Central nervous system relapse in a child with anaplastic large cell lymphoma: potential for new therapeutic strategies

Abstract Background Central nervous system (CNS) relapse is rare in childhood anaplastic large cell lymphoma (ALCL) and is associated with a poor prognosis. Case We describe an 8‐year‐old boy with ALCL who developed an early CNS relapse without initial CNS disease. Despite aggressive medical management, the patient's neurological status deteriorated rapidly and he died shortly after. Conclusion Optimal treatment for children with relapsed ALCL involving the CNS remains unclear. Novel agents, including ALK inhibitors, that have CNS‐penetration might be helpful and pediatric studies are warranted.


| INTRODUCTION
Anaplastic large cell lymphoma (ALCL) accounts for 20-30% of childhood non-Hodgkin lymphoma (NHL) 1,2 and often presents with advanced-stage disease. Disease recurrence develops in 20%-40% of patients. CNS involvement at the time of diagnosis and relapse remains rare. 3,4 There is currently no consensus on the optimal treatment for children with ALCL with CNS involvement at presentation and even less clarity on therapy for those with relapsed disease involving the CNS.
In this report, we describe a child with ALK+ ALCL with a CNS relapse during first-line therapy and review the literature on evolving therapeutic options.

| CASE
An 8-year-old young boy presented unwell with prolonged fevers, abdominal pain, and progressive respiratory distress. His physical exam was significant for adenopathy and splenomegaly.
Excisional cervical node biopsy revealed a dense proliferation of atypical lymphoid cells and multiple scattered "hallmark cells." Immunohistochemistry showed diffuse ALK1 expression (nuclear and cytoplasmic), CD30, CD4, focal staining with CD2, and negative CD3 confirming ALK+ ALCL. The pathology met the criteria for the lymphohistiocytic variant.
Diagnostic lumbar puncture (LP) and bone marrow (BM) exam were deferred as the patient could not be sedated due to significant respiratory distress. He was urgently started on therapy according to ALCL99 which includes a 5 day pre-phase and six alternating courses of intensive chemotherapy derived from the NHL-BFM protocol. 5,6 Secondary to his compromised clinical state, intrathecal (IT) chemotherapy due on day 1 of pre-phase could not be administered. Positive emission tomography (PET/CT), completed 1 week post-initiation of therapy showed multiple sites of disease including nodal involvement above and below the diaphragm, lung parenchyma, stomach, small bowel, and bilateral kidneys as well as hypermetabolic lytic bone lesions.
Due to his degree of illness including anasarca, high dose methotrexate (HD MTX) was omitted from cycle 1. He clinically improved and was discharged home briefly before the second cycle. LP with triple IT chemotherapy (15 mg MTX and hydrocortisone and 30 mg cytarabine) was given during his second cycle and his cerebrospinal fluid (CSF) analysis was negative at the time.

| DISCUSSION
CNS relapses, although rare, contribute to mortality in patients with ALK+ ALCL. Survival chance is 50% with intensive B-NHL-type CNSdirected therapy with or without cranial irradiation. 8,9 In the patient described, the involvement of the CNS or bone marrow at diagnosis cannot be excluded as these evaluations were Data pertaining to CNS penetrance of these agents are now emerging from a number of clinical trials in adults with ALK+ nonsmall cell lung cancer (NSCLC) where 7.5% of patients will have brain metastasis at the time of presentation and 25% to 30% will develop brain metastasis during the course of their illness. 11,12  Ceritinib, a potent oral second-generation ALK inhibitor, has been shown to have 20-fold greater potency than CRZ and highly effective against common CRZ associated mutations. 34 In phase II ASCEND 2 trial, ceritinib achieved intracranial responses in patients with baseline brain metastasis. Subsequent data from ASCEND 8 showed similar efficacy and tolerable gastrointestinal toxicity with reduced dosing. [35][36][37] Data is still lacking in the pediatric population. Final analysis from a pediatric phase I study (NCT01742286) in pediatric patients with advanced, mostly pre-treated, ALK-aberrant malignancies showed the toxicity profile is similar to that in adults. Of note, out of the 55 patients treated with ceritinib, eight had a diagnosis of ALCL.
The overall response rate (ORR) (95% CI) was 75% for the patients with ALCL. 38 Alectinib, another second-generation highly selective inhibitor, has been shown to have activity against L1196M, a common mutation causing CRZ resistance. 39 Based on the ALEX study of ALK+ NSCLC with brain metastasis, alectinib showed a higher ALK inhibitory potency, 40 BBB transport, superior CNS activity, and significantly delayed CNS progression, irrespective of prior CNS disease or radiotherapy when compared to CRZ. [41][42][43][44] The excellent intracranial control translated into survival benefit. 45 Results from a phase II trial evaluating alectinib in refractory/relapsed ALCL in 10 patients, four of which were pediatric patients, showed favorable clinical activity where eight out of 10 patients achieved complete response. 46,47 Brigatinib, another second generation, dual inhibitor of ALK and EGFR, showed activity in NSCLC with CNS lesions in an early phase I/II trials. 48 In the phase III ALTA-1L trial, brigatinib also demonstrated superior intracranial efficacy as compared to CRZ. 49 Lorlatinib is a third-generation ALK inhibitor designed to have a pan-inhibitory activity against ALK. In phase I, NSCLC study response rates with lorlatinib in patients with measurable and non-measurable brain metastases reached 39% and 31%, respectively. 50 In the phase II study, lorlatinib yielded intracranial overall response rates of 66.7% in treatment-naive patients with measurable brain metastases and 63% in those treated with at least one ALK inhibitor. 51

CONFLICT OF INTEREST
No potential sources of conflict of interest.

ETHICAL STATEMENT
Institutional approval was not required for a case report. All the patient information was de-identified for the purpose of this case report. Patient consent was therefore not obtained for publication.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.