, et al: Outcome of very late relapse in children with acute lymphoblastic leukemia. Haematologica 89:427-434, 2004[Abstract/Free Full Text]

27. Vora A, Frost L, Goodeve A, et al: Late relapsing childhood lymphoblastic leukemia. Blood 92:2334-2337, 1998[Abstract/Free Full Text]

28. Pui C-H, Relling MV: Topoisomerase II inhibitor-related acute myeloid leukaemia. Br J Haematol 109:13-23, 2000[CrossRef][Medline]

29. Relling MV, Rubnitz JE, Rivera GK, et al: High incidence of secondary brain tumors after radiotherapy and antimetabolites. Lancet 354:34-39, 1999[CrossRef][Medline]

30. Pui C-H, Boyett JM, Relling MV, et al: Sex differences in prognosis for children with acute lymphoblastic leukemia. J Clin Oncol 17:818-824, 1999[Abstract/Free Full Text]

31. Shuster JJ, Wacker P, Pullen J, et al: Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: A Pediatric Oncology Group Study. J Clin Oncol 16:2854-2863, 1998[Abstract]

32. Chessells JM, Richards SM, Bailey CC, et al: Gender and treatment outcome in childhood lymphoblastic leukaemia: Report from the MRC UKALL trials. Br J Haematol 89:364-372, 1995[Medline]

33. Harbott J, Viehmann S, Borkhardt A: Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse. Blood 90:4933-4937, 1997[Abstract/Free Full Text]

34. Seeger K, Adams HP, Buchwald D, et al: TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia: The Berlin-Frankfurt-Munster Study Group. Blood 91:1716-1722, 1998[Abstract/Free Full Text]

35. Seeger K, Buchwald D, Taube T, et al: TEL-AML1 positivity in relapsed B cell precursor acute lymphoblastic leukemia in childhood: Berlin-Frankfurt-Munster Study Group. Leukemia 13:1469-1470, 1999[CrossRef][Medline]

36. Pui C-H, Campana C, Evans WE: Childhood acute lymphoblastic leukaemia-current status and future perspectives. Lancet Oncol 2:597-607, 2001[CrossRef][Medline]

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40. Pui C-H: Toward optimal central nervous system-directed treatment in childhood acute lymphoblastic leukemia. J Clin Oncol 21:179-181, 2003[Free Full Text]

Submitted December 21, 2004; accepted June 21, 2005.




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