Patients with CLL or indolent NHL occasionally experience a significant clinical change in their disease where it becomes a lot more aggressive. When this happens, the formerly "slow growing" cancer becomes a lot more nasty and in many cases the prognosis gets a lot worse. In a number of publications, NHL, CLL) the average survival when this happens is about a year. A number of those are older articles (retrospective / in pre-rituximab era) which may have been confounded by patient selection bias. My own impression is that many patients do quite a bit better but that is at least what the literature reports.
In CLL/SLL this is called "Richter's Transformation (RT)" while in the indolent NHL's this is called, "Histologic Transformation (HT)." Sometimes docs jumble these terms and call it "Richter's Syndrome" or "transformation" regardless of which disease it started out as. There is a different discussion about what we call Grade 3 follicular lymphoma. Sometimes these can be confused by the patient. I will save the discussion of Grade 3 until an upcoming post. In follicular lymphoma HT occurs at a rate of about 3%/year. While that is a pretty small number, it is cumulative so by 10 years it may be as high as 30%. In CLL the rate appears to be a fair bit lower so that the cumulative risk is only about 10-15%.
The best clue that a patient has undergone RT/HT is when the disease acquires a bad attitude. Instead of just involving blood and lymph nodes, you see it in new places like liver, lung, intestine, bone nodules, sometimes even brain. Patients might experience increasing fevers, night sweats, weight loss. Laboratory changes are notable for a significant rise in a blood marker known as LDH (we are not talking about subtle changes, but 2-4x higher). If you get a PET scan (which measures metabolic activity of tissues), you might get one spot which is disproportionately "hot."
Traditional risk factors for developing this in CLL include an increasing number of prior therapies, CLL diagnosis at a younger age (longer exposure to risk), and more advanced disease. A number of newer studies show that pre-existing NOTCH mutations, "stereotyped B-cell receptors (a topic for a future post)," 17p deletions etc. also increase the risk. In indolent NHL, risk factors include the diagnosis of grade III follicular NHL, advanced disease, high flipi scores, and several lab variables (LDH, B2 microglobulin).
Under the microscope, the new disease most commonly resembles the "intermediate grade" Diffuse Large B Cell Lymphoma. Less commonly it can look like Hodgkin's Disease, and extremely rarely it may look like Burkitt's or Lymphoblastic Lymphoma. In any case, it goes from "indolent" to aggressive, or even the highly aggressive.
Because it is so easy to get samples of cancer cells from patients with CLL (blood draw), we know a lot more about transformation in CLL than we do in low grade lymphoma. It is probably worth while therefore writing about what occurs in CLL and then highlighting the differences that we know about in NHL.
In CLL there are two main and one uncommon way of experiencing RT. The most common way (80%) is for the dominant CLL clone to acquire more and more genomic mutations over time. Typically these involve several important genes including p53, Myc, and NOTCH. The second most common way (20%) is for a patient with CLL to "spontaneously" develop an entirely new diffuse large B cell lymphoma that is clonally unrelated to the original CLL. You might think no patient should ever have such bad luck, but in a prior post about 13q, I detailed how some genomic deletions can predisopose to lymphoid malignancies. Some patients who develop CLL may in fact be predisoposed to the spontaneous development of DLBCL.
The difference is significant. In the first case, you have a highly resistant clone - often with a p53 mutation - giving rise to an aggressive lymphoid malignancy. When p53 mutations are present, chemotherapy often does not work well. Just like every other cancer we have ever studied, p53 is a BAD THING to have mutated in DLBCL. Conversely, when DLBCL develops spontaneously, it is often a curable cancer. This plays out with regard to prognosis of the transformation. In the former, survival averages about a year, whereas in the latter a good number of patients are cured. Once again, I would point out that it is frustrating that we have no way to tell which one a patient has with testing that we would consider readily available. In indolent lymphoma, it seems far more likely that the new DLBCL is clonally related and p53 mutations are as high as 80%!
Treatment often consists of R-CHOP chemotherapy regardless of which sort of RT you have. While this is typically a well tolerated treatment, it is harder on the patient if they have already been exposed to a bunch of chemotherapy previously. You only get to beat up the bone marrow so many times (chemo) before it starts telling you it can't accept more flogging. It is not uncommon to run into dose delays, or reduced dosing, etc. Add this to more resistant disease and you can probably figure why it is less effective. Furthermore, a lot of patients with follicular lymphoma have been previously treated with the "H" in R-CHOP and you can only give so many doses of that drug before the heart starts to complain. Since treatment is less effective, some patients will be treated with an "auto" stem cell transplant but a lot depends on how robust the patient is at that point and how well they responded to therapy.
In the future, I think this may be one situation where the "engineered T cells" could become an important therapy. NOTCH antibodies have recently entered clinical trials and might be appealing. We have used brentuximab vedotin in one clinical trial and been pleased with the results for some of our patients. Hopefully these newer approaches will give a more favorable outlook to patients with RS/HT sometime soon.
Here is a video I did with Brian Koffman describing it all: Richters Transformation
