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Leukemia & Lymphoma Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ilal20
Cerebrospinal fluid analysis by flow cytometry in acute lymphoblastic leukemia: is it all that it is cracked up to be? a
ab
Ian R. Davis & David A. Westerman a
Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia b
University of Melbourne, Parkville, Victoria, Australia Published online: 01 Jun 2015.
Click for updates To cite this article: Ian R. Davis & David A. Westerman (2014) Cerebrospinal fluid analysis by flow cytometry in acute lymphoblastic leukemia: is it all that it is cracked up to be?, Leukemia & Lymphoma, 55:7, 1441-1443, DOI: 10.3109/10428194.2013.876499 To link to this article: http://dx.doi.org/10.3109/10428194.2013.876499
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Leukemia & Lymphoma, July 2014; 55(7): 1441–1443 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.876499
COMMENTARY
Cerebrospinal fluid analysis by flow cytometry in acute lymphoblastic leukemia: is it all that it is cracked up to be? Ian R. Davis1 & David A. Westerman1,2 1Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia and 2University of Melbourne,
Downloaded by [RMIT University] at 02:45 12 August 2015
Parkville, Victoria, Australia
risk) in a non-traumatic sample containing blasts with ⱖ 5 WBC/μL, or the presence of a cerebral mass or cranial nerve palsy with leukemic cells in the CSF regardless of WBC count. The probability of 5-year CNS leukemia-free survival for CNS1 is significantly greater than for CNS2 and CNS3 (96% vs. 87% vs.74%, respectively, p ⬍ 0.001), and the projected 5-year survival rates are 75%, 49% and 53%, respectively [11]. Further studies in the pediatric population utilizing this classification, however, have failed to confirm the results in the “intermediate risk” CNS2 population [12–14]. Additionally, similar studies using these criteria have not previously been performed within the adult ALL population where the diagnosis of CNS involvement is still classically based upon the definition outlined above. It is likely, however, that the presence of blasts in the CSF when the WBC is ⬍ 5/μL holds similar prognostic significance in adults. In this issue of Leukemia and Lymphoma, Mitri et al. report a retrospective analysis of the sensitivity and specificity of flow cytometry (FCM) in assessment of the CSF from 80 patients diagnosed with ALL from their institution over approximately a 5-year period [15]. The analyses include 800 CSF samples in total, comprising 80 at diagnosis, 687 follow-up samples and 33 at the time of relapse, with FCM performed on 267 of these samples in addition to conventional cytological assessment. Within this cohort, CNS disease at diagnosis was found in 1/80 (1%) patients (classified as CNS2 status) with FCM performed on 66/80 diagnostic samples. Fifteen patients (19%) experienced a clinical relapse (one isolated CNS, 14 systemic plus CSF involvement) at a median of 12 months from diagnosis (range 7–41 months), with CSF FCM assessment being performed in 7/10 samples collected in these patients. The authors demonstrated 100% sensitivity and 100% specificity for the diagnosis of leukemic meningitis by FCM within both the diagnostic and relapse settings, using conventional cytology as gold standard. Results published in this study are impressive, with the authors claiming no additional value of FCM over conventional cytology and questioning its economic value.
Central nervous system (CNS) involvement with acute lymphoblastic leukemia (ALL) at diagnosis is identified in less than 5% and 10% of children and adults, respectively [1–3]. When present at diagnosis, both the relapse-free survival and 5-year overall survival are reduced (29% vs. 38%) when compared to all other patients [4]. Prior to the advent of adequate CNS directed therapy and prophylaxis, CNS disease remained a major obstacle to cure, with CNS recurrence occurring in approximately 30–50% of such patients obtaining a complete response (CR) without prophylaxis [3,5]. Indeed, patients deemed high risk and whom receive intensified CNS directed chemotherapy (systemic and intrathecal), craniospinal radiation and/or hematopoietic stem cell transplant as part of contemporary induction protocols still have a 4–15% risk of developing CNS relapse, a complication with a poor prognosis [6–8]. Current and future risk adapted approaches in development for the treatment of ALL are aimed at optimizing this upfront prophylaxis/treatment further with early intensive systemic and risk adapted intrathecal chemotherapy alone. The aim should be to reduce the CNS relapse hazard to negligible levels but importantly also avoid the substantial rates of neurotoxicity, cognitive dysfunction, endocrinopathies and risk of secondary neoplasms associated with cranial radiation [9]. The importance, therefore, of accurate risk assessment and staging of the CNS at diagnosis is paramount. CNS involvement by ALL has historically been diagnosed using criteria established within pediatric populations, and is defined as the presence of at least five white blood cells (WBC)/μL of cerebrospinal fluid (CSF) associated with the presence of leukemic blasts or the presence of a cranial nerve palsy on physical examination [10]. Further attempts at refinement of this criterion confirmed the importance of accurate detection and staging at diagnosis, classifying patients into one of three risk profiles with regard to CNS relapse risk: CNS1 (low risk) denoting the absence of leukemic blasts in the CSF; CNS2 (intermediate risk) with the presence of blasts in a sample containing ⬍ 5 WBC/μL; and CNS3 (high
Correspondence: David A. Westerman, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. E-mail: david. [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
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I. R. Davis & D. A. Westerman
Despite this study confirming the importance of cytology for the diagnosis of CNS involvement, caution about blanket acceptance of these results is required with regard to the additional usefulness or lack thereof when performing routine FCM. Previous studies by Subira et al. and Sayed et al. have demonstrated an improved detection rate in two separate cohorts of patients confirmed to have CSF involvement by ALL using FCM alone (86% and 91%, respectively) as compared to cytological assessment alone (67% and 43%, respectively) [16,17]. The Mitri study results also are in contrast to CSF studies demonstrating the utility of FCM in detecting CSF disease in non-Hodgkin lymphoma (NHL) [18–20]. Indeed, early studies of conventional cytology alone have demonstrated false negative rates of up to 40% for the first lumbar puncture [21], with CNS disease being identified at autopsy in patients who were thought to have only bone marrow involvement with ALL [22]. Given this potential high false negative rate, unless repeated assessments are performed where experience with solid tumors demonstrates improved yield and sensitivity of cytological assessment at the time of diagnosis [23,24], a more sensitive method with FCM we believe is required to ensure accurate staging of a patient’s CNS at diagnosis. A number of factors may account for these resultant discrepancies and an underappreciation of FCM’s value, including: pre-analytical variables such as CSF volume and methods of CSF sampling, the number of cells required for analysis, time to analysis, and the utilization of a stabilizing solution at the bedside or in the laboratory. Samples should preferably be collected into a serum-containing medium (such as RPMI-1640 with HEPES (2-[4-(2-hydroxyethyl) piperazin-1-yl]ethanesulfonic acid), l-glutamine, penicillin/streptomycin, heat inactivated fetal bovine serum and heparin) to preserve CSF cells for up to 5 h after sampling [25,26] and to minimize the significant decline in cell numbers seen as early as 30 min after sampling [27]. In addition, samples should be rapidly transported to the laboratory for assessment. The antibody cocktails incorporated into panels are very important, and certainly can be a limiting factor in test sensitivity. Analysis and gating strategies are also pivotal post-analytical variables. Paucicellular samples, if tested on a hemocytometer, should still be assessed, in light of the findings by Craig et al. [28]. Traumatic taps are an additional complicating factor in interpretation, and important to prevent given the potential for an increase in CNS relapse risk and poor event-free survival seen in pediatric populations [14,29,30]. We believe that the Mitri study highlights the need for additional well-designed prospective studies on the utility of FCM in adult ALL at diagnosis and follow-up, given the known prognostic importance of CNS staging for patient care. Both cost-effective practice and further standardization should be important aims and outcomes of these studies.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Larson RA , Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and leukemia group B study 8811. Blood 1995;85:2025–2037. [2] Bleyer WA , Poplack DA . Prophylaxis and treatment of leukemia in the central nervous system and other sanctuaries. Semin Oncol 1985;12:131–148. [3] Cortes J, O’Brien SM, Pierce S, et al. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood 1995;86:2091–2097. [4] Lazarus HM, Richards SM, Chopra R, et al. Central nervous system involvement in adult lymphoblastic leukemia at diagnosis: results from the international ALL trial MRC UKALL XII/ECOG E2993. Blood 2006;108:465–472. [5] Omura GA , Moffitt S, Vogler WR, et al. Combination chemotherapy of adult acute lymphoblastic leukemia with randomized central nervous system prophylaxis. Blood 1980;55:199–204. [6] Suprapaneni UR, Cortes JE, Thomas D, et al. Central nervous system relapse in adults with acute lymphoblastic leukemia. Cancer 2002;94:465–472. [7] Reman O, Pigneux A , Huguet F, et al. Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis and/or at first relapse: results from the GET-LALA group. Leuk Res 2008;32:1741–1750. [8] Kantarjian HM, O’Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547–561. [9] Pui CH, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 2003;349:640–649. [10] Pinkel D, Woo S. Prevention and treatment of meningeal leukemia in children. Blood 1994;84:355–366. [11] Mahmoud HH, Rivera GK, Hancock ML, et al. Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 1993;329: 314–319. [12] Gilchrist GS, Tubergen DG, Sather HN, et al. Low numbers of CSF blasts at diagnosis do not predict the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: A Children’s Cancer Group report. J Clin Oncol 1994;12:2594–2600. [13] van der Berg H, Vet R, den Ouden E, et al. Significance of lymphoblast in cerebrospinal fluid in newly diagnosed pediatric acute lymphoblastic malignancies with bone marrow involvement: Possible benefit of dexamethasone. Med Pediatr Oncol 1995;25:22–27. [14] Burger B, Zimmermann M, Mann G, et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blast or traumatic lumbar puncture. J Clin Oncol 2003;21:184–188. [15] Mitri Z, Siddiqui MT, El Rassi F, et al. Sensitivity and specificity of cerebrospinal fluid flow cytometry for the diagnosis of leukemic meningitis in acute lymphoblastic leukemia/lymphoma. Leuk Lymphoma 2014;55:1498–1500. [16] Subira D, Castanon S, Roman A , et al. Flow cytometry and the study of central nervous disease in patients with acute leukaemia. Br J Haematol 2001;112:381–384. [17] Sayed D, Badrawy H, Ali AM, et al. Immunophenotyping and immunoglobulin heavy chain gene rearrangement analysis in cerebrospinal fluid of paediatric patients with acute lymphoblastic leukaemia. Leuk Res 2009;33:655–661. [18] Quijano S, Lopez A , Manuel SL, et al. Spanish group for the study of CNS disease in NHL. Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin’s lymphoma: improved sensitivity of flow cytometry. J Clin Oncol 2009;27:1462–1469. [19] Hegde U, Filie A , Little RF, et al. High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology. Blood 2005;105:496–502. [20] Di Noto R, Scalia G, Abate G, et al. Critical role of multi-dimensional flow cytometry in detecting occult leptomeningeal disease in newly diagnosed aggressive B-cell lymphomas. Leuk Res 2008;32:1196–1199. [21] Glass JJP, Melamed M, Chernik NL, et al. Malignant cells in cerebrospinal fluid: the meaning of a positive CSF cytology. Neurology 1979;29:1369–1375.
Commentary 1443
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[22] Stewart DJ, Keating MJ, McCredie KB, et al. Natural history of central nervous system acute leukemia in adults. Cancer 1981;47:184–196. [23] Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumours: experience with 90 patients. Cancer 1982;49:759–772. [24] DeAngelis LM, Cairncross JB. A better way to find tumor in the CSF? Neurology 2002;58:339–340. [25] de Graaf M, van den Broek P, Kraan J, et al. Addition of serum-containing medium to cerebrospinal fluid prevents cellular loss over time. J Neurol 2011;258:1507–1512. [26] Greig B, Stetler-Stevenson M, Lea J. Stabilization media increases recovery in paucicellular cerebrospinal fluid specimens submitted for flow cytometry testing. Cytometry B Clin Cytom 2013 May 14. [Epub ahead of print]
[27] de Graaf M, de Jongste AH, Kraan J, et al. Flow cytometric characterization of cerebrospinal fluid cells. Cytometry B Clin Cytom 2011;80:271–281. [28] Craig FE, Ohori P, Gorrill TS, et al. Flow cytometric immunophenotyping of cerebrospinal fluid specimens. Am J Clin Pathol 2011;135:22–34. [29] Marveska D, to Loo WM, Kamps WA , et al. Prognostic significance of blasts in the cerebrospinal fluid without pleocytosis or a traumatic lumbar puncture in children with acute lymphoblastic leukaemia: the experience of the Dutch Childhood Oncology Group. J Clin Oncol 2006;24:2332–2336. [30] Gajjar A , Harrison PL, Sandlund JT. et al. Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukaemia. Blood 2000;96:3381–3384.
Leukemia & Lymphoma Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ilal20
Cerebrospinal fluid analysis by flow cytometry in acute lymphoblastic leukemia: is it all that it is cracked up to be? a
ab
Ian R. Davis & David A. Westerman a
Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia b
University of Melbourne, Parkville, Victoria, Australia Published online: 01 Jun 2015.
Click for updates To cite this article: Ian R. Davis & David A. Westerman (2014) Cerebrospinal fluid analysis by flow cytometry in acute lymphoblastic leukemia: is it all that it is cracked up to be?, Leukemia & Lymphoma, 55:7, 1441-1443, DOI: 10.3109/10428194.2013.876499 To link to this article: http://dx.doi.org/10.3109/10428194.2013.876499
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Leukemia & Lymphoma, July 2014; 55(7): 1441–1443 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.876499
COMMENTARY
Cerebrospinal fluid analysis by flow cytometry in acute lymphoblastic leukemia: is it all that it is cracked up to be? Ian R. Davis1 & David A. Westerman1,2 1Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia and 2University of Melbourne,
Downloaded by [RMIT University] at 02:45 12 August 2015
Parkville, Victoria, Australia
risk) in a non-traumatic sample containing blasts with ⱖ 5 WBC/μL, or the presence of a cerebral mass or cranial nerve palsy with leukemic cells in the CSF regardless of WBC count. The probability of 5-year CNS leukemia-free survival for CNS1 is significantly greater than for CNS2 and CNS3 (96% vs. 87% vs.74%, respectively, p ⬍ 0.001), and the projected 5-year survival rates are 75%, 49% and 53%, respectively [11]. Further studies in the pediatric population utilizing this classification, however, have failed to confirm the results in the “intermediate risk” CNS2 population [12–14]. Additionally, similar studies using these criteria have not previously been performed within the adult ALL population where the diagnosis of CNS involvement is still classically based upon the definition outlined above. It is likely, however, that the presence of blasts in the CSF when the WBC is ⬍ 5/μL holds similar prognostic significance in adults. In this issue of Leukemia and Lymphoma, Mitri et al. report a retrospective analysis of the sensitivity and specificity of flow cytometry (FCM) in assessment of the CSF from 80 patients diagnosed with ALL from their institution over approximately a 5-year period [15]. The analyses include 800 CSF samples in total, comprising 80 at diagnosis, 687 follow-up samples and 33 at the time of relapse, with FCM performed on 267 of these samples in addition to conventional cytological assessment. Within this cohort, CNS disease at diagnosis was found in 1/80 (1%) patients (classified as CNS2 status) with FCM performed on 66/80 diagnostic samples. Fifteen patients (19%) experienced a clinical relapse (one isolated CNS, 14 systemic plus CSF involvement) at a median of 12 months from diagnosis (range 7–41 months), with CSF FCM assessment being performed in 7/10 samples collected in these patients. The authors demonstrated 100% sensitivity and 100% specificity for the diagnosis of leukemic meningitis by FCM within both the diagnostic and relapse settings, using conventional cytology as gold standard. Results published in this study are impressive, with the authors claiming no additional value of FCM over conventional cytology and questioning its economic value.
Central nervous system (CNS) involvement with acute lymphoblastic leukemia (ALL) at diagnosis is identified in less than 5% and 10% of children and adults, respectively [1–3]. When present at diagnosis, both the relapse-free survival and 5-year overall survival are reduced (29% vs. 38%) when compared to all other patients [4]. Prior to the advent of adequate CNS directed therapy and prophylaxis, CNS disease remained a major obstacle to cure, with CNS recurrence occurring in approximately 30–50% of such patients obtaining a complete response (CR) without prophylaxis [3,5]. Indeed, patients deemed high risk and whom receive intensified CNS directed chemotherapy (systemic and intrathecal), craniospinal radiation and/or hematopoietic stem cell transplant as part of contemporary induction protocols still have a 4–15% risk of developing CNS relapse, a complication with a poor prognosis [6–8]. Current and future risk adapted approaches in development for the treatment of ALL are aimed at optimizing this upfront prophylaxis/treatment further with early intensive systemic and risk adapted intrathecal chemotherapy alone. The aim should be to reduce the CNS relapse hazard to negligible levels but importantly also avoid the substantial rates of neurotoxicity, cognitive dysfunction, endocrinopathies and risk of secondary neoplasms associated with cranial radiation [9]. The importance, therefore, of accurate risk assessment and staging of the CNS at diagnosis is paramount. CNS involvement by ALL has historically been diagnosed using criteria established within pediatric populations, and is defined as the presence of at least five white blood cells (WBC)/μL of cerebrospinal fluid (CSF) associated with the presence of leukemic blasts or the presence of a cranial nerve palsy on physical examination [10]. Further attempts at refinement of this criterion confirmed the importance of accurate detection and staging at diagnosis, classifying patients into one of three risk profiles with regard to CNS relapse risk: CNS1 (low risk) denoting the absence of leukemic blasts in the CSF; CNS2 (intermediate risk) with the presence of blasts in a sample containing ⬍ 5 WBC/μL; and CNS3 (high
Correspondence: David A. Westerman, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. E-mail: david. [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
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Downloaded by [RMIT University] at 02:45 12 August 2015
1442
I. R. Davis & D. A. Westerman
Despite this study confirming the importance of cytology for the diagnosis of CNS involvement, caution about blanket acceptance of these results is required with regard to the additional usefulness or lack thereof when performing routine FCM. Previous studies by Subira et al. and Sayed et al. have demonstrated an improved detection rate in two separate cohorts of patients confirmed to have CSF involvement by ALL using FCM alone (86% and 91%, respectively) as compared to cytological assessment alone (67% and 43%, respectively) [16,17]. The Mitri study results also are in contrast to CSF studies demonstrating the utility of FCM in detecting CSF disease in non-Hodgkin lymphoma (NHL) [18–20]. Indeed, early studies of conventional cytology alone have demonstrated false negative rates of up to 40% for the first lumbar puncture [21], with CNS disease being identified at autopsy in patients who were thought to have only bone marrow involvement with ALL [22]. Given this potential high false negative rate, unless repeated assessments are performed where experience with solid tumors demonstrates improved yield and sensitivity of cytological assessment at the time of diagnosis [23,24], a more sensitive method with FCM we believe is required to ensure accurate staging of a patient’s CNS at diagnosis. A number of factors may account for these resultant discrepancies and an underappreciation of FCM’s value, including: pre-analytical variables such as CSF volume and methods of CSF sampling, the number of cells required for analysis, time to analysis, and the utilization of a stabilizing solution at the bedside or in the laboratory. Samples should preferably be collected into a serum-containing medium (such as RPMI-1640 with HEPES (2-[4-(2-hydroxyethyl) piperazin-1-yl]ethanesulfonic acid), l-glutamine, penicillin/streptomycin, heat inactivated fetal bovine serum and heparin) to preserve CSF cells for up to 5 h after sampling [25,26] and to minimize the significant decline in cell numbers seen as early as 30 min after sampling [27]. In addition, samples should be rapidly transported to the laboratory for assessment. The antibody cocktails incorporated into panels are very important, and certainly can be a limiting factor in test sensitivity. Analysis and gating strategies are also pivotal post-analytical variables. Paucicellular samples, if tested on a hemocytometer, should still be assessed, in light of the findings by Craig et al. [28]. Traumatic taps are an additional complicating factor in interpretation, and important to prevent given the potential for an increase in CNS relapse risk and poor event-free survival seen in pediatric populations [14,29,30]. We believe that the Mitri study highlights the need for additional well-designed prospective studies on the utility of FCM in adult ALL at diagnosis and follow-up, given the known prognostic importance of CNS staging for patient care. Both cost-effective practice and further standardization should be important aims and outcomes of these studies.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Larson RA , Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and leukemia group B study 8811. Blood 1995;85:2025–2037. [2] Bleyer WA , Poplack DA . Prophylaxis and treatment of leukemia in the central nervous system and other sanctuaries. Semin Oncol 1985;12:131–148. [3] Cortes J, O’Brien SM, Pierce S, et al. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood 1995;86:2091–2097. [4] Lazarus HM, Richards SM, Chopra R, et al. Central nervous system involvement in adult lymphoblastic leukemia at diagnosis: results from the international ALL trial MRC UKALL XII/ECOG E2993. Blood 2006;108:465–472. [5] Omura GA , Moffitt S, Vogler WR, et al. Combination chemotherapy of adult acute lymphoblastic leukemia with randomized central nervous system prophylaxis. Blood 1980;55:199–204. [6] Suprapaneni UR, Cortes JE, Thomas D, et al. Central nervous system relapse in adults with acute lymphoblastic leukemia. Cancer 2002;94:465–472. [7] Reman O, Pigneux A , Huguet F, et al. Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis and/or at first relapse: results from the GET-LALA group. Leuk Res 2008;32:1741–1750. [8] Kantarjian HM, O’Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547–561. [9] Pui CH, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 2003;349:640–649. [10] Pinkel D, Woo S. Prevention and treatment of meningeal leukemia in children. Blood 1994;84:355–366. [11] Mahmoud HH, Rivera GK, Hancock ML, et al. Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 1993;329: 314–319. [12] Gilchrist GS, Tubergen DG, Sather HN, et al. Low numbers of CSF blasts at diagnosis do not predict the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: A Children’s Cancer Group report. J Clin Oncol 1994;12:2594–2600. [13] van der Berg H, Vet R, den Ouden E, et al. Significance of lymphoblast in cerebrospinal fluid in newly diagnosed pediatric acute lymphoblastic malignancies with bone marrow involvement: Possible benefit of dexamethasone. Med Pediatr Oncol 1995;25:22–27. [14] Burger B, Zimmermann M, Mann G, et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blast or traumatic lumbar puncture. J Clin Oncol 2003;21:184–188. [15] Mitri Z, Siddiqui MT, El Rassi F, et al. Sensitivity and specificity of cerebrospinal fluid flow cytometry for the diagnosis of leukemic meningitis in acute lymphoblastic leukemia/lymphoma. Leuk Lymphoma 2014;55:1498–1500. [16] Subira D, Castanon S, Roman A , et al. Flow cytometry and the study of central nervous disease in patients with acute leukaemia. Br J Haematol 2001;112:381–384. [17] Sayed D, Badrawy H, Ali AM, et al. Immunophenotyping and immunoglobulin heavy chain gene rearrangement analysis in cerebrospinal fluid of paediatric patients with acute lymphoblastic leukaemia. Leuk Res 2009;33:655–661. [18] Quijano S, Lopez A , Manuel SL, et al. Spanish group for the study of CNS disease in NHL. Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin’s lymphoma: improved sensitivity of flow cytometry. J Clin Oncol 2009;27:1462–1469. [19] Hegde U, Filie A , Little RF, et al. High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology. Blood 2005;105:496–502. [20] Di Noto R, Scalia G, Abate G, et al. Critical role of multi-dimensional flow cytometry in detecting occult leptomeningeal disease in newly diagnosed aggressive B-cell lymphomas. Leuk Res 2008;32:1196–1199. [21] Glass JJP, Melamed M, Chernik NL, et al. Malignant cells in cerebrospinal fluid: the meaning of a positive CSF cytology. Neurology 1979;29:1369–1375.
Commentary 1443
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[22] Stewart DJ, Keating MJ, McCredie KB, et al. Natural history of central nervous system acute leukemia in adults. Cancer 1981;47:184–196. [23] Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumours: experience with 90 patients. Cancer 1982;49:759–772. [24] DeAngelis LM, Cairncross JB. A better way to find tumor in the CSF? Neurology 2002;58:339–340. [25] de Graaf M, van den Broek P, Kraan J, et al. Addition of serum-containing medium to cerebrospinal fluid prevents cellular loss over time. J Neurol 2011;258:1507–1512. [26] Greig B, Stetler-Stevenson M, Lea J. Stabilization media increases recovery in paucicellular cerebrospinal fluid specimens submitted for flow cytometry testing. Cytometry B Clin Cytom 2013 May 14. [Epub ahead of print]
[27] de Graaf M, de Jongste AH, Kraan J, et al. Flow cytometric characterization of cerebrospinal fluid cells. Cytometry B Clin Cytom 2011;80:271–281. [28] Craig FE, Ohori P, Gorrill TS, et al. Flow cytometric immunophenotyping of cerebrospinal fluid specimens. Am J Clin Pathol 2011;135:22–34. [29] Marveska D, to Loo WM, Kamps WA , et al. Prognostic significance of blasts in the cerebrospinal fluid without pleocytosis or a traumatic lumbar puncture in children with acute lymphoblastic leukaemia: the experience of the Dutch Childhood Oncology Group. J Clin Oncol 2006;24:2332–2336. [30] Gajjar A , Harrison PL, Sandlund JT. et al. Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukaemia. Blood 2000;96:3381–3384.
