Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children’s Oncology Group Study

Abstract

Purpose Fusions involving the ALK gene are the predominant genetic lesion underlying pediatric anaplastic large cell lymphomas (ALCL) and inflammatory myofibroblastic tumors (IMTs). We assessed the activity of the ALK inhibitor crizotinib in patients who had no known curative treatment options at diagnosis or with relapsed/recurrent disease. Methods In this study, 26 patients with relapsed/refractory ALK-positive ALCL and 14 patients with metastatic or inoperable ALK-positive IMT received crizotinib orally twice daily. Study objectives were measurement of efficacy and safety. Correlative studies evaluated the serial detection of NPM-ALK fusion transcripts in patients with ALCL. Results The overall response rates for patients with ALCL treated at doses of 165 (ALCL165) and 280 (ALCL280) mg/m were 83% and 90%, respectively. The overall response rate for patients with IMT (treated at 100, 165, and 280 mg/m/dose) was 86%. A complete response was observed in 83% (five of six) of ALCL165, 80% (16 of 20) of ALCL280, and 36% (five of 14) of patients with IMT. Partial response rates were 0% (none of six), 10% (two of 20), and 50% (seven of 14), respectively. The median duration of therapy was 2.79, 0.4, and 1.63 years, respectively, with 12 patients ceasing protocol therapy to proceed to transplantation. The most common drug-related adverse event was decrease in neutrophil count in 33% and 70% of the ALCL165 and ALCL280 groups, respectively, and in 43% of patients with IMT. Levels of NPM-ALK decreased during therapy in most patients with ALCL. Conclusion The robust and sustained clinical responses to crizotinib therapy in patients with relapsed ALCL and metastatic or unresectable IMT highlight the importance of the ALK pathway in these diseases.

Crizotinib in ALK+ inflammatory myofibroblastic tumors—Current experience and future perspectives

“…When including our two patients, we were able to retrieve detailed information of a total of 16 patients (nine male and seven female). In addition, a recent study by the Children´s Oncology Group (COG) reported on 14 patients with ALK + IMT to receive crizotinib, some of whom had been included in a previous phase I/II study . However, these studies did not report individual patient data.…”

“…The median age of the 16 patients included in case reports was 22 years (range 4–71 years), and five patients were younger than 18 years . The median age of the children included in the COG study was 7 years (range 2–13.5 years) …”

“…Among the 16 patients included in case reports, treatment duration with crizotinib highly varied with a median of 9 months (range 2–40 months). Treatment duration of the 14 patients included in the COG study ranged from 0.55 to 2.3 years (median 1.63 years) . Overall, CR was seen in 12 of the 30 patients (40%) (7/16 patients [44%] retrieved in the literature, and 5/14 patients [36%] included in the COG study), and PR was achieved in another 12 patients (40%) (5/16 patients [31%] retrieved from the literature and 7/14 patients [50%] treated in the COG study).…”

Efficacy of nivolumab in a patient with systemic refractory ALK+ anaplastic large cell lymphoma

“…However, while these targeted agents have shown good response rates, there are still patients who eventually relapse especially after the discontinuation of treatment and thus need other therapies . Thus, these drugs are now mostly used as a bridge for transplantation or as a life‐long therapy …”

Clinical Characteristics and Treatment Results of Pediatric Relapsed/Refractory Non-Hodgkin’s Lymphomas

“…В работе Y.P. Mosse было показано, что при использовании кризотиниба в дозе 165 мг/м 2 у больных с рецидивом АККЛ ALK+ частота ПР со-ставила 83 % [33]. Предложены схемы лечения, вклю-чающие кризотиниб и винбластин для лечения реци-дивов АККЛ у детей [34].…”