Xalkori (crizotinib) is being investigated as a treatment for certain types of non-Hodgkin lymphoma (NHL), including anaplastic large cell lymphoma (ALCL). Xalkori is developed by Pfizer and already has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALK-positive non-small cell lung cancer (NSCLC).
How Xalkori works
NHL is a type of blood cancer, caused by the abnormal behavior of a type of white blood cell called a lymphocyte. In ALCL, a type of lymphocyte called a T-cell starts to multiply uncontrollably and can build up to form tumors in different parts of the body.
About 50 percent of ALCL tumors are classified as ALK-positive. In this type of tumors, there is a mutation in the anaplastic lymphoma kinase (ALK) gene. ALK is a receptor tyrosine kinase, a protein that normally is found only on the surface of cells in the nervous system. When activated, it triggers signaling pathways that can affect the growth and development of the cell.
The mutation leads to the movement of pieces of DNA that make up the ALK gene to become attached to a second gene and results in the formation of a fusion protein. This fusion protein is expressed on the surface of cancer cells and is abnormally active, resulting in the increased proliferation of cancerous cells.
Xalkori is a receptor tyrosine kinase inhibitor. It can block the signal transmission from multiple proteins, including ALK. By stopping ALK from working it is hoped that the drug will reduce or stop the growth of the cancer cells, and cause their death.
Xalkori in clinical trials for lymphoma
Xalkori has been investigated in several clinical trials as a treatment for both adult and pediatric lymphoma patients, and more are ongoing.
Xalkori in clinical trials for adult lymphoma
Researchers at The University of Milano Bicocca reported positive results from lymphoma patients treated with Xalkori. They reported their findings in a short correspondence, published in the New England Journal of Medicine, describing the experiences of two ALK-positive ALCL patients, ages 26 and 20 years, who were given Xalkori. Both patients previously had tried and failed multiple other therapies. Following one month of treatment with Xalkori, they both achieved remission and were still in remission after six and five months of treatment, respectively.
Following treatment, these two patients were enrolled into a Phase 2 open-label pilot study (NCT02419287), run by the University of Milano Bicocca. The trial aims to test the effectiveness and safety of Xalkori following a relapse or where the cancer is resistant to standard therapy. So far, a total of 11 patients with ALCL of diffuse large B-cell lymphoma (DLBCL) have been recruited for the trial. Patients will be monitored for side effects for a five-year period and the effectiveness of the treatment will be assessed through the response rate, the duration of the response, and other measures, such as the effect of the drug on the patients’ quality of life.
Preliminary results from the trial have been published in the Journal of the National Cancer Institute. Ten of the eleven patients responded to Xalkori treatment, and at a two-year follow-up, the overall survival rate was 72.7 percent. The progression-free survival, where the disease has not worsened significantly, is at 63.7 percent. These results suggest that Xalkori could be effective in patients who previously received other cancer treatment.
Xalkori in clinical trials for pediatric lymphoma
A Phase 1/2 clinical trial (NCT00939770) aims to find a safe and effective dose of Xalkori to treat young patients (21 years or younger) with relapsed or drug-resistant ALCL, as well as solid or central nervous system tumors. The trial is being carried out as a collaboration between the Children’s Oncology Group and the U.S. National Cancer Institute (NCI).
The results from the dose escalation portion of the study, published in the scientific journal The Lancet Oncology, suggested that Xalkori could have an anti-tumor effect in ALCL. Seven out of nine ALCL patients given Xalkori achieved a complete response, where there was no sign of cancer.
Further results from the trial have been published recently in the Journal of Clinical Oncology. In total, 26 patients with ALCL were given a high (280mg/m2) or a low (165mg/m2) dose of Xalkori. The results are positive, with overall response rates of 83 percent and 90 percent for the low and high doses, respectively. The drug appeared to be well-tolerated with an acceptable safety profile. The most common side effect seen was a decrease in neutrophil count (a type of blood cell).
The Children’s Oncology group also is recruiting for a second open-label Phase 1 clinical trial (NCT01606878), assessing Xalkori in combination with standard chemotherapy in pediatric ALCL patients. This is to combat the potential damaging effect that Xalkori could have on the development of the young patients.
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