Original Article
Low Leukocyte Counts with Blast Cells in Cerebrospinal Fluid of Children with Newly Diagnosed Acute Lymphoblastic Leukemia
N Engl J Med 1993; 329:314-319July 29, 1993
- Abstract
Background
Treatment of the central nervous system is crucial to the successful treatment of acute lymphoblastic leukemia in children. The intensity and timing of the therapy are based on the presence or predicted risk of central nervous system leukemia as assessed according to criteria that remain controversial.
Methods
The clinical importance of leukemic blast cells detected in cerebrospinal fluid at the time of diagnosis was evaluated in 351 children with acute lymphoblastic leukemia in a randomized trial of intensive chemotherapy. All patients received intrathecal chemotherapy during the first year. Patients considered to be at high risk of relapse because of their clinical and cytogenetic features also received cranial irradiation and intrathecal chemotherapy one year after remission. Patients were considered to have central nervous system leukemia at diagnosis if they had at least 5 leukocytes per microliter of cerebrospinal fluid, with leukemic blast cells apparent in cytocentrifuged preparations, or cranial-nerve palsy; they received additional intrathecal injections of chemotherapeutic agents and cranial irradiation. Patients were retrospectively classified on the basis of cerebrospinal fluid findings: 291 patients had no detectable blast cells, 42 had fewer than 5 leukocytes per microliter and blast cells, and 18 had central nervous system leukemia as defined above. The clinical characteristics and outcomes of treatment in these groups were analyzed.
Results
The five-year probability of survival free of relapses confined to the central nervous system in patients with detectable blast cells and fewer than 5 leukocytes per microliter of cerebrospinal fluid was lower than in patients without blast cells (mean [±SE], 87 ±13 vs. 96 ±2 percent), but was not different from the probability in patients with central nervous system leukemia at diagnosis. All such isolated relapses of leukemia in patients with detectable blast cells occurred during the first year of treatment, before scheduled cranial irradiation. In a multivariate analysis, the presence of cerebrospinal fluid blast cells with fewer than 5 leukocytes per microliter was independently related to the risk of relapse confined to the central nervous system.
Conclusions
Patients with leukemic blast cells in their cerebrospinal fluid are at increased risk for central nervous system relapse when cranial irradiation is delayed. Such patients require intensified central nervous system treatment early in the course of therapy.
Media in This Article
Figure 1
Chemotherapy of Childhood Acute Lymphoblastic Leukemia in This Study.Figure 2
Kaplan-Meier Analysis of Five-Year Event-free Survival According to Findings in Cerebrospinal Fluid at Presentation.Article Activity
- Article
Although the incidence of acute lymphoblastic leukemia recurring in the central nervous system in children has decreased markedly since the introduction of effective therapy directed at the central nervous system, more than half the patients who have such early relapse die of their disease despite aggressive attempts at salvage1,2. Treatment regimens designed to prevent overt central nervous system disease have varied from cranial irradiation combined with intrathecal chemotherapy to intrathecal chemotherapy alone or combined with high-dose intravenous methotrexate3-8. For patients with central nervous system leukemia at diagnosis, intensified therapy (e.g., additional intrathecal injections of chemotherapeutic agents and higher doses of cranial or craniospinal radiation) is essential to optimize the likelihood of cure. Whether and when to administer such treatment are determined almost entirely by how central nervous system leukemia is defined. At most centers, this definition specifies the presence of at least 5 leukocytes per microliter of cerebrospinal fluid, with leukemic blast cells apparent in a cytocentrifuged sample of cerebrospinal fluid, or the presence of cranial-nerve palsies9. The clinical importance of blast cells in cerebrospinal fluid samples with fewer than 5 leukocytes per microliter is not clear. We addressed this issue by analyzing recurrences of central nervous system disease in a large series of patients who were being treated in a randomized trial of intensified systemic chemotherapy.
Methods
Patients
From February 1984 to September 1988, 358 consecutive patients 19 years of age or younger with newly diagnosed acute lymphoblastic leukemia were enrolled (the Total Therapy Study XI at St. Jude Children's Research Hospital10). All patients who met standard diagnostic criteria for acute lymphoblastic leukemia were eligible for the study, except those whose leukemic cells had a mature B-cell phenotype and L3 morphology as defined by the classification of the French-American-British working group. The diagnosis was based on morphologic evaluation of smears of bone marrow after Wright-Giemsa staining and the absence of myeloperoxidase staining in marrow preparations (<3 percent positive blast cells).
Cerebrospinal fluid leukocyte counts were performed with a hemocytometer. Samples of cerebrospinal fluid (1.5 ml from patients with fewer than 10 leukocytes per microliter and 0.5 ml from those with higher counts) were placed in a Cytospin sample chamber and cytocentrifuged at 1000 revolutions per minute for five minutes (Shandon centrifuge, Pittsburgh). All slides containing immature lymphoid cells were reviewed by at least three examiners (a hematopathologist, a pediatric oncologist, and a certified medical technician). Central nervous system leukemia was diagnosed if the mononuclear cell count was at least 5 leukocytes per microliter and leukemic blast cells were detected in Wright-stained cytocentrifuged samples of cerebrospinal fluid, or if cranial-nerve palsy was present. Cerebrospinal fluid samples were considered to be contaminated with peripheral blood if the ratio of red cells to white cells exceeded 10 according to the chamber count. Patients with contaminated cerebrospinal fluid and leukemic blast cells were excluded from outcome analyses.
Patients were assigned to treatment groups based on risk criteria derived from a retrospective analysis of institutional data11. Patients with an initial leukocyte count of at least 100,000 per cubic millimeter or two or more unfavorable prognostic features (age <2 years or ≥ 10 years, leukocyte count ≥ 25,000 per cubic millimeter, black race, chromosomal translocation in leukemic cells, and a DNA index <1.16) were considered to be at higher risk, and all others to be at low risk.
Treatment
The treatment protocol has been described in detail elsewhere10 and is outlined in Figure 1Figure 1
Chemotherapy of Childhood Acute Lymphoblastic Leukemia in This Study.. In brief, therapy for induction and consolidation of remission consisted of a six-drug regimen given over a six-week period followed by two high doses of methotrexate (2 g per square meter of body-surface area) weekly. When consolidation therapy was completed, the patients in both the higher-risk and the low-risk groups were randomly assigned in a stratified fashion to one of the three continuation-therapy groups (Figure 1).Intrathecal injections of methotrexate, hydrocortisone, and cytarabine (intrathecal chemotherapy) were given three times during induction and consolidation phases and then every eight weeks during the first year of continuation therapy to patients whose cerebrospinal fluid specimens contained either no leukemic blast cells or blasts cells and fewer than 5 leukocytes per microliter. The dosage of intrathecal chemotherapy was age-dependent, as recommended by Bleyer12. The higher-risk group also received 18 Gy of cranial irradiation combined with five injections of the three intrathecal drugs after one year of continuous complete remission. Patients with central nervous system leukemia at diagnosis received intrathecal chemotherapy weekly, five or six times during the induction and consolidation phases and every eight weeks during the first year of continuation therapy, as well as 24 Gy of cranial irradiation with five intrathecal injections after one year of continuous complete remission.
Study Design and Statistical Analysis
Patients were retrospectively divided into three groups based on findings of cerebrospinal fluid studies at diagnosis: patients without detectable blast cells, patients with fewer than 5 leukocytes per microliter and blast cells, and patients with central nervous system leukemia defined according to conventional criteria. The distributions of clinical and biologic features of the three groups at presentation were compared by Fisher's exact test. Because the comparisons are not independent, only those yielding a P value below 0.012513 are reported here. Survival without adverse events (event-free survival) and survival free of isolated central nervous system leukemia as of November 1992 were estimated by means of Kaplan-Meier analysis. Differences in the survival curves were assessed with the log-rank test, with P values adjusted for multiple comparisons as appropriate. Multivariate analysis (Cox proportional-hazards model) was used to identify independent prognostic factors; P values were derived from the likelihood ratio test. The resulting coefficients and standard errors were used to compute relative risks and their associated 95 percent confidence intervals. The covariates studied included features used to define the higher-risk and low-risk groups, as well as other features known or suspected to influence the outcome of treatment in patients with acute lymphoblastic leukemia.
Results
The outcome of treatment in relation to the cerebrospinal fluid findings at diagnosis could be evaluated in 351 of the 358 patients. The mean (±SE) five-year event-free survival in these 351 patients was 72 ±4 percent (Figure 2Figure 2
Kaplan-Meier Analysis of Five-Year Event-free Survival According to Findings in Cerebrospinal Fluid at Presentation.). The seven other patients had cerebrospinal fluid samples contaminated with peripheral-blood and leukemic blast cells at diagnosis, were treated as patients with central nervous system leukemia, and were excluded from the analysis. None of these seven patients had a relapse; at the most recent follow-up visit, three remained in remission, one had not had a remission, two had a bone marrow relapse, and one had secondary acute myeloid leukemia. Of the 351 patients evaluated, 291 (83 percent) had no detectable leukemic blast cells in their diagnostic cerebrospinal fluid samples (16 of these patients had at least 5 leukocytes per microliter), 42 (12 percent) had fewer than 5 leukocytes per microliter and blast cells, and 18 (5 percent) had central nervous system leukemia according to the standard definition.As compared with the patients with no detectable blast cells in cerebrospinal fluid, those with central nervous system leukemia were more likely at diagnosis to be less than one year of age and to have a leukocyte count of at least 100,000 per cubic millimeter, an anterior mediastinal mass, a T-cell phenotype, and blast cells not expressing the CD10 antigen (Table 1Table 1
Distribution of Clinical and Biologic Features of 351 Children with Acute Lymphoblastic Leukemia, According to Findings in Cerebrospinal Fluid.). Patients with fewer than 5 leukocytes per microliter of cerebrospinal fluid and blast cells were more likely than those without blast cells to have high serum lactate dehydrogenase levels at presentation (>400 U per liter).Nineteen patients had isolated central nervous system relapses: 10 of the 291 patients with no blast cells in cerebrospinal fluid (2 of whom had ≥ 5 leukocytes per microliter), 5 of the 42 with fewer than 5 leukocytes per microliter and blast cells, and 4 of the 18 with central nervous system leukemia at diagnosis. Notably, all nine of the relapses of disease confined to the central nervous system in the patients in both groups with detectable cerebrospinal fluid blasts occurred during the first year of therapy, before the scheduled delivery of cranial irradiation. Only 4 of the 109 patients (4 percent) at low risk, who received only intrathecal chemotherapy as central nervous system treatment, had relapses confined to the central nervous system (18, 22, 22, and 40 months after remission), whereas 15 of 242 patients at higher risk (6 percent) had such relapses; only 2 of these 15 patients had relapses after cranial radiation therapy (22 and 71 months after remission). Four other patients had relapses affecting both the central nervous system and bone marrow (two patients in the group with fewer than 5 leukocytes per microliter and blast cells, and one in each of the two other groups). Among the 42 patients with fewer than 5 leukocytes per microliter and blast cells, 5 of the 34 at higher risk had relapses affecting the central nervous system and 1 patient each in the higher-risk and low-risk groups had relapses affecting both the central nervous system and bone marrow.
The probability of survival free of relapse affecting only the central nervous system among the patients with fewer than 5 leukocytes per microliter and blast cells was significantly lower than that among the patients with no blast cells (P<0.01 by the log-rank test), but did not differ significantly from the probability among the patients with central nervous system leukemia (Figure 3Figure 3
Kaplan-Meier Analysis of Five-Year Survival without Relapse of Central Nervous System Leukemia, According to Findings in Cerebrospinal Fluid at Presentation.); the mean (±SE) five-year Kaplan-Meier estimates were 87 ±13 percent and 96 ±2 percent in the first two groups, respectively. As expected, patients with central nervous system leukemia at diagnosis had significantly poorer relapse-free survival than those with no detectable blast cells (P<0.001). Similar results were obtained in analyses that included relapses confined to the central nervous system and relapses involving both the central nervous system and bone marrow (Figure 3). The estimates of five-year event-free survival among patients with fewer than 5 leukocytes per microliter and blast cells and among patients with central nervous system leukemia (53 ±15 percent and 49 ±14 percent, respectively) were significantly lower than the estimates for the patients with no blast cells in the cerebrospinal fluid (75 ±4 percent; P<0.01) (Figure 2). Eight of the 19 patients with relapses confined to the central nervous system had subsequent relapses (affecting the blood in 4 patients and the central nervous system in 4) despite intensive reinduction chemotherapy and craniospinal irradiation on relapse.To identify factors independently related to the risk of relapse affecting the central nervous system, we constructed a proportional-hazards model with the use of clinical and biologic variables known or suspected to affect the outcome of treatment of childhood acute lymphoblastic leukemia: age, sex, race, size of the liver or spleen, presence or absence of a mediastinal mass, the peripheral-blood leukocyte count, hemoglobin level, platelet count, serum lactate dehydrogenase concentration, cerebrospinal fluid findings, French-American-British classification, immunophenotype, DNA index, number of chromosomes and presence of translocations, and risk-group assignment9,10. Multivariate analysis indicated that a presenting leukocyte count of at least 100,000 per cubic millimeter, the presence of the Philadelphia chromosome, and the presence of identifiable blast cells in the cerebrospinal fluid -- regardless of the cerebrospinal fluid leukocyte count -- were all independently associated with relapse confined to the central nervous system (Table 2Table 2
Independent Risk Factors Associated with Relapse Confined to the Central Nervous System.). Patients with fewer than 5 leukocytes per microliter and identifiable leukemic blast cells in their cerebrospinal fluid had a 3.2-fold increased risk (95 percent confidence interval, 1.1 to 9.5), as compared with patients with normal findings in cerebrospinal fluid. When multivariate analysis also included relapses confined to the central nervous system and those affecting both the central nervous system and bone marrow, the relative risk in the group with fewer than 5 leukocytes per microliter and blast cells was 4.1 (95 percent confidence interval, 1.5 to 10.7); neither the cerebrospinal fluid leukocyte count nor the proportion of blast cells identified the patients in this group who subsequently had relapses confined to the central nervous system.Discussion
Our results indicate that the most widely used definition of central nervous system leukemia is inadequate when applied to children with acute lymphoblastic leukemia who do not undergo cranial irradiation during the early phases of therapy. In most contemporary studies, the diagnostic criteria for central nervous system leukemia specify not only the detection of leukemic blast cells in cerebrospinal fluid but also a leukocyte count of at least 5 per microliter. We found that these criteria excluded a subgroup of patients (12 percent) with detectable blast cells but lower leukocyte counts, in whom the outcome of treatment was similar to that of patients who met the conventional criteria for central nervous system leukemia. Both groups had a significantly poorer outcome than patients with no evidence of central nervous system involvement.
Treating subclinical central nervous system leukemia is important for both preventing relapse affecting the central nervous system and its attendant morbidity and mortality and reducing the risk of relapse affecting the blood14-17. In earlier studies, the routine use of craniospinal or cranial irradiation and intrathecal chemoprophylaxis during the early phases of therapy contributed to substantial acute morbidity due to myelosuppression, frequent delays in systemic therapy, and long-term neurotoxicity18-23. Therefore, many contemporary clinical trials, including the one discussed here, were designed to reduce the intensity of central nervous system treatment and its associated toxicity without jeopardizing cure rates. Indeed, the one-year delay of radiation therapy in this trial allowed uninterrupted delivery of intensive, multiagent, systemic chemotherapy and may have contributed to the excellent overall outcome (72 ±4 percent event-free survival at five years),10 which is comparable to the best results reported in other clinical trials of treatment of childhood acute lymphoblastic leukemia24-28. However, the high frequency of relapse confined to the central nervous system among patients with leukemic blast cells in cerebrospinal fluid at diagnosis -- regardless of the cerebrospinal fluid leukocyte count -- is worrisome. These relapses occurred before scheduled cranial radiation therapy and despite the administration of methotrexate in a high dose as consolidation therapy and intrathecal chemotherapy every eight weeks during the first year after remission was induced. In an effort to improve the prognosis of these patients, we now administer intrathecal chemotherapy weekly during the induction and consolidation phases and every four weeks during the first year after remission in children who have any detectable leukemic blast cells in the cerebrospinal fluid at diagnosis.
Gilchrist and coworkers29 evaluated the prognostic influence of blast cells in cerebrospinal fluid among patients with low leukocyte counts. Their analyses showed no association between this factor and relapse confined to the central nervous system. However, their exclusion of patients at high risk, the use of early cranial irradiation in half their patients, and differences in systemic chemotherapy among their patients could explain the differences between our study and theirs30.
The length of time to an initial relapse affecting the central nervous system is an important predictor of treatment outcome: patients who have a relapse confined to the central nervous system before they have been in continuous remission for one year have a poorer prognosis than those who have a relapse after one year31-33. Whether the early relapses we observed stemmed from subclinical central nervous system leukemia present at diagnosis or from a biologically more aggressive form of the disease remains unclear. Nonetheless, effective early central nervous system treatment is clearly the best strategy for long-term control of leukemia and improved survival, since more than half of all patients who have early relapses affecting the central nervous system eventually die during subsequent relapses (which may or may not be confined to the central nervous system) despite aggressive salvage therapy14,16,17,32.
Our findings suggest that children with detectable leukemic blast cells in the cerebrospinal fluid at diagnosis are at high risk for relapses affecting the central nervous system despite the use of intensified systemic therapy. We believe that these findings justify a revision in the standard definition of central nervous system leukemia, set forth by the Rome Workshop and described by Mastrangelo et al.,9 to account for the degree of central nervous system involvement by leukemic cells. We recommend the following categories, based on the number of leukocytes in the cerebrospinal fluid and the presence of leukemic blast cells: central nervous system group 1, no detectable blast cells; central nervous system group 2, fewer than 5 leukocytes per microliter, with detectable blast cells in a cytocentrifuged preparation of cerebrospinal fluid; and central nervous system group 3, central nervous system leukemia as previously defined by the Rome Workshop (≥ 5 leukocytes per microliter and blast cells, or the presence of cranial-nerve palsies). The use of this classification system should improve comparisons of clinical trials of therapy directed at the central nervous system in children with acute lymphoblastic leukemia.
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, San Diego, California, May 1992.
Supported in part by grants (CA-20180 and CA-21765 [CORE]) from the National Cancer Institute and by the American Lebanese Syrian Associated Charities.
We are indebted to Christy Wright and John Gilbert for editorial review.
Source Information
From the Departments of Hematology-Oncology (H.H.M., G.K.R., R.A.K., R.C.R., J.T.S., W.M.C., C.-H.P.), Radiation Oncology (L.E.K.), Pathology and Laboratory Medicine (F.G.B., C.-H.P.), and Biostatistics (M.L.H.), St. Jude Children's Research Hospital, and the Departments of Pediatrics (H.H.M., G.K.R., R.A.K., R.C.R., J.T.S., W.M.C., C.-H.P.) and Radiation Oncology (L.E.K.), University of Tennessee, College of Medicine, both in Memphis.
Address reprint requests to Dr. Mahmoud at St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-0318.
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