As a rare disease that represents only 10-15% of all non-Hodgkin lymphomas (NHL) in children, systemic anaplastic large cell lymphoma (ALCL) remains a clinical challenge since optimal treatments are yet to be established.^1,2 Despite the utilization of reportedly successful chemotherapy at various pulse intensities, up to 35% of patients would relapse.² Among those who are refractory, about half of them would relapse further and the remaining therapeutic options are limited.² Fortunately, the remarkable results demonstrated by the new targeted therapy, crizotinib, had encouraged the Food and Drug Administration (FDA) to greenlight its use in pediatric patients aged 1 or above and young adults with relapsed or refractory, systemic, anaplastic lymphoma kinase (ALK)-positive ALCL earlier this year.^2,3

Crizotinib, a targeted inhibitor of a host of receptor tyrosine kinases including ALK, was evaluated in the Study ADVL0912, the basis on which FDA authorized its approval.^3,4 ADVL0912 was a multi-center, single-arm, open-label study designed with the primary endpoints of determining crizotinib’s maximum tolerated and recommended doses for phase 2 trials, toxicity profiles and pharmacokinetic studies.⁵ The study also included  the secondary endpoints of examining the best disease response to treatment and minimal residual disease monitoring.⁵ The study had been conducted in 121 patients aged 1 to ≤21 with various types of cancer, of which 26 patients had relapsed or refractory, systemic ALK-positive ALCL and had received at least one prior systemic treatment.⁴ Of the 26 patients, 20 received crizotinib 280mg/m², and 6 received crizotinib 165mg/m².⁴ Both groups were given oral crizotinib twice daily until disease progression or unacceptable toxicity.⁴

As assessed by an independent review committee, the efficacy was based on 2 parameters, objective response rate (ORR) and duration of response (DoR).⁴ According to the 26 patients, the ORR was 88% (95% CI: 71-96) and 81% of patients had achieved complete response.⁴ Whereas the DoR at 3 months was achieved by 57% of patients, 39% and 22% also managed to maintain a response for 6 months and 12 months respectively.⁴

In terms of safety, adverse reactions occurring in ≥35% of the study population were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritis.⁴ While 62% of patients experienced Grade 4 neutropenia, 35% and 19% had lymphopenia and thrombocytopenia, respectively.⁴ Another notable adverse reaction is the development of visual disorders, which occurred in 46% of the 121 patients.⁴ Specifically, 65% of the 26 patients with ALCL also developed visual disorders.⁴ The overall safety profile of crizotinib in children and young adults with ALK-positive ALCL was generally consistent with patients with ALK-positive and ROS1-positive metastatic non-small cell lung cancer (NSCLC).⁴ “We are proud to deliver the first biomarker-driven therapy for children and young adults with ALCL,” commented Dr. Chris Boshoff, Chief Development Officer, Oncology, Pfizer Global Product Development.

While the safety and efficacy of crizotinib for older adults have not been established yet, its approval has nonetheless offered an efficacious and safe therapeutic option for children and young adults that can potentially address the unmet medical needs in the treatment of relapsed and refractory ALCL.⁴ “Crizotinib represents an exciting new development in the treatment of this disease,” said Meghan Gutierrez, Chief Executive Officer at the Lymphoma Research Foundation. “Researchers have made significant progress in our understanding of ALCL, which we hope will continue to improve treatment strategies and options for children with ALCL.”