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Risk Factors and Therapy for Isolated Central Nervous System Relapse of Pediatric Acute Myeloid Leukemia

From the Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Department of Preventive Medicine, University of Southern California, Los Angeles; Children's Oncology Group, Arcadia, CA; Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; and Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University, Atlanta, GA

Address reprint requests to Donna Johnston, MD, Children's Hospital of Eastern Ontario, 401 Smyth Rd, Ottawa, Ontario K1H 8L1, Canada; e-mail: djohnston{at}cheo.on.ca

	ABSTRACT

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PURPOSE: CNS relapse of pediatric acute myeloid leukemia (AML) is an infrequent occurrence. This review examines the risk factors and therapy used for patients with an isolated CNS relapse.

PATIENTS AND METHODS: Records of 886 patients with de novo AML were reviewed, and patients who entered remission at the end of one course of therapy and developed an isolated CNS relapse as their first event were analyzed (n = 690).

RESULTS: Thirty-three patients developed an isolated CNS relapse. Factors at diagnosis significantly associated with an isolated CNS relapse, compared with no CNS relapse, included age 0 to 2 years (70% v 27%, respectively; P < .001), enlarged liver (79% v 39%, respectively; P < .001) or spleen (79% v 39%, respectively; P < .001) at diagnosis, CNS disease at diagnosis (33% v 9%, respectively; P < .001), median WBC count (79.2 v 19.3 x 10³ µL, respectively; P < .001), French-American-British M5 morphology (45% v 15%, respectively; P < .001), and chromosome 11 abnormalities (44% v 18%, respectively; P = .022). Treatment of the isolated CNS relapse varied from local therapy with intrathecal chemotherapy and/or radiation therapy to systemic therapy with chemotherapy with or without bone marrow transplantation. Survival rate in the patients treated with local therapy was only 31.5% compared with 21.4% in patients treated with systemic therapy. The 8-year overall survival for patients after an isolated CNS relapse was similar to patients after a bone marrow relapse (26% ± 16% v 21% ± 5%, respectively).

CONCLUSION: Significant predictors for isolated CNS relapse were identified. This study demonstrated that there may be no benefit to systemic therapy versus CNS-directed therapy in outcome. The data support CNS-directed therapy to treat isolated CNS relapse.

	INTRODUCTION

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CNS relapse of pediatric acute myeloid leukemia (AML) is known to occur; however, there is little reported on this subject in the literature. There are isolated reports of CNS relapse in pediatric patients but no in-depth analysis of this topic exists currently. In the literature examining AML therapy, the incidence of isolated CNS relapse ranges from 2% to 8.8%.^1-4 Risk factors identified for the development of meningeal leukemia include young age, high initial WBC count, male sex, leukemia cells in the CSF at diagnosis, M4 or M5 French-American-British (FAB) morphology, and inversion of chromosome 16.^3,5-7 There are previous publications addressing therapy for isolated CNS relapse^6,8; however, there is no generalized consensus on therapy.

This study examines the incidence and therapy of isolated CNS relapse in newly diagnosed pediatric patients with AML treated on the Children's Cancer Group (CCG) protocol 2891. CCG-2891 was a randomized trial comparing intensive versus standard-timing induction therapy as well as postremission allogeneic bone marrow transplantation (BMT), autologous BMT, and aggressive chemotherapy in pediatric patients with AML.

We analyzed the clinical features, therapy received, and outcome of pediatric patients with isolated CNS relapse in a cohort of 690 patients with de novo AML who achieved an initial complete remission (CR) after one course (two cycles) of chemotherapy. This analysis represents the largest cohort of patients studied for CNS relapse and describes features we found to be predictive for CNS relapse and the different therapies used for treatment.

	PATIENTS AND METHODS

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Patients and Therapy
Patients were enrolled onto CCG-2891 and treated as previously reported.⁹ A summary of their treatment is as follows: induction chemotherapy consisted of five drugs (dexamethasone, cytarabine, thioguanine, etoposide, and daunomycin) administered at diagnosis and then repeated after a 6-day rest in the intensive-timing arm or after marrow recovery or persistent leukemia on day 14 in the standard-timing arm. On the basis of initial random assignment, patients then received the second two cycles of the same chemotherapy as consolidation in an intensive or standard-timing fashion. Patients received intrathecal cytarabine at the start of each chemotherapy (dexamethasone, cytarabine, thioguanine, etoposide, and daunomycin) cycle and received a total of four doses. Patients with CNS leukemia at diagnosis received additional twice-weekly intrathecal cytarabine for a total of six doses, and if this failed to clear the leukemia cells, the patients then received twice-weekly triple intrathecal therapy for a total of six doses. All patients randomly assigned to chemotherapy also received intrathecal chemotherapy with each postconsolidation cycle, except Capizzi, for another three doses. No radiation therapy was included except if the patient had extramedullary leukemia at diagnosis in a CNS location. Patients who developed a CNS relapse while on therapy were prescribed to be treated with the same intrathecal regimen as patients with CNS disease at diagnosis.

Patients who achieved remission and had a five- or six-antigen HLA-matched family donor were allocated to allogeneic BMT. The remaining patients were randomly assigned to intensification with autologous BMT versus intensive-timing high-dose cytarabine. CNS involvement with leukemia was diagnosed if the patient had the presence of more than 5 WBCs in the CSF with the presence of blasts in the cytospin.⁹

Data Collection
Information regarding CNS relapse was obtained from the data submitted by institutions for patients enrolled onto the protocol. Only patients with de novo AML were included in the analysis, and patients with myelodysplastic syndrome, Down syndrome, and isolated extramedullary leukemia without marrow involvement at diagnosis were excluded. Eight hundred eighty-six patients were identified; 39 patients withdrew from the study before the determination of remission status and are not included in the analysis, and 690 patients (81.5%) achieved a CR after one course of induction chemotherapy. Patients who never entered remission after one course of induction therapy were not included in this analysis. Isolated CNS relapse was defined as a CNS relapse as a first event with no evidence of marrow relapse within 30 days. Patients with and without an isolated CNS relapse were compared with respect to sex, race, age, FAB leukemia subtype, organ enlargement, WBC count at diagnosis, cytogenetics, presence of CNS disease at diagnosis, induction timing received, postinduction therapy, and time from the end of course 1 of chemotherapy to CNS relapse. Liver or spleen size was classified as not enlarged, enlarged but not below umbilicus, and enlarged and below umbilicus on the study data forms, and we defined organ enlargement as the latter two categories.

Statistical Methods
This report analyzes data collected on CCG-2891 through January 14, 2004. The significance of observed differences in proportions was tested using the ² test and Fisher's exact test when data were sparse. The Mann-Whitney U test was used to determine the significance between differences in medians.¹⁰ The Kaplan-Meier method¹¹ was used to calculate estimates of overall survival, which was defined as the time from CNS or bone marrow relapse to death. Significant differences in overall survival were determined by the log-rank test. CIs were calculated using Greenwood's estimate of the SE. Cumulative incidence of CNS relapse was estimated by considering marrow relapses and deaths as competing events. Significant differences in cumulative incidence were determined by Gray's test.¹² A Cox regression model that included the occurrence of an isolated CNS relapse as a time-varying covariate was used to determine the prognostic significance of an isolated CNS relapse on overall survival from the end of the first course of therapy. Children lost to follow-up were censored at their date of last known contact or at the cutoff date of July 14, 2003.

	RESULTS

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Patient Characteristics
Thirty-three patients were identified who developed isolated CNS relapse of their AML. This corresponds to an 8-year cumulative incidence of 4.8% in patients who entered remission after one course of induction therapy. The median time to CNS relapse from the end of course 1 of induction therapy was 112 days (range, 0 to 935 days), and 31 of the 33 patients experienced their relapse within 1 year of entering remission. The patients who developed isolated CNS relapses had previously received a variety of postinduction therapies. Nine patients received allogeneic BMT, six received autologous BMT, 10 received chemotherapy according to the CCG-2891 protocol, and eight received other therapies (two patients had early relapse so they were treated off therapy, two patients received no therapy, two patients had unknown chemotherapy, one patient had unknown BMT, and treatment is unknown for one patient). The data for these 33 patients compared with the 657 patients who entered CR after one course of induction therapy but did not develop a CNS relapse are listed in Table 1. There was an equal male to female distribution, but a significantly higher number of white patients developed an isolated CNS relapse. The median age of patients at diagnosis who developed a CNS relapse was 1.22 years (range, 0.09 to 17.94 years). Twenty-three of the patients who developed a CNS relapse were age 0 to 2 years, which is a significantly higher proportion of patients than the proportions seen in the other age groups. Eleven of the patients who developed an isolated CNS relapse had CNS involvement of their leukemia at diagnosis, which is significant. There was also a significantly higher incidence of hepatic or splenic enlargement in patients at diagnosis who went on to develop an isolated CNS relapse compared with patients with no CNS relapse, as well as a significantly higher WBC count at diagnosis.

There was a cytogenetic abnormality in many of the patients who developed an isolated CNS relapse; however, only 52% of the patients in this study had cytogenetic data available. The only significant cytogenetic abnormality that was present more in patients with an isolated CNS relapse compared with the other patients was chromosome 11 abnormalities (P = .022).

The type of induction chemotherapy was unequally distributed among patients who had an isolated CNS relapse. Fourteen (6.0%) of 235 patients who received standard-timing chemotherapy and 17 (3.8%) of 444 patients who received intensive-timing chemotherapy had an isolated CNS relapse. Two (18.2%) of the 11 patients receiving combination standard and intensive therapy (crossed over once the standard arm was closed) had an isolated CNS relapse. There was no significant difference in the incidence of developing a CNS relapse between patients who received intensive-timing chemotherapy compared with standard-timing chemotherapy (P = .16).

All patients were required to undergo a bone marrow aspirate at the time of relapse. All marrows performed had less than 5% blasts present (M1 morphology), with a median blast count in the marrow of 1% at the time of CNS relapse.

Treatment
The treatments administered for the isolated CNS relapses were quite variable among the patients and are listed in Table 2. The most used therapy for treatment of the isolated CNS relapse was intrathecal chemotherapy only, followed by intrathecal chemotherapy with radiation therapy. A variety of other modalities of therapy were used, including systemic chemotherapy and BMT. Nineteen patients who developed a CNS relapse received only local therapy (intrathecal chemotherapy with or without radiation therapy). Eight of these patients subsequently developed a marrow relapse. Of the 19 patients who did not receive systemic therapy, six survived, 11 died of progressive disease, one died of toxicity, and one died of infection. Fourteen patients received various forms of systemic therapy, from chemotherapy only to chemotherapy plus radiation therapy and BMT. Eight of these patients also subsequently developed a marrow relapse. Three of these patients survived, seven died of progressive disease, three died of infection, and there is no data on cause of death for one patient.

The 8-year overall survival rate for patients after an isolated CNS relapse was 26% ± 16% (Fig 1). The overall survival rate after an isolated CNS relapse is similar to the survival rate of patients after a bone marrow relapse (21% ± 5%, P = .071). The survival after an isolated CNS relapse was the same for patients who received either the standard-timing or the intensive-timing induction therapy (P = .368). In analyzing patients who relapsed within 1 year of diagnosis, patients with a CNS relapse did significantly better than patients after a bone marrow relapse (survival rate, 22% v 8%, respectively; P = .0006; Fig 2). When analyzing the patients with a CNS relapse followed by a bone marrow relapse, 15 of the 16 patients died of their disease.

View larger version (10K): [in this window] [in a new window]   Fig 1. Kaplan-Meier figure for overall survival from an isolated CNS relapse or a bone marrow relapse.

View larger version (15K): [in this window] [in a new window]   Fig 2. Kaplan-Meier figure for survival from an isolated CNS relapse or a bone marrow relapse 1 year or more than 1 year from diagnosis (dx).

	DISCUSSION

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Histology has previously been shown to be predictive of a CNS relapse with an increased incidence in patients with M4 or M5 leukemia.^1,6,7 We found that patients with M5 leukemia had a significantly higher incidence of CNS relapse and that patients with M2 leukemia had a lower incidence of CNS relapse. However, there was no increased incidence of CNS relapse in patients with M4 FAB morphology in our study.

Young age has previously been attributed as a risk factor for the development of CNS relapse. It is postulated that this risk is a result of a greater proportion of vasculature in the leptomeninges in infants and preschool children.⁵ Another possible explanation is that certain FAB subtypes or cytogenetic abnormalities, which are more common in young children, lead to more extramedullary leukemia. Indeed, we found that 70% of patients with a CNS relapse were in the 0- to 2-year-old age range, but only 27% of patients without an isolated CNS relapse were in this age range. In addition, there is a much higher incidence of M5 disease in infants who are 2 years of age or younger, as well as more skin extramedullary leukemia in M5 patients, especially in this age group.¹³ Thus, a significant proportion of the patients with isolated CNS relapse were 2 years of age or younger at diagnosis of their leukemia and had M5 disease. This confirms previous studies identifying young age as a risk factor for CNS relapse.^5,6

A previous study from St. Jude Children's Research Hospital found that the presence of CNS disease at diagnosis was not an adverse prognostic factor.² Conversely, investigators from the Pediatric Oncology Group found patients who had CNS disease at diagnosis to be more likely to experience relapse in the CNS compared with other patients.³ In the pilot study for CCG-2891 (CCG-2861), patients with CNS disease at the time of diagnosis had a poor event-free survival compared with the other patients, and half of the patients developed a CNS relapse.¹⁴ In our analysis, 33% of the patients with isolated CNS relapse had CNS disease at diagnosis. This is significantly higher than the 9% incidence of CNS disease at diagnosis for patients who did not develop an isolated CNS relapse. Thus, given these results, we would argue that CNS disease at diagnosis is a risk factor for isolated CNS relapse.

Cytogenetics are often predictive of survival in pediatric AML, with certain cytogenetic abnormalities conferring a decrease in overall survival. In one large analysis with older, less adequate therapy than what is used today, patients with any type of 11q23 abnormality had a poor response to treatment, with a poor survival rate.¹⁵ Similarly from the same institution, in infants with AML, it was shown that t(9;11) conferred a favorable outcome, and other MLL/11q23 rearrangements lacked prognostic significance.¹³ In older children with AML, t(9;11) carries a favorable prognosis, whereas other 11q23 rearrangements carry a poor prognosis.^16,17 However, in current studies using aggressive induction and intensification therapy, 11q23 no longer remains an adverse prognostic factor.^4,18 In our study of non-CNS extramedullary leukemia, patients were more likely to show abnormalities of chromosome 11 than patients without extramedullary leukemia.¹⁹ In our current analysis, abnormality of chromosome 11 was significantly more common in patients with CNS relapse (P = .022).

An elevated WBC count at diagnosis has been reported to be predictive of a CNS relapse.⁶ It has also previously been reported that low WBC count at diagnosis confers a better prognosis,^3,13 but there are contradictory reports of high WBC count being a significant predictor of survival.¹ The results of the CCG-2861 and CCG-2891 studies showed that an elevated WBC count at diagnosis was associated with a lower rate of remission after induction therapy and a lower overall survival rate compared with low WBC count at diagnosis.¹⁴ We found that the WBC count was significantly higher at diagnosis in patients who experienced an isolated CNS relapse compared with patients with no isolated CNS relapse and would agree with the conclusion that a high WBC count at diagnosis confers a worse prognosis for CNS recurrence. There is a strong correlation between high WBC count, FAB M5 subtype, age 0 to 2 years, and 11q23 abnormalities in developing an isolated CNS relapse, and which factor is more important in CNS disease development is not known.

CNS relapse in more than half of the patients occurred while the patients were still receiving active induction and postremission therapy for their leukemia, and most patients had not yet completed therapy. Thirty (91%) of the 33 patients who developed an isolated CNS relapse did so within 1 year of diagnosis, which is earlier than patients on this protocol who developed a marrow relapse, of whom only 58% (156 of 268 patients, P < .001) developed relapse within 1 year of diagnosis.

There are no published reports with a consensus therapy for CNS relapse of AML. The therapies used on the patients in our analysis varied from intrathecal chemotherapy only, as proscribed in the protocol, to intensive therapy with systemic chemotherapy, radiation therapy, and BMT. There was no therapy that proved to be more effective than the other, and most of the patients who did not survive died from progressive disease rather than from the toxicity of the therapy. The patients who were treated with only local therapy (intrathecal chemotherapy with or without radiation therapy) had an overall survival rate of 31.5%, with 10.5% dying of complications and 58% dying of progressive disease. The patients treated with systemic therapy (chemotherapy and/or BMT) for their CNS relapse had an overall survival rate of 21.4%, with 28.6% dying of complications and 50% dying of progressive disease. Although this information is retrospective and has inherent biases, patients treated with CNS therapy alone did as well as or better than patients administered systemic therapy including BMT. The 8-year overall survival rate after an isolated CNS relapse was 26% ± 16%, which is similar to the overall survival rate of 21% ± 5% after a bone marrow relapse. Patients with a CNS relapse within 1 year of diagnosis had a significantly better 8-year overall survival rate than patients with a bone marrow relapse within 1 year of diagnosis (22% v 8%, respectively; P = .006). After an isolated CNS relapse, patients are 2.2 times (95% CI, 1.4 to 3.5 times) more likely to die than patients without an isolated relapse. So, as expected, the survival is diminished when a CNS relapse occurs. Previous studies have found that a CNS relapse did not preclude long-term survival,^6,7 but our data demonstrate that CNS relapse does diminish overall survival compared with all patients and that the overall survival is similar to patients with bone marrow relapse.

This study represents the largest cohort of pediatric patients with AML examined for the occurrence of an isolated CNS relapse. We conclude that the risk factors for isolated CNS relapse of pediatric AML are young age, presence of CNS disease or high WBC count or hepatomegaly or splenomegaly at diagnosis, M5 FAB subtype, and chromosome 11 abnormalities. Many of these presenting characteristics are interrelated (M5 infants with high WBC count and 11q23 abnormalities), and thus, it is not possible to state which is most important. Although this study is a retrospective analysis not powered to look at these variables, we feel that the conclusions are quite compelling, and further study would be beneficial to reinforce these findings. The therapy for isolated CNS relapse of AML is variable, but our data suggest that therapy directed at the CNS alone is equal or superior to systemic therapy including BMT. Thus, we would recommend CNS-directed therapy alone for the treatment of an isolated CNS relapse.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Presented at the 18th Annual Meeting of the American Society of Pediatric Hematology/Oncology, Washington, DC, May 13-17, 2005.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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14. Woods WG, Kobrinsky N, Buckley J, et al: Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: A Children's Cancer Group pilot study. J Clin Oncol 11:1448-1457, 1993[Abstract/Free Full Text]

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16. Kalwinsky DK, Raimondi SC, Schell MJ, et al: Prognostic importance of cytogenetic subgroups in de novo pediatric acute nonlymphocytic leukemia. J Clin Oncol 8:75-83, 1990[Abstract/Free Full Text]

17. Martinex-Climent JA, Espinosa R, Thirman MJ, et al: Abnormalities of chromosome band 11q23 and the MLL gene in pediatric myelomonocytic and monoblastic leukemias: Identification of the t(9;11) as an indicator of long survival. J Pediatr Hematol Oncol 17:277-283, 1995[Medline]

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Submitted May 26, 2005; accepted September 20, 2005.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johnston, D. L. Articles by Woods, W. G. Search for Related Content PubMed PubMed Citation Articles by Johnston, D. L. Articles by Woods, W. G. Social Bookmarking                            What's this?