Impact of central nervous system involvement in adult patients with Philadelphia-negative acute lymphoblastic leukemia: a GRAALL-2005 study

Abstract

Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial central nervous system (CNS) involvement has not been formerly re-evaluated. We report here the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (aged 18-59 years) with newly diagnosed Philadelphia-negative ALL were included, of whom 55 (7%) had CNS involvement. In CNSpositive patients, overall survival was shorter (median 1.9 years vs. not reached, HR=1.8 [1.3-2.6], P<0.001). While there was no statistical difference in cumulative incidence of relapse between CNS+ and CNS- patients (HR=1.5 [0.9-2.5], P=0.11), non-relapse mortality was significantly higher in those with initial CNS disease (HR=2.1 [1.2-3.5], P=0.01). This increase in toxicity was mostly observed in patients randomized to the high-dose cyclophosphamide arm and in those who received allogeneic stem cell transplantation. Exploratory landmark analyses did not show any association between either cranial irradiation or allogeneic stem cell transplantation and outcome. Despite improved outcome in young adult ALL patients with pediatric-inspired protocols, CNS involvement is associated with a worse outcome mainly due to excess toxicity, without improved outcome with allogeneic SCT.

Figure 1.

Flowchart of patients with central nervous system involvement at diagnosis. C: cyclophosphamide; CNS: central nervous system; CR1: first complete remission; SCT: stem cell transplantation.

Figure 2.

Outcomes according to central nervous system status at diagnosis. (A) Kaplan-Meier curves for overall survival, (B) cumulative incidence of relapse, and (C) cumulative incidence of non-relapse mortality according to (CNS) involvement at diagnosis.

Figure 3.

Outcomes of patients with central nervous system disease at diagnosis. (A) Overall survival of patients who received cranial radiation therapy by a 160-day landmark analysis and (B) overall survival of patients who received allogeneic stem cell transplantation (SCT) by a 170-day landmark analysis.