Transformation

Probably the biggest fear among Follicular NHL patients is that we will "transform." That is, some of our slow-growing, indolent cancer cells will turn into fast-growing, aggressive cancer cells, usually a form of lymphoma called Diffuse Large B Cell Lymphoma (DLBCL). On the one hand, DLBCL has a pretty high cure rate when it's caught early. On the other hand, it isn't always easy to know you've transformed. Plus, curing the DLBCL doesn't get rid of the fNHL.

(Incidentally, one of the reasons for watching and waiting is to hold off on using R-CHOP or a similar chemo, since it is pretty effective on DLBCL, but can only be used once. It keeps that arrow in the quiver, as Dr. C, the lymphoma specialist, put it to me.)

The issue of transformation has been discussed a lot lately in the support group. I'm not sure what prompted it -- I think it was someone's worrying about it. Which happens a lot. About 3% of people with Follicular NHL will transform each year. That number seems to slow down as time goes on, so chances are reduced over time. There's been some deabte about what all the statistics mean, but the upshot seems to be that about a third of fNHL patients will transform at some point.

Anyway, in the midst of our support group discussion came an article in the hematology journal Blood. I can't get access to the article, so there's no link, but the very dense, technical abstract is below.

Even our resident expert Karl had a little trouble with the language in the abstract, without seeing the whole article, but what we think it all means is this:

We still don't know how or why fNHL transforms. Dr. C told me that fNHL is especially "genetically unstable" for whatever reason. The researchers who wrote the article believe that the cells that transform are more present in particular stem cells, and less in other mature B cells. If they are right, they may be able to identify early on which patients are likely to transform. It's possible that currently-used treatments could then be used on these patients. Or, given the way research has been going, a whole new type of treatment could be developed that targets whatever unique characteristics are present on these cells that makes them different from the slower-growing fNHL cells.

It's exciting research, I think -- cause for optimism. It seems to be part of the larger trend toward researching the micro-environment (finding out what makes each cancer cell different -- just as two lung cancers might seem outwardly alike, but were caused by two different gene mutations, so might fNHL also have that kind of basis). And this leads to the larger trend toward "personalization" -- being able to identify which treatments will work best for an individual patient.

Something worth keeping an eye on, to be sure.


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"A pluripotency signature predicts histologic transformation and influences survival in follicular lymphoma patients."
Blood, 8 October 2009, Vol. 114, No. 15, pp. 3158-3166.
Prepublished online as a Blood First Edition Paper on July 27, 2009; DOI 10.1182/blood-2009-02-202465.

CLINICAL TRIALS AND OBSERVATIONS.

Andrew J. Gentles1,-, Ash A. Alizadeh2,3,-, Su-In Lee4, June H. Myklebust3, Catherine M. Shachaf5, Babak Shahbaba6, Ronald Levy2,3, Daphne Koller4, and Sylvia K. Plevritis11 Department of Radiology, Divisions of 2 Hematology and 3 Oncology, Department of Medicine, and Departments of 4 Computer Science and 5 Microbiology and Immunology, Stanford University School of Medicine, CA; and 6 Department of Statistics, University of California, Irvine.

Histologic transformation (HT) of follicular lymphoma to diffuse large B-cell lymphoma (DLBCL-t) is associated with accelerated disease course and drastically worse outcome, yet the underlying mechanisms are poorly understood. We show that a network of gene transcriptional modules underlies HT. Central to the network hierarchy is a signature strikingly enriched for pluripotency-related genes. These genes are typically expressed in embryonic stem cells (ESCs), including MYC and its direct targets. This core ESC-like program was independent of proliferation/cell-cycle and overlapped but was distinct from normal B-cell transcriptional programs. Furthermore, we show that the ESC program is correlated with transcriptional programs maintaining tumor phenotype in transgenic MYC-driven mouse models of lymphoma. Although our approach was to identify HT mechanisms rather than to derive an optimal survival predictor, a model based on ESC/differentiation programs stratified patient outcomes in 2 independent patient cohorts and was predictive of propensity of follicular lymphoma tumors to transform. Transformation was associated with an expression signature combining high expression of ESC transcriptional programs with reduced expression of stromal programs. Together, these findings suggest a central role for an ESC-like signature in the mechanism of HT and provide new clues for potential therapeutic targets