Combination crizotinib and chemotherapy is effective for pediatric patients with newly diagnosed anaplastic large-cell lymphoma (ALCL), but the treatment increases the risk of thrombotic events, a phase 2 trial suggests. 

The event-free survival (EFS) rate for patients who received this regimen was higher than that reported in most previous studies, researchers noted. However, 20% of patients who received crizotinib with chemotherapy experienced a thromboembolic event. These results were published in the Journal of Clinical Oncology

The phase 2 trial ( Identifier: NCT01979536) was designed to evaluate chemotherapy in combination with crizotinib or brentuximab vedotin. The current analysis included 68 patients who received crizotinib and chemotherapy. The patients had ALK-positive, CD30-positive, newly diagnosed ALCL. The median age at baseline was 14 (range, 6-20) years. 

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Treatment consisted of a 5-day prophase in which patients received cyclophosphamide, dexamethasone, and triple intrathecal therapy, followed by 6 chemotherapy cycles. On cycles 1, 3, and 5, chemotherapy consisted of methotrexate, dexamethasone, ifosfamide, etoposide, and cytarabine. On cycles 2, 4, and 6, chemotherapy consisted of methotrexate, dexamethasone, cyclophosphamide, and doxorubicin. Crizotinib was given at 165 mg/m2 twice daily during each 21-day cycle.

The 2-year EFS rate was 76.8%, and the 2-year overall survival rate was 95.2%. Fifteen patients relapsed, and the median time to relapse was 7.4 months. 

Patients who were negative for minimal disseminated disease (MDD) had better outcomes than MDD-positive patients. The EFS rate was 85.6% in MDD-negative patients and 58.1% in MDD-positive patients. Based on these data, the researchers concluded that evaluation of MDD “should be incorporated into initial staging of disease and selection of treatment.”

The crizotinib arm of this trial was temporarily closed in July 2016 due to toxicity but was reopened in October 2016 with an amendment to include the risk of thromboembolic events. The crizotinib arm was temporarily closed again in April 2017 and reopened in January 2018 with an amendment requiring prophylactic anticoagulation. 

Overall, 19.7% of patients experienced a grade 2 or higher thromboembolic event during treatment. Twenty-five patients had mandated prophylactic anticoagulation, and 2 of these patients had a grade 2 or higher thromboembolic event (8.0%). 

Crizotinib “has been previously associated with thrombosis at low levels when used as a single agent, or in combination with other agents,” the researchers noted. However, they were unsure of the reasons behind the unexpectedly high incidence of thrombosis in this trial. 

“Given the increased rate of thromboembolic events associated with CZ [crizotinib], it is unlikely to be preferred over brentuximab given on the chemotherapy backbone used in this trial,” the researchers wrote. “CZ’s activity in ALCL does warrant consideration for use in frontline ALCL, potentially in combination with brentuximab alone, rather than as part of a multiagent chemotherapy regimen.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Lowe EJ, Reilly AF, Lim MS, et al. Crizotinib in combination with chemotherapy for pediatric patients with ALK+ anaplastic large-cell lymphoma: The results of Children’s Oncology Group Trial ANHL12P1. J Clin Oncol. Published online December 19, 2022. doi:10.1200/JCO.22.00272