Stem Cell Transplants for Non-Hodgkin’s Lymphoma


In patients with aggressive non-Hodgkin’s lymphoma, early stem cell transplants do not improve the overall survival in high-risk patients, but are beneficial in those patients who are at the highest risk.

Lymphomas are cancers of the lymphocytes, which are a specific group of white blood cells. A particular type of lymphoma known as Non-Hodgkin’s lymphoma is more common than the other general type of lymphoma — Hodgkin lymphoma. There are several different subtypes of non-Hodgkin’s lymphoma. The most common non-Hodgkin’s lymphoma subtypes include diffuse large B-cell lymphoma and follicular lymphoma.

The symptoms of non-Hodgkin’s lymphoma include Non-Hodgkin’s lymphoma symptoms may include: swollen lymph nodes in the neck, armpits or groin, swelling of the abdomen and abdominal pain, Chest pain, coughing or trouble breathing, fatigue (tiredness), fever, night sweats, and weight loss.

The usual treatment for aggressive non-Hodgkin’s lymphoma is a combination of four different chemotherapeutic agents designated as “CHOP,” which stands for Cyclophosphamide (alkylating agent that rituximabdamages DNA), Hydroxydaunorubicin (also called doxorubicin or Adriamycin, also a DNA-damaging agent), Oncovin (vincristine, which binds to microtubules and prevents cells from dividing duplicating by binding to the protein tubulin), and Prednisone or prednisolone (corticosteroids). Recently, many oncologists are adding Rituximab to this drug regimen (but only if the lymphoma is of B-cell origin). Rituximab is a monoclonal antibody that binds to the surface of B-lymphocytes (the very cells that have become cancerous) and facilitates their destruction. This new five-drug regimen, R-CHOP, can drive many patients into remission. However, some relapse and go on to receive stem cell transplants.

This present study, which was directed by Patrick Stiff from the Loyola University Medical Center’s Cardinal Bernardin Cancer Center, was designed to determine if an early stem cell transplant before the patient relapsed increase patient survival. This study examined patients from 40 different clinical sites in the United States and Canada.

397 patients who were in defined groups of high risk or intermediate-high risk of relapsing. After initial chemotherapy treatment, those patients who responded to treatment were randomly assigned to receive an autologous stem cell transplant (125 patients) or to a control group (128 patients) who received three additional cycles of the R-CHOP regimen.

After two years, 69 percent of the transplantation patients had no disease progression, compared with 55 percent of the control group. This is a statistically significant difference, but the two-year survival rates in the transplantation group was 74 percent versus 71 percent in the control group, which was not statistically significant. However, patients in the control group who relapsed were later offered stem cell transplants, which is probably why the differences are not statistically significant.

However, mining the data further reveals something even more interesting. While the stem cell transplants did not improve overall survival among the entire group of high-risk and high-intermediate risk patients, the high-risk patients as an isolated subset rather clearly received a remission and survival benefit from the early stem cell transplants. The two-year survival rate was 82 percent in the stem cell transplant group and 64 percent in the control group, which is statistically significant.

Patrick Stiff and his colleagues concluded: “Early transplantation and late transplantation achieve roughly equivalent overall survival in the combined risk groups.” However, “early transplantation appears to be beneficial for the small group of patients presenting with high-risk disease.”

Stiff hopes that this finding will “trigger discussions between such patients and their physicians as to the feasibility of doing early transplants.”

Patients who receives doses of their own stem cells (so-called autologous stem cell transplants), can tolerate very high doses of chemotherapy and/or radiation. This high-dose treatment kills off many cancer cells, but it also destroys the patient’s immune system. Therefore, prior to the treatment, stem cells are removed from the blood or bone marrow of he patient and infused back into the patient. These stem cells then form a new immune set of immune cells that replace the ones destroyed by the chemotherapy.

Previous studies have shown that patients who undergo autologous stem cell transplants have a higher risk of developing secondary cancers that are caused by the chemotherapy or the radiation. However, this new study did not find a statistically significant difference (11 percent in the control group and 12 percent in the stem cell transplant group) in secondary tumor formation between the two groups.

Stiff and his crew are continuing to crunch the numbers and mine the data. “As years go by, there may be additional analysis that may help fine-tune the results so that we will be able to more carefully and concisely define any potential benefit,” said Stiff.

See Patrick J. Stiff, et al, New England Journal of Medicine 2013; 369(18):1681.

Leukemia Gene is a Key Factor for Nerve Cell Differentiation


Research from the laboratory of Pierre Vanderhaeghen from the Universite’ Libre de Bruxelles has provided a new perspective on brain development and neural stem cell biology.

The cerebral cortex is the most complex structure in the brain. It is the seat of such higher cortical functions as consciousness, learning and memory, emotion, motor control, and language. To execute these functions, the cerebral cortex is composed of an array of cortical neurons, and these cells are adversely affected in cases of neurological or even psychiatric disorders.

According to work from Vanderhaeghen’s laboratory, a gene known as BCL6 is a key element in the development of cortical neurons during development. BCL6 acts as a transcription factor, which is to say that it plays a role in gene expression. In the case of BCL6, this gene product prevents gene expression (functions as a repressor). In the immune system, BCL6 is made in antibody-producing cells (B cells) and it controls the response of B cells to a signaling protein called Interleukin 4 (IL-4). IL-4 drives the differentiation of B cells into antibody-making plasma cells and drives the maturation of plasma cells into those that make distinct types of antibodies. Even more interestingly, BCL6 is frequently abnormal in a blood cancer known as diffuse large B cell lymphoma (DLBCL),

Two members of Vanderhaeghen’s lab discovered BCL6 in a search for genes that modulate the production of new nerve cells from mouse embryonic stem cells. If they overexpressed BCL6 in neural stem cells made from mouse embryonic stem cells, these stem cells transformed en mass into cortical neurons. Because BCL6 is normally known for its role in blood cancers (lymphomas), this BCL6-medicated function was a complete surprise.

Because data from overexpression studies is always suspect without verification, Vanderhaeghen and his colleagues used mouse genetics to confirm the role of BCL6 in the production of cortical neurons. Vanderhaeghen’s team made mutant mice embryos that had lost a functional copy of the BCL6 gene. When these mice developed to the fetal stage, it was clear that they had small cerebral cortexes that consisted of far fewer cortical neurons. Therefore, BCL6 overexpression increases cortical neuron production and the absence of it decreases cortical neuron production. This certainly confirms the role of BCL6 in cortical neuron development.

Next, Vanderhaeghen’s lab determined how BCL6 was influencing the development of cortical neurons. A protein that is encoded by the Notch gene are essential in the self-renewal of neural stem cells. BCL6 works with another protein called SIRT1 to repress the Notch pathway, and this repression moves the progeny of neural stem cells to differentiate into cortical neurons.

Because cortical neurons are the main entities affected by neurological and psychiatric disorders, this understanding of cortical neuron development might provide insights into inherited forms of dementia, behavioral problems or other types of neurological problems. Also, Vanderhaeghen’s work bring together three major players involved in cancer BCL6), aging, Alzheimer’s disease, metabolism and diabetes (SIRT1), and brain and heart development and cancer (Notch). Because these three genes were not know to interact with each other prior to this work, Vanderhaeghen’s findings have opened up a new avenue of possible targets for therapies and model systems for understanding stem cell renewal and differentiation.