The long-term outcome of 1390 children with acute lymphoblastic leukemia (ALL), treated in two successive clinical trials (Taiwan Pediatric Oncology Group (TPOG)-ALL-97 and TPOG-ALL-2002) between 1997 and 2007, is reported. The event-free survival improved significantly (P=0.0004) over this period, 69.3±1.9% in 1997–2001 to 77.4±1.7% in 2002–2007. A randomized trial in TPOG-97 testing L-asparaginase versus epidoxorubicin in combination with vincristine and prednisolone for remission induction in standard-risk (SR; low-risk) patients yielded similar outcomes. Another randomized trial, in TPOG-2002, showed that for SR patients, two reinduction courses did not improve long-term outcome over one course. Decreasing use of prophylactic cranial irradiation in the period 1997–2008 was not associated with increased rates of CNS relapse, prompting complete omission of prophylactic cranial irradiation from TPOG protocols, beginning in 2009. Decreased use of etoposide and cranial irradiation likely contributed to the low incidence of second cancers. High-risk B-lineage ALL, T-cell, CD10 negativity, t(9;22), infant, and higher leukocyte count were consistently adverse factors, whereas hyperdiploidy >50 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained prognostic significance in both TPOG-97 and TPOG-2002 by multivariate analysis. Although long-term outcome in TPOG clinical trials is comparable with results being reported worldwide, the persistent strength of certain prognostic variables and the lower frequencies of favorable outcome predictors, such as ETV6-RUNX1 and hyperdiploidy >50, in Taiwanese children warrant renewed effort to cure a higher proportion of patients while preserving their quality of life.
In 1982, the first cooperative study for childhood acute lymphoblastic leukemia (ALL) was begun in Taiwan (population 23, million), with the participation of approximately half of the nation's institutions that offered treatment for ALL. In 1988, the Taiwan Pediatric Oncology Group (TPOG) was formed with the cooperation of all leukemia treatment centers and has since initiated national cooperative group studies. Before these developments, the 5-year event-free survival (EFS) rate in Taiwan was <50%, increasing to nearly 60% in the early 1990s. Activation of the National Health Insurance Program in 1995 placed affordable leukemia therapy within the reach of all families.
In the TPOG-ALL-97 study (1997–2001), patients with standard risk (SR; ‘low risk’ in other studies) were randomized to receive either L-asparaginase or epidoxorubicin (epirubicin) as the third drug during remission induction therapy. As our earlier experience had revealed that Escherichia coli L-asparaginase (Leunase) at 10 000 IU/m2 per dose led to a higher mortality rate,1 this agent has been used at 5000 IU/m2 since 1997. In the subsequent study, TPOG-ALL-2002 (2002–2007), we limited the use of cranial irradiation, replacing it with early intensification of triple intrathecal therapy;2, 3 SR patients were randomized to receive single or double reinduction therapy. We report here the results of these modifications in the large cohorts of consecutively treated children.
Materials and methods
From 1, January 1997 to 31 December 2007, 1407 consecutive patients aged 18 years or younger with newly diagnosed ALL were enrolled from all participating TPOG institutions in two successive treatment protocols, TPOG-ALL-97 and TPOG-ALL-2002. The diagnosis of ALL was based on immunophenotyping with panels of monoclonal antibodies directed toward lineage-associated antigens. Leukemic cells were classified as B-lineage or T-lineage and further by cytogenetic evaluation and/or molecular analysis, performed as described earlier.4 All protocols were approved by the Institutional Review Boards of the participating institutions. Written informed consent was obtained for all patients.
The treatment protocols have been described in earlier publications.1, 3 Table 1 shows the risk classification system used to stratify patients into very high risk (VHR; ‘high risk’ in other studies), high risk (HR; ‘intermediate risk’ in other studies), and SR groups. Tables 2 and 3 summarize the treatment of protocols TPOG-2002 SR and HR, and of protocols TPOG-2002 VHR, respectively. Table 4 highlights the major differences between TPOG-2002 and TPOG-97. A lower dosage of prednisolone, a higher dosage of high-dose methotrexate, and a longer reinduction therapy were administered in TPOG-2002 compared with TPOG-97. Etoposide was not used in SR and HR patients in TPOG-2002, whereas 300 mg/m2 for SR patients and 600 mg/m2 for HR patients were given in TPOG-ALL-97. In the TPOG-97 study, SR patients were randomized by each hospital to receive vincristine, prednisolone, and L-asparaginase or epirubicin, as remission induction therapy,1 whereas in the TPOG-2002 study, they were randomized by a central center to receive single or double reinduction courses.3
Triple intrathecal therapy was used for CNS-directed therapy and was intensified for patients with a CNS2 status5 in the TPOG-97 study. With the recognition of the prognostic impact of traumatic lumbar puncture with blasts,6, 7, 8 intrathecal therapy was also intensified for patients with this feature in the TPOG-2002 study. The total number of triple intrathecal injections ranged from 14 in SR patients to 30 in VHR patients with a CNS2, CNS3, or traumatic lumbar puncture with blasts status at diagnosis. Prophylactic cranial irradiation (18 Gy) was administered to 307 patients (53.1%) with HR and VHR ALL in the TPOG-97 study, but only to 42 VHR patients (5.5%) in the TPOG-2002 study. Beginning in 2000, a pilot study incorporating the elimination of prophylactic cranial irradiation for all patients was conducted at the Mackay Memorial Hospital, one of the participating hospitals of the TPOG.3 Infants were treated on VHR protocols, without cranial irradiation. In TPOG-2002, high-dose cytarabine, 3 g/m2 every 12 h for four doses, was given during consolidation and reinduction therapy. Twenty-four patients, 9 (1.6%) in TPOG-97 study and 15 (2.0%) in TPOG-2002, underwent hematopoietic stem-cell transplantion in first remission.
The duration of EFS was defined as the time from diagnosis to the date of failure (induction failure, relapse, death, or the development of a second malignancy) or until the last follow-up date for all patients without events. Patients who did not obtain a complete remission were considered to have an EFS of zero. EFS and overall survival (OS) rates were estimated by the Kaplan–Meier method and compared with the Mantel–Haenszel test.9 The Cox proportional hazards model was implemented to identify independent prognostic factors with respect to EFS and OS.
For patients who achieved complete remission, cumulative incidence functions of isolated CNS or any CNS relapse were estimated by the method of Kalbfleisch and Prentice,10 and the functions were compared by Gray's test,11 adjusting for competing events. An isolated CNS relapse was defined as one without simultaneous relapse at another site, whereas a combined CNS relapse was one in the CNS accompanied by relapse in the bone marrow or any other extramedullary site. The database used for these analyses was last updated on 31 December 2008.
There were 614 patients enrolled in TPOG-97 and 793 patients in TPOG-2002. Eight hundred and nine patients were boys and 598 were girls, with a male to female ratio of 1.35. A total of 55 patients were infants. The distributions of patients by risk classification were similar: TPOG-97, 271 patients (44.1%) SR, 174 (28.3%) HR, and 169 (27.5%) VHR; TPOG-2002, 320 patients (40.4%) SR, 272 (34.3%) HR, and 201 (25.3%) VHR. Seventeen patients were lost to follow up while in remission induction, with all remaining 1390 patients eligible for analysis of treatment outcome (Tables 5, 6, 7 and 8). Only 73 patients (5.2%) of the entire cohort were lost to subsequent follow-up (7.3% in TPOG-97 versus 3.5% in TPOG-2002). Among these 73 patients, 20 were classified as SR, 21 as HR, and 32 as VHR.
Outcome of protocol-specified therapy
The 5- and 10-year EFS (±s.e.) rates in TPOG-97 were 69.3±1.9 and 68.0±2.0%, respectively, whereas in TPOG-2002, the 5-year EFS was 77.4±1.7% (Table 5). Comparison of the EFS profiles of the two studies showed a significant better outcome over 5 years for patients enrolled in TPOG-2002 (P=0.0004). This improvement was most apparent in the outcome for HR patients treated in TPOG-2002 (see Table 6).
Table 5 also reports the induction failures, relapses, second cancers, infectious deaths in remission, other causes of remission deaths, and the cumulative risks of death in remission in the TPOG-97 and TPOG-2002 studies. The cumulative risk estimates for isolated CNS and any CNS relapses were 4.7±0.9 and 6.2±1.1% at 10 years, respectively, in TPOG-97 (Figure 1), and 3.8±0.8 and 5.4±0.9% at 5 years, respectively, in TPOG-2002 (Figure 2). Differences in these cumulative risks between the two studies are not significant (P=0.53), supporting the decision to eliminate prophylactic cranial irradiation for certain subsets of patients in TPOG-2002, and for all patients treated on TPOG protocols beginning in 2009. Thus far in the 2002 study, the development of second cancers has been limited to a single case of acute myeloid leukemia, whereas in TPOG-97, second cancers have been diagnosed in six patients: three with acute myeloid leukemia and three with lymphoma, rhabdomyosarcoma, or Langerhans cell histiocytosis. The relatively high (5%) rate of infectious deaths in remission in TPOG-97 was reduced to <1% in TPOG-2002.
Randomization of SR patients in TPOG-97 to receive vincristine, prednisolone, and L-asparaginase or the first two agents plus epirubicin for induction therapy did not lead to a significant difference in EFS (P=0.353; Figure 3; Table 6). Similarly, in TPOG-2002, patients treated with two reinduction courses had essentially the same EFS as those given a single reinduction (P=0.998; Figure 4; Table 6).
Treatment results according to presenting features
The impact of selected clinical and biological variables on EFS and OS was analyzed for both the TPOG-97 and TPOG-2002 studies (Tables 7 and 8). HR B-lineage leukemia according to NCI/Rome criteria (age<1 or >10 years and leukocyte count >50 × 109/l),12 T-cell immunophenotype, infant age group, higher leukocyte count, CNS3 status, CD10 negativity, and t(9;22) were consistently adverse prognostic factors by univariate analysis, whereas hyperdiploidy with a modal chromosome number of 51–68 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained significance in both studies in a multivariate analysis, with CD10 negativity showing significance in TPOG-97, but not in TPOG-2002, and t(4;11) in TPOG-2002, but not in TPOG-97. Intensification of triple intrathecal therapy for patients with a CNS2 status seems to have decreased the adverse prognostic significance of these features, whereas the favorable prognostic impact of ETV6-RUNX1 (also known as TEL-AML1) fusion diminished with improved EFS and OS rates for other B-lineage patients in TPOG-2002.
The 5-year EFS and OS rates in the TPOG-2002 study were significantly improved over those in TPOG-97: 77.4 and 83.5%, compared with 69.3 and 75.5%, respectively. We attribute this improved outcome to more effective chemotherapy, especially for patients with a HR of relapse, and to better supportive care. Indeed, the rate of death because of infection has markedly decreased from 6.8% in the TPOG-97 study to 0.8% in the TPOG-2002 study. However, invasive fungal infection is still a therapeutic challenge. Posaconazole, a new effective antifungal agent for invasive aspergillosis,13 was recently introduced to Taiwan and might well improve the control of fungal infections. An additional contributing factor may have been the ready access of all patients to effective treatment through the National Health Insurance Program and the Childhood Cancer Foundation established to support TPOG. Further improvement in outcome can be anticipated from the introduction of emerging antileukemic treatments, including new formulations of existing chemotherapeutics, new antimetabolites and nucleoside analogues, monoclonal antibodies (such as CD22-specific antibody14), and other targeted therapies.15
The randomized arm of the TPOG-97 study showed that L-asparaginase and epirubicin during remission induction yielded comparable treatment outcomes for patients with SR ALL. We, therefore, intend to use L-asparaginase instead of epirubicin for remission induction in the next protocol for SR ALL to decrease potential anthracycline-related cardiotoxicity. Second cancers were infrequent in these studies, most likely because of our limited use of prophylactic cranial irradiation and etoposide (when used, etoposide was given on a less carcinogenic schedule, as described earlier16).
With growing recognition of the long-term sequelae of ionizing radiation effects and the refinement of intrathecal chemotherapy,8 use of prophylactic cranial irradiation has decreased progressively in TPOG clinical trials. Thus, among 788 patients enrolled in the TPOG-2002 study, only 42 (each with VHR ALL) received prophylactic cranial irradiation, without any loss of antileukemic efficacy based on the similarity of cumulative CNS relapse frequencies in the two trials. (Figures 1 and 2). This finding supports the notion that intensification of systemic and intrathecal therapy can improve CNS control.8 Encouraged by the results of our pilot study3 and the recent Total XV study of St Jude Children's Research Hospital,17 we have eliminated the use of prophylactic cranial irradiation from all TPOG protocols, beginning in January 2009, to avoid radiation-associated sequelae, especially second cancers.18, 19 Special precautions are also being taken to reduce the risk of traumatic lumbar puncture.8 Although two courses of reinduction treatment have been shown to benefit patients with intermediate-risk ALL,20 this approach failed to improve the outcome of SR patients in TPOG-2002.
Despite the overall improvement in leukemia control achieved in TPOG-2002, age, leukocyte count, immunophenotype, CNS status, the presence of t(9;22) or t(4;11), CD10 expression, and ploidy continued to show prognostic significance. Although the t(1;19) has no prognostic impact in our studies, the outcome of these cases who were treated with HR regimens has improved over the years, a finding consistent with the notion that intensified therapy would improve outcome of this group of patients.21 With improved outcome for B-lineage ALL, however, the prognostic impact of t(12;21)[ETV6-RUNX1] has lessened. In this regard, the frequency of ETV6-RUNX1 fusion in Taiwan, 18–19% in B-lineage ALL, has been consistently lower than that (∼25%) in western countries.4, 22 In Japan, the frequency of ETV6-RUNX1 fusion in children with ALL seems to be even lower than in Taiwan (13%).23 The frequency of hyperdiploidy with a modal chromosome number of 51–68 is also lower (11.9%) in childhood ALL cases in Taiwan than in western countries (25–27%). Careful epidemiologic studies are needed to determine whether these findings reflect differences in host pharmacogenetics or environment factors, or both, in ALL pathogenesis.
Our ongoing efforts focus on improving risk assessment by measuring minimal residual disease, the most important prognostic indicator for newly diagnosed and relapsed ALL,24, 25, 26, 27, 28, 29, 30 and by identifying new genetic subtypes with prognostic relevance.31, 32, 33 We will also study inherited genetic variations of the patients to elucidate (i) the pharmacogenetic basis for the observed differences in treatment responses and (ii) the biology of the leukemic cells.34
Conflict of interest
The authors declare no conflict of interest.
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We thank Ching-Hon Pui, MD, St Jude Children's Research Hospital, Memphis, USA, for his supervision in protocol design, critical comments, and continuous support. We are also grateful to the Data Managers of the Biostatistics Department, the Childhood Cancer Foundation, Taiwan: Ms Hsiu-E Hsu, Hsiu-Chuan Lin, Shiow-Lian Wang, and Pi-Ju Wu for their assistance. This work was supported by the Childhood Cancer Foundation of the ROC, Taipei, Taiwan.
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Liang, D., Yang, C., Lin, D. et al. Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia. Leukemia 24, 397–405 (2010) doi:10.1038/leu.2009.248
- acute lymphoblastic leukemia
- treatment results
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