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© 1999 American Society for Clinical Oncology Improved Survival of Children With Isolated CNS Relapse of Acute Lymphoblastic Leukemia: A Pediatric Oncology Group StudyFrom the Department of Pediatrics, West Virginia University Health Sciences Center, Morgantown, WV; Pediatric Oncology Group Statistical Office and Department of Statistics, University of Florida, Gainesville, FL; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; Department of Radiation Therapy, Walter Reed Medical Center, Washington, DC; and Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX. Address reprint requests to A. Kim Ritchey, MD (#9061), c/o Pediatric Oncology Group, 645 N Michigan Ave, Suite 910, Chicago, IL 60611.
PURPOSE: Isolated meningeal relapse in children with acute lymphoblastic leukemia (ALL) usually has been followed by bone marrow relapse and limited survival. The purpose of this study was to prevent marrow relapse by administering intensive therapy before delayed craniospinal radiation. PATIENTS AND METHODS: Eighty-three patients with ALL in first bone marrow remission with an isolated CNS relapse were treated with systemic chemotherapy known to enter into the CSF and intrathecal chemotherapy for 6 months. Craniospinal irradiation (24 Gy cranial/15 Gy spinal) was then administered, followed by 1.5 years of maintenance chemotherapy.
RESULTS: All 83 patients achieved a second remission. The 4-year event-free survival (EFS) rate was 71.1% ± 5.3%. There was a fourfold increased risk of relapse for children whose initial remission was less than 18 months. The 4-year EFS rate for patients with a first complete remission
CONCLUSION: For children with ALL and an isolated CNS relapse, treatment that delays definitive craniospinal irradiation by 6 months to allow for more intensive systemic and intrathecal chemotherapy results in better EFS than has been previously reported. Using this approach, the long-term prognosis for children with first complete remission
BEFORE THE INCORPORATION of prophylactic CNS therapy into the treatment of acute lymphoblastic leukemia (ALL) in children, meningeal relapse was the major impediment to cure. CNS relapse usually presaged the inevitable bone marrow relapse. However, with modern treatment, only 5% to 10% of children with ALL relapse in the CNS. Unfortunately, for children who sustain a meningeal relapse, the outlook, until recently, has been poor. In the past, treatment for a child with CNS relapse of ALL consisted of intrathecal chemotherapy followed by cranial or craniospinal irradiation (CSI); systemic therapy has varied. Throughout the 1970s and 1980s, the outcomes reported for patients with an isolated CNS relapse have generally been poor, with subsequent bone marrow relapse the major obstacle to cure.1-3 In 1990, the Pediatric Oncology Group (POG) initiated a study to address this problem. Our hypothesis was that intensive systemic chemotherapy using agents known to cross into the CSF would improve survival by preventing marrow relapse. Because the ability to deliver intensive chemotherapy can be compromised by poor marrow reserve after CSI, we deferred radiotherapy for 6 months. During the initial 6 months of treatment, an aggressive regimen of intrathecal and systemic chemotherapy was used. Systemic drugs with a history of use in the treatment of CNS leukemia were preferentially used. This report describes the improved outcome of 83 children treated with this approach.
Patients Between April 1990 and June 1993, 84 patients were registered onto the study (POG 9061). One patient was excluded from analysis because of the detection of overt testicular disease after registration but before initiation of induction chemotherapy. The follow-up period was to November 1, 1998. All patients had ALL in first bone marrow remission (during or after cessation of primary therapy) with an isolated CNS relapse. Criteria for relapse were CSF WBC count more than 5/µL with blasts present on cytocentrifuge examination using Wright stain. Slides from all but six patients were reviewed by one of the investigators (S.L.). CNS leukemia was confirmed in all cases except two (insufficient cells present on the submitted slide). All patients met the following additional eligibility criteria: age between 1 and 22 years at the time of relapse, no prior brain irradiation, total prior anthracycline dose less than 375 mg/m2, and written informed consent according to the guidelines of the respective institutional review boards. Treatment for ALL before relapse varied, although most patients had been enrolled onto front-line POG protocols. One patient was enrolled onto POG 8035,4 39 onto POG 8602 (AlinC 14),5 26 onto POG 9005/9006 (AlinC 15),6,7 or their pilot studies, and 17 were enrolled onto other protocols. The POG front-line ALL protocols consisted primarily of antimetabolite-based therapy with extended triple intrathecal chemotherapy for CNS prophylaxis. Cranial radiation has not been used as initial CNS prophylaxis in any of the aforementioned POG front-line trials. The general design of the recent POG trials for newly diagnosed ALL includes standard three- or four-drug induction, an intensification phase that lasts approximately 6 months during which a randomized question is asked, and maintenance with oral 6-mercaptopurine (MP) and intramuscular methotrexate (MTX) plus intermittent vincristine and prednisone pulses for a total of 2.5 to 3 years. In the POG 8062 intensification phase, the addition of intensive L-asparaginase or cytarabine was added to the standard regimen of intermediate-dose MTX (1 g/m2 administered intravenously over 24 hours). In POG 9005 (for standard-risk patients), an intensive regimen of intermediate-dose MTX with or without intravenous MP was compared with an intensive oral MTX regimen with intravenous MP. In the protocol for high-risk patients, POG 9006, standard intermediate-dose MTX plus intravenous MP was compared with alternating chemotherapy (MTX and MP; teniposide and cytarabine; daunomycin, cytarabine, vincristine, prednisone, and asparaginase).
Treatment
Induction of CNS remission consisted of weekly triple intrathecal therapy with MTX, hydrocortisone, and cytarabine in age-adjusted doses, as follows: age 1 to 2 years: MTX 8 mg, hydrocortisone 8 mg, cytarabine 16 mg; age 2 to 3 years: MTX 10 mg, hydrocortisone 10 mg, cytarabine 20 mg; age 3 to 8 years: MTX 12 mg, hydrocortisone 12 mg, cytarabine 24 mg; age The systemic (nonintrathecal) induction chemotherapy consisted of dexamethasone 10 mg/m2/d administered orally or intravenously in three divided doses for 28 days, vincristine 1.5 mg/m2 (maximum dose, 2 mg) administered intravenously weekly for 4 weeks, and daunorubicin 25 mg/m2 administered intravenously weekly for 3 weeks. During the following 6-week consolidation phase, cytarabine 3 g/m2 as a 3-hour intravenous infusion every 12 hours for 4 doses followed 3 hours later by L-asparaginase 10,000 IU/m2 was administered intramuscularly on the first and third week. L-Asparaginase 10,000 IU/m2 was also given intramuscularly on the first and fourth days of weeks 2 and 5 of consolidation. Throughout the 12-week intensification phase, chemotherapy was administered weekly. During the first week, MTX 1 g/m2 was given as an intravenous infusion over 24 hours (with leucovorin rescue) followed immediately by MP 1 g/m2 by intravenous infusion over 8 hours. The second-week drugs were etoposide 300 mg/m2 administered intravenously over 1 hour followed by cyclophosphamide 500 mg/m2 administered as an intravenous push (with mesna). During the third week, three intrathecal drugs in age-adjusted doses were given. This three-week cycle was repeated four times during intensification. The 4-week irradiation phase consisted of simultaneous radiation and chemotherapy. Radiation was delivered to the entire craniospinal axis using megavoltage equipment. The cranium was treated by two equally weighted opposed lateral beams matched to a spinal field treated by a single posterior beam. All fields were treated at 1.5 Gy per daily fraction with the cranium receiving 2.4 Gy and the spine 1.5 Gy total dose. Review of radiation therapy was performed by one of the investigators (Y.A.) and the Quality Assurance Review Center (Providence, RI). Chemotherapy consisted of dexamethasone 10 mg/m2/d administered orally or intravenously divided in three doses for 21 days, vincristine 1.5 mg/m2 (maximum dose, 2 mg) administered intravenously weekly for 3 weeks, and L-asparaginase 10,000 IU/m2 administered intramuscularly three times per week for 3 weeks. The 76-week maintenance treatment completed the planned 102 weeks of total therapy. MP at 75 mg/m2/d orally and MTX 20 mg/m2/wk intramuscularly were given for 6 weeks, alternating with 4 weekly doses of intravenous vincristine 1.5 mg/m2/wk (maximum dose, 1.5 mg) plus intravenous cyclophosphamide 300 mg/m2/wk. During the study, there were two changes in protocol therapy. Because of a high incidence of severe local reactions to intramuscular Escherichia coli L-asparaginase, polyethylene glycol (PEG) L-asparaginase was substituted after approximately 20 patients had been enrolled onto the study. During consolidation, intramuscular PEG L-asparaginase 25,000 IU/m2 replaced the dose of L-asparaginase given after the cytarabine. The two doses of L-asparaginase during the second and fifth weeks were omitted. During the irradiation phase, PEG L-asparaginase 25,000 IU/m2 was administered intramuscularly in the first and third week instead of the nine doses of thrice-weekly L-asparaginase. The second change to the protocol was the addition of filgrastim after cytarabine during the consolidation phase because of a high frequency of hospital admissions for fever and neutropenia and one death from sepsis. This protocol change was initiated after approximately 40 patients had been enrolled onto the study. This study was performed after approval by local human investigations committees, and informed consent was obtained from each subject or subject's guardian before initiation of treatment.
Statistical Methods
Patient Characteristics Table 2 lists the characteristics of the 83 patients at both original diagnosis of ALL and relapse. No patients had received prior radiation. Risk classification for patients with B-precursor disease, based on WBC count greater than 50,000/µL and/or age  10 years at diagnosis, was retrospectively assigned using the uniform approach developed by the National Cancer Institute and the major pediatric oncology clinical trials groups.12 There were 48 patients classified as standard risk and 35 as high risk. Patients with T-lineage ALL (n = 3) were classified as high risk. CNS status at diagnosis of ALL was also determined. CNS 1 was defined as WBC count less than 5 cells/µL of CSF and no identifiable blasts on cytocentrifuge examination; CNS 2 was defined as WBC count less than 5 cells/µL of CSF and blasts present on cytocentrifuge examination; and CNS 3 was defined as WBC count 5 cells/µL with blasts present on cytocentrifuge examination.
Most patients (75%) were asymptomatic at the time of discovery of their CNS relapse. Of the 21 symptomatic patients, nine had only headache and/or vomiting, whereas the remainder had additional neurologic findings (papilledema, transient sixth nerve palsy, hyperphagia).
Outcome
Twenty-eight patients were removed from the study because of relapse (n = 14), toxicity (n = 5), secondary malignancy (n = 5), bone marrow transplantation in remission (n = 3), or because they were lost to follow-up (n = 1). All of the 14 patients who experienced relapse were within 29 months of enrollment onto the study (Table 3.) Only two of the 14 relapses occurred before radiation at 6 months, one in a patient with T-lineage ALL who had a brief first remission duration (7 months) and a marrow relapse just before irradiation at 6 months. The other patient was originally diagnosed with B-lineage ALL at age 17 months, had been off therapy for 2.75 years, and had symptoms of hypothalamic syndrome for 3 months before documentation of CNS relapse. Her second CNS and initial marrow relapse occurred 1 month before scheduled irradiation.
Eleven patients were removed from the study before completion of planned therapy for reasons other than relapse. Three patients received a bone marrow transplant while in remission, one withdrew because of fungal sepsis precluding protocol therapy, another developed ascending paralysis consistent with Guillain-Barré syndrome during induction, and two were lost to follow-up (one refused further therapy and one moved.) Two patients died during remission, one with septic shock during consolidation and one with congenital heart disease (Ebstein's anomaly) and endomyocarditis during maintenance therapy. Two patients developed secondary acute nonlymphocytic leukemia that involved translocation of chromosome 11q23 during maintenance therapy after 9 and 10 months on study. One of these two patients had T-lineage ALL and had previously received considerable exposure to epipodophyllotoxin agents during initial therapy. Three patients had off-study events that occurred after completion of treatment. One developed a secondary myelodysplasia and died during bone marrow transplantation. Two patients died from brain tumors, a grade 3 anaplastic astrocytoma and a glioblastoma, that developed after they were 1.5 and 2 years off therapy, respectively. Participation in the MP window study immediately before induction therapy had no significant impact on EFS (PHR = 1.40; 95% CI, 0.61 to 3.20; P = .43). The addition of filgrastim to the protocol had no significant impact on EFS (PHR = 1.33; 95% CI, 0.58 to 3.04; P = .50). Prior frontline treatment (POG v non-POG) also had no significant impact on EFS (PHR = 1.25; 95% CI, 0.43 to 3.67; P = .68).
Predictors of EFS
Toxicity There was an unexpectedly high rate of reactions to L-asparaginase. Of the 21 patients who received E coli L-asparaginase, 15 experienced severe local toxicity, including pain, marked swelling, and erythema, whereas one patient had a systemic reaction. On the basis of this toxicity, the protocol was amended to substitute PEG for E coli L-asparaginase, as previously noted. Unfortunately, not only did the reaction rate remain high (63%), but more than half of the reactions were systemic, including anaphylaxis. However, there were no deaths or apparent long-term toxicity from either form of L-asparaginase. The most common and recurring toxicity was myelosuppression, especially during the consolidation phase. Sixty-one percent of patients were hospitalized at least once during this phase of treatment for fever and neutropenia, and one death occurred from Clostridium sepsis. After the addition of filgrastim to the protocol, there was a decrease in both the frequency of hospitalizations for fever and neutropenia as well as delays in therapy because of myelosuppression. Myelotoxicity was also common during intensification, irradiation, and especially early in maintenance; however, admissions to the hospital for fever and neutropenia were uncommon. Overall, treatment was delivered according to schedule. The average delay before the initiation of irradiation, scheduled at study week 23, was 4 weeks (range, 0 to 16 weeks). Three episodes of Candida sepsis were documented, one each during induction, consolidation, and intensification. One patient was removed from study, another relapsed shortly after Candida sepsis, and the third continued on study and remains in remission. Approximately half of the patients developed transient asymptomatic liver enzyme elevations during the last 2 weeks of induction therapy that was not associated with an increase in serum bilirubin concentration. Treatment was rarely delayed because of this toxicity.
This study of a large group of uniformly diagnosed and treated children with ALL and isolated CNS relapse achieved an excellent 4-year EFS rate of 71.1% ± 5.3%. The outcome for the children who had an initial remission that lasted more than 18 months was particularly striking, with a 4-year EFS rate of 83.3% ± 5.3%. These results are superior to those of other comparably sized series of children with isolated CNS leukemia and are even similar to the results of treatment of children with newly diagnosed ALL. Recent reports of initial treatment of children with ALL from the major pediatric oncology clinical trials groups indicate EFS rates of 75% to 85% for standard-risk patients and 65% to 75% for high-risk patients.13-16 Studies of children with CNS relapse of ALL treated in the 1970s and early 1980s described continuous complete remission rates of 10% to 60%, with most reporting 25% to 50%.1-3,17-20 CNS disease was reasonably well controlled by neuraxis radiation, with most failures occurring in the bone marrow. In the past 10 years, these children seem to have a better outcome, primarily as a result of more intensive chemotherapy. In two prior POG studies, Land et al21 reported a 70% 4-year disease-free survival rate for 20 children treated with intensified systemic therapy plus craniospinal radiation, and Winick et al22 reported a 4-year EFS rate of 46% for 120 children treated with intensified systemic therapy plus cranial radiation and extended intrathecal chemotherapy. From St. Jude Children's Research Hospital, Riberio et al23 recently reported a 70% 5-year disease-free survival rate for 20 children who received intensive chemotherapy with CSI delayed in most patients for 1 to 4 months, and Kumar et al24 reported a 56% 3-year EFS rate in 18 patients with CNS relapse treated in a similar fashion. We believe that the excellent results of our study can be attributed to the coordination of intensive intrathecal and systemic chemotherapy having a known CNS effect while delaying CSI to allow for the safe and timely administration of chemotherapy. CSI has been associated with subsequent marrow compromise and difficulty in delivering dose-intensive chemotherapy. Prior studies suggested that delaying radiation would not result in an excessive number of early relapses, as long as intensive chemotherapy was administered during the preradiation phase.25-27 Although there were two relapses before radiation in our study, the 6-month delay in administering radiation seemed effective in allowing for the administration of intensive chemotherapy. The choice of chemotherapeutic drugs given before CSI in this protocol was based on their ability to enter the CSF, prior use in the treatment of CNS leukemia, and their proven efficacy when used systemically. Use of drugs not previously received by most patients was also preferred. Dexamethasone was chosen because of better penetration into the CSF than prednisone.28 High-dose cytarabine has been shown to have efficacy in the treatment of both CNS and systemic ALL.29-31 Both intravenous MTX and MP cross into the CSF and have been associated with a low CNS relapse rate when used in during initial therapy of ALL.32 The combination of etoposide and cyclophosphamide has been used effectively in the treatment of ALL in relapse with acceptable toxicity and is not used in the in treatment of ALL in POG front-line studies. Moreover, etoposide as administered during intensification has recently been shown to achieve cytotoxic levels in the CSF.33 Because of the anticipated myelosuppression after CSI, the combinations of oral MP and MTX and intravenous vincristine and cyclophosphamide were chosen for maintenance therapy. Both combinations have been used in a previous POG relapse protocol with minimal toxicity.22 There are other possible explanations for these good results. First, inclusion of patients with "reactive" pleocytosis in the CSF could favorably bias outcomes, but the diagnostic criteria for CNS leukemia used in the study are considered conservative, and all but eight patients had central review and confirmation of diagnosis. The correct diagnosis of CNS relapse in these unconfirmed patients was likely inasmuch as their diagnostic CSF WBC count ranged from 11 to 5,160 cells/µL with blasts identified by local pathologists in each instance. Second, there has been a suggestion in the literature that patients who receive cranial radiation as part of their initial ALL therapy have a worse outcome after CNS relapse.34 None of the patients on this study received cranial radiation as part of their primary treatment. Interpretation of the results in the literature is complicated by the small numbers of patients treated with a variety of regimens both before and after their CNS relapse. However, in the prospective randomized POG study reported by Land et al,21 there was no significant difference in outcome between patients who had previously received cranial radiation versus those who had not. Finally, most of the patients in this study were initially treated according to antimetabolite-based POG protocols that include minimal to no exposure to anthracyclines, alkylating agents, and epipodophyllotoxins, all of which were used in our study. Whether children treated with other regimens that include more anthracyclines and alkylating agents during initial therapy would have an equally high rate of EFS on this study protocol is unknown. Previous studies of isolated CNS relapse have identified a number of prognostic factors, including initial remission duration, WBC count at diagnosis of ALL, age at diagnosis of ALL or at relapse, and race.2,3,20,22 In this study population, however, the only clinical prognostic factor associated with EFS was length of first remission. It is possible that the failure of previously identified prognostic factors to be statistically significant may be a result of small numbers and not a lack of biologic or clinical significance. Alternatively, the effectiveness of intensified systemic therapy may have diminished the prognostic value of these clinical variables. Although patients with meningeal relapse of ALL are at high risk of CNS injury, there was a very low incidence of symptomatic leukoencephalopathy in our study. The degree of CNS injury associated with the treatment of ALL is related to three factors: the neurotoxicity of intrathecal and systemic chemotherapy, the deleterious effect of ionizing radiation, and damage from CNS leukemia itself. A number of studies have shown that CNS-active drugs (eg, MTX and cytarabine) when given in high doses intravenously are more damaging to the CNS when given after CNS irradiation. The low incidence of CNS toxicity noted in this study probably relates to the delivery of intensive therapy before as opposed to after irradiation. Long-term neurotoxicity of treatment is also of concern. Although there has not been an excess of reported late neurotoxicity, two study patients developed brain tumors after completion of therapy. Neurocognitive assessments were not incorporated into the study. In conclusion, isolated CNS relapse of childhood ALL no longer need carry the poor prognosis that was attributed to it in the past. This study provides evidence in a large group of children with isolated CNS disease that CNS-directed irradiation can safely be delayed for at least 6 months while intensive systemic and intrathecal therapy are administered. A high EFS rate was achieved with acceptable toxicity. This treatment approach addresses both the risk of marrow relapse and CNS relapse in a coordinated fashion and offers an excellent chance for long-term survival that parallels that at initial diagnosis of leukemia.
The POG plans to build on the results of this study by using the initial remission duration to separate patients into high- and low-risk groups (first remission duration < or
Supported in part by the following grants from the National Cancer Institute: CA-03161, CA-05587, CA-07431, CA-11233, CA-15525, CA-15989, CA-20549, CA-25408, CA-28383, CA-28476, CA-29139, CA-29293, CA-29691, CA-30969, CA-32053, CA-33587, CA-33603, CA-33625, CA-53128, CA-69177, and CA-69428 We thank Dr Donald Pinkel, who has supported this study from its inception and provided critical analysis, the POG clinical research associates, and the many patients and their families who joined the study.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
