Targeted Therapy in a Young Adult With a Novel Epithelioid Tumor Driven by a PRRC2B-ALK Fusion

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  • 1 Department of Pediatric Oncology, Roswell Park Comprehensive Cancer Institute, and
  • | 2 Department of Pediatrics, University of Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York;
  • | 3 Department of Pathology and Laboratory Medicine, and
  • | 4 The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, Ohio;
  • | 5 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee;
  • | 6 Department of Pediatrics, and
  • | 7 Department of Pathology, The Ohio State University, Columbus, Ohio;
  • | 8 Department of Neurosurgery, The Ohio State University College of Medicine, Columbus, Ohio; and
  • | 9 Department of Hematology/Oncology/BMT, Division of Pediatrics, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, Ohio.

This case report describes an 18-year-old woman with an unusual epithelioid tumor of the omentum with a novel PRRC2B-ALK fusion. Although the atypical pathologic features raised significant diagnostic challenges, expression of CD30 on tumor cells and detection of an ALK rearrangement provided critical information for selecting targeted therapy in a patient not suitable for surgical resection. Despite an initially promising therapeutic response, the patient died. The efficacy of treatment was confirmed by the lack of viable tumor cells at autopsy. This case highlights the role of timely targeted therapy in patients with rare tumors and novel actionable molecular targets.

Background

Molecular diagnostics and targeted therapies have altered the paradigm of cancer diagnosis and treatment. In histologically ambiguous tumors, molecular methodologies are increasingly used to further inform diagnosis. However, in cases in which the molecular findings are novel, no specific diagnosis may be ultimately rendered, and targeting the positive results may not have medical precedent, leading to hesitancy in obtaining and applying these therapies.

This case report describes a patient with a malignant epithelioid tumor with atypical morphologic features, an unusual immunophenotype, anaplastic lymphoma kinase (ALK) and CD30 positivity, and a novel gene fusion. We also discuss the diagnostic difficulties, therapeutic challenges, and complications faced when treating a novel tumor in a critically ill patient.

Case Report

An 18-year-old previously healthy woman was transferred from an outside hospital after presenting with 1 week of progressive abdominal pain, nausea, bloating, and vomiting. Imaging studies revealed multiple PET-avid omental masses, the largest measuring 4.9 × 3.5 × 3.9 cm in the central abdomen (Figure 1), and a large amount of ascites. The ascitic fluid was initially negative for tumor cells. A biopsy performed by the outside hospital was sent away for diagnosis, with no immediate result. The extensive tumor burden was deemed unresectable at presentation, and rebiopsy was performed 4 days into hospitalization. The second biopsy showed sheets of loosely cohesive epithelioid tumor cells with pink cytoplasm, a moderate nuclear/cytoplasmic ratio, round to oval nuclei, fine open chromatin, and prominent eosinophilic nucleoli (Figure 2). Mitotic figures were seen along with scattered apoptotic bodies. There were rare, scattered foci of inflammatory infiltrate consisting of small mature lymphocytes and/or neutrophils. The finding in tumor cells was positive for CD30 (strong, membranous), CD138, ALK (cytoplasmic), smooth muscle actin (SMA; (weak, patchy), desmin (focal, weak), epithelial membrane antigen (EMA; patchy), Sal-like protein 4 (SALL4; weak), and Wilms tumor 1 (WT1)–amino and WT1-carboxy (variable) (Figure 2). The tumor finding was negative for cytokeratins (calmodulin 5.2 and AE1/AE3), lymphoid markers, CD163, glypican-3, granzyme B, HMB45, OCT4, and S-100. The result of in situ hybridization for Epstein-Barr virus–encoded small RNA was negative. Several days later, cytogenetic analysis revealed an apparently balanced translocation between chromosomes 2p and 9q involving the ALK locus: 45,X,-X,t(2;9)(p23;q34.3),der(15)t(7;15)(p13;p11.2),i(17)(q10)[15]/46,XX[5].ish t(2;9)(5′ALK+;3′ALK+,ABL1+).

Figure 1.
Figure 1.

Tumor burden at diagnosis. Imaging studies (PET/CT on the left; dedicated CT of the abdomen on the right) on presentation show multiple metabolically active mesenteric and omental masses.

Citation: Journal of the National Comprehensive Cancer Network 19, 10; 10.6004/jnccn.2021.7056

Figure 2.
Figure 2.

Atypical histologic features of the tumor. Pathology of the omental mass biopsy shows an epithelioid tumor with sheets of loosely cohesive epithelioid cells in a myxoid background (left panels, hematoxylin and eosin stain [H&E]; original magnifications, ×100 and ×400). The tumor cells are large with moderate pink cytoplasm and prominent nucleoli and vesicular chromatin. Mitotic figures and apoptotic bodies are easily seen. Inflammatory infiltrates are nearly absent except in rare foci with few infiltrating small mature lymphocytes. By immunohistochemistry, the tumor cells are positive for ALK1 (cytoplasmic), CD30, desmin (rare), smooth muscle actin (SMA; rare), CD138, and epithelial membrane antigen (EMA; patchy) (center and right panels).

Citation: Journal of the National Comprehensive Cancer Network 19, 10; 10.6004/jnccn.2021.7056

Initially, a null-cell phenotype of anaplastic large cell lymphoma (ALCL), ALK-positive, was favored because of complete lack of lymphoid marker expression and coexpression of CD30, ALK, and EMA in epithelioid tumor cells. Based on the clinical presentation of omental masses in a young adult, consulting pathologists favored a diagnosis of epithelioid inflammatory myofibroblastic sarcoma (EIMS), a rare tumor also defined by ALK rearrangement. Several features typical of EIMS, including marked inflammatory infiltrate and diffuse desmin and SMA staining, were not seen, precluding definitive diagnosis. A PRRC2B-ALK fusion was identified on day 21 of hospitalization using the Archer FusionPlex Solid Tumor Panel targeted sequencing assay, corresponding to the t(2;9) translocation identified by cytogenetic analysis (Figure 3A). The predicted chimeric protein product retains the coiled-coil domain of PRRC2B, which drives expression of the ALK protein kinase domain (Figure 3B). This exact fusion was previously described in a ventricular subependymal giant cell astrocytoma,1 but it did not help to provide a definitive pathologic diagnosis in this atypical case. Concurrent with diagnostic testing, this patient was enrolled in an institutional translational research protocol (details are provided in supplemental eAppendix 1, available with this article at JNCCN.org). Enhanced exome sequencing of the comparator normal and disease-involved samples and RNA sequencing of the disease-involved tissue were performed to assess for single-nucleotide variants and insertions/deletions, copy number alterations, gene fusions, and aberrant expression. Through RNA sequencing, we confirmed the presence of the PRRC2B-ALK fusion. Compared with a cohort of soft tissue and bone sarcomas in our internal cancer cohort and those publicly available in the University of California, Santa Cruz Treehouse Initiative, ALK was found to be overexpressed (Figure 3C). In addition, the tumor was found to harbor 2 somatic alterations in the NF1 gene: a missense variant (NM_001042492.3:c.3634G>C; p.Val1212Leu) and a subclonal nonsense variant (NM_001042492.3:c.2041C>T; p.Arg681Ter). Notable copy number alterations included focal biallelic loss of BAP1, gains of 7p and 7q, and loss of X, consistent with the described karyotype (Figure 3D, E).

Figure 3.
Figure 3.

Molecular characterization of PRRC2B-ALK fusion and genomic profiling. (A) Sanger sequencing chromatogram of the PRRC2B-ALK fusion. This fusion results in exon 13 of PRRC2B (NM_013318.3) joined to exon 20 of ALK (NM_004304.4). (B) Protein domains corresponding to PRRC2B-ALK fusion. (C) ALK expression for the patient case (red point) compared with our internal cohort of bone and soft tissue sarcomas and those publicly available from the University of California, Santa Cruz Treehouse Initiative. (D) Genome-wide somatic copy number alterations (CNAs). Top plot: Tumor CNA relative to comparator normal in log2 scale. Blue points represent log2 values based on sequence depth in 100-bp windows. Red lines indicate segmented CNA calls. Bottom plot: Tumor variant allele frequency for variants that are heterozygous, nonreference calls in the comparator normal. Points in gold indicate significant loss of heterozygosity. The x axis denotes the chromosome number. (E) Same as D but for chromosome 3.

Abbreviations: LDLa, low-density lipoprotein receptor domain class A; MAM, meprin, A-5 protein, and receptor protein tyrosine phosphatase μ.

Citation: Journal of the National Comprehensive Cancer Network 19, 10; 10.6004/jnccn.2021.7056

Comprehensive workup, including PET/CT, lumbar puncture, and bone marrow biopsies, showed no disease outside the abdomen. The patient had persistent massive peritoneal drainage leading to hypovolemia and hypoalbuminemia. The ascites fluid was again analyzed and was found to be positive for tumor cells, <5% by morphology and 1.82% by flow cytometry in one sample. Without a clear diagnosis, the patient’s clinical deterioration prompted the administration of steroids on day 13 of hospitalization, given the consideration of ALCL as a possible diagnosis. No immediate improvement was observed. With the identified ALK rearrangement and literature support for upfront use of ALK inhibitors in ALK-positive tumors, including unresectable inflammatory myofibroblastic tumor (IMT) and EIMS,2 targeted therapy with crizotinib, an ALK inhibitor, was pursued next. The treatment team was unable to obtain crizotinib for inpatient use because of hospital–pharmaceutical company contracting issues, partly due to a lack of diagnosis. Ultimately, alectinib, a highly selective and potent second-generation ALK inhibitor, was initiated on day 19 of hospitalization. Administration of the drug twice per day to a patient with severe nausea and vomiting proved challenging, and 7 doses of alectinib were administered over 3 days with no obvious clinical improvement. The medication was stopped secondary to patient refusal of oral medications due to severe nausea and the team’s concern for poor absorption in the setting of high-output ascites.

The patient’s clinical condition continued to deteriorate with the development of an acute pulmonary embolus, an inferior vena cava thrombosis, and Streptococcus viridans sepsis that required intubation and initiation of broad-spectrum antibiotics and micafungin on day 23 of hospitalization. A common regimen for sarcoma, ifosfamide and doxorubicin, was considered but aborted due to concerns about hydration requirements with ifosfamide. Instead, brentuximab vedotin (BV), an antibody–drug conjugate targeting CD30, was chosen based on demonstrated preclinical efficacy in ALK-rearranged IMT3,4 and strong tumor CD30 expression. Doxorubicin is active against sarcoma and has been used together with BV for relapsed Hodgkin’s lymphoma,5 thus this combination was administered as follows: BV 1.8 mg/kg on day 1 and doxorubicin 37.5 mg/m2 on days 1 and 2. Vinblastine was added on day 8 in an attempt to get additional tumor response. Marked clinical improvement was observed over the week after administration. The patient was extubated to room air within 3 days of chemotherapy, her ascites dramatically decreased, and tumor imaging confirmed the response. Unexpectedly, on day 31 of admission, she developed acute hemoptysis and pulmonary hemorrhage followed by acute respiratory distress syndrome, multiple organ dysfunction syndrome, cytomegalovirus viremia, and prolonged pancytopenia. She died of multiple organ dysfunction syndrome on day 49 of admission (timeline of events per Figure 4).

Figure 4.
Figure 4.

Timeline of events.

Abbreviations: AKI, acute kidney injury; ALK, anaplastic lymphoma kinase; ARDS, acute respiratory distress syndrome; BV, brentuximab vedotin; CRRT, continuous renal replacement therapy; RA, room air.

Citation: Journal of the National Comprehensive Cancer Network 19, 10; 10.6004/jnccn.2021.7056

Autopsy showed diffuse alveolar injury with pulmonary hemorrhage and fungal infection (Candida parapsilosis) as the cause of death. Remarkably, the omental masses showed extensive necrosis without residual viable tumor cells, consistent with a complete response to chemotherapy.

Discussion

In this case, we describe the evaluation and treatment of an aggressive CD30-positive malignant neoplasm with a PRRC2B-ALK fusion using a novel anti-CD30 targeted approach that led to tumor remission. The presence of omental masses and strong positivity for ALK and CD30 were suggestive of an unusually aggressive IMT within the spectrum of EIMS, a tumor that typically presents with large peritoneal masses, widespread omental involvement, and responds poorly to traditional chemotherapy. The immunohistochemical profile was not classic for EIMS, however, and raised other diagnostic possibilities, such as atypical ALCL. Reported fusions in EIMS are typically seen at the ALK locus on chromosome 2p23, resulting in activation of the kinase domain. ALK-RANBP2 is the most commonly reported fusion in EIMS,6 with others less frequently described.79 By contrast, ALCL is most commonly characterized by NPM1-ALK fusions, but up to 20% contain variant fusions.10 To complicate the picture, fusions with TMP3-ALK and TMP4-ALK have been identified in both ALCL and IMT.10

Expression of CD30 on tumor cells and ALK rearrangement in this patient’s tumor provided 2 biomarkers considered for targeted therapy. An important issue raised in this case is the potential to select targeted therapy regardless of pathologic diagnosis, especially in challenging cases. The recent FDA approval of a biomarker-based indication for pembrolizumab, regardless of tumor type, may be expanded to other biomarker-based targeted therapies, such as ALK inhibitors and BV. Several generations of tyrosine kinase inhibitors have been developed and have demonstrated efficacy in treating ALK-rearranged malignancies, including non–small cell lung cancer, ALCL, and IMT.6,7,1113 With the detection of ALK alterations in many different tumor types and with >20 different partner genes, large-scale clinical trials to validate the efficacy of ALK inhibitors in rare tumors and/or those with rare or novel ALK fusion partners are not feasible. In addition, differential sensitivity to ALK inhibitors has been shown in tumors with different fusion partners, raising the question of how to select a specific ALK inhibitor in an individual with a novel ALK fusion. An unexpected issue encountered in this case was the difficulty in obtaining crizotinib, the agent best described for EIMS, for inpatient use, partly due to a lack of a definitive diagnosis. Ultimately, the efficacy of alectinib cannot be evaluated accurately because of difficulties with drug administration and concerns regarding absorption and bioavailability.

Many ALK-altered tumors express the membrane protein CD30, a member of the tumor necrosis factor receptor superfamily with limited expression in normal tissues. BV is an antibody–drug conjugate that targets CD30 on tumor cells and has been used successfully as a single agent or in combination with traditional chemotherapeutic agents for classic Hodgkin lymphoma, ALCL, and other CD30-positive T- and B-cell lymphomas.810,14 The role of BV in nonlymphoid malignancies has been tested only in 3 small-scale studies, including CD30-expressing germ cell tumors (5 patients), sex cord stromal tumors (2 patients), and systemic mastocytosis (14 patients), with partial responses seen in a few patients.1517 A recent preclinical study explored CD30 as a single agent and in combination with an ALK inhibitor to treat EIMS with RANBP2-ALK rearrangement with a xenograft model generated from patient-derived tumor cells. Prolonged tumor-free survival was observed only with combinations of BV and either crizotinib or ceritinib (third-generation ALK inhibitor).4 In our case, the combination of BV, doxorubicin, and vinblastine was chosen in an effort to target CD30 and also to provide broad antineoplastic coverage, given the limited data supporting BV in solid tumors.18 The excellent immediate clinical response and the lack of viable tumor at autopsy support the efficacy of this combination in treating this rare CD30-positive, ALK-rearranged malignancy. Large-scale clinical trials are needed to further validate the efficacy and safety of this approach in treating similar solid tumors. In addition, it is not clear whether the limited use of an ALK inhibitor immediately before BV may increase the sensitivity of the tumor cells to the combination regimen.

The fatal lung injury in this case was ultimately believed to be multifactorial, most likely the result of pulmonary embolus followed by pulmonary hemorrhage while receiving anticoagulants and concurrent infections with cytomegalovirus and Candida. However, we must also consider drug adverse effects from alectinib and/or BV, given several case reports of rare, severe pulmonary complications. In a phase II trial of alectinib with 87 patients, a single instance of fatal hemorrhage was reported in a patient receiving anticoagulation and was believed likely to be related to alectinib.19 There is also a case report of an 8-year-old girl with IMT who was believed to have fatal diffuse alveolar hemorrhage secondary to crizotinib.20 Overall, the rates of lung toxicity are particularly low in patients with non–small cell lung cancer receiving ALK inhibitors, approximately 1% to 3%, but the severity of those episodes can be considerable; among those with a pulmonary adverse effect, there was a mortality rate of 9% and a 25% discontinuation rate of drug due to lung toxicity.21 Alectinib has been associated with rare cases of interstitial pneumonitis with ground-glass opacities that generally occur after 1 to 12 months of therapy,22 a situation different from what occurred in this patient, who only received limited dosing and did not have those findings. In addition, alectinib has been considered the safest ALK inhibitor in a large meta-analysis.23 Despite a favorable pulmonary toxicity profile compared with bleomycin in Hodgkin lymphoma treatment, severe pulmonary toxicity has been reported with BV exposure.24,25 Thus, although other factors likely led to the fatal outcome in this case, further investigations using ALK inhibitors and BV for similar cases should be monitored closely for lung injury.

Conclusions

This report describes a fatal case of a patient with an aggressive malignant neoplasm with a PRRC2B-ALK fusion and illustrates the clinical challenges raised when tumors demonstrate pathologic ambiguity and rare molecular findings. Ultimately, genomic profiling provided comprehensive diagnostic information, and tumor remission was induced by a combination regimen that included targeted therapy based on molecular findings. It is unclear whether earlier availability of this molecular information could have affected the outcome in this case. As technology advances, it is critical that patients with novel tumors or unique presentations undergo comprehensive molecular evaluations as quickly as possible to facilitate the rapid administration of targeted therapies.

Acknowledgments

We thank the Nationwide Foundation Pediatric Innovation Fund for generously supporting sequencing, data production, and analysis. We acknowledge the Treehouse Childhood Cancer Initiative at the University of California, Santa Cruz Genomics Institute. All patients or their guardians provided written informed consent for genomic sequencing, and all research was performed in accordance with the Declaration of Helsinki. This research is under a protocol approved by the Institutional Review Board at Nationwide Children’s Hospital (IRB18-00662). Molecular data from the diagnostic case have been deposited to dbGAP (accession no. phs001820.v1.p1) under submitter: Institute for Genomic Medicine Clinical Laboratory, Nationwide Children’s Hospital. Details are provided in the Methods. The PRRC2B-ALK fusion has been submitted to ClinVar (accession no. SCV001499894).

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Submitted March 15, 2021; final revision received May 3, 2021; accepted for publication May 3, 2021.

Author contributions: Data analysis and interpretation: Schieffer, Koo, Cottrell, Mardis. Manuscript writing – original draft: Gupta. Manuscript writing – review and editing: Gupta, Liu, Schieffer, Koo, Cottrell, Roberts, Yeager.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This research was supported by the Diagnostic Immunology Laboratory, Nationwide Children’s Hospital. Sequencing, data production, and analysis were supported by funding from Nationwide Foundation Pediatric Innovation Fund.

Correspondence: Ajay Gupta, MD, MS, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY 14263. Email: ajay.gupta@roswellpark.org

Supplementary Materials

  • View in gallery

    Tumor burden at diagnosis. Imaging studies (PET/CT on the left; dedicated CT of the abdomen on the right) on presentation show multiple metabolically active mesenteric and omental masses.

  • View in gallery

    Atypical histologic features of the tumor. Pathology of the omental mass biopsy shows an epithelioid tumor with sheets of loosely cohesive epithelioid cells in a myxoid background (left panels, hematoxylin and eosin stain [H&E]; original magnifications, ×100 and ×400). The tumor cells are large with moderate pink cytoplasm and prominent nucleoli and vesicular chromatin. Mitotic figures and apoptotic bodies are easily seen. Inflammatory infiltrates are nearly absent except in rare foci with few infiltrating small mature lymphocytes. By immunohistochemistry, the tumor cells are positive for ALK1 (cytoplasmic), CD30, desmin (rare), smooth muscle actin (SMA; rare), CD138, and epithelial membrane antigen (EMA; patchy) (center and right panels).

  • View in gallery

    Molecular characterization of PRRC2B-ALK fusion and genomic profiling. (A) Sanger sequencing chromatogram of the PRRC2B-ALK fusion. This fusion results in exon 13 of PRRC2B (NM_013318.3) joined to exon 20 of ALK (NM_004304.4). (B) Protein domains corresponding to PRRC2B-ALK fusion. (C) ALK expression for the patient case (red point) compared with our internal cohort of bone and soft tissue sarcomas and those publicly available from the University of California, Santa Cruz Treehouse Initiative. (D) Genome-wide somatic copy number alterations (CNAs). Top plot: Tumor CNA relative to comparator normal in log2 scale. Blue points represent log2 values based on sequence depth in 100-bp windows. Red lines indicate segmented CNA calls. Bottom plot: Tumor variant allele frequency for variants that are heterozygous, nonreference calls in the comparator normal. Points in gold indicate significant loss of heterozygosity. The x axis denotes the chromosome number. (E) Same as D but for chromosome 3.

    Abbreviations: LDLa, low-density lipoprotein receptor domain class A; MAM, meprin, A-5 protein, and receptor protein tyrosine phosphatase μ.

  • View in gallery

    Timeline of events.

    Abbreviations: AKI, acute kidney injury; ALK, anaplastic lymphoma kinase; ARDS, acute respiratory distress syndrome; BV, brentuximab vedotin; CRRT, continuous renal replacement therapy; RA, room air.

  • 1.

    Tsurubuchi T, Nakano Y, Hirato J, et al. Subependymal giant cell astrocytoma harboring a PRRC2B-ALK fusion: a case report. Pediatr Blood Cancer 2019;66:e27995.

  • 2.

    Theilen TM, Soerensen J, Bochennek K, et al. Crizotinib in ALK+ inflammatory myofibroblastic tumors—current experience and future perspectives. Pediatr Blood Cancer 2018;65:e26920.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Fordham AM, Blackburn J, Heyer EE, et al. Targeting CD30 as a novel treatment strategy in RANBP2-ALK-rearranged inflammatory myofibroblastic tumor [abstract]. Cancer Res 2019;79(13 Suppl):Abstract 4824.

    • Search Google Scholar
    • Export Citation
  • 4.

    Fordham AM, Xie J, Gifford AJ, et al. CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma. Br J Cancer 2020;123:11011113.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Straus DJ, Długosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood 2020;135:735742.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Fang H, Langstraat CL, Visscher DW, et al. Epithelioid inflammatory myofibroblastic sarcoma of the ovary with RANB2-ALK fusion: report of a case. Int J Gynecol Pathol 2018;37:468472.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Liu Q, Kan Y, Zhao Y, et al. Epithelioid inflammatory myofibroblastic sarcoma treated with ALK inhibitor: a case report and review of literature. Int J Clin Exp Pathol 2015;8:1532815332.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Connors JM, Ansell SM, Fanale M, et al. Five-year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced-stage classical Hodgkin lymphoma. Blood 2017;130:13751377.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Lowe EJ, Reilly AF, Lim MS, et al. Brentuximab vedotin in combination with chemotherapy for pediatric patients with ALK+ALCL: results of COG Trial ANHL12P1. Blood 2021;137:35953603.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Foyil KV, Bartlett NL. Brentuximab vedotin and crizotinib in anaplastic large-cell lymphoma. Cancer J 2012;18:450456.

  • 11.

    Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 2010;363:17271733.

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