Monday, December 15, 2014

Up-to-date Info on Transformed Follicular Lymphoma

Blood journal recently published an article called "Transformed Follicular non Hodgkin Lymphoma," by Carla Casulo, W. Richard Burack, and Jonathan W. Friedberg of the James P. Wilmot Cancer Center at the University of Rochester Medical Center. I believe it gives as up-to-date information about Transformed Follicular Lymphoma as is possible to give.

As Follicular Lymphoma patients, Transformation might be as scary as it gets. Our often slow-growing, well-behaved cancer turns nasty and aggressive. We've probably all seen statistics and heard nightmare stories about Transformation, and they haven't helped us feel any better.

I can't say the Blood article tells us we have nothing to worry about (which would have been nice), but it does offer lots of review of previous studies, and does point to some hopeful developments that might shed some light of Transformation in the future.

I'm not going to summarize the entire 30 page article, but I will give you what I think are some of the highlights:
  • We often think of Transformed Follicular Lymphoma as "binary." In other words, one day you have FL, and then the next you have DLBCL. Those same cells just switch from one type to another.  However, with better tools, we can see genetic differences in FL cells, and when researchers compare FL cells from before a transformation to those after a transformation, they find that there are several "drivers" in the cells. In other words, any of those things could be the cause of the transformation. It's possible that we actually undergo several transformations during our time with Follicular Lymphoma -- not necessary to an aggressive lymphoma, but to different types of Follicular Lymphoma. This makes a lot of sense -- it could explain why the disease keeps coming back, and why it is resistant to some treatments, but not others. So it's possible that researchers can identify those different mutations in each patient, at each stage of their disease, and use a targeted treatment to more effectively get to the problem.
  • There is probably not one single driver that transforms indolent FL into something more aggressive. But they are beginning to identify some of those drivers. The good news is that they seem related to a lot of the newer treatments we keep reading about, like immunotherapies and pathway targets.
  • As for predicting whether or not someone's FL might transform, there have been some mixed results. Studies have shown that there might be a micro-environment issue that allows transformation to happen, or that blocks the immune system from stopping it, but the evidence available so far kind of contradicts itself, so it's hard to say for sure.
  • As for confirming that a patient has transformed, the "gold standard" is a biopsy that looks at the cells and sees that they have changed. However, clinical symptoms seem to be just as accurate: increased swelling of nodes, disease spreading to sites other than the nodes, rising LDH levels in the blood, etc. PET scans are also used to confirm transformation. All of them are fairly accurate, so a biopsy isn't absolutely necessary if a biopsy site it hard to get to, or things are progressing so rapidly that time is an issue.
  • As for the question of the risk of transformation (what percentage of patients will transform), the authors note that studies have been all over the place, with overall risk at anywhere from 24% to 70%. However, most recent studies seem to confirm that 2% to 3% of patients will transform each year. Some studies suggest a plateau at 16 years, meaning, if you didn't transform by then, you probably aren't going to. More recent studies have focused on patients in the Rituxan Era, with the same 2% to 3% figure, which means Rituxan doesn't seem to affect transformation. It is more likely some genetic factor unaffected by Rituxan.
  • Can risk be lessened? That is, is there less chance of transformation if the patient has R-CHOP early on, or Rituxan Maintenance, or some other treatment? The answer is No, or at least, we're not sure. Some studies suggest it's a possibility, but others say it isn't.
  • However, Rituxan does seem to improve Overall Survival. Before Rituxan, survival was 1-2 years, and now, chemo-immunotherapy (say, R-CHOP) leads to Overall Survival of 4-5 years. (Median OS of 5 years in one study was 73%, about the same as non-transformed DLBCL).
  • There is some suggestion that Transformation soon after diagnosis led to worse outcomes than Transformation later on, though there's no real standard definition of what "earlier" and "later" actually mean, so it's hard to hold on to that one.
  •  Patients who have transformed are (according to the authors) often excluded from clinical trials, so it's difficult to get hard data on which treatments work best. That said, it seems like high-dose chemotherapy, followed by an Autologous Stem Cell Transplant (with the patient's own stem cells being harvested and reintroduced after chemo) is the most effective option. (The authors review a whole bunch of studies related to this option.) Less well studied are Allogeneic Stem Cell Transplants (where the patient receives a donor's cells instead of her own.) While Allo SCTs also have some success, there is also the risk of Graft versus Host Disease (where the body rejects the foreign cells -- not a problem with an Auto SCT).
  • There have been some attempts to incorporate RadioImmunoTherapy (RIT) into an Allo STC regiment. 
  • The authors note that newer treatments like Lenalidomide (Revlimid), Ibrutinib, Idelalisib, and others hold lots of promise for Follicular Lymphoma, DLBCL, and thus perhaps Transformed FL. Because we are learning more about the pathways that these treatments target, there's a good chance that we may find that those pathways are involved with Transformed FL.
  • As for the future, the authors say that "the two most prominently deregulated pathways in HT [Histologic Transformation] involve apoptotic resistance and epigenetic modification, two seemingly promising targets, for which trials are already underway (ie, GDC-0199/ABT199)." In other words, the things that likely cause Transformation already have treatments being studied. 
  • Finally, the authors discuss their own approach to treating Transformed FL. First, they use PET scans to choose the best site for a biopsy (they choose the one that is most aggressive). From there, if the patient has not yet had CHOP (or another treatment with anthracycline, which can damage the heart if used too much), they try 6 cycles of R-CHOP. They then follow up with High Dose Therapy and an Auto Stem Cell Transplant, if the patient is young and fit enough, and had prior treatment for FL. If this is a first treatment, they may follow the R-CHOP with Rituxan Maintenance. Older or less fit patients may have R-CHOP followed with RIT.
You're caught up now. As I said, it doesn't tell us we don't have to worry. But it's nice to see a lot of this stuff in one place, and it gave me some stuff to look forward to. Not bad for something so scary.


Anonymous said...


MD Anderson in Houston is starting a CAR-T therapy trial in 2015 for transformed FL (and DLBCL).

Lymphomaniac said...

Glad to hear about that trial. CAR-T therapy looks like it's going to really make a difference for a lot of cancers in the future. Let's hope Follicular Lymphoma is one of them.