Page 256 - Haematologica Vol. 107 - September 2022

LETTER TO THE EDITOR
Profound and sustained response with next-generation ALK inhibitors in patients with relapsed or progressive ALK-positive anaplastic large cell lymphoma with central nervous system involvement
Anaplastic large cell lymphoma (ALCL) is a rare disease accounting for less than 15% of all non-Hodgkin lympho- mas in childhood. In children and adolescents, more than 90% of cases of ALCL harbor a translocation involving the anaplastic lymphoma kinase (ALK) gene, leading to con- stitutive activation of the ALK-kinase.1 Outcome is good in most patients with a 5-year overall survival reaching 90% according to recent reports.2 Involvement of the central nervous system (CNS) at diagnosis or at relapse/progres- sion is uncommon with a 5-year cumulative risk of 4%.3 ALK inhibitors have now been used for several years in pa- tients with relapsed ALK-positive ALCL with response rates ranging from 53% to 90%.4–6 Most previous trials were based on the first-generation ALK inhibitor, crizoti- nib, which is known to have poor CNS penetration. By contrast, next-generation ALK inhibitors, which have been developed for lung cancer and brain metastases, have good CNS penetration and could therefore be of great in- terest for treating patients with ALK-positive ALCL and CNS involvement. We prospectively collected data on all French patients <22 years old treated between 2017 and 2020 with next-generation ALK inhibitors for a CNS re- lapse/progression of ALK-positive ALCL.
Ten patients, suffering from 11 CNS relapses/progression, were identified. Data for each individual and details of each CNS relapse/progression are available in Tables 1 and 2 and Online Supplementary Table S1.
One patient only had CNS involvement at diagnosis. Of note, all patients underwent a diagnostic cerebrospinal fluid evaluation as routine staging. CNS imaging was only performed in cases of clinical suspicion. Three patients had a leukemic presentation or bone marrow involvement at diagnosis and six had no particular clinical risk factor for CNS evolution (Table 1). Of note, at frontline therapy, all patients at diagnosis, except for one, were at high risk of relapse or progression with minimal disseminated dis- ease and minimal residual disease after one course of treatment. Five patients experienced disease progression while on frontline therapy. For the five others who achieved complete remission and completed the frontline therapy schedule, the time from end of treatment to the first relapse ranged from 0.6 to 2.1 months.
CNS disease was diagnosed during frontline treatment in one patient, at the first relapse in five and after the sec-
ond or further relapse in four. The median age at CNS re- lapse/progression was 11 years (range, 1.8-19). The median delay between diagnosis and CNS relapse/progression in the nine patients free of CNS involvement at diagnosis was 9 months (range, 1.6-54). Before the initiation of treatment with next-generation ALK inhibitors, all patients had received one to three previous treatment lines and four of them had received crizotinib (Online Supplemen- tary Table S1). Interestingly, nine patients had positive minimal residual disease while on the treatment line preceding CNS relapse/progression although eight were in complete clinical and radiological remission. Of note, six patients had CNS relapse while on treatment, with either vinblastine (n=3) or crizotinib (n=3). At the time of CNS progression/relapse, four patients had only CNS involve- ment and the six others also had systemic disease. CNS involvement was restricted to the presence of tumor cells on cytological examination in the cerebrospinal fluid in three patients, while seven had intracranial masses, as- sociated with cerebrospinal fluid positivity on cytological examination in three of the five in whom the cerebrospinal fluid could be examined.
Among the 11 episodes of CNS relapse/progression re- ported here, the next-generation ALK inhibitor used was ceritinib (n=3), lorlatinib (n=3) or alectinib (n=5). The median duration of the treatment with a next-generation ALK inhibitor was 11.3 months (range, 1.2- 27.2). Regarding response to these ALK inhibitors, we report ten responses in the 11 episodes of CNS relapse/progression. One pro- gression of disease occurred on ceritinib in patient #5 who finally achieved complete remission after being switched to high-dose methotrexate followed by alectinib. The median time to best response was 1.5 months (range, 0.5-6) (Figure 1). Only one patient experienced systemic and CNS disease relapse after achieving complete re- mission on alectinib (patient #9). This progression was not well documented either on a molecular level (i.e., resis- tance mutation) or on a pharmacokinetic level. Alectinib was stopped and this patient benefited from CNS-di- rected chemotherapy and finally achieved third complete remission. She unfortunately died while in this third com- plete remission in the context of an invasive mucormyco- sis infection.
Regarding the nine patients with prolonged complete re-
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