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Who Is Driving the Bus?

Date: February 26, 2024

Two days ago we published an article titled "Dawn of a New Era". Little by little, the experts are putting together the complex jigsaw puzzle of CLL. Gone are the days of one-size-fits-all therapy decisions. If you want the best possible outcome of your own CLL, it is time to learn more about it, up close and personal. The life you may save will be your own.

The Rai, Chiorazzi, et al. paper suggests that chronic goading of the CLL cells by specific antigens can drive them into a proliferative frenzy, sending the lymphocyte counts rocketing through the roof. Among the potential culprits, the villains that supply the antigen drivers of your CLL, are familiar viruses such as Epstein Barr virus, Herpes Simplex, Hepatitis C, Human Pappiloma virus, Cytomegalovirus, to name a few. There is no clear smoking gun yet. But a new era is dawning, and we are hot on the trail of these culprits. Down the road I expect we will find several major "clumps" of patients whose disease is driven by one or more ubiquitous viruses that stay dormant in our bodies for the rest of our lives once we have been infected. Just about every body in society has one or more of these viruses as permanent resident guests. The same culprit or the same mechanism may not be involved in all cases of CLL, this disease seems to come in many flavors and sizes.

The first abstract below makes interesting reading. The incidence of Richter's transformation (where your garden variety CLL is 'transformed' to a much more dangerous large diffuse B-cell cancer, one that does not respond well to therapy and comes with a very short fuse of less than 6 months to a year median survival) used to be about 3-5%. Not any more. There seems to be reason for concern, this dangerous transformation is seen more and more often, now it is up to the tune of about 12%. What has changed? This high pedigree research team suggests the transformation may be due to out-of-control Epstein-Barr viral proliferation, the dormant virus using a window of vulnerability to grow out of control. What gives the virus this chance to take control? Immune suppression, a fact of life for CLL patients and one that can be made a whole lot worse by therapy using heavily immune suppressive drugs. Fludarabine is one such culprit, among others. The rapid and documented rise in Richter's transformation may be due to more aggressive therapy with powerful chemotherapy cocktails, which leave patients vulnerable to reactivation of an old enemy lurking in the shadows up to that point. Fludarabine "gold standard" therapy may carry a heavy price tag.

A 2024 article in the New England Journal of Medicine reported a study that had 15 patients with Splenic Lymphoma. Nine of the patients also tested positive for the Hepatitis C virus, 6 did not. All 15 patients were treated with interferon alpha, the standard therapy today for viral infections such as Hepatitis C. Out of the 9 patients who were positive for Hepatitis C virus to start with, 8 had complete remission of their lymphoma, the 9th one had a partial remission. There was no tumor response to the interferon therapy among the 6 patients who were not Hepatitis C positive to begin with. Sounds crazy, but according to this study, you were luckier if in addition to splenic lymphoma, you also had Hepatitis C! Killing off of the Hepatitis C infected cells with interferon meant killing off of the lymphoma cells as well, since the Hepatitis C virus uses B-cells as its home. The second abstract below is from Stanford Medical school, it too suggests Hepatitis C may drive proliferation of B-cells, the viral antigen transmitting proliferative signals to the B-cell through its B-cell receptor (IgVH).

Even if they are not the sole cause of the origin of CLL, evidence is mounting that viruses seize a window of opportunity in people who are already cancer patients, or have a genetic predisposition to cancer. Time will tell how all this plays out. For now, it surely makes sense to take anti-viral medications as needed and not let these villains get out of control and thereby accelerate the proliferation of the CLL cells. Drugs such as fludarabine, Campath, high dose steroids (or combination of these drugs with others) are powerful allies in our fight against CLL, but they also carry the penalty of deep immune suppression, viral reactivation, and potential problems when the bus is hijacked by these viral drivers. The Mayo "Best Practices" paper suggests mandatory pre-emptive treatment of patients undergoing fludarabine therapy with Famcyclovir (or Acyclovir and the like) to protect against reactivation of Herpes virus, guilty of causing very painful episodes of shingles. Similar guidance is in place for Campath therapy as well. If your oncologist is not on the ball, does not get around to recommending these protective measures ahead of therapy with immune suppressive drugs, perhaps you should bring these facts to his attention (or perhaps better still, find yourself another oncologist).

Below are some of the articles that you may want to read on this website:

Viral Drivers;
Are We There Yet?;
Dawn of a New Era;
Mayo Best Practices.

Be well.

Chaya
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Abstracts

Leuk Res. 2024 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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Leuk Lymphoma. 2024 Jul;44(7):1113-20.

Hepatitis C virus (HCV) and lymphomagenesis.

Weng WK, Levy S.

Department of Medicine, Division of Oncology, CCSR 1105a, Stanford University School of Medicine, Stanford, CA 94305, USA.

Hepatitis C virus (HCV) is the major cause for non-A, non-B hepatitis. Most HCV-infected individuals do not clear the virus resulting in a chronic infection that may potentially lead to liver cirrhosis and hepatocellular carcinoma. In addition to hepatic manifestations, HCV infection is associated with B cell lymphoproliferative disorders, including mixed cryoglobulinemia, usually a benign condition, and overt B cell lymphoma. A direct role of HCV infection in the genesis of these B cell lymphoproliferative disorders has been suggested initially by epidemiological studies and is supported by recent studies, which analyzed the monoclonal B cells that proliferate in these disorders. How HCV induces B cell lymphoproliferative disorders is still unclear, it is probably not due to direct change of phenotype in B cells after viral infection, but may be due to an HCV-antigen driven process. Support for this hypothesis comes from the analysis of monoclonal B cells found in these disorders, which use a restricted repertoire of immunoglobulin variable region genes that are similar to those used by B cells that secrete anti-HCV antibodies. The fact that monoclonal IgM is resolved in HCV-infected patients who responded to anti-viral treatment supports the linkage between antigen persistence and B cell proliferation. Finally, the linkage between benign B cell proliferation and overt lymphoma is supported by the identification of a pre-malignant B cell clone that subsequently converted to an overt B cell lymphoma. The molecular basis for viral induced B cell proliferation is still unknown. One possibility is that HCV stimulates the proliferation of monoclonal B cells via their HCV-specific B cell receptor (BCR) on the cell surface. Binding of the HCVenvelope proteins to a cellular ligand, CD81, may also enhance this antigen-driven process. A recent report on regression of splenic marginal zone lymphoma after anti-viral treatment with interferon and ribavirin has significantly strengthened the cause-effect relationship between HCV infection and lymphoma. Further studies should determine whether BCRs expressed on HCV-associated lymphomas, particularly those that regress in response to anti-viral therapy, bind HCV antigens that stimulate their proliferation.

PMID: 12916862
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