It is important to know all you can about your enemy

Most of us who have been around the CLL scene for a couple of years have heard of Richter’s syndrome.  Development of Richter’s syndrome carries with it ominous risks and it is a subject we cannot ignore.  Early and accurate diagnosis followed by prompt treatment greatly improves chances of survival. One more case where what you (and your oncologist) do not know can kill you.

Below are the abstracts of two state-of-the-art papers from very credible researchers, published in the last week or so.  I found some of the comments a little startling and I would like to share them with you.  They also shed light on profiles of patients who are more at risk of developing Richter’s syndrome.  If you want to read the full text of these articles send me a personal email and I will try to help you locate them.

What is Richter’s syndrome?

CLL and some types of NHL are called indolent leukemia and lymphoma respectively.  In other words, both of these cancers are slow growing and most patients have one or more years before they need therapy.  Under a microscope the cancerous B-cells in both cases are seen to be small and rather non-descript, with clear cell boundaries. 

Both the clinical progression of CLL (slow) and the appearance of the cells (small, well defined cells) set it apart from a far more dangerous and fast growing lymphoma called DLBCL (diffuse, large B-cell lymphoma).  As the acronym points out, under a microscope the cell type of DLBCL is seen to be large B-cells with diffuse cell boundaries.  It is still B-cells that are cancerous, but DLBCL is a very different from CLL.  This one has fangs and it is a very dangerous beast. When a patient with CLL starts showing symptoms of aggressive lymphoma – usually  DLBCL, he is said to have undergone Richter’s transformation – named after  Maurice Richter who first described this in 1928.

What causes Richter’s transformation?

The frank answer is that we do not yet know.

There are two ways in which DLBCL can happen.  First, it can show up on the scene as an entirely new cancer.  By now you should know that CLL patients are more at risk of getting secondary cancers.  Skin cancer is a prime example, but it is by no means the only secondary cancer that can happen as a result of the poor immune surveillance baked into the cake of CLL patients.  When DLBCL shows up as a second cancer, a new clone that does not originate from the original CLL clone, it is called “de-novo” DLBCL (just a fancy way of saying it is a brand new cancer)

The other way in which DLBCL can happen is if your CLL cells pick up additional chromosomal abnormalities and morph into these large diffuse B-cells typical of DLBCL.  When this happens the newly formed DLBCL cells share a lot of genetic features in common with the original CLL clone and this can be identified in the lab. Majority of DLBCL cases are of this variety, where the DLBCL cells are transformed CLL cells – hence the name Richter’s transformation.

Hematol Oncol. 2009 Mar;27(1):1-10.

Richter syndrome: molecular insights and clinical perspectives.

Rossi D, Gaidano G.

Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont and Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy.

Richter syndrome (RS) represents the clinico-pathologic transformation of chronic lymphocytic leukaemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). The clinical definition of RS is heterogeneous, and encompasses at least two biologically different conditions: (i) CLL transformation to a clonally related DLBCL, that accounts for the majority of cases; (ii) development of a DLBCL unrelated to the CLL clone. In clonally related RS, the pathogenetic link between the CLL and the DLBCL phases is substantiated by the acquisition of novel molecular lesions at the time of clinico-pathologic transformation. RS is not a rare event in the natural history of CLL, since the cumulative incidence of RS at 10 years exceeds 10%. Prompt recognition of RS is known to be clinically useful, and may be favoured by close monitoring of CLL patients harbouring clinical and/or biological risk factors of RS development. Conventional risk factors that are independent predictors of RS development at the time of CLL diagnosis include: (i) expression of CD38; (ii) absence of del13q14 and (iii) lymph node size > or =3 cm.Other risk factors of RS development include CD38 genotype and usage of specific immunoglobulin variable genes. The molecular pathogenesis of RS has been elucidated to a certain extent. Acquisition of TP53 mutations and/or 17p13 deletion is a frequent molecular event in RS, as it is in other types of transformation from indolent to aggressive B-cell malignancies. Additional molecular alterations are being revealed by genome wide studies. Once that transformation has occurred, RS prognosis may be predicted by the RS score, based on performance status, LDH, platelet count, tumour size and number of prior therapies.Depending on patient’s age and RS score, the therapeutic options for RS may range from conventional immunochemotherapy to allogeneic bone marrow transplantation.

Copyright 2009 John Wiley & Sons, Ltd.
PMID: 19206112

Who is more at risk?

Earlier articles put the risk of developing Richter’s syndrome at 2-3 % of CLL patients.  However, based solely on my anecdotal database of patients writing to me, this has seemed low to me. Now the paper by Rossi et al below confirms my suspicion.  They put the risk of Richter’s syndrome at a whopping 10% for patients who have had CLL for more than a few years. The authors identified the following risk factors:

  • Elevated CD38
  • Absence of 13q14 deletion, the “favorable” FISH abnormality
  • Lymph nodes larger than 3 cm
  • 17p53 deletion or mutation.  This is important. We discussed in a previous article “How to make a good roach killer” that even if  FISH report says there is no 17p53 deletion, it is entirely possible to have mutations or epigenetic silencing of the 17p53 gene, preventing it from making proper TP53 protein. The goose is cooked either way.
  • High white blood cell counts (WBC), swollen spleen or even percentage or type of bone marrow involvement (diffuse or nodular) did not increase risk of Richter’s transformation, though these factors obviously point to increasing Rai stage of the CLL.
  • The authors point out: “The extent of disease has been shown to influence the outcome of RS patients. Consequently, prompt recognition of RS may be clinically useful, and may be favoured by close monitoring of CLL patients harbouring clinical and/or biological risk factors of RS development.”

The link between increased risk of RS and high CD38 expression is interesting.  It has been known for a while that CLL cells tucked away in lymph nodes express higher levels of CD38 than CLL cells found in open blood circulation or even the bone marrow.  In other words, the CD38 level your lab reported on the basis of a blood test is likely to be an underestimation of the level of CD38 expressed by your CLL cells residing in swollen lymph nodes. Most experts agree that CLL which likes to sit around in lymphoid tissues (“bulky disease”) is more likely to be associated with lymphoma-like tumor, and therefore more likely to increase risk of RS.

The second abstract below from M. D. Anderson highlights another potential risk factor, namely Epstein-Barr virus (EBV).  The same group also reported that patients who have had clinically diagnosed mononucleosis in their youth are more likely to have reactivation of EBV infection.  As we have pointed out in several articles, once a person is infected with EBV virus, traces of the virus linger in the body for the rest of the life of the patient.  Vast majority of our population are carriers of this virus.  It seems patients who had full blown mono as kids are more likely to have reactivation of this virus and this abstract suggests it might increase risk of Richter’s transformation as well.  We discussed this and several other aspects of EBV ion in an article titled “EBV: the enemy within” and I strongly urge you to read it.

Med Oncol. 2007;24(1):17-32.

Recent advances in the diagnosis and therapy of Richter’s syndrome.

Swords R, Bruzzi J, Giles F.

Department of Haematology, University College Hospital Galway, Galway, Ireland.

Richter’s syndrome (RS) denotes the development of aggressive lymphoma that arises in patients with chronic lymphocytic leukemia (CLL). Presenting features typically include a rapid clinical deterioration with fever in the absence of infection, progressive lymph node enlargement, and an elevation in serum LDH. Diagnostic biopsy of affected sites usually reveals large cell lymphomas; however, Hodgkin variant cases have been described. Richter’s transformation occurs in approx 5% of CLL patients and may be associated with infection with Epstein-Barr virus (EBV).Chromosome 11 and 14 abnormalities have also been described as well as tumor suppressor gene defects involving p53, p21, and p27. Treatment options for these patients are limited and includecombination chemotherapy with or without the addition of monoclonalantibodies and stem cell transplantation. Response to therapy is variable and generally short-lived. Median survival is usually in the order of 5-8 mo. More effective management for RS is needed as well as prognostic models that will identify CLL patients at risk of transformation. This review will address the current status of RS and deal with the pathophysiology, diagnostic approach, and treatment of this challenging disease.

PMID: 17673808

“RS Score”

The Rossi article points out that while the prognosis for RS patients is generally considered to be grim, not every RS patient has the same unfavorable prognosis.  In their cohort of 148 patients with RS survival ranged from just a few weeks to 15 years!  The authors came up with what they call the “RS SCORE” to try and predict who may have a relatively easy time of it and who may not.  Patients get one point (demerit) for each of the following:

  • Elevated LDH (lactate dehydrogenase)
  • Platelet count below 100K
  • Reduced physical performance
  • Lymph nodes larger than 5 cm
  • More than two prior therapies

Patients are assigned to low risk (0-1 demerit points), high to intermediate risk (2-3 points) and high risk (4-5 points).

Please understand their RS score does not predict the likelihood of developing Richter’s syndrome, it tries to predict patient’schances of survival after RS has been diagnosed.  Fine need aspiration of the actual contents of the lymph nodes and examination of the sample by a competent pathologist is the most useful method for accurate diagnosis of Richter’s syndrome.

Therapy options

Many of the therapy regimens used to treat RS have their origins in treating aggressive lymphomas.  Since the advent of Rituxan, many of these protocols have been changed to add our favorite monoclonal to the line up of other chemotherapy drugs.  At present, some of the combinations used to treat RS are

  • R-CHOP (Rituxan, cyclophosphamide, vincristine, doxorubicin, prednisone)
  • R-hyper CVAD (Rituxan, cyclophosphamide, vincristine, doxorubicin, dexamethasone)
  • OFAR(oxaliplatin, fludarabine, cytarabine and Rituxan)

OFAR is the latest and greatest, but even with this combination the median duration of response is only 10 months and 6 month survival rate is a disappointing 60%.  The good news is that younger and fitter patients can hope to go through a consolidation therapy with one of these combinations and follow it up with a mini-allo transplant.  The estimated cumulative survival at 3 years has been reported to be 75% for patients who received allogeneic SCT after getting a CR or at least PR from the prior consolidation therapy, while patients who responded to consolidation therapy but did not go on to get a SCT the 3 year survival was a bleak 27%.  Moral of the story, if you are unfortunate enough to be one of the RS cases, get thee to heavy duty consolidation therapy right away and back it up with a mini-allo transplant! 

For patients who are not good candidates for mini-allo transplant, the authors suggest backing up consolidation therapy options listed above with newer drugs such as Bexxar, Zevalin (both of these are variants of Rituxan, anti-CD2o monoclonals, with the big difference that they carry a radioactive payload), Humax-CD20, Revlimid and flavopiridol.


There is still a lot that we do not understand about Richter’s syndrome.  Giles et al point out that the rate at which CLL patients transform to this much more deadly aggressive lymphoma has been increasing over time.  Just in the last decade or so, the incidence has increased from 1-2% to 10-12%.  This opens up a can of worms, does the increased rate of Richter’s transformation have anything to do with use of more aggressive chemotherapy drugs? Our favorite villain fludarabine is always good for another black mark in my book.

Giles et al discuss the possible role of EBV viral infection in Richter’s transformation and I suggest you read their actual article to get all the details.  While the role of EBV in RS is still an open question, this nasty virus has clearly been identified with the development of other lymphoid cancers such as Burkitt’s lymphoma and Hodgkin’s lymphoma.

While as many as 90% of our population have been exposed to EBV at some point in their lives, the percentage of that come down with full blown and clinically diagnosed mononucleosis is quite small.  A while back we did a straw poll on CLL Topics, asking our members to tell us if they have had mononucleosis as kids.  A surprisingly large percentage of our people have had full blown mono.  This is a potential lead that I hope will be followed up some day by researchers. 

You and I can talk about this and other potential linkages until we are blue in the face, nothing will get done and we will get no respect.  My goal is to see if I can get a credible research outfit to work with our patient community by following up on leads such as this.  Your part of the bargain is that if and when I succeed, each and every one of you promises to spend the 15-20 minutes to participate in an on-line survey.  Agreed?  Who is going to help us if we don’t help our selves?