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TreatmentsRisks & Benefits - about therapy-related risks

Fludarabine and Transformation:
Natural history or therapy-related complications?

Last update: 02/14/2004

The following was posted on the LRF support forum by Andrew M.  We think Andy did a great job describing how to evaluate scientific papers.  And in the process he provided a broader perspective on the question of fludarabine and how it may or may not increase the risk of transformation. 

I decided to follow up on the fludarabine-rituximab - transformation article by actually reading the article. A handy thing to do if one has access. I can't possibly analyze the biology discussed in the article but I can look at it from a logical viewpoint.

First, the title is formed as a question about whether the observed transformations are the result of natural history or therapy-related complications. Sometimes scientists will form a title as a question because it is a good hook to get people to read the paper and then try to answer the question in the paper. This paper does not pretend they can answer this question.

In the other thread A pointed to, someone asked if they had calculated any p-values. They did not compute any p-values and I don't think it is clear that the statistics of transformation are sufficiently well understood to allow them to do so and they don't mention other patients for comparison.

An interesting part of the paper is a discussion of other studies. They cite 7 papers that discuss, at least in part, a possible role of fludarabine in transformation. Two studies of about 50 patients showed an increased risk of Richter's syndrome or prolymphocytic transformation (about 15% of the patients transformed) and this was further supported by two more smaller studies or observations. 

But, then came 3 studies that didn't find a relationship. This includes a 938 patient, prospective randomized study that was comparing fludarabine, CAP, and CHOP in previously untreated stage B and C CLL patients. This study is cited as having looked at the transformation issue and did not find a relationship between fludarabine and transformation. 

So, there are other studies on this topic and they have been split. But, I would be tempted to give the largest study the most credence. If anyone wants to look at it the reference is Leporrier et al., Blood, 2001, volume 98, 2319-2325. From the title, the main focus wasn't transformation so the information on that might not be in the abstract.

As R mentioned, this paper is just an observation that seemed unusual to the authors. It seemed sufficiently unusual that the journal was willing to publish it and publishing such unusual and unexplained observations is critical. 

It is part of my view that the scientific literature is an ongoing conversation. This paper is essentially someone yelling, "Hey, look out!" or as the authors put it in the abstract, "we draw attention to this phenomena." But the response from the rest of the field could be either "Wow, thanks for the tip" or "Never mind."

So, feel free to factor it into your decisions but also think about the other studies on this topic.

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