By Brian Koffman, MD and Anthony Mato, MD
As we are getting better at controlling CLL and living longer, there is increasing concern about serious late complications including Richter’s Transformation (RT) or Richter’s Syndrome (RS) where the CLL “transforms” into a new more aggressive type of lymphoma.
Here is our review article on RT by Dr. Wiestner from the NIH.
Though it is a rare complication, it carries an extremely poor prognosis and is treated differently than chronic lymphocytic leukemia. It is therefore important to be able to differentiate RT from CLL.
While a biopsy is the gold standard in making the diagnosis, the PET-CT has been the most useful noninvasive tool for ruling in or out RT in CLL patients when patients relapse after chemo-immunotherapy (CIT).
That may not be the case when patients relapse after ibrutinib.
Dr. Anthony Mato, former of U. Penn and now at Memorial Sloan Kettering Cancer Center shares his finding on the ability of PET-CT to identify Richter’s Transformation.
Key Take Aways:
- PET-CT rely on the amount of uptake by a tumor or lymph node of radioactive labeled sugar to assess its metabolism and its likelihood to be malignant. Cancers tends to high metabolic activity and as a result, “light up” the PET scans. Here is a link to an article written by a radiologist on all the imaging used in CLL including PET-CT.
- PET-CT are proven to have great value in differentiating RT from CLL in patients progressing after CIT.
- In contrast, in this new study looking at patients who were relapsing after ibrutinib, PET-CT was only 26% sensitive. Since in medical statistics, sensitivity is the ability of a test to correctly identify those with the disease, in our case those with RT, PET-CT is not very helpful.
- Post ibrutinib, CLL is often much more metabolically active, making the PET-CT light up and thus difficult to differentiate RT from faster-growing CLL.
We learn from this research that PET-CT are less helpful in identifying RT in post-ibrutinib versus CIT patients.
But it more importantly reminds us that we need to know the patient population we are dealing with when we look at any prognostic testing. What made good sense before with chemotherapy may not apply in the new treatment paradigms.
Another example of the need to reset predictive testing models is found in this ASH abstract referenced by Dr. Mato during the interview: Applicability of the Chronic Lymphocytic Leukemia (CLL)-IPI on Patients Treated with Front-Line Ibrutinib….
Here is a link to the article we discussed titled Analysis of PET-CT to Identify Richter’s Transformation in 167 Patients with Disease Progression Following Kinase Inhibitor Therapy.
You can view or read my interview with Dr. Mato discussing the trial below.
Dr. Brian Koffman – Hi. Dr. Brian Koffman, the medical director of the CLL Society here at ASH 2017.
Dr. Anthony Mato – Anthony Mato, Director of the Center for CLL at the University of Pennsylvania.
BK – Dr. Mato, one of the concerns everyone has with CLL is Richter’s transformation and you’ve looked at some ways to identify that. Can you help us understand that?
AM – Sure. Richter’s transformation is when CLL can transform into either diffuse large B-cell lymphoma or Hodgkin lymphoma. It’s an event that’s been associated with poor outcomes for patients. And you’re right, it’s a relatively rare event. There have been data that have been presented, largely from patients who have received chemotherapy, using PET imaging, which is a nuclear imaging examination using radioactive sugar, which can identify Richter’s transformation and discern it from patients who have progression of CLL. And the way that that technology works is that these sugars are taken up by cells, and the more metabolically active or aggressive the cell is, the more likely it is to be seen as a quote/unquote bright image on a PET scan. More aggressive lymphomas, like Richter’s transformation, should be brighter than CLL. What we’ve noticed is that, you know, we don’t necessarily have information about how PET imaging should be interpreted following novel agents, like ibrutinib. And so, we were lucky enough to have the opportunity to analyze 167 patients, all of whom discontinued ibrutinib, all of whom went on to receive treatment with venetoclax. And those PET images were performed in the context of a clinical trial looking at the role for venetoclax in patients who had failed a prior kinase inhibitor. So, we thought this was a great opportunity to try to validate whether or not the PET has the same characteristics. And I can tell you anecdotally, in my clinic, when I’ve had patients have PET imaging, it often looks like Richter’s transformation in terms of the brightness, even though it turns out to be CLL progression. And so, the hypothesis was that the PET is no longer as sensitive or specific in distinguishing CLL from Richter’s transformation following a new therapy. And so, what we did was, we calculated the test characteristics for the PET scan, the sensitivity, the specificity, the positive and negative predictive values, to see how that compared. And what I can tell you is that the original reports looking at PET following chemotherapy had a sensitivity of 91% and a specificity of 95% using a cutoff of 10, for being bright versus not being bright.
BK – So, a strong, helpful test.
AM – Very strong, helpful test. And, you know, not surprised, but we found that the PET, using that same cutoff, was not as helpful following chemo…following ibrutinib -based therapy. Sensitivity, for example, was around 26%.
BK – Oh my gosh.
AM – Marked difference.
AM – And the cutoffs that we looked at were a cutoff of 5 or a cutoff of 10, really suggesting to me that CLL is a much more metabolically active malignancy than had been previously thought following a new therapy. And just to give you an example, 35 patients had a biopsy performed from that data set. 25 of the 35 had CLL progression. And those were patients who had a high suspicion of Richter’s transformation.
BK – Because, you wouldn’t biopsy a patient unless you were worried that they had Richter’s.
AM – Right. They had to have a cutoff of 10 or more or be between 4 and 10, but have high-risk clinical and genetic features that were highly suggestive of Richter’s. So, these were the patients we would have previously thought have Richter’s transformation. And so, the PET by itself is probably not a great predictor. The other thing that came out of this project, which I think is important, is of the 167 patients, 127 went on to get venetoclax. We then followed them over time and tried to identify what are the characteristics of patients who develop Richter’s transformation while on venetoclax. Only 6 patients out of that series developed Richter’s, but we report on those characteristics. And then lastly, probably the most important point here is that there is an older literature suggesting that PET, even with CLL patients, can distinguish patients with a good or a poor prognosis following chemotherapy. We tested that same hypothesis following venetoclax, and what we found is that even though PET wasn’t associated with response, having a bright PET with CLL was associated with an inferior progression-free survival while on venetoclax. And those weren’t patients with Richter’s transformation, those were patients with CLL progression. Even the Richter’s on venetoclax, half of those patients had PETs that weren’t bright at the time of screening. So, it turns out that PET may be an important tool for helping to risk-stratify patients receiving venetoclax-based therapy. And in my mind, that’s a great opportunity for venetoclax combinations, or to try to overcome that metabolically active disease. So, a couple of different lessons learned from this: PET by itself is probably not a great tool for identifying Richter’s, and that for patients who are treated with venetoclax, we may gain some insights into what their outcomes are, based on their pre-venetoclax PET imaging and how bright that PET scan is.
BK – So, I think one of the takeaways for me is that you can’t move from things that seem to be true in the chemo-immunotherapy world of treating CLL to the novel agents…
AM – Completely agree.
BK – … that what seemed to make sense in that world may not make sense in the new world that’s emerging in treating CLL.
AM – And we presented a poster yesterday looking at the validation of the CLLIPI, or the C-L-L-I-P-I (the CLL-International Prognostic Index) in frontline ibrutinib, and we found that that model was not able to distinguish patient outcomes in that particular patient setting.
BK – That was a prognostic sort of… a lot of work went into putting these prognostic tools together and it just didn’t make sense in the new world.
AM – Right. So, same theme: Any time you’re looking at a prognostic model, you have to look at the patient population in which they’re validated before you decide whether or not it makes sense for your patients.
BK – Dr. Mato, I’m so appreciative of the work that you do. Thanks, so much.
AM – Thank you so much.
Dr. Anthony Mato is the Director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York City.
Dr. Brian Koffman, a well-known doctor, educator and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the medical director of the CLL Society Inc.
Originally published in The CLL Tribune Q1 2018.