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Diagnostic Cerebrospinal Fluid Examination in Children With Acute Lymphoblastic Leukemia: Significance of Low Leukocyte Counts With Blasts or Traumatic Lumbar Puncture

Britta Bürger, Martin Zimmermann, Georg Mann, Joachim Kühl, Lutz Löning, Hansjörg Riehm, Alfred Reiter, Martin Schrappe

From the Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover; University Children’s Hospital, Würzburg; Children’s Hospital, Klinikum Oldenburg; Department of Pediatric Hematology/Oncology, University of Giessen, Germany; and St. Anna Children’s Hospital, Vienna, Austria.

Address reprint requests to Britta Bürger, MD, Department of Pediatric Hematology/Oncology, Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany; email: buerger.britta{at}mh-hannover.de.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To determine the significance of leukemic blasts or traumatic lumbar puncture (TLP) in diagnostic CSF of children enrolled in the Berlin-Frankfurt-Münster (BFM) Acute Lymphoblastic Leukemia–BFM-95 trial.

Patients and Methods: A total of 2,021 patients were retrospectively evaluated according to initial central nervous system (CNS) status. Patients were classified as follows: CNS1 (CNS negative, n = 1,605), CNS2 ( 5 WBC/µL CSF with blasts, n = 103), CNS3 (CNS positive, n = 58), TLP+ (TLP with blasts, n = 135), or TLP- (TLP without blasts, n = 111). Patients with CNS2 and TLP+ status were eligible for two additional doses of intrathecal (IT) methotrexate (MTX). CNS3 patients received additional IT MTX and cranial irradiation (18 Gy).

Results: CNS2, CNS3, and TLP+ groups contained a higher percentage of patients with unfavorable characteristics. Cox regression analysis identified TLP+ and CNS3 status as prognostically significant (CNS3): risk ratio (RR) = 2.3; 95% confidence interval [CI], 1.4 to 3.6; P = .0005; TLP+: RR = 1.5; 95% CI, 1.02 to 2.2; P = .04. Overall 5-year event-free survival (EFS) is 79%, for CNS1 it is 80%, and for TLP- it is 83%. CNS2 patients have an EFS of 80%, but the cumulative incidence of relapses with CNS involvement is higher compared with CNS1 patients (0.10 v 0.04). TLP+ patients have a significantly reduced EFS (73%, P = .003) because of an increased incidence of CNS relapses. CNS3 patients suffer from more systemic and CNS relapses (EFS 50%).

Conclusion: CNS2 patients have the same prognosis as patients with CNS1 status, whereas the EFS of TLP+ patients is inferior to CNS1 but superior to CNS3 patients (P = .001). Both subgroups may have benefitted from additional IT MTX.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
FOR SUCCESSFUL treatment of childhood acute lymphoblastic leukemia (ALL), it is mandatory to give sufficient therapy directed to the central nervous system (CNS) to treat subclinical or overt CNS leukemia. Without CNS-directed therapy, relapses originating from the CNS in up to 75% of cases can be expected.¹ With the introduction of effective prophylactic CNS treatment, such as intrathecal chemotherapy and cranial irradiation, up to 80% of patients in current studies are finally regarded as cured and only about 5% relapse with involvement of the CNS.² Patients with CNS leukemia, however, which is commonly defined as more than five leukocytes per microliter CSF in the presence of lymphoblasts after cytocentrifugation, suffer from more relapses with CNS involvement and have a significantly poorer outcome compared with CNS-negative patients.^3–5 At a time when the intensity of CNS-directed therapy is being reduced, it is even more important to identify patients with meningeal leukemia at the time of initial diagnosis, as they require more CNS-directed therapy.^6,7

There has been controversy about the significance of blasts detected in CSF without pleocytosis. Investigators from the Children’s Cancer Group reported that patients with blasts in CSF preparations, in the presence of five or fewer WBCs per microliter CSF, are not at greater risk for CNS or other relapse compared with CNS-negative patients.^8,9 In contrast, investigators from St. Jude Children’s Research Hospital have shown that CNS2 status (< 5 WBC/µL CSF with blasts) resulted in a higher risk of relapse and would, thus, require more intensive intrathecal therapy.^10,11 In addition, most studies looking at outcome within CNS status subgroups, to date had not evaluated that particular subset of patients with traumatic lumbar punctures at diagnosis. Gajjar et al¹¹ recently published data demonstrating that initial traumatic lumbar punctures (TLPs) combined with the presence of blasts negatively affect treatment outcome. In this study, we wanted to elucidate the prognostic significance of blast cells in CSF without pleocytosis and of TLPs at the time of initial diagnosis for event-free survival (EFS) and types of relapse.

	PATIENTS AND METHODS

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A total of 2,021 patients (from 85 centers in Germany, Austria, and Switzerland) with newly diagnosed ALL were enrolled in trial Acute Lymphoblastic Leukemia–Berlin-Frankfurt-Münster-95 (ALL-BFM 95) of the Berlin-Frankfurt-Münster Study group between April 1995 and June 1999. Informed consent was obtained from the guardians of all patients, and the protocol was approved by local and central ethical committees. Only patients with a minimum follow-up of 2 years were included in this retrospective analysis. Nine patients had to be excluded from the analysis because of missing CNS data. According to protocol, patients underwent diagnostic lumbar puncture and received their first intrathecal (IT) methotrexate (MTX) on day 1 of induction therapy. CSF evaluation was done at the treating hospitals. A total of 974 patients (48%) had centrally reviewed CSF cytocentrifuge preparations. CNS status was defined as follows: CNS1 (puncture nontraumatic without leukemic blasts after cytocentrifugation), CNS2 (puncture nontraumatic, 5 WBC/µL CSF with identifiable blasts), CNS3 (puncture nontraumatic, > 5 WBC/µL CSF with identifiable blasts), TLP+ (TLP with blasts), and TLP- (TLP without blasts). CNS3 definition was derived from Mastrangelo et al.¹² A TLP was defined as 10 or more erythrocytes per microliter CSF or macroscopically contaminated CSF. In addition to the CNS3 group as defined above, patients with a cerebral mass or patients with cranial nerve palsy in combination with blasts after cytocentrifugation were regarded as having CNS3 disease.

Treatment
Patients were treated according to the protocols of the ALL-BFM 95 trial. In contrast to the ALL-BFM 90 trial, which has been described previously,¹³ a new stratification system was introduced. In ALL-BFM 95, patients were stratified according to age, initial WBC count, day 8 response to prednisone, T immunology, and molecular rearrangements such as t(9;22) and t(4;11) into standard-risk (SR), medium-risk (MR), and high-risk (HR) groups. SR and MR therapy consisted of an eight-drug induction, consolidation with four times high-dose (HD) MTX, and an eight-drug reintensification, followed by maintenance therapy. HR patients were treated with a five-drug induction, followed by six intensive multiagent blocks and the identical reintensification as SR and MR patients. CNS-directed therapy consisted of 11 doses of IT MTX for both SR and MR, whereas HR patients received five doses of IT MTX and six doses of triple intrathecal therapy. Prophylactic cranial irradiation was given after reintensification only to patients with T immunology or to HR patients (12 Gy). Patients with CNS2 and TLP+ disease received two additional doses of IT MTX during induction. Some TLP+ patients (n = 7) were treated as having CNS3 disease although CSF findings were not consistent with the CNS3 definition described previously. Patients with CNS3 status received four (five for HR patients) additional doses of IT therapy and therapeutic cranial irradiation with 18 Gy. Maintenance therapy was without IT therapy.

Statistical Analysis
The duration of EFS is defined as the time from diagnosis until the date of the first adverse event (relapse, death for any reason, or the development of a second malignancy) or, if no such event occurred, until the date of last contact. Patients who did not attain a complete remission were considered failures at time zero. Duration of disease-free survival for patients who achieve remission is defined as the time from attainment of a complete remission until the date of an adverse event (relapse, death, second malignancy) or, if no such event occurred, until the date of last contact. Distributions of EFS and continuous complete remission were estimated by the methods of Kaplan and Meier with SE according to Greenwood,¹⁴ and were compared using the log-rank test.^14,15 All analyses were performed on the basis of "intent-to-treat." Cumulative incidence functions of CNS relapse were constructed by the method of Kalbfleisch and Prentice¹⁶ for patients who achieved a complete remission.¹⁶ Incidence functions for all competing factors of failure were also calculated. Functions were compared with Gray’s test.¹⁷ A CNS relapse is defined as an isolated CNS relapse or a CNS relapse in combination with another type of relapse or failure.

Differences in the distribution of variables among patient subsets were analyzed using the ² test for categorized variables and the Wilcoxon rank sum test for continuous variables. The prognostic relevance of the different CNS groups compared with CNS-negative patients was examined by Cox regression analysis with known prognostic factors as covariables.¹⁸ The database for all analyses was "frozen," meaning that no data about patients who became known to the study center were entered, on August 1, 2001.

	RESULTS

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The number of patients classified into each of the different CNS status groups is shown in Table 1. CNS1 status was diagnosed in 79.77% of patients; 2.88% were found to have CNS leukemia (CNS3). The remaining 17.34% of patients are divided among the other groups: CNS2 (5.12%), TLP+ (6.71%), and TLP- (5.51%). Among the 58 patients diagnosed with CNS3 status, six were defined as having CNS leukemia by demonstration of a cerebral/meningeal mass only, and three could be defined as having CNS3 status by presence of blasts without CSF pleocytosis in combination with cranial nerve palsy.

View larger version (25K): [in this window] [in a new window]   Fig 1. Event-free survival (EFS) for the five CNS status groups is shown. Only patients enrolled in the ALL-BFM 95 trial with a minimum follow-up of 2 years were evaluated. The EFS of TLP+ patients is significantly inferior to CNS1 patients (P = .003), but superior to CNS3 patients (P = .001).

The distribution of relapses within the different CNS status groups is shown in Table 3. From 2,012 patients, 20 were excluded from the analysis because of death before complete remission (n = 15) or nonresponse (n = 5). For CNS1 patients, the cumulative incidence (CI) for any relapse is 0.17, of which the CI for an isolated or combined CNS relapse is 0.04 and for other relapses (bone marrow, testes, other) it is 0.13. This distribution is also found among TLP- patients. For CNS2 patients, the overall CI for relapses is identical to that of the CNS1 group. However, among the CNS2 group, there is a higher proportion of relapses with CNS involvement (CI 0.10) and a reduction in CI regarding other relapses (0.07). For the TLP+ group, an increase in CI for all relapses is observed (0.20), the CI for relapses with CNS involvement (0.08) being comparable to the CNS2 group, whereas the CI for other relapses (0.12) is closer to the CNS1 group. As expected, the CNS3 status patients experience the highest overall relapse rate (CI 0.35), relapses without CNS involvement being the major problem in this subgroup (CI 0.22).

	DISCUSSION

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The distribution of patients within CNS status groups is similar to the distribution reported by Gajjar et al,¹¹ although group sizes of CNS2, TLP-, and TLP+ patients are smaller in our study (5%, 6%, and 7% v 15%, 10%, and 11%). This might be the effect of our study being a multicenter study with 85 participating institutions in Germany, Austria, and Switzerland, in which CSF samples have not always been centrally evaluated. Another explanation could lie in the fact that thrombocytopenic patients in most participating institutions of the ALL-BFM trials usually receive platelet transfusions before lumbar puncture, especially if platelet counts are below 50,000/µL, although serious complications are an extremely rare event.¹⁹ However, the size of the CNS3 group (3%) is identical in both studies and matches that of most other reported trials, indicating that a multicenter approach allows a valid data collection.

The CNS2 group contains higher percentages of patients with unfavorable prognostic parameters. In this group, there are fewer SR and more HR patients, more T and pro-B immunology, and more patients with higher WBC counts at diagnosis. The CSF findings can be interpreted as an expression of "minimal meningeal leukemia," which might correlate with a poorer prognosis. However, with additional IT therapy and a total of four courses HD MTX, these patients have a good prognosis, as previously described by the Children’s Cancer Group and van den Berg et al.^8,9,20 Our result of an EFS of 80% is strikingly different than the experience from St. Jude’s Hospital, where CNS2 patients with regular CNS therapy had a survival of only 55%¹¹ or 53%,¹⁰ respectively. This result is remarkable, as the number of IT chemotherapy applications (nine to 13 times for lower-risk and 13 to 20 times for higher-risk patients) is comparable to trial ALL-BFM 95, and the percentage of patients receiving cranial radiotherapy (RT) is higher in the St. Jude trials (21% in BFM-ALL 95 v 63% in study XI and 30% in study XII).⁵ One explanation for this difference might be the fact that, in the St. Jude trials, IT therapy was generally not given at the time of the diagnostic lumbar puncture, but 24 to 48 hours later, and the second IT therapy was not given until 3 weeks later, whereas in our study, the second IT MTX was always instilled on day 12. One could also argue that systemic treatment has improved with time; thus, a comparison between trials from 1984 up to 1991 and one starting in 1995 is not appropriate. However, in the ALL-BFM 90 trial (1990 to 1995), we found that survival of patients with CNS2 status was identical to the EFS in CNS1 and TLP- groups (80%, 80%, and 79% respectively; CNS2 group n = 30; M. Schrappe, unpublished data). In a subsequent study of 165 patients from 1991 to 1994, St. Jude investigators reported that early intensification of IT therapy resulted in a reduced cumulative risk for all relapses with CNS involvement of 4.4%.²¹ This result, which is similar to our overall cumulative incidence for relapses with CNS involvement (CI 0.043), was achieved, first, by intensifying IT therapy early in induction (weekly for CNS2, CNS3, and TLP+ patients) and, second, by increasing the total number of IT chemotherapy applications from 21 to 26. Another difference between the ALL-BFM 95 trial and the St. Jude studies XI and XII is the number of courses with HD MTX. In the BFM trial, patients are exposed to HD MTX (5 g/m²) four times, whereas patients received two courses HD MTX (2 g/m²) in study XI and five courses of MTX (1.5 g/m²) in study XII.^10,22

Compared with CNS1 patients, of whom the majority are suffering systemic relapses, the relapses among CNS2 patients seem to be more equally divided between those with CNS involvement and all other relapses. This distribution (50% relapses with CNS involvement, 50% bone marrow and other relapses) was also found by Children’s Cancer Group investigators.⁹ As overall outcome is identical when compared with the CNS1 group, a modification of the treatment strategy for CNS2 patients does not seem mandatory. It could be of interest, however, to examine whether the percentage of blasts in CSF differential cell counts can identify a subgroup among CNS2 patients with an inferior prognosis compared with the overall CNS2 group.

The outcome for the TLP+ group also differs from the results reported by Gajjar et al,¹¹ although the variation is not as pronounced as for the CNS2 group. Reasons for this may be the time interval between diagnostic and TLP and the interval to the second instillation of IT therapy. One has to ask, however, why TLP+ patients have an inferior outcome, especially when compared with CNS2 patients. One explanation could be that this difference is the result of an iatrogenic introduction of blasts into the CSF. But it is not easy to understand why a single, iatrogenic introduction of blasts should cause a difference in overall outcome, when patients with "minimal meningeal leukemia," as in the CNS2 group, can be handled quite easily with two additional applications of IT MTX. Another hypothesis to explain the inferior outcome in TLP+ patients could be more advanced disease, for example, with more perivenular or parameningeal leukemic infiltrates, or a biologically different disease, permitting migration of leukemic blasts more easily. Bleyer²³ reported that certain types of leukemia penetrate the CNS with a higher rate (eg, T-cell leukemias) and that other factors such as blast and platelet count, patient’s age, or maturity of the blood-brain barrier are factors that influence ingress of leukemic cells into the CNS. We did not find significantly more T-ALL or lower platelet counts among the TLP+ patients, but we did find a significant number of patients had higher initial WBC counts compared with CNS1 patients. But by Cox regression analysis, TLP+ status maintains prognostic significance, indicating that the higher incidence of unfavorable patient characteristics cannot account for the observed difference in EFS. Also, when comparing TLP+ patients with those in the CNS2 group, which has a good prognosis, TLP+ patients do not seem to have more advanced disease. On the contrary, the CNS2 group comprises more patients with initial hyperleukocytosis, T immunophenotype, and prednisone poor-response or high-risk disease than does the TLP+ group. A third explanation for the inferior EFS in the TLP+ group could be that, among TLP+ patients, there are hidden CNS3 patients who are simply not identified at the time of initial diagnosis. Because the other possible explanations for the inferior outcome in TLP+ patients seem unlikely, we favor the latter possibility—unidentified CNS3 patients—as the most likely explanation for the observed difference in outcome.

How can we identify true CNS3 patients within the TLP+ group? First, one could compare the CSF with the peripheral blood differential cell count. If the percentage of blasts in the CSF is significantly higher than in the peripheral blood, CNS3 disease is likely. One could also compare the ratio of erythrocytes to leukocytes in the CSF and in peripheral blood. If this ratio is smaller in the CSF compared with peripheral blood, CNS3 status might also be assumed. In our study, seven patients in the TLP+ group were treated as having CNS disease because of their CSF findings. Among those, two suffered a relapse. Although these numbers are small, one could expect more relapses if this group consisted of true CNS3 patients.

What can we do for TLP+ patients? An introduction of cranial RT for all patients with B-precursor ALL in this subgroup still remains an option in trying to improve outcome, as the increased incidence of CNS relapses is the major problem among TLP+ patients. However, cranial RT might lead to significant toxicity or second malignancies in patients who otherwise have a good prognosis. There was also no statistically significant difference in TLP+ patients treated as CNS negative (EFS 66%) versus those treated with additional IT MTX (EFS 77%). However, we will continue to treat CNS2 and TLP+ patients with two additional doses of IT MTX.

In conclusion, this study has shown that CNS2 patients have a good prognosis (EFS 80%) that does not require any intensification of CNS-directed therapy. TLP+ patients have an inferior prognosis compared with the CNS1 group (73% v 80%) but a superior EFS compared with the CNS3 group (50%). In our opinion, further intensification of CNS-directed therapy is not mandatory at this time if the treatment schedule is comparable to the ALL-BFM strategy. Evaluation of the ongoing ALL-BFM 2000 trial for CNS status and survival will further clarify the prognostic significance of CNS2 and TLP+ findings.

	ACKNOWLEDGMENTS

 
We thank E. Odenwald, B. Puttkamer, and T. Büchner for expert cytology; the data managers N. Götz, U. Meyer, I. Krämer, and K. Mischke for precise data management; and the nurses and doctors of all participating hospitals.

	NOTES

 
Supported by grants from the Deutsche Krebshilfe.

	REFERENCES

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Submitted April 15, 2002; accepted October 5, 2002.

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