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Dangerous definitions – what is pre-leukemia?

Posted By Connections Editor, Monday, August 31, 2015
Updated: Tuesday, August 25, 2015

David Kent, University of Cambridge WT/MRC Stem Cell Institute 


Earlier this month, ISEH posted its 7th webinar entitled “Clonal Evolution of Pre-Leukemic HSCs in AML”. Webinars are a funny thing – we are so used to “seeing” the speaker, observing their reaction to questions, seeing the excitement (or lack of it!) for particular ideas, etc, and a webinar strips all of this away. I admit that I was skeptical when ISEH pitched the idea of webinars, but this particular webinar really opened my eyes to the value of this mode of communication.

I’ve seen Ross Levine several times before and emerged thinking “Wow, now that was a lot of data” and “I wish I could write faster”. However, in the webinar format, Ross seemed like he was sat in his office sipping a glass of wine – he was extremely relaxed and well-paced, I could even hit pause and rewind. In fact, I think Ross delivered one of the first lectures that I’ve heard in science where I did not really need slides to follow - a real treat.

Importantly, these webinars become an excellent resource for those that have yet to see talks from these researchers. It is a wonderful way to share science across the world and extend the live academic discussion beyond the boundaries of conference sessions.

However, the question and answer period was by far the best aspect of the webinar format because it captures the spontaneous and unplanned responses – where real academic discussion can occur. I thought that Ann Mullally did a brilliant job as moderator – she’d clearly done her homework and prepared some really tough philosophical questions for Drs. Levine and Majeti. She also adapted to the Q/A from other listeners, posing really interesting additional questions and giving context to those questions – a real model for how to moderate these webinars. Framing a question about where MDS fit in the pre-leukemic context, Ann made Ross and Ravi engage on the term itself. The exchange underscored for me the danger in perpetuating terms that are not accurate and Ross captured it perfectly:

“I’m gonna make Ravi respond to me – I think pre-leukemia is not the right term here. Pre-leukemia implies a likely certain probabilistic progression to leukemia and most of these people will never do that…. Most people stay there… for every one that gets leukemia, 15 are just gonna hang out.” Ross continued saying “terms: scientifically don’t mean that much, but clinically… it could mean a whole lot”

This highlighted the very important point that clinicians confused by the term “pre-leukemia” could deliver some very poor advice to their patients and raise unnecessary worries. Ross suggests that we need to engage with the idea of probabilities of progression and not use the term irresponsibly. Overall, I would say that Ravi agreed that the term shouldn’t be used for elderly patients who have a clonally dominant mutation in an epigenetic regulator, suggesting that the term should not be applied to people who simply have a clonal expansion.

However the point from Ross stands and I hear many people continue to use the term pre-leukemia irresponsibly, making the waters very murky for the non-aficionado. As a community we need to be careful about terms and their potential implications and I think having three clinician scientists argue the term really highlighted the need to get this right in the clinic.

A related question from Ann was what the therapeutic implications of leukemic complexity were - Ross took this question on and identified three main concepts that we need to master as a community. First, we need to “believe in combinations” to try and tackle the complexity. Second, we need to understand the convergence of different mutational mechanisms and whether they are therapeutically tractable. Third, the data so far suggest that we need to limit the ability of the leukemic cell to sample different states (e.g., to prevent it from evolving).

Ann also queried whether either Ravi or Ross could imagine a situation where clinicians might treat people with suspected “pre-leukemia”. Ross’ answer was fairly blunt - “not any time soon” citing the toxicity tradeoff as being too high at present. Ravi suggested clinicians would need to understand which patients would progress and any therapy would need to be done in a way that’s safe.

Overall – this is a webinar that is definitely worth your time, I hope you’ll take the time to have a listen, I certainly enjoyed it.

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