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/m² were 83% and 90%, respectively. The overall response rate for patients with IMT (treated at 100, 165, and 280 mg/m²/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.

Fig 1.

Response characteristics in patients with ALK-translocated ALCL and IMT who are receiving crizotinib. The three panels show response onset and duration for patients in the ALCL165, ALCL280, and IMT groups treated with crizotinib. The length of the bar shows the time until the patient had a CR or PR, along with the duration of response up to 24 months. Therapy duration exceeded 24 months for three patients at the ALCL165 dose (71.24, 65.75, and 58.88 months, respectively), one patient at the ALCL280 dose (39.88 months), and four patients with IMTs (63.45, 41.59, 27.58, and 25.08 months, respectively). ALCL, anaplastic large cell lymphoma; ALCL165, patients with anaplastic large cell lymphoma receiving a 165 mg/m² dose of crizotinib; ALCL280, patients with anaplastic large cell lymphoma receiving a 280 mg/m² dose of crizotinib; CR, complete response; IMT, inflammatory myofibroblastic tumor; PD, progressive disease; PR, partial response.

Fig 2.

Images of representative patient. (A) Coronal maximum projection intensity positron emission tomography (PET) images taken after administration of ¹⁸F-labeled fluorodeoxyglucose (¹⁸F-FDG) show multiple sites of FDG-avid metabolically active anaplastic large cell lymphoma tumor at baseline, including left cervical chain, mediastinal, retroperitoneal, and iliac chain lymph nodes. After one cycle of therapy, pathologic FDG uptake resolved completely (uptake in the right lower quadrant reflects physiologic FDG accumulation in distal small bowel, confirmed on coregistered and fused PET/computed tomography (CT) images(not shown). (B) Baseline whole-body ¹⁸F-FDG-PET and chest CT images show multiple FDG-avid pulmonary nodules, confirmed by biopsy specimen to be IMT. After one cycle of therapy, no residual abnormal FDG accumulation is seen (metabolic complete response [CR]). The lesions also decreased significantly in size, on CT image, meeting criteria for partial response, but not CR.

Fig 3.

Detection and quantification of NPM-ALK in bone marrow (BM) and peripheral blood (PB). (A) NPM-ALK fusion transcript was quantified in 18 paired pre-enrollment BM and PB samples using quantitative reverse transcriptase polymerase chain reaction. The blue circles represent the NPM-ALK levels in BM, and the gold circles represent the NPM-ALK levels in PB. Of the 18 paired samples, five patients had no quantifiable levels of NPM-ALK in BM, and PB. Only one patient had quantifiable NPM-ALK level in PB but not in BM. The levels of NPM-ALK in BM are lower than in PB in most of the paired samples (10 of 13). (B) The change of NPM-ALK transcript levels in the PB over 6 months of treatment is represented for 23 patients for whom NPM-ALK was detected and quantified at the time of enrollment. Except for one patient, NPM-ALK transcript levels decreased as early as 1 month of treatment. Thirteen patients had a reduction > 75% of NPM-ALK levels in PB within the first month. BM, bone marrow; PB, peripheral blood.