Clinical significance of occult central nervous system disease in adult acute lymphoblastic leukemia. A multicenter report from the Campus ALL Network

Maria Ilaria Del Principe, Elisa Buzzatti, Alfonso Piciocchi, Fabio Forghieri, Massimiliano Bonifacio, Federica Lessi, Silvia Imbergamo, Enrico Orciuolo, Giovanni Rossi, Nicola Fracchiolla, Silvia Trappolini, Benedetta Neri, Chiara Sarlo, Patrizia Zappasodi, Michelina Dargenio, Mariagiovanna Cefalo, Maria Antonietta Irno-Consalvo, Consuelo Conti, Giovangiacinto Paterno, Gottardo De Angelis, Mariarita Sciumè, Irene Della Starza, Adriano Venditti, Robin Foà, Anna Rita Guarini, Maria Ilaria Del Principe, Elisa Buzzatti, Alfonso Piciocchi, Fabio Forghieri, Massimiliano Bonifacio, Federica Lessi, Silvia Imbergamo, Enrico Orciuolo, Giovanni Rossi, Nicola Fracchiolla, Silvia Trappolini, Benedetta Neri, Chiara Sarlo, Patrizia Zappasodi, Michelina Dargenio, Mariagiovanna Cefalo, Maria Antonietta Irno-Consalvo, Consuelo Conti, Giovangiacinto Paterno, Gottardo De Angelis, Mariarita Sciumè, Irene Della Starza, Adriano Venditti, Robin Foà, Anna Rita Guarini

Abstract

In acute lymphoblastic leukemia, flow cytometry detects more accurately leukemic cells in patients' cerebrospinal fluid compared to conventional cytology. However, the clinical significance of flow cytometry positivity with a negative cytology - occult central nervous system disease - is not clear. In the framework of the national Campus ALL program, we retrospectively evaluated the incidence of occult central nervous system disease and its impact on outcome in 240 adult patients with newly diagnosed acute lymphoblastic leukemia. All cerebrospinal fluid samples were investigated by conventional cytology and flow cytometry. The presence of ≥10 phenotypically abnormal events, forming a cluster, was considered as flow cytometry positivity. No central nervous system involvement was documented in 179 patients, while 18 were positive by conventional morphology and 43 were occult central nervous system disease positive. The relapse rate was significantly lower in central nervous system disease negative patients and the disease-free and overall survival were significantly longer in central nervous system disease negative patients than in those with manifest or occult central nervous system disease positive. In multivariate analysis, the status of manifest and occult central nervous system disease positivity was independently associated with a worse overall survival. In conclusion, we demonstrate that in adult acute lymphoblastic leukemia patients at diagnosis flow cytometry can detect occult central nervous system disease at high sensitivity and that the status of occult central nervous system disease positivity is associated with an adverse outcome. (Clinicaltrials.gov NCT03803670).

Figures

Figure 1.
Figure 1.
Flow cytometry detection of occult central nervous system (CNS) involvement in a patient with B-lineage acute lymphoblastic leukemia (ALL). The blast population is shown in gray which denotes a cluster of few cells CD19 (C) and CD10 (D) positive, and CD34, CD22 negative (E and F) and CD20 weak (F).
Figure 2.
Figure 2.
Disease-free survival (DFS) based on central nervous system (CNS) status. Kaplan-Meier plot comparing DFS of cerebrospinal fluid (CSF) samples negative by both flow cytometry (FCM) and conventional cytology (CC) (CNSneg), occult CSF samples positive by FCM and negative by CC (OCNSDpos), and CSF positive by both FCM and CC (MCNSDpos).
Figure 3.
Figure 3.
Overall survival (OS) based on the central nervous system (CNS) status. Kaplan-Meier plot comparing OS of patients’ cerebrospinal fluid (CSF) samples negative by both flow cytometry (FCM) and conventional cytology (CC) (CNSneg), occult CSF samples positive by FCM and negative by CC (OCNSDpos), and CSF positive by both FCM and CC (MCNSDpos).

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