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Alert Number 97

Fludarabine: Risk of Richter’s Transformation

Date: May 26, 2005

A couple of patients wrote and asked for clarification on the role of fludarabine therapy in precipitating Richter's transformation ("A morality tale of two friends" Topics Alert 95, May 21, 2005).

Richter's Transformation is the name given to the transformation of garden variety CLL into a variety of lymphoma with large cells. The large cell lymphoma could be an entirely new cancer, or a daughter clone rising out of the original CLL. Independent of how it originates, Richter's transformation is invariably bad news, with very bleak prognosis. None of the kinder and gentler therapies work with Richter's, and the median survival statistics are an alarming 5 - 8 months (see third abstract below).

Used to be, Richter's transformation happened in about 3-5% of CLL patients. The latest paper from the highly regarded Royal Marsden group suggests the transformation happens much more frequently in fludarabine treated patients, to the tune of a whopping 12%. Half of these patients were documented to have transformed to Richter's within 4 months of treatment with fludarabine.

One of the intriguing leads that has been researched is the connection between Richter's transformation and Epstein-Barr virus. You may have heard of EBV, the virus that causes mononucleosis (or plain 'mono'), fondly called 'the kissing disease' since it is passed from person to person through saliva. EBV is one of those viruses that is impossible to get rid of completely. Once you are infected, and believe me, most of us in the Western world are infected, the virus stays dormant in your body for the rest of your life. Under normal circumstances there is a truce/stalemate in existence between the virus and your immune system: the virus cannot be killed entirely but the immune system keeps it under check and does not allow its rampant proliferation.

As CLL patients our immune systems are hardly what one would call 'normal', and the situation can be made a whole lot worse by the deep and long lasting immune suppression brought about by chemotherapy. That may then be the link between fludarabine therapy and increased incidence of Richter's transformation. It is well known that fludarabine can cause deep and across-the-board immune suppression. We are all familiar with the risk of painful episodes of shingles after fludarabine therapy, in which the long dormant chicken-pox virus from your childhood uses the window of opportunity to mount an attack. What if the period of immune vulnerability leads to reactivation of dormant EBV? There is increasing evidence that this may increase the risk of developing the dreaded Richter's transformation.

Is fludarabine the only agent which can expose us to this risk? No. Any of the heavy duty combo therapies such as RF, FRC, RPC or even plain vanilla Campath may cause dangerously low immune protection and thereby expose you to the reactivation of any one of the viruses that may be lurking in the background. Among the potential bad actors are EBV, Herpes (shingles), HPV (can cause genital warts, cervical cancer, skin cancer), Cytomegalovirus (CMV), tuberculosis and no doubt others that I have not listed.

The moral of the story? It might not be such a smart thing to be in a big hurry to hit a home run and go for the biggest and most potent therapy combination out there, without taking stock of the cost side of the equation. None of these therapies have yet been shown to positively cure the CLL. Even patients with the coveted PCR negative complete responses have been known to relapse. What is the cost of the remission? How much immune suppression is involved? How long does it last? Is it across-the-board with every immune cell line out for the count? How effective are the mandated pre-emptive protective measures (such as anti-viral therapy with Famvir or Valtrex, Neupogen/Neulasta shots as needed to combat severe neutropenia, IVIG, etc.) in keeping you safe? Should you be checked to see if you are positive for traces of lurking EBV, CMV or TB viruses ahead of time, so that sterner protective measures may be implemented in your case? If you are getting the therapy in a clinical trial, how much flexibility is there in the research protocol?

There are no clear or easy answers, yet. Weighing the risks versus rewards in any therapy decision depends to some degree on your personality, your level of risk tolerance. It is a little bit like investing in the stock market, balancing risk versus return on your investment. Are you the type that puts your entire nest egg in the hands of a 'financial expert' and lets him make the investment calls? Does that personality trait mean you will be equally pliant in letting the expert wearing the white coat make all the therapy decisions? Me, I have too much angst in me for such a laid back approach. I listen to all the experts, then I counsel PC to make his own best decisions.

It is foolish to be so scared of the risks of chemotherapy that you dither while the cancer grows unchecked. It is equally foolish, in my opinion, to go for the biggest gun out there, in some macho desire for control, when you can just as well get by with lower risk choices. I am truly convinced a whole lot of new therapies are becoming available to us, backed by a better understanding of this disease. Playing for time is not a bad game plan. Frankly, I think that is called 'living', right?

Below are a bunch of links to relevant articles on this site, for your reading pleasure. Remember, the life you save may be your own.

Viral Drivers;
Clonal Evolution;
Fludarabine No Longer the Gold Standard;
Are We There Yet?;
Fludarabine, FISH and Prognostic Indicators.

Be well,

Chaya
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Abstract

Leuk Res. 2005 Apr;29(4):389-95.

Richter's transformation of chronic lymphocytic leukemia. The possible role of fludarabine and the Epstein-Barr virus in its pathogenesis.

Thornton PD, Bellas C, Santon A, Shah G, Pocock C, Wotherspoon AC, Matutes E, Catovsky D.

Section of Haemato-Oncology, Institute of Cancer Research, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.

Transformation of CLL into a large cell lymphoma has an incidence of 3-5%. We have studied 101 cases of CLL treated with fludarabine over a 10-year period (1990-2000) and observed a 12% incidence of transformation. In six of 12 patients, transformation was documented within 4 months following treatment with fludarabine. Pathological material, available in nine cases, was investigated for latent EBV by staining for LMP-1 by immunohistochemistry and EBERs-1 and 2 by in situ hybridisation. LMP-1 and EBERs were demonstrated in three of the nine samples. In two cases there was a different pattern of immunoglobulin gene rearrangement in the transformed cells assessed by PCR (FR3 fragment) compared to the original CLL clone. One of these two cases showed evidence of latent EBV. The other seven cases, of which two were EBV positive, showed identical pattern of Ig gene rearrangement in both the CLL and the transformed cells. We suggest that the relatively high incidence of transformation in this series may be due to immunosuppression mainly related to fludarabine, although other agents and prior therapies may have also contributed.

PMID: 15725472
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Int J Hematol. 1999 Feb;60(2):99-104.

Epstein-Barr virus infection in Richter's transformation.

Ansell SM, Li CY, Lloyd RV, Phyliky RL.

Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN

Chronic lymphocytic leukemia (CLL) may convert to a diffuse large cell lymphoma (Richter's syndrome) over time. In occasional cases of Richter's transformation, Epstein-Barr virus (EBV) has been identified in the lymphoma cells. To evaluate the association of EBV infection with Richter's syndrome, the biopsy specimens and clinical records of 25 patients who were seen at the Mayo Clinic between 1984-1996 were retrospectively evaluated for the presence of EBV by immunoperoxidase staining for expression of EBV latent membrane protein (LMP), as well as the expression of EBV RNA and DNA in the cells by in situ hybridization. Four of the 25 patients showed evidence of EBV in the diffuse large cell lymphoma cells-three patients with a B-cell phenotype were positive for LMP, EBV DNA, and RNA; and one patient with a T-cell phenotype had positive EBV RNA in the large cell lymphoma cells. The Richter's syndrome was treated with combination chemotherapy in 15 patients, three received radiotherapy, three were followed without further therapy after a splenectomy, two died before treatment could be started, and one patient had insufficient follow-up. One patient with evidence of EBV in large cell lymphoma cells was treated with acyclovir as initial therapy. The median survival of EBV-positive patients was three months compared with nine months for EBV-negative patients, but this difference was not statistically significant (P = 0.385). Evidence for EBV infection related to Richter's transformation was present in 16% of the patients in this study and may be associated with a poorer outcome. Primary therapy with acyclovir in one patient did not seem to be beneficial and other therapeutic modalities in patients with EBV-positive Richter's transformation need to be explored.

PMID: 9929100
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Cancer. 2005 Jan 15;103(2):216-28.

Richter syndrome: biology, incidence, and therapeutic strategies

Tsimberidou AM, Keating MJ.

Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX

Richter's transformation denotes the development of high-grade non-Hodgkin lymphoma, prolymphocytic leukemia, Hodgkin disease, or acute leukemia in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. A search of published articles in Medline (PubMed) and abstracts from professional meetings was performed. An electronic database search of patients with CLL at The University of Texas M. D. Anderson Cancer Center (Houston, TX) determined the incidence of Richter syndrome (RS) in patients with CLL between 1992 and 2002. RS occurs in approximately 5% of patients with CLL. The large cells of RS may arise through transformation of the original CLL clone or represent a new neoplasm. RS may be triggered by viral infections, such as Epstein-Barr virus. Trisomy 12 and chromosome 11 abnormalities are more frequent in patients with RS than in the overall population of patients with CLL. Multiple genetic defects, such as mutations of the p53 tumor suppressor gene, p16INK4A, and p21, loss of p27 expression, deletion of retinoblastoma, increased copy number of C-MYC, and decreased expression of the A-MYB gene, have been described. These abnormalities may cause CLL cells to proliferate and-by facilitating the acquisition of new genetic abnormalities-to transform into RS cells. Therapeutic strategies include intensive chemotherapy, monoclonal antibodies, and stem cell transplantation. The response rates range from 5% to 43% (complete response, 5-38%), and the median survival duration ranges from 5 months to 8 months. In conclusion, RS may be triggered by viral infections or by genetic defects. Current treatments are aggressive, but prognosis is poor. Novel curative treatment strategies are needed. (c) 2004 American Cancer Society.

PMID: 15578683
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