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Journal of Clinical Oncology, Vol 24, No 19 (July 1), 2006: pp. 3142-3149 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.3373 Isolated CNS Relapse of Acute Lymphoblastic Leukemia Treated With Intensive Systemic Chemotherapy and Delayed CNS Radiation: A Pediatric Oncology Group Study
From the Department of Pediatrics, Medical University of South Carolina, Charleston, SC; Children's Oncology Group Statistics & Data Center, University of Florida, Gainesville, FL; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; Department of Pediatrics, Dana-Farber Cancer Institute, Boston, MA; Radiation/Oncology, Northwestern University, Chicago, IL; Department of Pediatrics, University of Mississippi, Jackson, MS; Midwest Children's Cancer Center, Medical College of Wisconsin, Milwaukee, WI; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX; Department of Pediatrics, New York University Medical Center, New York, NY; and the Division of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh, Pittsburgh, PA Address reprint requests to Julio C. Barredo, MD, Pediatric Hematology-Oncology, MUSC Children's Hospital, 135 Rutledge Ave, Charleston, SC 29425; e-mail: barredjc{at}musc.edu
PURPOSE: Prognosis and outcome of children with isolated CNS relapse of acute lymphoblastic leukemia (ALL) has depended on duration of first complete remission (CR1). This study intensified systemic therapy by delaying CNS radiation for 12 months and tailored CNS radiation by CR1 duration. PATIENTS AND METHODS: Seventy-six children with first isolated CNS relapse of ALL were treated with systemic chemotherapy that effectively penetrates into the CSF and intrathecal chemotherapy for 12 months. Patients with CR1 of less than 18 months received craniospinal radiation (24 Gy cranial/15 Gy spinal), whereas those with CR1 of 18 months or more received cranial radiation only (18 Gy), followed by maintenance chemotherapy. Additionally, asymptomatic patients were enrolled in a thiotepa up-front therapeutic window. RESULTS: Seventy-four (97.4%) of 76 eligible patients achieved a second remission. Overall 4-year event-free survival (EFS) for the 71 precursor B-cell patients was 70.1% ± 5.8%. CR1 duration and National Cancer Institute (NCI; National Institutes of Health, Bethesda, MD) risk group at initial diagnosis predicted outcome. Patients with CR1 of less than 18 months and 18 months or more had a 4-year EFS of 51.6% ± 11.3% and 77.7% ± 6.4% (P = .027), respectively. NCI high- versus standard-risk 4-year EFS was 51.4% ± 10.8% and 80.2% ± 6.3% (P = .0018), respectively. A significant difference in EFS between standard risk/CR1 of at least 18 months and both high risk/CR1 of less than 18 months and high risk/CR1 of at least 18 months groups was detected (P = .0068 and .0314, respectively). Response rate to thiotepa was 78%. Most relapses involved the bone marrow, and three second malignancies were reported. CONCLUSION: Twelve months of intensive systemic chemotherapy with reduced dose cranial radiation (18 Gy) is highly effective for children with isolated CNS relapse and CR1 of 18 months or more. Novel strategies are needed for patients with CR1 of less than 18 months.
The outcome for children with acute lymphoblastic leukemia (ALL) continues to improve, with 5-year event-free survival (EFS) rates approaching 80%. These advances, together with effective CNS prophylaxis, have led to significant decreases in incidence of meningeal leukemia.1,2 However, the outlook, until recently, for children with isolated CNS relapses had been poor.3-5 An improved outcome for these patients was recently reported by the Pediatric Oncology Group (POG) study 9061 (71% 4-year EFS).1 This was achieved by delaying craniospinal radiation for 6 months to allow initial intensification of systemic chemotherapy with drugs known to have effective CNS penetration.
In POG 9061, duration of initial remission (CR1) was an important prognostic factor for children with isolated CNS leukemia,1 resulting in 4-year EFS for patients with CR1 of at least 18 months of 83% ± 5% versus 46% ± 10% for those with CR1 of less than 18 months (P = .0002).1 The Children's Cancer Group experience showed a 2.8 times higher relative risk of death for patients relapsing early ( We now report the results of POG's more recent regimen for isolated CNS relapse of ALL, POG 9412. Our hypothesis was that 6 additional months of intensive systemic chemotherapy (delaying CNS radiation until 1 year) would improve survival by decreasing subsequent systemic relapses while still eradicating meningeal leukemia. We included systemic antileukemic drugs with effective CSF penetration. To minimize long-term neurocognitive sequelae, and because duration of CR1 had predicted outcome, patients with CR1 of at least 18 months received 18 Gy of cranial radiation only, whereas those with CR1 of less than 18 months received conventional craniospinal radiation (24 Gy cranial/15 Gy spinal). The study design also allowed asymptomatic patients to be enrolled in a single-dose thiotepa (TT) up-front therapeutic window evaluating CSF blast clearance. The rationale for evaluating TT included reported short-term remissions in children with leukemia and non-Hodgkin's lymphoma,7-9 plus favorable CSF pharmacokinetics in pediatric patients.10
Patients Between January 1996 and August 2000, POG 9412 enrolled 78 patients. All had ALL in first bone marrow remission with isolated CNS relapse. Criteria for relapse were more than 5 WBC/µL in CSF with blasts, or any number of WBC in CSF with immunophenotypic proof of leukemic relapse (terminal deoxynucleotidyl transferase [TdT] or CD-10 for B lineage; TdT and/or CD-7 for T lineage) on two consecutive CSF samples 3 weeks apart. Eligibility age was 6 months to 21 years at relapse, and prior brain radiation was permitted. Institutional review board–approved informed consent was obtained before enrollment. Two patients were ineligible; one had started therapy before signing informed consent, and a second had negative CSF on central review. Therefore, analysis was limited to 76 eligible patients. Nineteen of these were also enrolled in the TT window. The follow-up period was until April 2005. Initial treatment for B-lineage ALL patients varied. Most had received POG front-line protocols consisting primarily of antimetabolite-based therapy with extended triple intrathecal therapy (TIT) for CNS prophylaxis.11-13 All five enrolled T-cell ALL patients were treated with POG 9404, using a Dana-Farber Cancer Institute (Boston, MA) ALL Consortium treatment schema with added random assignments to high-dose methotrexate and dexrazoxane,14 plus cranial radiation as CNS prophylaxis.
Treatment
The initial 6-month therapy consisted of induction, consolidation, and intensification I, as per POG 9061.1 Induction of CNS remission included age-adjusted weekly TIT with methotrexate, hydrocortisone, and cytarabine. Therapy intensification during the subsequent 6 months consisted of sequentially administered drug pairs with effective CNS penetration (reinduction and intensification II; Table 1). Radiation was administered with concomitant chemotherapy at week 51 and was tailored according to duration of CR1 (Table 1). Patients with CR1 of less than 18 months received craniospinal radiation (24 Gy cranial/15 Gy spinal), whereas those with CR1 of 18 months or more received 18 Gy to the cranium only (1.5 Gy daily dose). The Quality Assurance Review Center (Providence, RI) reviewed radiation therapy delivery. Finally, maintenance chemotherapy continued through week 104 (Table 1).
Study Design
Sample-size calculations were originally based on detecting a difference in 3-year EFS irrespective of CR1 duration (CR1 < 18 months, early relapse; CR1
Up-Front Window
Patient Characteristics Table 2 presents the patient characteristics. Of 76 eligible patients, 19 asymptomatic patients (25%) were also enrolled onto the TT window. Five of 76 eligible patients exhibited T-cell immunophenotype and were the only ones who had received previous CNS radiation. The median age at study entry was 7.4 years. Sixty-one percent of patients were white, whereas the breakdown of nonwhite patients was Hispanic, 19; African American, five; Native American, one; Hawaiian, one; Asian, one; and other, three. Patient distribution according to CR1 duration was similar to that of POG 9061. The median CSF WBC at study entry was 39.5/µL (1 to 8,400/µL). Most patients had at least 5 WBC/µL in CSF plus blasts, whereas only three patients had less than 5 WBC/µL in CSF plus immunophenotypic proof of meningeal leukemia. All three patients had precursor B-cell with one, three, and three CSF blasts, respectively, at enrollment. One was an early death on therapy (41 days; CR1 < 18 months). The other two (CR1  18 months) have not experienced treatment failure (1,611 and 1,879 days of follow-up, respectively). Twenty-nine percent of patients presented with CNS signs/symptoms. Of these, only three patients had neurologic findings (papilledema or cranial nerve palsy), whereas all remainder had headache and/or vomiting.
Response to Therapy Nineteen asymptomatic patients were enrolled on the TT up-front window. Table 3 summarizes the response by CR1 duration, per dose level. The only T-cell patient enrolled (level 1) was not assessable. The patients' characteristics of this group were similar to the entire cohort. Table 4 summarizes the CSF WBC and blasts before and after TT. Response was evaluated 1 week after a single 5-minute intravenous injection of TT. At 65 mg/m2 (level 2), there were three CR and four PR, for an overall response rate of 78%. There were no delays in starting induction therapy, and only two patients at dose level 2 experienced a 2-week delay in commencing consolidation.
Seventy-four (97.4%) of 76 patients achieved a complete response after induction chemotherapy. One patient who did not achieve a CR had persistence of CSF blasts and cranial nerve palsy, and one was an early death on therapy.
EFS
Cox regression analysis was conducted on the 71 precursor B-cell patients to study the prognostic effect of race, sex, WBC at diagnosis, age at diagnosis, NCI risk group at initial diagnosis, CSF blasts at diagnosis, CR1 duration, and WBC in CSF at relapse (Table 5). NCI risk group at initial diagnosis was the most significant prognostic factor, with a four-fold higher risk of failure for NCI high-risk patients (proportional hazards ratio, 4.57; 95% CI, 1.34 to 15.53). In the presence of NCI risk, CR1 duration was no longer significant. Figure 2 gives the EFS by NCI risk (4-year EFS, 51.4% ± 10.8% v 80.2% ± 6.3%; P = .0018). Figure 3 gives the four curves for the combination of NCI risk and CR1 duration. Pair-wise comparisons showed that there was a significant difference between standard risk/CR1 of at least 18 months group and both high risk/CR1 of less than 18 months and also high risk/CR1 of at least 18 months groups (P = .0068 and .0314, respectively). Note that the small sample sizes in each subgroup and the significant correlation between NCI risk and CR1 duration limits the interpretation of this analysis.
All relapses occurred within 36 months of study enrollment. Table 6 gives the breakdown of sites of relapse by CR1 duration B-precursor ALL (Bp-ALL). There were 11 relapses: five in the CNS alone and six involving the marrow (three in the marrow alone; two in the marrow and CNS; and one in the marrow, testes, and kidney). Only one of the CNS relapses (at 3 months) occurred before CNS radiation.
Two patients developed second malignancies as the first event on study (myelodysplastic syndrome and eosinophilic leukemia 3.6 and 6.5 years, respectively, from study enrollment). A third patient was diagnosed with acute monocytic leukemia after relapsing in the marrow, testes, and kidney. Twenty-eight patients were removed from protocol therapy because of relapse (n = 11), toxicity (n = 5), death on study (n = 3), second malignancy (n=1), BMT in remission (n = 2), other (n = 4), lost to follow-up (n=1), and refusal of further therapy (n = 1). All five T-cell patients had received prior cranial radiation and hence were excluded from the primary analysis. Table 7 summarizes these data. Among the early relapses, one patient experienced failure in the CNS (retinal and optic nerve) within 2.76 months of enrollment and died 7 months later, and was the only T-cell patient who received TT (50 mg/m2). Of the remaining two early relapses, one died as a result of infection (12.25 months), and the other remains in remission (66.23 months). Of the two late relapses, one remains in remission (64.39 months) and the second had a CNS relapse (21.98 months from study entry) and died 8 months later.
Toxicity Toxicity was acceptable despite 12 months of intensive systemic chemotherapy. By study design, a maximum 8-week delay for commencement of radiation (week 50) was allowed. Most patients commenced radiation between weeks 51 and 53, and only 11 (15%) were delayed beyond 2 weeks. Therefore, the safety and feasibility of administering 12 months of intensive systemic chemotherapy and delayed CNS radiation was demonstrated. The most common toxicity was myelosuppression, with 70 and 66 episodes of grade 3/4 neutropenia and thrombocytopenia, respectively. Induction toxicity was not significantly different between patients receiving TT and the remaining cohort. There were four septic deaths, three from bacterial sepsis (Staphylococcus aureus, Enterobacter species, and multiple organisms, respectively), and one from cytomegalovirus pneumonitis. Myelotoxicity was most severe after high-dose cytarabine. Nevertheless, overall treatment was delivered on schedule as attested by on-time delivery of radiation in 85% of patients. Four patients developed uncomplicated seizures, and four patients developed grade 3/4 soft tissue reactions after L-asparaginase injection, two requiring surgical debridment. Once switched to Erwinia, most patients were able to complete all doses of L-asparaginase.
This report describes 76 children with first isolated CNS relapse of ALL treated with a regimen of intensive chemotherapy for 12 months and delayed CNS radiation. The 4-year EFS of 77.7% ± 6.4% for patients with CR1 of at least 18 months was similar to that in the predecessor study POG 9061, despite reduced dose of cranial radiation (18 Gy) and elimination of spinal radiation. For patients with CR1 of less than 18 months, the EFS of 49.4% ± 11.1% was also comparable.1 The 4-year overall survival rate for the entire group was 77.2% ± 5.3%. Therefore, intensive systemic and intrathecal chemotherapy for 12 months with delayed, and reduced-dose CNS radiation for late relapses, followed by maintenance therapy, is a highly efficacious retrieval regimen for this cohort. The treatment philosophy of intensive systemic therapy with antileukemic drugs that penetrate the CNS plus delayed CNS radiation used by POG, has resulted in significant improvements in outcome for patients with isolated CNS relapse of ALL. Previously, most studies had reported EFS rates below 50%,3,4,15,16 whereas more recently, two small studies reported 4-year EFS of approximately 70%.5,17 This shift in treatment philosophy resulted from the realization that most failures after isolated CNS relapse occurred in the bone marrow. Therefore, we designed a regimen that intensified systemic therapy for 12 months while delaying radiation. Although our results proved the feasibility of delaying CNS radiation for 12 months, this regimen did not offer better systemic disease control.1 This pattern of failure supports our hypothesis that extramedullary relapse of ALL constitutes an early manifestation of systemic relapse. Indeed, three studies reported molecular evidence of bone marrow involvement at the time of CNS relapse.18-20 Available data would suggest that hematologic relapse after CNS relapse arises through persistence of refractory bone marrow disease, rather than reseeding from the CNS. It is tempting to speculate that intrinsic molecular differences within leukemic clones or differences in host somatic gene polymorphisms may influence the site of relapse. These questions are being addressed in the ongoing Children’s Oncology Group trial for extramedullary relapse of ALL (AALL02P2). NCI risk group was an independent prognostic factor on this study. When both NCI risk and CR1 duration were combined, patients with standard risk/CR1 of at least 18 months group did significantly better than both the high risk/CR1 of less than 18 months and high risk/CR1 of at least 18 months groups (P = .0068 and .0314, respectively). All other factors analyzed did not predict outcome. CR1 duration has been reported as independently prognostic on most other relapse studies. Therefore, the two major contributions of POG 9412 are the demonstration of the predictive value of NCI risk group in isolated CNS relapse and the achievement of a 4-year EFS of 83.9% ± 6.5% (P = .0085) for patients with standard risk/CR1 of at least 18 months. The small number of patients in each subgroup and the fact that NCI risk at initial diagnosis and CR1 duration are highly correlated limits the interpretation of the prognostic factor analysis. Additionally, patients with CR1 of at least 18 months likely benefit from exposure to lower doses of CNS radiation. Data from the NCI's Surveillance, Epidemiology, and End Results (SEER) program indicate that by 2010, one in 250 adults will likely be childhood cancer survivors.21 Therefore, efficacious therapeutic strategies aimed at ameliorating long-term adverse effects are essential. The development of progressive neurocognitive deficits and second neopalsms in children receiving whole-brain radiotherapy is well documented.22-29 Spinal axis radiation also contributes to long-term cardiopulmonary, renal, and growth impairment in cancer survivors.30-32 Consequently, it is significant that our regimen maintained efficacy despite reduction of radiation therapy for patients with CR1 of at least 18 months. Our data suggest that further reduction in dose or elimination of CNS radiation is feasible in patients with CR1 of at least 18 months and should be considered to decrease long-term disabilities in childhood cancer survivors. A secondary objective of this study was to determine the efficacy and toxicity of systemic intravenous TT in clearing CSF blasts. An in vitro 50% inhibitory concentration of 1.5 to 8 µmol/L was reported for leukemia,7,8,33,34 and more importantly, a pediatric phase I study demonstrated CSF plasma area-under-the-concentration-time-curve ratios for the two active metabolites, TT and Tepa (TP), of 1.02 and 0.96 respectively.10 TT at 65 mg/m2 exhibited and overall response rate of 78% and may be useful in future regimens for CNS relapse. In conclusion, our data demonstrate that reduced cranial radiation (18 Gy) without spinal radiation is the treatment of choice for Bp-ALL patients with isolated CNS relapse and CR1 of at least 18 months. In contrast, the added risk of chemotherapy-induced toxicities associated with 6 additional months of intensive chemotherapy without improvement in EFS does not warrant this approach for patients with CR1 of less than 18 months. Therefore, new strategies need to be explored for early-relapse patients.35,36
The authors indicated no potential conflicts of interest.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential con- flicts of interest and author contributions are found at the end of this article.
1. Ritchey AK, Pollock BH, Lauer SJ, et al: Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: A pediatric oncology group study. J Clin Oncol 17:3745-3752, 1999 2. Silverman LB, Declerck L, Gelber RD, et al: Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia 14:2247-2256, 2000[CrossRef][Medline] 3. Winick NJ, Smith SD, Shuster J, et al: Treatment of CNS relapse in children with acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Clin Oncol 11:271-278, 1993 4. Henze G, Fengler R, Hartmann R, et al: Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85): A relapse study of the BFM group. Blood 78:1166-1172, 1991 5. Mandell LR, Steinherz P, Fuks Z: Delayed central nervous system (CNS) radiation in childhood CNS acute lymphoblastic leukemia: Results of a pilot trial. Cancer 66:447-450, 1990[CrossRef][Medline] 6. 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] 7. Shay H, Zarafonetis C, Smith N, et al: Treatment of leukemia with triethylene thiophosphoramide (thio-TEPA): Preliminary results in experimental and clinical leukemia. AMA Arch Intern Med 92:628-645, 1953[Medline] 8. Rundles RW, Barton WB: Triethylene melamine in the treatment of neoplastic disease. Blood 7:483-507, 1952 9. Gutin PH, Weiss HD, Wiernik PH, et al: Intrathecal N, N', N'-triethylenethiophosphoramide [thio-TEPA (NSC 6396)] in the treatment of malignant meningeal disease: Phase I-II study. Cancer 38:1471-1475, 1976[CrossRef][Medline] 10. Heideman RL, Cole DE, Balis F, et al: Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: Evidence for dose-dependent plasma clearance of thiotepa. Cancer Res 49:736-741, 1989 11. Mahoney DH Jr, Shuster J, Nitschke R, et al: Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: A Pediatric Oncology Group phase III trial. J Clin Oncol 16:246-254, 1998 12. Pullen J, Boyett J, Shuster J, et al: Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Clin Oncol 11:839-849, 1993 13. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
18 months v 
