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Crizotinib Combined With Chemotherapy in Pediatric ALK-Positive Anaplastic Large Cell Lymphoma


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As reported in the Journal of Clinical Oncology by Lowe et al, findings in an arm of the Children’s Oncology Group phase II ANHL12P1 trial (arm CZ) showed high event-free and overall survival rates with the addition of crizotinib to chemotherapy in newly diagnosed pediatric patients with nonlocalized ALK-positive, CD30-positive anaplastic large cell lymphoma (ALCL). However, the addition of crizotinib was associated with an unexpected risk of thromboembolic events.

Study Details

In the multicenter trial, patients with body surface ≥ 0.9/m2 were randomly assigned to the addition of brentuximab vedotin or crizotinib to chemotherapy; reported findings are from the crizotinib group. This group consisted of 66 patients with a median age of 14 years (range = 6–20 years) enrolled between December 2013 and January 2019.

Patients were to receive a 5-day lead-in phase with cyclophosphamide, dexamethasone, and age-based triple intrathecal therapy, followed by six 21-day cycles of crizotinib at 165 mg/m2 twice daily in combination with methotrexate, dexamethasone, ifosfamide, etoposide, and cytarabine during cycles 1, 3, and 5, and with methotrexate, dexamethasone, cyclophosphamide, and doxorubicin during cycles 2, 4, and 6. Measurement of NPM-ALK fusion transcripts in peripheral blood was performed at diagnosis to identify minimal disseminated disease (MDD).

Accrual to the crizotinib arm was closed for two periods (a total of 12 months), during which crizotinib was discontinued: from July to October 2016 to update study risks to include thromboembolic events, and from April 2017 to January 2018, when it then reopened with a protocol amendment requiring prophylactic anticoagulation for thromboembolic events.

Arm CZ of ANHL12P1 demonstrated that the addition of crizotinib to standard treatment prevented relapses during therapy for children with ALCL, MDD predicted event-free survival, and the addition of crizotinib resulted in unexpected thromboembolic events. Overall survival and event-free survival rates are consistent with the highest reported outcomes for children with ALCL.
— Lowe et al

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Outcomes

In total, 66 patients received at least one dose of crizotinib and completed 384 cycles of chemotherapy. Complete response/unconfirmed complete response was achieved in 55 (91.7%) of 60 evaluable patients after cycle 2 and in 59 (98.3%) of 60 patients after cycle 6.

Median follow-up for patients alive at last contact was 3.4 years. Estimated 2-year event-free survival was 76.8% (95% confidence interval [CI] = 68.5%–88.1%) and estimated 2-year overall survival was 95.2% (95% CI = 85.7%–98.4%). Relapse occurred in 15 patients at a median time from diagnosis of 7.4 months; all relapses occurred after completion of chemotherapy.

Among patients with available data, 2-year event-free survival was 85.6% (95% CI = 68.6%–93.8%) among 37 MDD-negative patients and 58.1% (95% CI = 33.4%–76.4%) among 20 MDD-positive patients.

Adverse Events

Overall, 13 (19.7%, 95% CI = 11.1%–31.3%) of 66 patients had grade ≥ 2 thromboembolic events. Among the 25 patients who received mandated prophylactic anticoagulation, thromboembolic events occurred in 2 (8.0%, 95% CI = 0.01%-26.0%). Four patients (6.1%) had grade ≥ 2 pulmonary embolisms, with all occurring prior to institution of mandatory prophylaxis.

Nonhematologic grade 3 or 4 adverse events occurring in > 5% of patients included febrile neutropenia (56%), oral mucositis (39%), hypokalemia (23%), alanine aminotransferase elevation (18%), infections-other (9%), hypophosphatemia (8%), and thromboembolic events (8%). No cases of visual disturbance and no cases of liver failure were observed. No deaths due to adverse events were reported.

The investigators concluded, “Arm CZ of ANHL12P1 demonstrated that the addition of crizotinib to standard treatment prevented relapses during therapy for children with ALCL, MDD predicted event-free survival, and the addition of crizotinib resulted in unexpected thromboembolic events. Overall survival and event-free survival rates are consistent with the highest reported outcomes for children with ALCL.”

Eric J. Lowe, MD, of the Department of Pediatric Hematology/Oncology, Children’s Hospital of the King’s Daughters, Norfolk, Virginia, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by National Clinical Trial Network grants and St. Baldrick’s Foundation. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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