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© 2003 American Society for Clinical Oncology Patient Stratification Based on Prednisolone-Vincristine-Asparaginase Resistance Profiles in Children With Acute Lymphoblastic Leukemia
From the Department of Pediatric Oncology and Hematology, Erasmus MC/Sophia Children’s Hospital, Rotterdam; The Dutch Childhood Leukemia Study Group, The Hague; Department of Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, the Netherlands; and The German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany. Address reprint requests to M.L. Den Boer, PhD, Erasmus MC/Sophia Children’s Hospital, Department of Pediatric Oncology and Hematology, PO Box 2060, 3000 CB Rotterdam, the Netherlands; e-mail: m.l.denboer{at}erasmusmc.nl.
Purpose: To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and L-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol. Patients and Methods: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol.
Results: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate ± SE was 69% ± 7.0%, 83% ± 4.4%, and 84% ± 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P Conclusion: Drug resistance profiles identify patients at higher risk of early treatment failures and may, therefore, be used to improve risk-group stratification of children with ALL.
CURRENT PROTOCOLS for treatment of children with acute lymphoblastic leukemia (ALL) result in more than 95% of patients entering complete remission within 4 to 6 weeks of combination chemotherapy.1–8 Unfortunately, approximately 25% of these children relapse, and the event-free survival rate after relapse is less than 50% at 5-years of follow-up.9,10 The unfavorable prognosis at relapse warrants the need for improvement of therapy at initial diagnosis. The conventional risk factors of age, immunophenotype, WBC count, Philadelphia (Ph) chromosome/t(9;22)(q34;q11) translocation, and the response to a prednisone window at the start of treatment are often used to stratify patients for risk group–dependent therapy. However, a considerable number of low-risk patients still experience a relapse. Moreover, a considerable number of high-risk patients unnecessarily receive intensive treatment. Therefore, a better identification of patients at low and high risk of treatment failure is required to further improve clinical outcome in pediatric ALL. Cellular resistance to drugs, as measured with an in vitro drug cytotoxicity assay, is associated with unfavorable risk factors, such as age more than 10 years, proB- and T-cell ALL immunophenotype, and presence of chromosomal abnormalities, such as 11q23/MLL gene rearrangements and Ph chromosomes.11,12 Patients with acute myeloid leukemia or relapse also are, in vitro, more resistant to drugs compared with ALL patients at initial diagnosis.13–15 Drug resistance profiles that combine the in vitro cytotoxicity of glucocorticoids (prednisolone [PRD] and dexamethasone), vincristine (VCR), and L-asparaginase (ASP) have prognostic value in childhood ALL.16,17 Our first prospective study was performed in children with ALL treated according to the Berlin-Frankfurt-Münster group–oriented protocols of the Dutch Childhood Leukemia Study Group (DCLSG).16 In this article, we present the second prospective study that was conducted to investigate the prognostic value of PRD, VCR, and ASP (PVA) resistance profiles in a different group of patients treated according to an independent protocol (ie, the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia [COALL]-92 protocol). The present study also includes an update of the long-term predictive value of drug resistance profiles in patients treated in the DCLSG ALL-VII/VIII protocols. The use of drug resistance profiles for patient stratification into the successive COALL-97 treatment protocol will be discussed.
Patients and Leukemic Cell Samples Between February 1, 1992, and August 1, 1997, 521 children (age 1 to 18 years) with ALL at initial presentation were registered onto the German COALL-92 study. Patient characteristics (sex, age, WBC count, immunophenotype, and Ph chromosome) were collected by the COALL study center in Hamburg, Germany. Characteristics of children with ALL entering the DCLSG protocols ALL-VII/VIII have previously been described.16 To compare the clinical value of drug resistance profiles in COALL- and DCLSG-treated patients, six infants (age < 12 months) were excluded in the present analysis of DCLSG patients. Bone marrow (BM) and peripheral-blood (PB) samples were sent by courier service to the laboratory of Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, the Netherlands. Within 24 hours after sampling, the mononuclear cells were isolated by density gradient centrifugation (Lymphoprep, 1.077 g/mL; Nycomed Pharma, Oslo, Norway) at x 480 g for 15 minutes. Contaminating normal cells were eliminated using monoclonal antibodies linked to magnetic beads (Dynal, Oslo, Norway). All samples contained more than 80% leukemic cells, which was morphologically determined using May-Grünwald-Giemsa staining (Merck, Darmstadt, Germany).
In Vitro Drug Resistance Assay
Drug Resistance Profile
Treatment Complete remission (CR) was defined as less than 5% leukemic blasts in BM, regeneration of normal hematopoietic cells, and no indication of extramedullary leukemia. The failure to achieve a CR at day 56 (ie, nonresponse) was considered an event at day 56. Early death was defined as death before completion of induction therapy. A relapse was defined by the reoccurrence of leukemic cells in BM, PB, spinal fluid, or other extramedullary sites of a patient who initially achieved CR. The disease-free survival was defined as the time from first diagnosis to a leukemia-related event (nonresponse or relapse). Second malignancy, early death, and toxic death in remission are most likely unrelated to cellular drug resistance and were, therefore, censored at the time of occurrence. The survival analyses are based on follow-up data of COALL-92 patients collected until September 1, 2001, with a median follow-up of 6.2 years (range, 4.1 to 9.3 years). DCLSG children with ALL at initial diagnosis were treated according to comparable ALL-VII and ALL-VIII protocols, which included a PRD therapeutic window at the start of treatment.5,21 The clinical response to induction therapy was evaluated at day 42 (ALL-VII) or at day 33 (ALL-VIII). The failure of DCLSG patients to achieve a CR at these days was considered an event at day 56 in the present analysis to facilitate the comparison of drug resistance profiles in COALL- and DCLSG-treated patients. The clinical follow-up of ALL-VII/VIII patients was updated until January 1, 2001, with a median follow-up of 7.5 years (range, 4.4 to 10.8 years).
Statistics
MTT Assay Success Rate in COALL-92 Patients From the start of the COALL-92 treatment protocol on February 1, 1992, until August 1, 1997, samples for 354 out of 520 registered patients with newly diagnosed leukemia were collected. Samples of 166 ALL children were not included because of a lower priority rating of the in vitro drug resistance assay compared with other research projects. In 202 patients, the in vitro cytotoxicity of PRD, VCR, and ASP was determined; in 39 patients, other drugs were tested; and in 77 patients, no assessable cytotoxicity data were obtained. In the remaining 36 patients, the number of cells were too limited to perform an MTT assay (n = 27), or cells were not viable because of delayed transport by courier service (n = 9). Therefore, the technical success rate of the MTT assay in this study was 76% (241 of 318 samples).
As shown in Table 1
Drug Resistance Profile and Clinical Outcome in the COALL-92 Study The number of leukemia-related events in the COALL-92 study significantly increases with increasing (more resistant) PVA scores (P = .008, Table 2  ). The 5-year pDFS ± SE was 84% ± 6.8% for patients with the most sensitive profile (PVA score 3 to 4), 83% ± 4.4% for patients with an intermediate-sensitive profile (PVA score 5 to 6), and 69% ± 7.0% for patients with the most resistant profile (PVA score 7 to 9; P  .05 for resistant v sensitive/intermediate-sensitive profile, risk-group stratified; P = .02, nonstratified; Fig 1A). A considerable number of leukemia-related events (13 [31%] of a total of 42 events) were found in the low-risk patient group. Within low-risk patient group, the prognosis of patients with a resistant profile was clearly distinguished from the prognosis of patients with sensitive and intermediate-sensitive profiles (P = .009; Fig 1B); whereas within the high-risk group, the resistant profile was not discriminative in COALL-92–treated patients (Fig 1C). Within this high-risk group, patients with PVA scores of 8 and 9 relapsed more often (38%, 10 of 26 of patients, Table 2) and had the most unfavorable outcome, with a 5-year pDFS ± SE of 61% ± 11.4% compared with 79% ± 5.5% for intermediate (PVA score 5 to 7) and 82% ± 10% for sensitive patients (PVA score 3 to 4; P = .03). Patients with PVA scores of 8 and 9 also had the poorest outcome of the total group (pDFS ± SE, 54% ± 10.6%; P = .0002) and within the low-risk patient group only (pDFS ± SE, 20% ± 17.9%; P < .0001).
The resistant profile (PVA 7 to 9) especially detects patients at higher risk of early events, such as nonresponse and relapse within 2.5 years after initial diagnosis (P = .03, Table 3 ). Multivariate analysis with risk-group stratification in 202 patients revealed that the resistant profile was the strongest prognostic factor, although of borderline significance, in a model that also included age, immunophenotype, WBC count, and Ph chromosome (P = .07; hazard ratio, 1.83; 95% confidence interval [CI], 0.94 to 3.55; all others, P > .1). Analysis of PVA score 8 to 9 in this model revealed that these patients are at a 4.3-fold higher risk of relapse compared with the remaining, relatively more sensitive patients with PVA scores of 3 to 7 (P < .0001; 95% CI, 2.0 to 9.2).
Inclusion of the DNR window response in the multivariate model improved the prognostic value of the resistant profile (P = .003; hazard ratio, 5.74; 95% CI, 1.78 to 18.5; all others, P > .1), but this analysis could only be performed on a subset of 95 patients for whom the DNR window response was known.
Prognostic Value of the Drug Resistance Profile in DCLSG Patients
Drug resistance profiles that combine the in vitro cytotoxicity of glucocorticoids (PRD and dexamethasone), VCR, and ASP were shown to be an independent prognostic factor in children with ALL treated by the DCLSG ALL-VII/VIII and Japanese treatment protocols.16,17 A major drawback is the relatively short follow-up in both studies (median follow-up, 3.9 and 1.7 years after diagnosis in the DCLSG ALL-VII/VIII and Japanese treatment protocols, respectively). In this study, we confirm the prognostic value of the drug resistance profile at a longer follow-up of a median of 6.2 years (range, 4.1 to 9.3 years) in a different (and larger) group of 202 children with ALL at initial diagnosis treated according to the German COALL-92 protocol. The data indicate that patients with a resistant profile are at higher risk of leukemia-related events than sensitive or intermediate-sensitive patients. The predictive value is independent from other risk factors as well as the clinical response to a therapeutic window with DNR. In both the present and previous study,16 patients with high WBC counts (a high-risk feature) are relatively overrepresented. However, in both studies, the predictive value for nonresponse and relapse by the drug resistance profile is independent of WBC count. Moreover, patients with unfavorable WBC counts are not more resistant to PRD, VCR, and ASP than patients with favorable WBC counts.24 In addition, we show that the drug resistance profile has predictive value within the group of low-risk patients who have the features of low WBC count (< 25/nL), common/preB-cell ALL, and age 1 to 10 years. In this study, infants with ALL (< 12 months) have been excluded because they are not eligible for COALL-92 treatment. The six infants of the previously reported DCLSG study were, therefore, omitted from the present analysis at longer follow-up.16 These infants all had a PVA score between 7 and 9. Each of these infants relapsed, and therefore, inclusion of these infants would have further improved the prognostic value of the drug resistance profile.
The drug resistance profile of DCLSG ALL-VII/VIII–treated patients discriminates patients at low, intermediate, and high risk of relapse more markedly than among COALL-92–treated patients (Fig 2 v The present study does not include the analysis of the low-risk genetic features of hyperdiploidy and TEL-AML1 positivity because both features were not determined in the COALL-92 study. The favorable prognosis associated with hyperdiploidy may strongly depend on the study protocol because controversial data about its predictive value are reported.7,21 Previous studies by our group showed that hyperdiploid and nonhyperdiploid patients did not differ in sensitivity to PRD, VCR, and ASP.25 In addition, the predictive value of the drug resistance profile was independent of the ploidy status in our previous DCLSG study.16 The TEL-AML1 translocation was not known to be a prognostic factor at the start of the COALL-92 study in 1992. We previously reported that TEL-AML1–positive patients are, in vitro, more sensitive to ASP compared with TEL-AML1–negative patients, whereas no difference in in vitro responsiveness to PRD and VCR was observed.26 However, despite being more sensitive to ASP, the prognosis of TEL-AML1–positive leukemias didnot differ from negative leukemias in children treated in the DCLSG ALL-VIII protocol.27
It is remarkable that the occurrence of late relapses in both COALL-92– and DCLSG ALL-VII/VIII–treated patients is not associated with a resistant drug profile. Therefore, we conclude that the resistant profile can discriminate patients at higher risk of early events (ie, nonresponse and relapse within 2.5 years after diagnosis) but is not suitable for the identification of patients at higher risk of late relapse. At present, none of the currently used risk factors of age, immunophenotype, WBC count, Ph chromosome, 11q23/MLL gene rearrangements, and prednisone window response is capable of identifying patients at risk for late relapse. The cause(s) of late relapses may differ from that of early relapses. Late relapses may develop from leukemic cells hidden in sanctuary sites or from leukemic cells that are unresponsive to chemotherapy by dormancy and start regrowing after chemotherapeutic pressure has been stopped.28 Early relapses may develop as a result of insufficient clearance from BM during the first months of chemotherapy, (re)growth of leukemic cells despite chemotherapy, or both.29 The identification of patients at high risk of early relapse should especially be improved because early relapses are associated with a poor prognosis (5-year event-free survival rate less than 20%) despite intensive therapy schedules.10,30 Moreover, 30% of all relapses occur in the group of apparently low-risk patients. The risk of leukemia-related events in both the low-risk and high-risk groups was most pronounced in patients having a drug-resistant profile (38% and 29%, respectively; Table 2 The prognosis of late relapse patients is much more favorable compared with early relapse patients, and current treatment protocols result in 5-year event-free survival rates of 30% to 50% for late BM relapse9,10,31 and even up to 70% to 75% for late extramedullary relapse.9,10,30 A promising predictive factor for late relapse may be the analysis of minimal residual disease during and after chemotherapy, although, at this moment, follow-up of well-defined patient groups is still too short to know its discriminative power for late relapses.29 A second and novel risk indicator may be based on microarray analysis of gene expression patterns in leukemic cells. Recent data from St Jude Children’s Research Hospital (Memphis, TN) showed that specific gene expression patterns can be identified in children with ALL that are linked with a clear (and impressive) difference in prognosis, with more than 95% accuracy.32 It has yet to be shown whether this profile also predicts the occurrence of late relapse in these children. In an ongoing collaborative study with St Jude Children’s Research Hospital, we are currently addressing the relationship between gene expression profiles, clinical risk factors (including the drug resistance profile), and the prognosis of children with ALL. The present and previous studies support the use of drug resistance profiles for risk-group stratification in childhood ALL. Patients with a resistant profile may benefit from an intensification of therapy. However, patients with a sensitive profile may be treated less intensively, thereby reducing the possibility of both short-term and long-term side-effects. In the current DCLSG ALL-IX study, the prognostic value of the drug resistance profile is prospectively being validated in patients who are treated according to the successful DCLSG ALL-VI treatment schedule.33 In the COALL-97 treatment protocol, which is successive to the COALL-92 study, therapy of children with newly diagnosed ALL is currently being adapted based on the patient’s drug resistance profile. Patients are first stratified into low-risk and high-risk groups using the conventional risk criteria of age, immunophenotype, and WBC count, which are identical to the risk criteria used in the COALL-92 treatment protocol. A second stratification is based on the PVA score. Patients with a sensitive profile receive a mild therapy reduction in the reinduction phase of both the low- and high-risk regimens. In the reinduction phase of the COALL-92 protocol, morbidity (infections) occurred in the majority of patients. The high occurrence of side-effects led to the choice of a mild therapy reduction in the COALL-97 study by decreasing the doxorubicin and dexamethasone cumulative dosages in the reinduction phase for children having sensitive profiles. Low- and high-risk patients with an intermediate-sensitive profile receive a standard low-risk and standard high-risk treatment schedule, respectively. The therapy of low-risk patients with a resistant profile (± 20% of low-risk patients) is intensified by treating these patients with the standard high-risk protocol. A further therapy intensification of high-risk patients with a resistant profile (± 40% of high-risk patients) is not implemented because of the expected severe toxicities.34 Because the prognosis among high-risk COALL-92 patients with a PVA score of 8 and 9 (± 20% of high-risk patients) was very unfavorable (5-year event-free survival rate ± SE, 61% ± 11.4%), these patients will be eligible for BM transplantation. The use of these drug resistance profiles for stratification of patients depends on the success rate of the drug resistance assay. In the present study, the success rate of the MTT assay was approximately 76%. Assay failures were mainly caused by less than 70% leukemic cells in the control wells without drug after 4 days of culture. This percentage should be at least 70%, so the assay results reflect the toxicity of drugs toward leukemic cells and not toward normal cells.18 The success rate of in vitro drug cytotoxicity tests can be improved by performing a differential staining cytotoxicity assay, which actually counts the number of leukemic cells based on their morphology. We and others showed that both assays yield identical results.35–38 In the currently ongoing COALL-97 study, the success rate has increased to approximately 85% because the assay is mandatory for the stratification of patients; therefore, samples of all patients are included, and a differential staining cytotoxicity assay is performed if indicated. In conclusion, in vitro resistance to PRD, VCR, and ASP is of predictive value in childhood ALL, especially for identifying patients at higher risk of leukemia-related events within 2.5 years after diagnosis. Therefore, the drug resistance profile may be used to better stratify children with ALL to prevent overtreatment of those patients who may be cured by relatively mild chemotherapy and to identify those patients who are at high risk of treatment failure and who, therefore, may benefit from more intense treatment at initial diagnosis.
We thank all the hospitals participating in the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL) and the Dutch Childhood Leukemia Study Group.
Supported by grant nos. VU 93-641 (M.L.D.B.) and IKA 89-06 (G.J.L.K.) from The Dutch Cancer Society, Amsterdam, the Netherlands.
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34. Nachman J, Sather HN, Gaynon PS, et al: Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: A report from the Children’s Cancer Group. J Clin Oncol 15:2222–2230, 1997 35. Hwang WS, Chen LM, Huang SH, et al: Prediction of chemotherapy response in human leukemia using in vitro chemosensitivity test. Leuk Res 17:685–688, 1993[CrossRef][Medline] 36. Pieters R, Huismans DR, Leyva A, et al: Comparison of the rapid automated MTT-assay with a dye exclusion assay for chemosensitivity testing in childhood leukaemia. Br J Cancer 59:217–220, 1989[Medline] 37. Kirkpatrick DL, Duke M, Goh TS: Chemosensitivity testing of fresh human leukemia cells using both a dye exclusion assay and a tetrazolium dye (MTT) assay. Leuk Res 14:459–466, 1990[CrossRef][Medline] 38. Twentyman PR, Fox NE, Rees JKH: Chemosensitivity testing of fresh leukaemia cells using the MTT colorimetric assay. Br J Haematol 71:19–24, 1989[Medline] Submitted November 7, 2002; accepted June 10, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1,000 leukemic cells per µL PB after 7 days, was not used for treatment stratification. After 1 week, all patients received 4-week induction therapy with PRD, VCR, and DNR. Thereafter, patients received risk-adapted therapy (ie, low- or high-risk treatment). The inclusion criteria for high-risk treatment were one or more of the following: WBC 
2 test. The probability of disease-free survival (pDFS) was calculated using the Kaplan-Meier method,
