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Journal of Clinical Oncology, Vol 25, No 36 (December 20), 2007: pp. 5800-5807 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.7508 Outcome After Relapse Among Children With Standard-Risk Acute Lymphoblastic Leukemia: Children's Oncology Group Study CCG-1952
From the Department of Pediatrics, Oregon Health and Science University, Portland, OR; Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles; and Children's Oncology Group, Arcadia, CA Address reprint requests to Suman Malempati, MD, Department of Pediatrics, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, CDRC-P, Portland, OR 97239-3098; e-mail: malempat{at}ohsu.edu
Purpose The event-free survival (EFS) of children with standard-risk acute lymphoblastic leukemia (SR-ALL) is now more than 80%. However, prognosis after relapse continues to be poor. We examined postrelapse outcomes of children initially treated on the Children's Cancer Group CCG-1952 study. Patients and Methods We evaluated outcomes after bone marrow (BM) relapse and isolated extramedullary (EM) relapse for 347 patients with SR-ALL (WBC < 50,000/µL; age, 1 to 9 years). The prognostic significance of several factors for EFS after relapse (EFS2) was assessed by Cox regression analysis. Stem-cell transplant (SCT) was compared with chemotherapy as salvage treatment. Results The mean ± SE times to isolated central nervous system relapse, BM relapse, and isolated testicular relapse were 23 ± 1 months (range, 1 to 88 months), 36 ± 1 months (range, 2 to 79 months), and 40 ± 2 months (range, 16 to 64 months), respectively. The estimated percent ± SE 3-year EFS2 and overall survival rates after BM relapse were 37% ± 4% and 46% ± 4%, respectively, and rates after isolated EM relapse were 57% ± 5% and 71% ± 5%, respectively. By multivariate analysis, we found the duration of first remission to be the most significant predictor of EFS2 for either BM relapse or isolated EM relapse. Outcome was equivalent with SCT or chemotherapy after early or late relapse of SR-ALL at any site. Conclusion Duration of first remission remains the most significant predictor of outcome after either BM or isolated EM relapse of SR-ALL. Prognosis after early BM relapse remains poor and is not improved with SCT in this cohort.
Remarkable improvements in the outcome for children diagnosed with acute lymphoblastic leukemia (ALL) have been made during the last 30 years. However, ALL is the most common pediatric malignancy, and children who relapse from this disease account for a large proportion of pediatric patients with cancer.1,2 Although the majority of patients will achieve a second remission, outcome after relapse is generally poor.3-5 Factors predictive of survival after relapsed pediatric ALL include the site of relapse and the length of the first complete remission (CR1).3,6 Survival after bone marrow (BM) relapse is generally worse than after extramedullary relapse (EM). In addition, despite varied definitions of early and late relapses, it is clear that prognosis after early BM or early EM relapse is much worse than after later relapse.3,7,8 For patients with relapsed ALL who attain a second remission, no consensus on optimal therapy exists. Attempts to compare intensified chemotherapy versus stem-cell transplant (SCT) for pediatric patients with ALL in second remission have been difficult. Several published retrospective studies suggest some benefit for SCT, particularly for patients with early BM relapse.9-13 National Cancer Institute (NCI) criteria have been used by the Children's Cancer Group (CCG) to distinguish newly diagnosed patients with standard-risk ALL (SR-ALL) from those with high-risk ALL (HR-ALL).14 A subset of children with ALL, defined as having SR-ALL (ie, WBC < 50,000/µL; age, 1 to 9 years) have a long-term event-free survival (EFS) rate of > 80%.15 It is unclear whether risk group stratification at initial diagnosis remains a significant prognostic factor after relapse. Nonetheless, there is some evidence that, among children with relapsed ALL, those who were younger than 10 years and had WBC counts < 50,000/µL at initial diagnosis are more likely to have favorable outcomes after relapse.3,16,17 Previous studies of outcome after ALL relapse have not distinguished between patients with SR- or HR-ALL at initial diagnosis. In this report, we describe the EFS and overall survival (OS) after relapse for children with SR-ALL who were initially treated on the CCG-1952 study, and we report that the outcome for these children is equivalent with either SCT or intensive chemotherapy alone.
Study Population Data used in this study were collected as part of the multi-institutional CCG-1952 study. Parental informed consent was required for enrollment on the CCG-1952 study, and institutional review board approval was obtained at each participating institution. Between May 1996 and February 2000, 2,174 eligible children with newly diagnosed precursor-B or T-cell ALL who met NCI criteria for SR-ALL (age, 1 to 9 years; WBC < 50,000/µL) were enrolled on CCG-1952. Fifty-six percent of enrolled patients were male. Patients were randomly assigned in a 2 x 2 factorial design to receive either oral mercaptopurine or oral thioguanine and either intrathecal methotrexate or intrathecal triple therapy (ie, methotrexate, cytarabine, and hydrocortisone). Patients with M3 bone marrow status (> 25% blasts) at day 14 of induction and those with unfavorable cytogenetics (ie, Philadelphia chromosome, hypodiploidy, or mixed-lineage leukemia gene rearrangements) were nonrandomly assigned to receive intensified therapy designed for HR-ALL.18 The participants for the present study include all patients treated on CCG-1952 who had BM, EM, or combined BM and EM relapse after attaining first remission. Therapy after relapse was at the discretion of the treating physician. Data specifically captured for CCG-1952 after relapse included subsequent relapse, secondary malignancy, death, and performance of SCT. Data not directly captured included time to second remission, details of salvage chemotherapy, and conditioning regimens and sources of stem cells for patients receiving SCT. In this analysis, patients who did not undergo SCT were included in the chemotherapy cohort. For the purpose of this study, relapses were grouped as BM and isolated EM relapses. The BM relapse group consisted of all isolated BM relapses and of combined BM and EM relapses. The isolated EM relapse group was comprised of all central nervous system relapses, testicular relapses, or relapses at other extramedullary sites without a concomitant BM relapse. Definition of early and late relapse varied with the site of relapse. A relapse was defined as early if CR1 lasted < 18 months for isolated EM relapse and < 36 months for BM relapse.3,19,20 These definitions are similar to those being used in current Children's Oncology Group trials for the treatment of relapsed ALL.
Statistical Analysis Cox regression analysis was performed to determine the prognostic significance of several factors in relation to EFS2. Univariate analysis was performed initially for each potential predictor of outcome. All factors were then entered into a multivariate Cox regression model in a forward stepwise manner from the most significant to the least significant. Relative hazard ratios (RHR) with 95% CIs were determined for each factor while controlling for the others. Comparison of EFS2 and OS between patients who did and did not undergo SCT was also performed. For the SCT cohort, EFS2 and OS were determined from the date of transplant. For the chemotherapy cohort, EFS2 and OS2 were calculated from 130 days after relapse, which was the median time to transplant for the SCT cohort. Therefore, patients in the chemotherapy cohort who did not survive in second remission for at least 130 days from relapse were excluded from the comparative analysis. EFS2 and OS were assessed for the SCT and chemotherapy cohorts by Kaplan-Meier life table analysis and were compared with the log-rank test. All statistical analyses were performed using SPSS statistical software for Windows, version 14.0 (SPSS Inc, Chicago, IL).
Of the 2,174 patients enrolled on CCG-1952, 347 patients relapsed after achieving a complete remission by day 28 of induction therapy. For the 2,027 patients randomly assigned to one of the four treatment arms, the 6-year estimated EFS (mean ± standard deviation [SD]) was 81.6% ± 1.3%, and OS (mean ± SD) was 92.3% ± 0.9%.18 Among the relapsed patients, 149 (42.9%) had isolated BM relapses and 68 (19.6%) had combined BM and EM relapses. Isolated EM relapse occurred in 130 patients (37.5%); this included 92 relapses in the CNS, 30 in the testicles, and 8 either combined or in other EM sites. The mean ± standard error (SE) age at diagnosis and at relapse for the entire relapsed cohort was 56.8 ± 1.5 months and 90.6 ± 1.8 months, respectively. Further clinical characteristics of the study population are listed in Table 1.
The mean ± SE interval between day 28 of induction and relapse for all patients was 32.8 ± 0.9 months (range, 0.6 to 87.7 months). Duration of the CR1 varied with the site of relapse. CNS relapses tended to occur earlier, and testicular recurrences tended to occur later than BM relapses (Appendix Fig A1, online only). The mean lengths of CR1 for isolated CNS relapse, BM relapse, and isolated testicular relapse were 23.1 ± 1.4 months (range, 0.6 to 87.7 months), 36.2 ± 1.1 months (range, 2.0 to 78.8 months), and 40.5 ± 1.9 months (range, 15.6 to 64.3 months), respectively.
Outcome After Relapse Figure 1A shows the estimated EFS2 and OS for the entire relapsed cohort. The outcome is significantly worse after BM relapse than after isolated EM relapse. The 3-year estimated EFS2 and OS (percent ± SE) after BM relapse were 37.4% ± 4.1% and 45.6% ± 4.1% (Fig 1B), respectively and after isolated EM relapse were 57.1% ± 5.3% and 71.4% ± 4.8% (Fig 1C), respectively (log-rank P < .001 for EFS2 and OS). The 3-year EFS2 was 32.4% ± 4.9% after isolated BM relapse and was 48.4% ± 7.2% after combined BM and EM relapse (log-rank P = .08; data not shown).
Comparison of Early and Late Relapses One hundred five patients (48.4%) experienced early BM relapse, and 112 (51.6%) had late BM relapse. The outcome after early BM relapse was significantly worse than after late BM relapse (Fig 2A). The 3-year estimated EFS2 and OS (percent ± SE) were 30.1% ± 4.9% and 35.0% ± 5.1%, respectively, after early BM relapse compared with 44.5% ± 7.1% and 58.2% ± 6.6%, respectively, after late BM relapse (log-rank P = .002 for EFS2 and P = .001 for OS).
As with BM relapse, the outcome after isolated EM relapse varied with the duration of CR1. The probabilities of EFS2 and OS at 3 years for early isolated EM relapse were 36.8% ± 8.4% and 55.3% ± 8.6%, respectively, compared with 71.4% ± 5.7% and 81.5% ± 5.0%, respectively, for late isolated EM relapse (log-rank P = .01 and .039, respectively; Fig 2B).
Factors Predictive of EFS2
Treatment After Relapse Eighty-nine patients were treated with SCT after relapse, and the median time to transplant was 130 days (range, 56 to 505 days). Reliable data on the stem cell source was available for 50 patients. Among these patients, 20 (40%) had matched sibling SCT, 14 (28%) had matched unrelated donor SCT, and 14 (28%) had unrelated cord SCT. One patient received a haploidentical SCT from a parent, and one patient had an autologous SCT. We compared outcomes for the SCT cohort with patients who did not receive SCT (ie, the chemotherapy cohort). In an attempt to minimize therapy selection bias, we excluded 34 patients from the chemotherapy cohort who had a second relapse or who died within 130 days of first relapse (ie, median time to transplant) and 37 patients whose follow-up time was < 130 days after relapse. Thus, the chemotherapy cohort consisted of 187 patients. In addition, the durations of EFS2 and OS were redefined for the comparative analysis of salvage therapy. EFS2 and OS were determined from date of transplant for patients who received an SCT and from 130 days (ie, median time to transplant) for the chemotherapy cohort. There was no difference between the SCT and chemotherapy cohorts with respect to age, race/ethnicity, gender, immunophenotype, and initial day 7 or day 14 induction marrow status. The mean length of CR1 before BM relapse (36 v 35 months) and isolated CNS relapse (19 v 23 months) were equivalent in the SCT and chemotherapy groups (Table 3).
For BM relapse, we found no significant difference in EFS2 or OS between treatment with SCT (n = 77) or chemotherapy (n = 81). The 2-year estimated EFS2 (percent ± SE) was 49.5% ± 6.1% with SCT compared with 49.1% ± 6.4% with chemotherapy (P = .39; Fig 3A). For early BM relapse, we also found no difference in treatment modality; the 2-year estimated EFS2 was 43.1% ± 8.2% with SCT (n = 38) and 38.0% ± 7.9% with chemotherapy (n = 41; Fig 3B). There was also no significant difference in EFS2 for late BM relapse by treatment type: 2-year estimated EFS2 was 56.1% ± 8.8% with SCT (n = 39) and 61.5% ± 10.2% with chemotherapy (n = 40; Fig 3C). Similarly, 3-year estimated EFS2 after isolated CNS relapse was equivalent with either SCT (n = 10) or chemotherapy (n = 76) at 45.0% ± 16.6% and 56.1% ± 6.8%, respectively (P = .52; data not shown).
Management of relapsed ALL remains a major challenge for pediatric oncologists. Despite second remission rates of > 90% in some series, the long-term survival of children with relapsed ALL remains poor.5-7,16,21 Previous studies have revealed that survival after relapse varies significantly with the duration of CR1 and the site of relapse. The CCG-1952 study provided a unique opportunity to assess EFS after relapse in a cohort of NCI-defined SR-ALL patients who all received similar pre-relapse therapy and who have been followed since initial diagnosis. In accordance with other studies of relapsed ALL, we found that the duration of CR1 was the most significant predictor of EFS after either BM or isolated EM relapse. Although we did not find the T-cell immunophenotype to predict poorer outcome after relapse of SR-ALL by univariate or multivariate analysis, our conclusions were limited by the relatively small number of patients in this study with T-cell ALL. The importance of initial risk stratification is reflected in previous studies of outcome after relapse. Both age and WBC count at diagnosis have been used for many years in risk stratification for the upfront treatment of ALL.22,23 In a review of outcomes after relapse for children with ALL who were treated on previous CCG studies, Gaynon et al3 showed that an initial WBC < 50,000/µL was the strongest predictor of survival after relapse by univariate and multivariate analysis. Age younger than 10 years at initial diagnosis has also been shown to predict a more favorable outcome after relapse.6,16 Nguyen et al17 report a higher survival rate for SR- versus HR-ALL patients after intermediate BM relapse (time to relapse, 18 to 36 months) and late BM relapse. The same retrospective study revealed that patients who received initial treatment in a more recent era with more intensive up-front therapy have poorer survival rates after relapse.17 These data suggest that a greater intensity of up-front therapy may negatively impact salvage rates after relapse. With current risk stratification, therapy is more intensive for HR-ALL than for SR-ALL. Therefore, analysis of outcomes after relapsed ALL should take into account risk stratification at initial diagnosis and treatment intensity in CR1. Current therapy for patients with relapsed ALL is suboptimal. SCT has been used for many years as salvage consolidation therapy for children in second remission of ALL.24 Several previous retrospective studies have shown an advantage to SCT compared with intensified chemotherapy for relapsed ALL, particularly for early BM relapse.9-13,25-28 Long-term EFS rates from 50% to 60% have been reported with HLA-matched sibling donor SCT in second remission.13,26,27,29 However, other studies suggest that the type of therapy after relapse does not affect outcome,30-33 and certain subsets with relapsed ALL can receive salvage treatment with intensive chemotherapy alone. Moreover, several studies have shown no advantage to SCT for late BM relapse or for isolated EM relapse.11,16,27,34 A recent meta-analysis demonstrated the variability of outcomes and conclusions among studies comparing SCT with chemotherapy for the treatment of ALL in second remission.35 No study other than this one has separated patients with a relapse of SR-ALL from those with a relapse of HR-ALL in the assessment of outcomes after relapse. In our cohort of SR-ALL patients, we found no significant advantage to SCT compared with chemotherapy for any site of relapse or CR1 duration. Although the outcome was poor after early BM relapse, it was not significantly improved with SCT in this cohort. For isolated CNS relapse, the comparison was hindered by the small number of patients who received SCT. Our conclusions are somewhat limited by selection bias, as the decision about whether or not to perform SCT was at the discretion of treating physicians. Moreover, uniformity among both chemotherapy regimens and transplant protocols was not possible in this study. In addition, as our follow-up time is relatively short, it is possible that a disproportionate number of later relapses will occur in one of the treatment cohorts. Finally, because of the small number of patients in each subset analysis, the finding of a lack of benefit to SCT requires validation in a larger study. We were able to determine the stem cell source for a subset of patients. Fewer than half of patients received matched sibling donor SCT. However, with improved supportive care and better donor selection, the outcome after unrelated donor and matched sibling SCT for relapsed ALL has become more equivalent, particularly in this young age group.6,36-38 Therefore, it is unlikely that the lack of benefit of SCT compared with chemotherapy in our study reflects the inclusion of unrelated donor transplants in the comparison. However, the lack of information on conditioning regimens is a limitation of this study, as total-body irradiation–based regimens have been shown to decrease the risk of subsequent relapse.39 In conclusion, our data suggest that new approaches to the treatment of relapsed SR-ALL are critically needed. Although EFS2 for our SR-ALL cohort appears somewhat better than historical controls, outcomes are still poor regardless of salvage therapy. Future strategies should include the assessment of minimal residual disease in second remission to help identify patients at risk for poor outcome after subsequent intensive therapy, including SCT.40,41 Further development and the use of targeted therapies or immune modulators may decrease residual disease and may improve the outcome for children with relapsed ALL treated with either intensive chemotherapy or SCT.
The author(s) indicated no potential conflicts of interest.
Conception and design: Suman Malempati, Paul S. Gaynon, Linda C. Stork Provision of study materials or patients: Paul S. Gaynon, Linda C. Stork Collection and assembly of data: Suman Malempati, Harland Sather, Mei K. La, Linda C. Stork Data analysis and interpretation: Suman Malempati, Paul S. Gaynon, Harland Sather, Linda C. Stork Manuscript writing: Suman Malempati, Paul S. Gaynon, Linda C. Stork Final approval of manuscript: Suman Malempati, Paul S. Gaynon, Harland Sather, Mei K. La, Linda C. Stork
Supported in part by the Children's Oncology Group (COG) Chairman's Grant Nos. CA 98543, CA 13539, and CA 98413 from the National Cancer Institute, National Institutes of Health. A complete listing of grant support for research conducted by the Children's Cancer Group and Pediatric Oncology Group before initiation of the COG grant in 2003 is available online at http://www.childrensoncologgroup.org/admin/grantinfo.htm. Presented in part at the 46th annual meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
