Page 259 - Haematologica Vol. 107 - September 2022

LETTER TO THE EDITOR
grade 3 gastrointestinal and/or hepatic adverse events in three patients.
In contrast to the overall population of patients with ALK- positive ALCL, patients with CNS involvement any time during the course of their disease are known to have a dismal outcome.7,8 This was recently confirmed in a report from the European Inter-Group for Childhood Non-Hodg- kin Lymphoma, in which the 3-year overall survival of pa- tients after CNS relapse was less than 50%, and the median time to death after CNS relapse was 3.5 months in the 4% of patients experiencing such relapses.3
The range of therapeutic options for relapsed/refractory ALK-positive ALCL has increased significantly during the past decades. Besides conventional chemotherapy, sev- eral targeted therapies such as brentuximab vedotin and ALK inhibitors are now widely used to treat patients with ALCL at relapse.4,9 However, there is no evidence that vin- blastine and the antibody-drug conjugate brentuximab vedotin cross the blood-brain barrier,10 and several cases of CNS relapses occurring in ALCL patients treated with vinblastine or brentuximab for systemic disease have been reported.11,12
ALK inhibitors have been used for several years now, with some success. The first-in-class, crizotinib, showed quite good results in relapsed/refractory ALK-positive ALCL.4–6 However, it might not be efficient for CNS prophylaxis. In- deed, CNS progression during crizotinib treatment is one
of the common modes of failure in patients treated for ALK-rearranged non-small cell lung cancer, accounting for nearly 70% of the treatment failures in some studies.13 This might be attributed to poor CNS penetration of crizotinib, with a concentration in cerebrospinal fluid almost 400- fold lower than that in the serum.14 This lack of ALCL CNS disease control with crizotinib was also evidenced in a brief report by Ruf and colleague in 2018.11 To overcome this problem, next-generation ALK inhibitors were de- signed to cross the blood-brain barrier more efficiently, thus achieving a higher concentration in the cerebrospinal fluid. As a result these molecules, which include ceritinib, alectinib, brigatinib and lorlatinib, demonstrated a promi- nent ability to control CNS disease in ALK-rearranged non-small cell lung cancer.15
We report here 11 neuro-meningeal relapses or progres- sions in ten patients with ALK-positive ALCL treated with next-generation ALK inhibitors. We first want to empha- size that this number is quite high as we report here ten patients with CNS relapses in 3 years compared to the previous 25 CNS relapses in nearly 20 years reported in the already mentioned European Inter-Group for Child- hood Non-Hodgkin Lymphoma report.3 This could be caused by some changes in our practices such as the wider use of vinblastine and the introduction of prolonged crizotinib treatment in a relapse setting, especially in pa- tients with high-risk disease and in those who are positive
Figure 1. Swimmer-plot of French pediatric patients treated with next-generation ALK inhibitors for central nervous system re- lapse or progression of ALK-positive anaplastic large cell lymphoma. ALKi: ALK inhibitor; CNS: central nervous system; FU: fol- low-up.
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