Unifying the diagnosis of isolated central nervous system relapse in acute lymphoblastic leukaemia based on minimal residual disease testing

The 1986 Rome Workshop defined central nervous system (CNS) involvement at diagnosis for children with acute lymphoblastic leukaemia (ALL) as lymphoblasts on cytospin and a cerebrospinal fluid (CSF) white blood cell (WBC) count >5 × 106/l (Mastrangelo et al, 1986). The definition for isolated CNS relapse (iCNSr) has been based on the initial diagnostic definition for CNS leukaemia, requiring patients to have lymphoblasts on cytospin and CSF WBC >5× 106/l, and generally, study groups have followed this definition (Hagedom et al, 2007; Krishnan et al, 2010). However, even at the time of the Rome criteria, it was noted that the majority of iCNSr patients were found to have abnormal cells on routine surveillance in the absence of symptoms, and that patients might be diagnosed based on positive immunohistochemistry when there were equivocal results on cytospin (Veerman et al, 1985; Bleyer, 1988). The Pediatric Oncology Group POG9412 trial (NCT00002704) and Children's Oncology Group (COG) pilot AALL02P2 (NCT00096135) for iCNSr allowed patients with immunophenotypic proof of leukaemic relapse to be eligible regardless of CSF WBC count, yet current COG relapse trials that include patients with iCNSr have reverted to the previous definition (Barredo et al, 2006). Similarly, the previous high-risk ALL COG study AALL0232 (NCT00075725) defined iCNSr as two consecutive abnormal CSF ≥4 weeks apart in the absence of WBC ≥5 × 106/l, while the open high-risk study uses the current definition. Gassas et al (2014) noted that the majority of patients with iCNSr (16 of 22) over a 10-year period at The Hospital for Sick Children in Toronto were diagnosed on routine surveillance rather than symptomatically. Empirically, we have noted that the majority of children who present with iCNSr are found to have morphological blasts on routine surveillance without pleocytosis, leading to a delay in diagnosis while waiting to meet the current definition of CSF WBC ≥5 × 106/l. Older studies have reported that isolated lymphoblasts without pleocytosis may or may not be consistent with iCNSr, thus partly explaining the continued reliance on the standard definition (Odom et al, 1990; Tubergen et al, 1994). After institutional review board approval, we reviewed all CSF cytology reports for ALL patients treated at our institution between 1980 and 2010. Over the study period, 35 patients had iCNSr based on the current definition. Twenty-three (71%) had morphological evidence of relapse on cytospin at a median of 16 weeks (range 3–43 weeks) prior to reaching WBC ≥5 × 106/l, with no patient developing bone marrow involvement during this period. We subsequently reviewed all cytology slides from patients with iCNSr between 2000 and 2010, comparing the pre-relapse and relapse specimens, applying the method of Goldsby et al (1997). During this period, 239 patients had 3245 CSF cytological examinations after induction, with 8 patients meeting the current definition of iCNSr, 5 of whom had morphological evidence of early CSF leukaemic involvement (two additional patients with presumed iCNSr were treated prior to WBC ≥5 × 106/l due to persistent blasts over 4 consecutive cytospins in both cases). All 5 patients had consecutively abnormal CSF on cytospin, compared with 3 of 227 (1%) patients without eventual CNS relapse (P < 0·0001 by Fisher's exact test). Two patients had combined relapse, both with CSF WBC ≥5 × 106/l at relapse. Although the comparison between relapse and non-relapse patients was highly significant, it was concerning to note that 3 patients without eventual CNS relapse had consecutively positive cytospins. Additionally, 1 of these 3 (with T cell ALL), initially had a WBC of 10 × 106/l, meeting the current definition, though without eventual “true” relapse. However, these 3 patients generally had rare blasts that all decreased on consecutive cytospin, differentiating them from those with iCNSr. Although none of our patients with iCNSr progressed to bone marrow involvement during the interval before CSF WBC reached ≥5 × 106/l, it is troublesome to tell families they must wait a median of 16 weeks prior to a definitive diagnosis, while continuing a failing regimen. We conclude that consecutive positive cytospin examinations with stable to increasing blast percentage and demonstration of immunophenotypic evidence consistent with the patient's initial bone marrow blasts is sufficient to diagnose iCNSr. We have therefore moved to minimal residual disease (MRD) assessment for proof of iCNSr in patients with consecutively positive abnormal CSF without WBC ≥5 × 106/l. Our most recent four patients with presumed iCNSr all presented with consecutive concerning morphological findings on cytospin, none of which had a WBC > 1 × 106/l (Table 1). MRD testing was requested at a median of the second positive cytospin, with patients having a median of 8% blasts noted on these cytospins. Three of the 4 had corroborative MRD positivity; the fourth patient (Patient 3) was initially MRD negative but found to be MRD positive on the subsequent check 1 month later. We believe that MRD positive cells found in consecutively abnormal cytospin samples should replace the current definition of iCNSr. AKA, AA and JF contributed to the design of the research study, collection and analysis of research data, writing of the manuscript, and final approval of the manuscript in its current form. This study has not been presented prior in any form. There was no research funding to support this project. There are no disclosures or relevant conflicts of interest.

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