Low Leukocyte Counts with Blast Cells in Cerebrospinal Fluid of Children with Newly Diagnosed Acute Lymphoblastic Leukemia
Hazem H. Mahmoud, Gaston K. Rivera, Michael L. Hancock, Robert A. Krance, Larry E. Kun, Frederick G. Behm, Raul C. Ribeiro, John T. Sandlund, William M. Crist, and Ching-Hon Pui
Background Treatment of the central nervous system is crucialto the successful treatment of acute lymphoblastic leukemiain children. The intensity and timing of the therapy are basedon the presence or predicted risk of central nervous systemleukemia as assessed according to criteria that remain controversial.
Methods The clinical importance of leukemic blast cells detectedin cerebrospinal fluid at the time of diagnosis was evaluatedin 351 children with acute lymphoblastic leukemia in a randomizedtrial of intensive chemotherapy. All patients received intrathecalchemotherapy during the first year. Patients considered to beat high risk of relapse because of their clinical and cytogeneticfeatures also received cranial irradiation and intrathecal chemotherapyone year after remission. Patients were considered to have centralnervous system leukemia at diagnosis if they had at least 5leukocytes per microl of cerebrospinal fluid, with leukemicblast cells apparent in cytocentrifuged preparations, or cranial-nervepalsy; they received additional intrathecal injections of chemotherapeuticagents and cranial irradiation. Patients were retrospectivelyclassified on the basis of cerebrospinal fluid findings: 291patients had no detectable blast cells, 42 had fewer than 5leukocytes per microl and blast cells, and 18 had central nervoussystem leukemia as defined above. The clinical characteristicsand outcomes of treatment in these groups were analyzed.
Results The five-year probability of survival free of relapsesconfined to the central nervous system in patients with detectableblast cells and fewer than 5 leukocytes per microl of cerebrospinalfluid was lower than in patients without blast cells (mean [±SE],87 ±13 vs. 96 ±2 percent), but was not differentfrom the probability in patients with central nervous systemleukemia at diagnosis. All such isolated relapses of leukemiain patients with detectable blast cells occurred during thefirst year of treatment, before scheduled cranial irradiation.In a multivariate analysis, the presence of cerebrospinal fluidblast cells with fewer than 5 leukocytes per microl was independentlyrelated to the risk of relapse confined to the central nervoussystem.
Conclusions Patients with leukemic blast cells in their cerebrospinalfluid are at increased risk for central nervous system relapsewhen cranial irradiation is delayed. Such patients require intensifiedcentral nervous system treatment early in the course of therapy.
Although the incidence of acute lymphoblastic leukemia recurringin the central nervous system in children has decreased markedlysince the introduction of effective therapy directed at thecentral nervous system, more than half the patients who havesuch early relapse die of their disease despite aggressive attemptsat salvage1,2. Treatment regimens designed to prevent overtcentral nervous system disease have varied from cranial irradiationcombined with intrathecal chemotherapy to intrathecal chemotherapyalone or combined with high-dose intravenous methotrexate3,4,5,6,7,8.For patients with central nervous system leukemia at diagnosis,intensified therapy (e.g., additional intrathecal injectionsof chemotherapeutic agents and higher doses of cranial or craniospinalradiation) is essential to optimize the likelihood of cure.Whether and when to administer such treatment are determinedalmost entirely by how central nervous system leukemia is defined.At most centers, this definition specifies the presence of atleast 5 leukocytes per microl of cerebrospinal fluid, with leukemicblast cells apparent in a cytocentrifuged sample of cerebrospinalfluid, or the presence of cranial-nerve palsies9. The clinicalimportance of blast cells in cerebrospinal fluid samples withfewer than 5 leukocytes per microl is not clear. We addressedthis issue by analyzing recurrences of central nervous systemdisease in a large series of patients who were being treatedin a randomized trial of intensified systemic chemotherapy.
Methods
Patients
From February 1984 to September 1988, 358 consecutive patients19 years of age or younger with newly diagnosed acute lymphoblasticleukemia were enrolled (the Total Therapy Study XI at St. JudeChildren's Research Hospital10). All patients who met standarddiagnostic criteria for acute lymphoblastic leukemia were eligiblefor the study, except those whose leukemic cells had a matureB-cell phenotype and L3 morphology as defined by the classificationof the French-American-British working group. The diagnosiswas based on morphologic evaluation of smears of bone marrowafter Wright-Giemsa staining and the absence of myeloperoxidasestaining in marrow preparations (<3 percent positive blastcells).
Cerebrospinal fluid leukocyte counts were performed with a hemocytometer.Samples of cerebrospinal fluid (1.5 ml from patients with fewerthan 10 leukocytes per microl and 0.5 ml from those with highercounts) were placed in a Cytospin sample chamber and cytocentrifugedat 1000 revolutions per minute for five minutes (Shandon centrifuge,Pittsburgh). All slides containing immature lymphoid cells werereviewed by at least three examiners (a hematopathologist, apediatric oncologist, and a certified medical technician). Centralnervous system leukemia was diagnosed if the mononuclear cellcount was at least 5 leukocytes per microl and leukemic blastcells were detected in Wright-stained cytocentrifuged samplesof cerebrospinal fluid, or if cranial-nerve palsy was present.Cerebrospinal fluid samples were considered to be contaminatedwith peripheral blood if the ratio of red cells to white cellsexceeded 10 according to the chamber count. Patients with contaminatedcerebrospinal fluid and leukemic blast cells were excluded fromoutcome analyses.
Patients were assigned to treatment groups based on risk criteriaderived from a retrospective analysis of institutional data11.Patients with an initial leukocyte count of at least 100,000per cubic millimeter or two or more unfavorable prognostic features(age <2 years or 10 years, leukocyte count 25,000 per cubicmillimeter, black race, chromosomal translocation in leukemiccells, and a DNA index <1.16) were considered to be at higherrisk, and all others to be at low risk.
Treatment
The treatment protocol has been described in detail elsewhere10and is outlined in Figure 1. In brief, therapy for inductionand consolidation of remission consisted of a six-drug regimengiven over a six-week period followed by two high doses of methotrexate(2 g per square meter of body-surface area) weekly. When consolidationtherapy was completed, the patients in both the higher-riskand the low-risk groups were randomly assigned in a stratifiedfashion to one of the three continuation-therapy groups (Figure 1).
Figure 1. Chemotherapy of Childhood Acute Lymphoblastic Leukemia in This Study.
Continuation therapy included central nervous system treatment with intrathecal methotrexate, hydrocortisone, and cytarabine, given every eight weeks for one year, followed by cranial irradiation in the higher-risk patients (18 Gy) and the patients with central nervous system leukemia at diagnosis (24 Gy). MP denotes mercaptopurine, MTX methotrexate, Pred prednisone, VCR vincristine, VP-16 etoposide, Cyclo cyclophosphamide, VM-26 teniposide, and ara-C cytarabine.
Intrathecal injections of methotrexate, hydrocortisone, andcytarabine (intrathecal chemotherapy) were given three timesduring induction and consolidation phases and then every eightweeks during the first year of continuation therapy to patientswhose cerebrospinal fluid specimens contained either no leukemicblast cells or blasts cells and fewer than 5 leukocytes permicrol. The dosage of intrathecal chemotherapy was age-dependent,as recommended by Bleyer12. The higher-risk group also received18 Gy of cranial irradiation combined with five injections ofthe three intrathecal drugs after one year of continuous completeremission. Patients with central nervous system leukemia atdiagnosis received intrathecal chemotherapy weekly, five orsix times during the induction and consolidation phases andevery eight weeks during the first year of continuation therapy,as well as 24 Gy of cranial irradiation with five intrathecalinjections after one year of continuous complete remission.
Study Design and Statistical Analysis
Patients were retrospectively divided into three groups basedon findings of cerebrospinal fluid studies at diagnosis: patientswithout detectable blast cells, patients with fewer than 5 leukocytesper microl and blast cells, and patients with central nervoussystem leukemia defined according to conventional criteria.The distributions of clinical and biologic features of the threegroups at presentation were compared by Fisher's exact test.Because the comparisons are not independent, only those yieldinga P value below 0.012513 are reported here. Survival withoutadverse events (event-free survival) and survival free of isolatedcentral nervous system leukemia as of November 1992 were estimatedby means of Kaplan-Meier analysis. Differences in the survivalcurves were assessed with the log-rank test, with P values adjustedfor multiple comparisons as appropriate. Multivariate analysis(Cox proportional-hazards model) was used to identify independentprognostic factors; P values were derived from the likelihoodratio test. The resulting coefficients and standard errors wereused to compute relative risks and their associated 95 percentconfidence intervals. The covariates studied included featuresused to define the higher-risk and low-risk groups, as wellas other features known or suspected to influence the outcomeof treatment in patients with acute lymphoblastic leukemia.
Results
The outcome of treatment in relation to the cerebrospinal fluidfindings at diagnosis could be evaluated in 351 of the 358 patients.The mean (±SE) five-year event-free survival in these351 patients was 72 ±4 percent (Figure 2). The sevenother patients had cerebrospinal fluid samples contaminatedwith 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 patientshad a relapse; at the most recent follow-up visit, three remainedin remission, one had not had a remission, two had a bone marrowrelapse, and one had secondary acute myeloid leukemia. Of the351 patients evaluated, 291 (83 percent) had no detectable leukemicblast cells in their diagnostic cerebrospinal fluid samples(16 of these patients had at least 5 leukocytes per microl),42 (12 percent) had fewer than 5 leukocytes per microl and blastcells, and 18 (5 percent) had central nervous system leukemiaaccording to the standard definition.
Figure 2. Kaplan-Meier Analysis of Five-Year Event-free Survival According to Findings in Cerebrospinal Fluid at Presentation.
One group of patients had no detectable blast cells, another group (Blasts) had fewer than 5 leukocytes per microl and blast cells, and a third group had central nervous system (CNS) leukemia. Survival was significantly better in the group with no blast cells than in the other two groups (P<0.01). Plus-minus values are means ±SE.
As compared with the patients with no detectable blast cellsin cerebrospinal fluid, those with central nervous system leukemiawere more likely at diagnosis to be less than one year of ageand to have a leukocyte count of at least 100,000 per cubicmillimeter, an anterior mediastinal mass, a T-cell phenotype,and blast cells not expressing the CD10 antigen (Table 1). Patientswith fewer than 5 leukocytes per microl of cerebrospinal fluidand blast cells were more likely than those without blast cellsto have high serum lactate dehydrogenase levels at presentation(>400 U per liter).
Table 1. Distribution of Clinical and Biologic Features of 351 Children with Acute Lymphoblastic Leukemia, According to Findings in Cerebrospinal Fluid.
Nineteen patients had isolated central nervous system relapses:10 of the 291 patients with no blast cells in cerebrospinalfluid (2 of whom had 5 leukocytes per microl), 5 of the 42with fewer than 5 leukocytes per microl and blast cells, and4 of the 18 with central nervous system leukemia at diagnosis.Notably, all nine of the relapses of disease confined to thecentral nervous system in the patients in both groups with detectablecerebrospinal fluid blasts occurred during the first year oftherapy, before the scheduled delivery of cranial irradiation.Only 4 of the 109 patients (4 percent) at low risk, who receivedonly 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 patientsat higher risk (6 percent) had such relapses; only 2 of these15 patients had relapses after cranial radiation therapy (22and 71 months after remission). Four other patients had relapsesaffecting both the central nervous system and bone marrow (twopatients in the group with fewer than 5 leukocytes per microland blast cells, and one in each of the two other groups). Amongthe 42 patients with fewer than 5 leukocytes per microl andblast cells, 5 of the 34 at higher risk had relapses affectingthe central nervous system and 1 patient each in the higher-riskand low-risk groups had relapses affecting both the centralnervous system and bone marrow.
The probability of survival free of relapse affecting only thecentral nervous system among the patients with fewer than 5leukocytes per microl and blast cells was significantly lowerthan that among the patients with no blast cells (P<0.01by the log-rank test), but did not differ significantly fromthe probability among the patients with central nervous systemleukemia (Figure 3); the mean (±SE) five-year Kaplan-Meierestimates were 87 ±13 percent and 96 ±2 percentin the first two groups, respectively. As expected, patientswith central nervous system leukemia at diagnosis had significantlypoorer relapse-free survival than those with no detectable blastcells (P<0.001). Similar results were obtained in analysesthat included relapses confined to the central nervous systemand relapses involving both the central nervous system and bonemarrow (Figure 3). The estimates of five-year event-free survivalamong patients with fewer than 5 leukocytes per microl and blastcells and among patients with central nervous system leukemia(53 ±15 percent and 49 ±14 percent, respectively)were significantly lower than the estimates for the patientswith no blast cells in the cerebrospinal fluid (75 ±4percent; P<0.01) (Figure 2). Eight of the 19 patients withrelapses confined to the central nervous system had subsequentrelapses (affecting the blood in 4 patients and the centralnervous system in 4) despite intensive reinduction chemotherapyand craniospinal irradiation on relapse.
Figure 3. Kaplan-Meier Analysis of Five-Year Survival without Relapse of Central Nervous System Leukemia, According to Findings in Cerebrospinal Fluid at Presentation.
Survival free of relapse affecting the central nervous system (upper panel) was significantly higher in the group with no blast cells than in the group with fewer than 5 leukocytes and blast cells (Blasts) (P<0.01 by the log-rank test) and the group with central nervous system (CNS) leukemia (P<0.001); there were no other significant differences in survival between the groups (P = 0.58). Survival free of central nervous system relapse that was either isolated or combined with bone marrow relapse (lower panel) was significantly higher in the group with no blast cells than in the other two groups (P<0.001). Plus-minus values are means ±SE.
To identify factors independently related to the risk of relapseaffecting the central nervous system, we constructed a proportional-hazardsmodel with the use of clinical and biologic variables knownor suspected to affect the outcome of treatment of childhoodacute lymphoblastic leukemia: age, sex, race, size of the liveror spleen, presence or absence of a mediastinal mass, the peripheral-bloodleukocyte count, hemoglobin level, platelet count, serum lactatedehydrogenase concentration, cerebrospinal fluid findings, French-American-Britishclassification, immunophenotype, DNA index, number of chromosomesand presence of translocations, and risk-group assignment9,10.Multivariate analysis indicated that a presenting leukocytecount of at least 100,000 per cubic millimeter, the presenceof the Philadelphia chromosome, and the presence of identifiableblast cells in the cerebrospinal fluid -- regardless of thecerebrospinal fluid leukocyte count -- were all independentlyassociated with relapse confined to the central nervous system(Table 2). Patients with fewer than 5 leukocytes per microland identifiable leukemic blast cells in their cerebrospinalfluid had a 3.2-fold increased risk (95 percent confidence interval,1.1 to 9.5), as compared with patients with normal findingsin cerebrospinal fluid. When multivariate analysis also includedrelapses confined to the central nervous system and those affectingboth the central nervous system and bone marrow, the relativerisk in the group with fewer than 5 leukocytes per microl andblast cells was 4.1 (95 percent confidence interval, 1.5 to10.7); neither the cerebrospinal fluid leukocyte count nor theproportion of blast cells identified the patients in this groupwho subsequently had relapses confined to the central nervoussystem.
Table 2. Independent Risk Factors Associated with Relapse Confined to the Central Nervous System.
Discussion
Our results indicate that the most widely used definition ofcentral nervous system leukemia is inadequate when applied tochildren with acute lymphoblastic leukemia who do not undergocranial irradiation during the early phases of therapy. In mostcontemporary studies, the diagnostic criteria for central nervoussystem leukemia specify not only the detection of leukemic blastcells in cerebrospinal fluid but also a leukocyte count of atleast 5 per microl. We found that these criteria excluded asubgroup of patients (12 percent) with detectable blast cellsbut lower leukocyte counts, in whom the outcome of treatmentwas similar to that of patients who met the conventional criteriafor central nervous system leukemia. Both groups had a significantlypoorer outcome than patients with no evidence of central nervoussystem involvement.
Treating subclinical central nervous system leukemia is importantfor both preventing relapse affecting the central nervous systemand its attendant morbidity and mortality and reducing the riskof relapse affecting the blood14,15,16,17. In earlier studies,the routine use of craniospinal or cranial irradiation and intrathecalchemoprophylaxis during the early phases of therapy contributedto substantial acute morbidity due to myelosuppression, frequentdelays in systemic therapy, and long-term neurotoxicity18,19,20,21,22,23.Therefore, many contemporary clinical trials, including theone discussed here, were designed to reduce the intensity ofcentral nervous system treatment and its associated toxicitywithout jeopardizing cure rates. Indeed, the one-year delayof radiation therapy in this trial allowed uninterrupted deliveryof intensive, multiagent, systemic chemotherapy and may havecontributed to the excellent overall outcome (72 ±4 percentevent-free survival at five years),10 which is comparable tothe best results reported in other clinical trials of treatmentof childhood acute lymphoblastic leukemia24,25,26,27,28. However,the high frequency of relapse confined to the central nervoussystem among patients with leukemic blast cells in cerebrospinalfluid at diagnosis -- regardless of the cerebrospinal fluidleukocyte count -- is worrisome. These relapses occurred beforescheduled cranial radiation therapy and despite the administrationof methotrexate in a high dose as consolidation therapy andintrathecal chemotherapy every eight weeks during the firstyear after remission was induced. In an effort to improve theprognosis of these patients, we now administer intrathecal chemotherapyweekly during the induction and consolidation phases and everyfour weeks during the first year after remission in childrenwho have any detectable leukemic blast cells in the cerebrospinalfluid at diagnosis.
Gilchrist and coworkers29 evaluated the prognostic influenceof blast cells in cerebrospinal fluid among patients with lowleukocyte counts. Their analyses showed no association betweenthis factor and relapse confined to the central nervous system.However, their exclusion of patients at high risk, the use ofearly cranial irradiation in half their patients, and differencesin systemic chemotherapy among their patients could explainthe differences between our study and theirs30.
The length of time to an initial relapse affecting the centralnervous system is an important predictor of treatment outcome:patients who have a relapse confined to the central nervoussystem before they have been in continuous remission for oneyear have a poorer prognosis than those who have a relapse afterone year31,32,33. Whether the early relapses we observed stemmedfrom subclinical central nervous system leukemia present atdiagnosis or from a biologically more aggressive form of thedisease remains unclear. Nonetheless, effective early centralnervous system treatment is clearly the best strategy for long-termcontrol of leukemia and improved survival, since more than halfof all patients who have early relapses affecting the centralnervous system eventually die during subsequent relapses (whichmay or may not be confined to the central nervous system) despiteaggressive salvage therapy14,16,17,32.
Our findings suggest that children with detectable leukemicblast cells in the cerebrospinal fluid at diagnosis are at highrisk for relapses affecting the central nervous system despitethe use of intensified systemic therapy. We believe that thesefindings justify a revision in the standard definition of centralnervous system leukemia, set forth by the Rome Workshop anddescribed by Mastrangelo et al.,9 to account for the degreeof central nervous system involvement by leukemic cells. Werecommend the following categories, based on the number of leukocytesin the cerebrospinal fluid and the presence of leukemic blastcells: central nervous system group 1, no detectable blast cells;central nervous system group 2, fewer than 5 leukocytes permicrol, with detectable blast cells in a cytocentrifuged preparationof cerebrospinal fluid; and central nervous system group 3,central nervous system leukemia as previously defined by theRome Workshop ( 5 leukocytes per microl and blast cells, orthe presence of cranial-nerve palsies). The use of this classificationsystem should improve comparisons of clinical trials of therapydirected at the central nervous system in children with acutelymphoblastic leukemia.
Supported in part by grants (CA-20180 and CA-21765 [CORE]) fromthe National Cancer Institute and by the American Lebanese SyrianAssociated Charities.
We are indebted to Christy Wright and John Gilbert for editorialreview.
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. Presented in part at the Annual Meeting of the American Society of Clinical Oncology, San Diego, California, May 1992.
Address reprint requests to Dr. Mahmoud at St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-0318.
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