crizotinib and Lymphoma--Non-Hodgkin

Pediatric patients with newly diagnosed, non-Hodgkin Lymphoma (NHL) have an excellent overall survival. However, therapy regimens are associated with acute toxicity and late effects. Furthermore, patients with relapsed or refractory disease have relatively few options with proven clinical benefit. Both histologic and molecular differences exist between adult and pediatric NHL preventing simple translation of adult NHL successes into improvements in pediatric NHL treatment. This review summarizes the introduction of targeted therapies into frontline treatments for patients with anaplastic large-cell lymphoma and CD20-positive tumors, with the goal of improving overall survival while limiting both short- and long-term toxicities. In addition, newer approaches that have limited data in children but may have a significant role in how we treat pediatric NHL in the future are reviewed, which include CD19 directed therapy, Notch inhibition, the tri-functional antibody, FBTA05, and EZH2 inhibition.

Topics: Adult; Antibodies, Bispecific; Antigens, CD19; Antigens, CD20; Brentuximab Vedotin; Child; Crizotinib; Disease-Free Survival; Enhancer of Zeste Homolog 2 Protein; Humans; Immunoconjugates; Immunoglobulin G; Lymphoma, Large-Cell, Anaplastic; Lymphoma, Non-Hodgkin; Medical Oncology; Polycomb Repressive Complex 2; Pyrazoles; Pyridines; Treatment Outcome

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that affects a number of biological and biochemical functions through normal ligand-dependent signaling. It has oncogenic functions in a number of tumors including non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma, and neuroblastoma when altered by translocation or amplification or mutation. On August 2011, a small molecule inhibitor against ALK, crizotinib, was approved for therapy against NSCLC with ALK translocations. As we determine the molecular heterogeneity of tumors, the potential of ALK as a relevant therapeutic target in a number of malignancies has become apparent. This review will discuss some of the tumor types with oncogenic ALK alterations. The activity and unique toxicities of crizotinib are described, along with potential mechanisms of resistance and new therapies beyond crizotinib.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Lymphoma, Non-Hodgkin; Models, Genetic; Mutation; Neuroblastoma; Oncogene Proteins, Fusion; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Translocation, Genetic

Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Crizotinib; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Lymphoma, Non-Hodgkin; Male; Middle Aged; Molecular Targeted Therapy; Prospective Studies; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome