Category: Research Publications

Classical Hodgkin Lymphoma Genome Sequenced by Research Team

In a recent study first published online, then as a plenary paper in the February 12 issue of Blood an inter-institutional team of researchers sequenced the genome of classical Hodgkin lymphoma (cHL). This sequencing allowed researchers to study the changes in proteins in individual patients, which could potentially lead to the development of new therapies targeting the cells affected by cHL. Their findings are especially notable as,

“Now we have a better idea of what mutations there are, and going forward therapies can be adapted to specific patient populations according to their genomic composition,” said senior author Dr. Ethel Cesarman, a professor of pathology and laboratory medicine at Weill Cornell Medical College.

Although scientists have sequenced the genomes of many other diseases, the cHL genome has remained elusive due to the difficulty of isolating Reed-Sternberg cells, which usually comprise less than 1 percent of a total cHL tumor. The team employed a technique that separates larger cells and looks at the proteins on their surface, called fluorescence-activated cell sorting, to successfully isolate the Reed-Sternberg cells and sequence the cancer genome, said senior author Dr. Mikhail Roshal, an assistant member in the Department of Pathology at Memorial Sloan Kettering Cancer Center.

These findings could potentially lead to more personalized treatment options for patients with cHL. They exemplify the bench to bedside approach taken by the Lymphoma Program and Meyer Cancer Center. Please look to this space for further updates about lymphoma news and clinical trials.

The Randomness of Cancer and the Implications in Lymphoma

Picture1By Peter Martin, MD

In a study recently published in the journal Science, researchers Bert Vogelstein and Christian Tomasetti at Johns Hopkins University sought to explain why some tissues give rise to human cancers more often than others. Using existing data, the researchers found that the lifetime risk of cancer was strongly correlated with increased numbers of stem cell divisions. In recent years, basic scientists have provided more information about the size of the stem cell compartment and the frequency of stem cell mutations in various tissue types. Vogelstein and Tomasetti used the existing literature to plot the total number of stem cell divisions against the lifetime risk of cancer in 31 tissue types, finding an essentially linear correlation.

Adult stem cells are specialized cells that are capable of cell division without differentiation and are required to regenerate and repair tissue. For example, bone marrow stem cells are required to maintain stable levels of red blood cells, white blood cells, and platelets over a lifetime. Scientists have long known that the process of DNA replication, essential for cell division, is prone to errors, and that random genetic changes are more likely to accumulate in tissues where cells divide more frequently. Since cancer is likely a result of errors in DNA replication, it follows that cancer is more likely to occur in tissues that have a lot of stem cells and in tissues with more frequent stem cell divisions; i.e., the probability of a cancer randomly developing in a specific tissue is proportional to the total number of stem cell divisions in that tissue. The work by Vogelstein and Tomasetti strongly supports this hypothesis.

Compared to other cancers, lymphomas are unique because they arise from cells that undergo additional stages of replication beyond the stem cell compartment. Moreover, during these additional periods of lymphocyte replication, DNA mutation is encouraged to occur at a rate unlike that seen in any other cell. We all benefit from the ability of our normal lymphocytes to evolve as they mature—our immune systems will have the capacity to fight infections that have not even been invented yet. However, as a result of changes to DNA in the stem cell compartment, the bone marrow, and the lymph nodes, we are also constantly at risk of accumulating mutations that predispose us to lymphoid malignancies. Unremarkably, these mutations appear to be quite common. For 20 years lymphoma researchers have recognized that a substantial proportion of the population has circulating lymphocytes that have acquired genetic changes during normal periods of maturation in the bone marrow that predispose us to various types of lymphoma . These findings support the concept that the number of cell divisions with associated DNA replication and mutation is proportional to the incidence of neoplasms arising from a given tissue.

Despite the apparent randomness of cancer, it is probably not accurate to assume that all cancers, and especially not all lymphomas, are explained solely by bad luck. For example, the normal immune system appears to play a major role in the emergence of lymphomas. People with inherited or acquired immunodeficiencies are predisposed to some lymphomas while people with overactive, auto-reactive immune systems (e.g., rheumatoid arthritis, Sjogren’s syndrome, ulcerative colitis) are predisposed to others, while still other people may be at increased risk for lymphoma as a result of viral or bacterial infections. Some lymphomas appear to cluster in families or races, suggesting a potentially heritable trait. Some lymphomas appear to cluster geographically, suggesting potential environmental factors. There may be a role for behaviors like exercise or diet. Even height has been associated with increased risk for lymphoma. Ambinder and colleagues from Emory have written an excellent review exploring risk factors for follicular lymphoma.

In their recent report, Vogelstein and Tomasetti found a creative way to use existing data to lend strong support to a widely held hypothesis. It is exciting to think what other answers might already exist in current literature, just waiting for a creative mind to ask the right question.

A New Era of Immunotherapy in Lymphoma: Nivolumab and Pembrolizumab Give New Hope to People with Lymphoid Malignancies

Picture1By Peter Martin, MD

Nivolumab and pembrolizumab are members of a class of drugs known as immune checkpoint inhibitors. Both drugs are monoclonal antibodies that bind to and inhibit the programmed death 1 receptor (PD-1) on the surface of T-cells, thereby improving the ability of the immune system to fight against cancer. The concept is especially attractive because it capitalizes on the ability of the immune system to fight cancer rather than relying on drugs that are toxic to cancer cells. Both drugs (as well as other immune checkpoint inhibitors) have demonstrated significant promise in various solid tumors (e.g., melanoma) but are only now entering the world of lymphoma. On December 7, during a morning session at the 56th annual meeting of the American Society of Hematology, we saw some early evidence of the promise that this class of drugs represents.

In the first abstract, Dr. Philippe Armand presented preliminary results from a phase I trial of nivolumab in patients with previously treated Hodgkin lymphoma (HL). These results were simultaneously published in the New England Journal of Medicine and led the FDA to grant nivolumab the breakthrough therapy designation for patients with relapsed/refractory HL. A total of 23 patients with relapsed or refractory HL were enrolled on the trial and every patient experienced reduction of tumor burden, including 70% achieving a partial response and 17% experiencing a complete response. Of the 18 patients who had previously received brentuximab vedotin, the overall response rate was 89%. Longer follow up will be required to better estimate the duration of benefit.

In a second abstract, Dr. Alexander M. Lesokhin presented the results from the same phase I trial of nivolumab in patients with relapsed or refractory lymphoid malignancies, including B-cell and T-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). The overall response rate in patients with B-NHL was 28%, including 40% of patients with DLBCL. Nivolumab appeared less promising in patients with T-NHL and MM.

In a final abstract Dr. Craig H. Moskowitz presented preliminary results from a phase I trial with pembrolizumab in patients with Hodgkin lymphoma after failure of brentuximab vedotin. Almost 70% of patients had also previously received prior autologous stem cell transplantation and the median number of prior therapies was 4. The reported response rate was 53%, including a 20% complete response rate.

The results from these trials confirm the activity and safety of anti-PD-1 antibodies in patients with Hogkin and non-Hodgkin lymphomas. For information regarding ongoing trials at Weill Cornell Medical College with nivolumab for treatment of Hodgkin and non-Hodgkin lymphomas, follow the links for Hodgkin lymphoma, follicular lymphoma, and DLBCL, or contact us at (212) 746-1362. Look to this space for more news concerning nivolumab.