What Is Richter Syndrome?

One Blood Cancer Type Transforms Into Another

What is meant by Richter's syndrome?. Istockphoto.com/Stock Photo©jarenwicklund

Richter’s Syndrome (RS), also known as Richter’s transformation, refers to the transformation of one specific blood cancer type into a different, more aggressive type.

RS refers to the development of high-grade non-Hodgkin lymphoma in a person who has chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Other variants of RS are also known to occur, such as transformation to Hodgkin lymphoma.

An explanation of these terms and their significance follows.

Overview

RS develops in someone who already has a cancer of the white blood cells. This first cancer has two different names, depending on where in the body the cancer is found: It's called CLL if the cancer is mostly found in the blood and bone marrow, or SLL if found mostly in the lymph nodes.

CLL is used to cover both entities, going forward in this article.

Not Everyone with CLL Develops Richter Syndrome

The development of RS in people with CLL is relatively uncommon. Estimates published in 2016 are that Richter’s transformation occurs in only about 5 percent of patients with CLL. Other sources cite a range between 2 and 10 percent. If RS does happen to you, it is very unusual that it would occur at the same time the CLL is diagnosed. People who develop RS from CLL commonly do so several years after the CLL diagnosis.

The New Cancer Behaves Aggressively

The new cancer occurs when a person with CLL goes on to develop what’s known as a transformation, most often to a high-grade non-Hodgkin lymphoma (NHL). "High grade" means the cancer tends to grow more rapidly and be more aggressive. Lymphoma is a cancer of the lymphocyte white blood cells.

According to one study, about 90 percent of transformations from CLL are to a type of NHL called diffuse large B-cell lymphoma (DLBCL), while about 10 percent transform to Hodgkin lymphoma.

It is actually termed "Hodgkin variant of Richter syndrome (HvRS)" in that case, and it is not clear whether the prognosis is any different. Other transformations from CLL are also possible.

Why is it Called Richter Syndrome?

A man named Maurice N. Richter first described the syndrome in 1928. He wrote about a 46 year old shipping clerk who was admitted to the hospital and had a progressively downward course leading to death. In the autopsy analysis, he determined that there had been one previously existing malignancy but that from it, an new malignancy seemed to have sprung that was more rapidly growing and encroached upon and destroyed the tissue that had been the old CLL.

He theorized that the CLL had existed for much longer than anyone knew about in this patient, also writing about the two cancers, or lesions, stating, “It is possible that the development of one of the lesions was dependent on the existence of the other.”

Characteristics

People with RS develop aggressive disease with rapidly enlarging lymph nodes, enlargement of the spleen and liver, and elevated levels of a marker in the blood known as serum lactate dehydrogenase, or LDH.

Survival Rate

As with all lymphomas, survival statistics can be hard to interpret.

Individual patients differ in their general health and strength prior to their diagnosis. Additionally, even two cancers with the same can behave very differently in different individuals. With RS, however, the new cancer is more aggressive. In some people with RS, survival has been reported with a statistical average of less than 10 months from diagnosis. However, some studies have shown 17 months average survival, and other people with RS may live longer; stem-cell transplantation may offer a chance for prolonged survival.

Signs and Symptoms 

If your CLL has transformed to DLBCL, you will notice a distinct worsening of your symptoms.

The characteristics of RS include rapid tumor growth with or without extranodal involvement—that is, new growths may be confined to the lymph nodes, or the cancer may involve organs other than the lymph nodes, such as the spleen and liver.

You may experience:

Risk Factors for Transformation

The risk of developing RS from CLL is not related to the stage of your leukemia, how long you have had it, or the type of response to therapy you have received. In fact, scientists do not fully understand what actually causes the transformation.

Recently, some studies have revealed that patients whose CLL cells show a specific marker called ZAP-70 may have an increased risk of transformation. Other markers such as patients having NOTCH1 mutations at diagnosis have been of research interest. Still other studies have suggested that younger CLL patients—that is, younger than 55 years of age—may have an increased risk as well.

Another theory is that it is the prolonged length of time with a depressed immune system from CLL that causes the transformation. In other types of patients who have had decreased immune function for a long time, such as in human immunodeficiency virus (HIV) or in people who have had organ transplants, there is also an increased risk of developing NHL.

Whatever the case may be, it does not appear that there is anything you can do to cause or prevent your CLL from transforming.

Treatment and Prognosis 

Treatment of RS usually involves chemotherapy protocols that are commonly used for NHL. These regimens have typically produced overall response rates of about 30 percent. Unfortunately, the average survival with regular chemotherapy is less than six months after RS transformation. New therapies and combinations are continually being tried in clinical trials, however.

In recent years, studies have investigated the use of Fludarabine chemotherapy protocols as they have been shown to improve outcomes in patients with complicated CLL. The average survival with this type of chemotherapy was increased to 17 months in one study.

Something else that is underway is the use of ofatumumab -- a fully human anti-CD20 monoclonal antibody that targets a unique tag on B lymphocytes. The CHOP-O study is evaluating the safety, feasibility and activity of a CHOP chemotherapy in combination with ofatumumab in induction and subsequent maintenance for patients with newly diagnosed RS. On interim analysis, more than 7 of the first 25 participants achieved a complete or partial response after six cycles of CHOP-O.

Some smaller studies have looked at the use of stem cell transplant to treat this population. Most of the patients in these studies had received a lot of prior chemotherapy. Of the types of stem cell transplants that were tested, non-myeloablative transplant had less toxicity, better engraftment, and a possibility of remission. Further studies will be needed to see if this is a viable option for RS patients.

Future Research

In order to improve survival in patients with RS, scientists need to gain a better understanding of what causes the transformation from CLL to occur. With more information about RS at a cellular level, better targeted therapies could be developed against those specific abnormalities. However, experts caution that since there are a number of complicated molecular changes associated with RS, there may not ever be a single “all-purpose” targeted treatment, and that any of these medications would likely need to be combined with regular chemotherapy to get their best effect. As scientists unfold the causes of RS, they are seeing that RS is not a single uniform or consistent process.

In the meantime, patients who have had their CLL transform to RS are encouraged to enroll in clinical studies in the effort to improve treatment options and outcomes from the current standards.

Sources:

Richter, M. Generalized reticular cell sarcoma of the lymph nodes associated with lymphatic leukemia. The American Journal of Pathology. 1928;4;4. 285-292.

New Developments in Richter Syndrome. Eyre TA, Clifford R, Roberts C, et al. Single arm NCRI phase II study of CHOP in combination with Ofatumumab in induction and maintenance for patients with newly diagnosed Richter’s syndrome. BMC Cancer. 2015;15:52.

Rossi D, Gaidano G. Richter syndrome. Adv Exp Med Biol. 2013;792:173-91.

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