Case 1: Expert Panelist Commentary


Expert panelists reflect on the case presented by Dr Garcia-Manero and share their unique perspectives on how they might have approached treatment and followup for this patient in their own practice.


Rami Komrokji, MD: Maybe we’ll start trying to address some of this. So, if you saw those patients from the beginning, would you have started ESA [erythropoiesis-stimulating agent]?

Guillermo Garcia-Manero, MD: I think one of the first questions was, what is the importance of molecular testing? And you come to us, and it’s very nice to see this gigantic data set but that’s really not how we practice. So I’m very fortunate that I work with Sanam Loghavi, MD, and I get the NGS [next-generation sequencing] in 3 days, I get cytogenetics in 5 days, I can discuss this in real time. But I see that in practice in the United States that this takes maybe a month, that’s the reality and if the case is difficult, it may take a couple of weeks so do people wait?

I see in the United States many times patients are started on ESA very quickly. If I had had this data, I would not have started the patient on ESA, I would have started them on some other therapy. The reality is, if you had asked me this question let’s say 6 months ago, I would have told you I would never use lenalidomide, I would use a hypomethylating agent. Today, based on some of this European data, maybe this trial is giving us better clarity in terms of these low level p53 mutations, maybe they are not that important and I think I will feel a bit more confident perhaps using lenalidomide in this context.

But I would like to ask the experts, what would you do, because I think this is evolving, this is not so clear cut, so I don’t know. Do you want to direct it to Uwe or Thomas?

Rami Komrokji, MD: Thomas first? Thomas?

Thomas Cluzeau, MD, PhD: It’s not an easy question. For me, I think I would try ESA first because I think we could obtain a low rate of transfusion independency, but it could be possible. Even if the median duration of response is short it’s something I will try. After, for the lenalidomide, it’s complicated because before I said no lenalidomide with a TP53 mutation but now we have tools more powerful so we are able to detect a minor clone of a TP53 mutation and I’m not sure we could exclude lenalidomide for the whole patient so I think I would do like you did. So, I would treat the patient with lenalidomide with a short follow-up with the bone marrow follow-up to see if we observe an increase of the clone and if we have observed an increase I think I would stop the treatment. I don’t know if it’s something we have to do or not, but I would think I would do that. Uwe?

Uwe Platzbecker, MD: It’s indeed a very interesting case. No. 1, I was a little bit not astonished but it was interesting to see that the patient achieved a complete cytogenetic response [CR], which is in my experience very uncommon if you have large p53 clones.

Guillermo Garcia-Manero, MD: This patient has a very low CR.

Uwe Platzbecker, MD: This was my immediate reaction then, that this clone although being detectable is obviously a minor clone and the longer the disease is there of course it will evolve, it’s just a question of time. But I think that’s a reflection for the specific nature of this patient. You may call it a rare case, but I would call it a typical case where we basically have to personalize medicine, also with drugs being available and widely used. So, I would fully agree with Thomas that just some ESA therapy can be considered and should be given for 4 months at least to help try in this given patient. I would also monitor p53 clones, but I would also monitor cytogenetics because this is sometimes forgotten and we just look at the clone p53 sometimes from the peripheral blood and not go for another bone marrow testing, but I think I have seen patients where their cytogenetic abnormalities evolved before the p53 clone came up and I forgot the age, I’m sorry— aged 55 years.

So, this is of course all about surveyance and it’s all about the timing of transplant because the patient will definitely undergo disease evolution at some point. But I think these minor p53 clones, they are really interesting and we don’t have a systematic clue on how to handle those therefore it’s very important to exchange and, maybe, also gather more information on this small subset of patients.

Guillermo Garcia-Manero, MD: I was going to ask, does it mean anything, these 2% to 5%?

Sanam Loghavi, MD: I think more than likely not. But let me go back to something. I think this case is very interesting because there’s a lot of details in this case that you have to consider. If you just present the case without the details and tell me this patient has an MDS [myelodysplastic syndrome] with a TP53 mutation with a del(5q) and a del(20q) and then I’m like, this sounds like a bad case. But if you really think about this, the clone that’s driving this patient’s MDS is not the p53 clone. The p53 clone more than likely is a coincidental chip clone that’s there and you can find that in people who are completely asymptomatic that don’t have MDS. So, what’s driving the MDS here and what I think you’re trying to treat are the del(5q) and the del(20q). I think you definitely want to observe the TP53 mutation to make sure that it doesn’t expand but 2% to 5% can be inter assay variability. If you use different time points using the same assay you may get some variability in the VAF [variant allele frequency] and so I think 2% to 5% is not something to jump the gun on.

And I think the other thing you want to recognize and realize is especially looking at the newer classifications, there are 2 things: one is that in MDS we know that having biallelic loss of a TP53 mutation is more important so even if this patient had a slightly higher TP53 mutation VAF, it still wouldn’t qualify as an MDS with a TP53 mutation because you would want to see either cytogenetic shown loss of the other allele or another mutation. So, biallelic loss of the gene and then also the VAF. The VAF of 10% is used in ICC [Integrated Comprehensive Care] project and not in the WHO [World Health Organization] because I think in a way it’s similar. When you have a loss of both copies you’re going to have a high VAF anyway. So, I think the disease in this patient is really not driven by this TP53 mutation. That would be my best guess.

Guillermo Garcia-Manero, MD: I totally agree.

Transcript edited for clarity.

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