Richter’s Syndrome

Richter’s Syndrome (RS), also known as Richter’s Transformation, is a rare complication of Chronic Lymphocytic Leukaemia (CLL) and/or Small Lymphocytic Lymphoma (SLL).

It is characterised by the sudden transformation of the CLL/SLL into a significantly more aggressive form of large cell lymphoma.

Richter’s Syndrome occurs in approximately 2-10% of all CLL/SLL patients during the course of their disease. In the most cases the normally slow growing, or indolent, CLL transforms into a common type of non-Hodgkin lymphoma (NHL) known as Diffuse Large B-Cell Lymphoma (DLBCL). Rarer cases transform into Hodgkin lymphoma(HL)/Hodgkin Disease (HD), and some types of T-cell lymphomas also have been reported.

How does Richter’s Syndrome affect the body?

The most common symptoms of Richter’s Syndrome arise from a sudden and dramatic increase in the size of lymph nodes (also known as ‘lymphadenopathy’) characterised by usually painless areas of swelling in the neck, axilla, abdomen (most commonly in the spleen, also known as ‘splenomegaly’) or groin. Patients also often experience a dramatic increase in unexplained weight loss, fevers and night sweats (often collectively referred to as ‘B-symptoms’).

Other signs and symptoms may include low haemoglobin (anaemia) characterised by:

• increasing fatigue
• shortness of breath
• dizziness and possible palpitations
• low platelets (thrombocytopaenia) characterised by excessive bruising or bleeding
• an increase in serum lactate dehydrogenase (LDH) or elevated serum calcium (hypercalcaemia) on routine blood tests.

It is important to note that whilst some of these signs and symptoms may already be present to a lesser degree in people with previously diagnosed CLL/SLL, the possibility of Richter’s Syndrome needs to be considered if there is a sudden and dramatic increase in these symptoms, which is not generally considered to be a typical feature of normally relatively indolent CLL/SLL disease.

Richter’s syndrome is a serious complication of CLL/SLL and unfortunately is often fatal. If Richter’s syndrome is diagnosed, it is advised that the person should seek recommended treatments, but also to get their lives in order to prepare for any outcome. You may wish to discuss an advanced health directive with your treatment team, to let them and your family know how you would like your health to be managed if your treatments are not successful.

Who does Richter’s Syndrome commonly affect?

Richter’s Syndrome affects approximately 2-10% of patients with a prior diagnosis of CLL/SLL and can occur at any time throughout the course of the disease.

Do we know what causes Richter’s Syndrome?

While the exact causes of Richter’s Syndrome remain unclear, certain factors are thought to increase the risk of developing RS in patients already diagnosed with CLL/SLL. These risk factors include:

• certain inherited genetic characteristics (e.g., BCL-2, CD38, LRP4 genotypes)
• specific genetic mutations
• biological characteristics and clinical features in the CLL cells, often associated with poorer prognostic/more aggressive CLL/SLL disease.

For example, patients harbouring 11q and 17p chromosome deletions, un-mutated IGVH gene, NOTCH -1 mutations, shortened telomere length, elevated zeta associated protein (ZAP-70) beta 2 microglobulin (B2M) and CD38 levels and/or with advanced stage disease at first CLL diagnosis (Rai Stage III-IV with lymph nodes >3 cm) are all thought to be at a greater risk of developing RS. The exact relationship between these various factors and the actual risk of developing RS is yet to be determined and is the subject of ongoing investigation.

How is Richter’s Syndrome diagnosed?

The definitive or differential diagnosis of Richter’s Syndrome is achieved by an excisional biopsy or CT/ultrasound guided core needle biopsy of an enlarged lymph node that is thought to be indicative of the Richter’s transformation. This biopsy is crucial to the accurate diagnosis of RS as it allows clinicians to differentiate between a simple progression of an existing CLL/SLL and a transformation into a more aggressive form of large cell lymphoma, e.g., DLBCL/HD etc. which is the defining feature of RS. The selection of the most appropriate lymph node for biopsy is also crucial. Imaging studies using CT/PET scans often are used to assess the exact extent of widespread lymphadenopathy, thought to indicate RS and also to select the most appropriate lymph node for biopsy.

The biopsied lymphatic tissue is then assessed for various molecular, genetic and morphological abnormalities to distinguish it from the pre-existing CLL/SLL. Flow cytometry is used to assess specific cell surface antigens (also known as ‘cluster differentiation’ or CD markers). In some cases a bone marrow biopsy and trephine (BMA/T) may be considered to assess possible presence of the lymphoma cells in the bone marrow, and/or a lumbar puncture if infiltration of the lymphoma cells into the cerebral spinal fluid is suspected. This process allows clinicians to classify the exact sub-type, grade, and stage of the specific lymphoma in question and, hence, consider the best possible treatment options.

How is Richter’s Syndrome treated?

The treatment for Richter’s Syndrome depends upon the exact sub-type of lymphoma in question, as revealed by the diagnostic excisional or core biopsy. In most RS cases, transformation to DLBCL is confirmed. The current standard first-line treatment for this type of lymphoma is the immuno-chemotherapy using a combination of chemo drugs and a targeted anti-CD 20 monoclonal antibody. Other second-line chemotherapy regimens often used to treat this type of lymphoma (if non-responsive or ‘refractory’ to R-CHOP) include R-ICE, D-HAC, R-DHAP, GIVE, etc. If Hodgkin lymphoma is confirmed, the current first-line is combination chemotherapy alone. Stem cell transplant using a patient’s own stem cells (autologous) or a sibling or unrelated donor (allogeneic) stem cells may also be considered in some patients if deemed clinically appropriate.

Several newer, targeted oral therapies and monoclonal antibodies for the treatment of some types of NHL and/or poorer prognostic CLL are currently showing very promising results in clinical trials and may soon become available for use in the clinical setting. While their possible role in the treatment of RS is potentially promising, it is yet to be fully understood and will be the subject of further investigation.