Richter’s Syndrome

Richter transformation, Richter’s transformation

Richter’s syndrome is a rare but serious complication where chronic lymphocytic leukemia transforms rapidly into a more aggressive form of cancer, usually an aggressive type of lymphoma, requiring immediate medical attention and specialized treatment.

Table of contents

• What is Richter’s Syndrome?
• How Common is This Condition?
• Symptoms and Warning Signs
• Causes and Risk Factors
• Getting Diagnosed
• Treatment Options
• Outlook and Survival

What is Richter’s Syndrome?

Richter’s syndrome, also called Richter’s transformation, is a rare and serious complication that can develop in people who have chronic lymphocytic leukemia (CLL), which is a type of cancer that affects white blood cells and bone marrow^[1]. This condition occurs when CLL suddenly changes into a much more aggressive form of cancer^[2].

In most cases, the transformation leads to a fast-growing type of non-Hodgkin lymphoma called diffuse large B-cell lymphoma (DLBCL). Around 90 out of 100 cases (around 90%) of Richter’s syndrome transform into DLBCL^[2]. Less commonly, about 10 out of 100 cases (around 10%) transform into Hodgkin lymphoma^[2]. Rarely, CLL can transform into other types of cancer such as prolymphocytic leukemia, lymphoblastic lymphoma, or even acute leukemia^[3].

The condition was first described by Maurice Richter in 1928, though it became known as Richter’s syndrome in 1964^[3]. Most often, Richter’s transformation happens in someone already diagnosed with CLL, but doctors can sometimes diagnose it in someone who hasn’t had a previous CLL diagnosis^[2].

How Common is This Condition?

Richter’s syndrome is quite rare. Between 2 and 10 out of every 100 people (2-10%) with CLL develop Richter’s syndrome during the course of their disease^[2][4]. The transformation occurs at a rate of about 0.5% to 1% per year^[5].

One study from 2022 that looked at data from over 74,000 people with CLL found a transformation rate of about 0.7%. However, different studies have reported rates ranging from about 1% to 23%, depending on the population studied^[4]. The number of people with this condition is growing because advances in CLL treatment mean that more people are living longer^[14].

Symptoms and Warning Signs

The transformation from CLL to Richter’s syndrome can happen quickly, and you might become unwell quite suddenly^[2]. The most common symptom is the sudden appearance of rapidly growing lymph nodes, which are bean-shaped glands that are part of your immune system^[5]. You may notice swelling in your neck, abdomen (often involving the spleen), armpit, or groin^[4].

Other symptoms that people with Richter’s syndrome commonly experience include:

• Fever that isn’t caused by an infection^[2]
• Drenching night sweats^[5]
• Unexplained weight loss^[2]
• Sickness or stomach pain, caused by an enlarged spleen^[2]
• Worsening fatigue or tiredness^[4]
• Shortness of breath^[4]
• Dizziness^[4]

While some of these symptoms are associated with CLL itself, a sudden or dramatic worsening of them can signal the development of Richter’s syndrome^[5]. Healthcare professionals may also discover increases in certain blood markers, such as serum lactate dehydrogenase (an enzyme that can indicate tissue damage) or elevated calcium levels in the blood^[4].

Causes and Risk Factors

The exact cause of Richter’s syndrome is unclear and may involve several factors^[4]. Doctors and scientists don’t fully know what causes CLL to transform into this more aggressive condition^[5]. However, research suggests the transformation may be triggered by a viral infection, such as Epstein-Barr virus, or by the buildup of genetic changes in cancer cells that lead to a more aggressive form of disease^[9].

Recent studies have identified important genetic changes that play a role in the transformation from CLL to Richter’s syndrome. These include loss of CDKN2A, disruption of TP53, activation of C-MYC, and mutations in NOTCH1^[3][20].

Several risk factors have been identified that may increase the chance of developing Richter’s syndrome:

• Previous treatment for CLL^[5]
• Advanced stage of CLL at diagnosis (such as Rai stage III or IV)^[20]
• Loss of a section of chromosome 17p in tumor cells^[5]
• Loss of a section of chromosome 11q in tumor cells^[20]
• An abnormal Notch protein in tumor cells^[5]
• Certain biological features of CLL cells, such as being positive for markers called ζ-associated protein-70 (ZAP-70), CD38, or CD49d^[20]
• Unmutated IGHV gene status^[3]
• Certain inherited genetic characteristics, including LRP4, BCL-2, or CD38 genotypes^[4]

Getting Diagnosed

Most people contact their doctor because they have developed new symptoms or have noticed a sudden worsening of existing symptoms^[2]. Since the same symptoms can be caused by infections or other conditions, patients with these symptoms should be evaluated by a doctor^[5].

If Richter’s syndrome is suspected, several tests may be performed:

PET-CT scan: A PET scan (positron emission tomography) combined with a CT scan can detect areas of increased activity in the body and help doctors determine which lymph node should be examined more closely^[5]. The scan shows FDG-avid (actively growing) lymph nodes with high standardized uptake values (SUV), which suggest aggressive disease^[3].

Lymph node biopsy: An excisional lymph node biopsy is considered the gold standard for diagnosis^[20]. During this procedure, a doctor removes part or all of a swollen lymph node and sends it to a laboratory. A specialist examines the tissue under a microscope to see if the CLL has transformed into a more aggressive type of lymphoma and to identify what specific type it is^[2].

Blood tests: Various blood tests may be performed to look for changes in blood cell counts and markers of disease activity^[2].

Bone marrow biopsy: A sample of bone marrow may be taken to examine the cancer cells more closely^[2].

Treatment Options

Unfortunately, Richter’s syndrome means your CLL has changed into a fast-growing lymphoma that can be difficult to treat^[2]. The treatment depends on several factors, including what type of lymphoma you develop, whether you have certain genetic changes in your cancer cells, and your general health^[2].

The goal of treatment is to generate remissions that make patients eligible for a stem cell transplant or other consolidation therapy, which holds the potential for long-term survival^[5].

Standard first-line treatment: The most common initial treatment is a chemotherapy combination called R-CHOP, which includes the drugs rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone^[5]. This treatment combines chemotherapy (drugs that kill cancer cells) with immunotherapy (treatment that helps your immune system fight cancer)^[2].

Combination approaches: Researchers have tested adding newer targeted drugs to standard chemotherapy. One approach combines the EPOCH-R chemotherapy regimen with venetoclax, a targeted drug. While this combination produced promising results in achieving complete remissions, it also caused significant side effects^[5].

Clinical trials: Several new treatment combinations are being studied in clinical trials, including:

• Copanlisib (a drug targeting the PI3K protein) combined with nivolumab (an immunotherapy agent)^[5]
• The PI3K inhibitor duvelisib combined with venetoclax^[5]
• Bispecific T cell engagers, which are drugs that help immune cells find and attack cancer cells^[9]

CAR T-cell therapy: Some patients who don’t achieve remission with standard chemotherapy may be treated with CAR T-cell therapy, which uses genetically modified versions of a patient’s own immune system cells to generate a powerful attack on lymphoma cells^[5].

Stem cell transplant: A stem cell transplant is currently the only therapy associated with long-term survival for Richter’s syndrome^[5]. This procedure should be considered for appropriate patients who achieve remission with initial treatment^[2].

Outlook and Survival

Richter’s syndrome is generally associated with a negative outlook^[4]. This is essentially a disease of older age, with a median survival with conventional chemotherapy of less than six months^[3]. For patients with the type of Richter’s syndrome that is clonally related to their original CLL (about 80% of cases), the median survival is approximately one year^[20].

However, outcomes vary depending on several factors. According to a 2020 study of over 200 people, individuals with the best outlook had cases of untreated CLL before their diagnosis of Richter’s syndrome^[4]. About 20% of patients have what’s called clonally unrelated DLBCL, meaning the aggressive lymphoma is not directly related to their CLL. These patients have a prognosis similar to people with DLBCL who never had CLL^[20].

While standard chemotherapy approaches are often successful in producing remissions, these remissions tend not to be long-lasting^[5]. Improvements in the outcome of patients with Richter’s syndrome may come from a more comprehensive understanding of how the disease develops, which could allow doctors to target treatments against specific abnormalities in the cancer cells^[3].

Researchers are currently conducting studies to better understand Richter’s syndrome and develop new treatment approaches that show promise of improving outcomes for patients^[5].