Title: The role of routine surveillance for silent central nervous system relapse in children with acute lymphoblastic leukaemia
Abstract: Isolated central nervous system (CNS) relapse of childhood acute lymphoblastic leukaemia (ALL) is uncommon. The cumulative incidence of isolated CNS relapse is 0·6–5% (Pui & Howard, 2008). Risk factors for CNS relapse include T cell immunophenotype, hyperleucocytosis and high-risk genetic abnormalities, such as Philadelphia chromosome (Pui & Thiel, 2009). The prognostic effect of leukaemia cells in the cerebrospinal fluid (CSF) (CNS3, CNS2) or traumatic lumbar puncture with blasts (TLP+) at diagnosis as a risk factor for subsequent CNS relapse varies in different trials (Pui et al, 2009); this probably reflects differences in treatment, such as the use of cranial irradiation and high dose methotrexate. The diagnosis of CNS relapse is characterised by the presence of positive cytomorphology on a CSF cytospin (white blood cells [WBC] >5/μl) and/or clinical signs of CNS leukaemia. While CSF cytology is considered to be the gold standard for diagnosis of CNS leukaemia, false negatives and false positive may occur (Glantz et al, 1998). Potential causes of false negatives include small CSF volume, delays in transit time of the sample to the laboratory and the detection of blasts below the threshold of 5/μl. False positives can occur due to CNS infection leading to a lymphocytosis. While the identification of leukaemic clones in the CSF by flow cytometry (TDT, CD10, and CD19) or fluorescence in situ hybridization for a diagnostic karyotypic abnormality may be helpful, their role has not been validated in large patient numbers and thus CSF cytology is still required for diagnosis of CNS relapse in the absence of unequivocal clinical symptoms of CNS leukaemia. Within the UK and Berlin-Frankfürt-Münster (BFM) ALL subgroups, determination of cell count and cytomorphology of CSF is often done at every therapeutic lumbar puncture even in patients without initial CNS involvement, in order to detect silent CNS relapse. The effectiveness of this approach is unclear. We therefore undertook a retrospective analysis to determine the efficacy of routine surveillance of CNS cytospins. The records of children enrolled on UKALL2003 who had completed treatment by May 2011 at two units (Great Ormond Street Hospital & University College Hospital, London) were reviewed. At diagnosis, patients were classified into the following groups: CNS1 (<5 WBC/μl and no detectable blasts), CNS2 (<5 WBC/μl with blasts and atraumatic), CNS3 (>5 WBC/μl with blasts and atraumatic) and TLP+ (traumatic lumbar puncture with blasts). Exclusion criteria for the analysis included CNS3, presence of Philadelphia chromosome and refractory disease. Depending on National Cancer Risk Institute risk status and response to therapy, children received between 19–28 doses of intrathecal methotrexate to prevent CNS relapse. Details of the trial have been previously reported (Qureshi et al, 2010). To determine the detection rate of positive cytospins, the number of asymptomatic children with a positive cytospin was divided by the total number of cytospins in the whole cohort. CNS relapse was diagnosed on cytospins that were positive for blasts (>5 WBC/μl) and/or clinical signs of CNS leukaemia. Relapses were classified as symptomatic if they had signs suggestive of CNS leukaemia, such as headache, diplopia or cranial nerve palsies or asymptomatic if they were absent. The characteristics of the 331 patients in the analysis are shown in Table 1. Twelve children had a CNS relapse. Six of these had a combined CNS and bone marrow relapse (1·8%) and six had an isolated CNS relapse (1·8%). Five of these 12 children were symptomatic (headache, vomiting and/or visual disturbance) and thus had a diagnostic lumbar puncture. Four of the five children with symptomatic CNS relapse had bone marrow involvement. The 5th patient developed bone marrow disease within two weeks of diagnosis of the CNS relapse. Seven children were asymptomatic and thus were detected on routine surveillance. Only one of these children had concurrent bone marrow disease (see Table 2). The detection rate of asymptomatic CNS relapse using CSF cytospin surveillance was 0·09%. There was a disproportionately high representation of T cell immunophenotype and hyperleucocytosis amongst the patients with asymptomatic CNS relapse. All seven patients with silent relapse were classified as CNS1 at diagnosis. There were no asymptomatic CNS relapses in regimen A patients. Three children with asymptomatic CNS relapse died; all had a very early relapse (duration of complete remission was 15 weeks, 41 weeks and 49 weeks). The approximate cost of performing routine CSF cytospin surveillance was £67 000·00. Our data suggests that the incidence of asymptomatic CNS relapse as detected by routine CSF surveillance is low. Our analysis excluded children who were at significant risk for CNS relapse, such as CNS3 status and refractory disease, and for these high risk populations, regular CSF surveillance is probably still required. As the majority of patients with isolated CNS relapse have detectable minimal residual disease (Hagedorn et al, 2007), they are at significant risk of developing disease recurrence elsewhere other than just the CSF. In our series, symptomatic patients appeared to be more likely to have concurrent bone marrow disease than asymptomatic patients, though the numbers of patients in each arm were too small for any statistical comparisons. Whilst routine CSF cytospins may very rarely detect an asymptomatic CNS relapse, it is unlikely that this would impact on survival outcome as this is dependent on the duration of first haematological remission (Nguyen et al, 2008), as is evident in our report. Similarly, there is no evidence that early detection of bone marrow relapse by frequent surveillance in children who have completed therapy improves outcome (Gandhi et al, 2003; Rubnitz et al, 2005). Our analysis is limited by small numbers and its retrospective nature; thus it cannot be known whether earlier detection of asymptomatic patients using CSF surveillance cytomorphology might have prevented progression to symptoms and long term disability. In order to maximise efficiency we suggest that CSF cytomorphology be performed only when the automated CSF WBC count is positive (>1/μl). Whilst there have been conflicting reports on the effectiveness of automated CSF counting replacing manual counting (Zimmermann et al, 2011), due to the low incidence of silent CNS relapse, this strategy should minimise unnecessary time and expense without compromising clinical care. MJ, ZA and DC collected data. RH, NG, VG, AS & AV edited the paper and contributed to patient care. SS wrote the paper. The authors declare no conflict of interest.
Publication Year: 2012
Publication Date: 2012-08-25
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 5
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