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Hairy Cell Leukemia (HCL): Treatment of Relapsed Disease (EHA2024) · EHA Unplugged

• 0:06
  In this episode of EHA Unplugged, we will revisit a
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  spotlight talk from EHA 2024. Professor Torsen Zenz from the
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  University Hospital in Zurich discusses current approaches to
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  the treatment of relapsed hairy cell leukemia.
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  So my name is Torsten Zenz. I'm, I work in Zurich and my
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  task is to discuss relapse treatment of hairy cell.
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  So I'm only going to speak about classical hairy cell leukemia.
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  So this this is B RAF mutant classical hairy cell.
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  You, you will be aware that there's a lot of discussions
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  ongoing with the new classifications, but I think for
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  the content of this talk, we'll make it simple.
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  So we're only talking on, on, on classical hairy cell.
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  So, so the, the first part is, is really going to be a personal
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  topic. I'm, I'm going to tell you the
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  story how I got engaged in, in Harry cell leukemia.
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  And so, so Harry cell is, is a very rare lymphoma.
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  Patients usually present with cytopenia, large spleen.
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  And then if someone actually does the marrow, the, the
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  diagnosis is really very straightforward.
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  When Enrico Tiaci found that that classical hairy cell, these
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  patients always have the B RAFV 600 EI got interested because
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  the B RAFV 600 E is a, is a classic precision oncology
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  target. We have drugs that that we can
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  inhibit. And, and when, when you think
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  about the 100% now, now that that's very likely that hairy
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  cell depends on active B RAF signaling.
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  So that's how I kind of from the precision oncology angle got
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  interested. And, and this is linked to a, to
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  a patient that I saw many years ago in Heidelberg.
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  And, and this is the history which which allows us to revisit
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  how we treat her classical hairy cell.
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  So this particular patient was treated somewhere else with
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  quadrubin and didn't respond. Then he was according to
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  guidelines that didn't work and he got pentastatin, which is
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  reasonable because there was a 2, two year period.
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  And then he was actually referred to our centre here also
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  to consider should we do a transplant.
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  I said, OK, let's just add the antibody and, and maybe this
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  will help. But in this particular patient
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  that didn't lead to a, to a remission.
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  So, and this is very unusual, like very unusual case.
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  And this was in 2012 and the report had just come out that
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  all these patients have AB RAAF mutation.
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  So when we could get our hand on the B RAF inhibitor, we, we, we
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  put the patient on the B RAF inhibitor and very quickly
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  counts go up. And I don't, I'm, I'm, I'm sure
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  many of some of you have used B RAF inhibitor in, in, in air.
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  So it's phenomenal. I mean, it's just phenomenal how
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  quickly, how quickly this works. So I, I, when trying to get the
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  drug, I, I looked up the initial Melanoma trial and for someone
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  not from the field, I couldn't see any difference in response
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  regardless of dose, right? So I chose the, I chose the
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  lowest dose. After 14 days, you could clearly
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  see that the disease disappears. And then it took about a month
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  to get a, a complete remission. And, and I was, I was trying to
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  get a deeper remission. So I, I increased the the dose
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  of the mammorphonate, but still to this date, I've not been able
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  to extract the dose response. It's, it's probably somewhere
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  between the low dose and the and the Melanoma dose.
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  We use some of the immune histochemistry studies to to
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  look at what's actually happening.
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  The marrow is full of mutant cells.
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  And then you can also measure the pathway activity by looking
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  at phosphoric in an immunochemistry and, and the
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  tunnel essay shows you number of dead cells which there are,
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  there aren't any in the beginning.
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  And then we gave 6 days of treatment and, and this
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  massively changes the the patterns.
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  You still have a lot of tumor cells, but none of with the
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  inhibitor, none of them have active signalling and this leads
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  to apoptosis. So this is a clear demonstration
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  of oncogen dependence. And the cells may react in
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  different ways. They may just sit there and not
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  do anything. But here the cells depend on it.
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  They die if you if you remove B RAF signaling.
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  We then started to treat more and more patients and and have
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  no nicer images of this phosphoric signaling.
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  But we also saw that in only a proportion of patients you will
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  actually be able to to remove all the cells.
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  Enrique Tiace says it's a microenvironment.
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  I would say I don't know, I don't know what it is, some
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  something in addition. So this already alludes to what
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  you know, what should we be doing clinically.
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  The B RAAF inhibitor itself is not going to going to do the
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  trick for all patients. So to conclude this, it's clear
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  Harry Cell is addicted to active signalling.
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  The the B RAAF inhibitors work phenomenally.
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  If you have patients who are sick from infections, any
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  problems, just just start with the B RAAF inhibitor and then
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  take care of the disease later. So there are some situations
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  where BRF inhibitors are standard of care.
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  We also saw side effects like all the side effects at the
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  lowest dose, skin, skin problems, arthralgia kind of
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  inflammatory reaction. So, so I, I still think that,
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  that the, the, some of the hair cell experience may also affect
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  dosing or has the potential to affect dosing in other, in other
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  cancers. While we were starting to treat
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  patients off trials, obviously both in the US and in, in Italy,
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  you guys had set up the trial and, and, and enrolled patients
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  and the, the results are published in the, in the New
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  England Journal. So, so the trial showed very,
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  very similar results. About 1/3 of patients will get a
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  complete remission. Most patients respond, it takes
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  a few weeks. Usually platelets come up first
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  and then the the rest of the count improve and because of the
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  toxicity of the B Ralf inhibitors, you need to stop
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  treatment right for a disease that doesn't impair survival for
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  for the vast majority of patients, you cannot continue B
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  Ralf inhibitor because of the side effect profile.
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  So and recourse group has combined vemirafinib with
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  rituximab CD20 antibody and this is what we currently do.
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  So when we treat patients or we usually start with them Rafa
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  NIB, but try to get to a complete remission by
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  combination with the toximab. And so I think one of the the
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  topics to discuss, you know, when should we use this regimen
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  over repeating pure and pure and analogues.
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  So there, there's so many great drugs in B cell lymphoma.
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  So the temptation is to use the BTK inhibitor, the venetoclax
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  all all the other drugs. So, so ibrutinib has been tried
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  in this trial, which included classical as well as as hairy
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  cell variants. Quite a few patients actually
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  still on treatment. So my take home is if it works,
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  it's it's good, but it's only a, a small fraction of patients
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  where this works. You will get complete remission
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  in about 40% of patients, but you need to hold your breath,
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  you need to keep them on treatment for a while.
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  And so, so this like to me, this is clearly an active drug, I've
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  not used it very much because all the other things work so
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  well. So it really depends on what,
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  what you have access to. So I'm already heading towards
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  the end, all those different treatment options, they're
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  hugely confusing anyway. So, so a lot of times it's about
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  access to drugs. So there's the moxetumumab which
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  we don't in Europe we don't have access to.
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  So we've had, we've been able to put patients on the trial and
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  it's clearly an active drug. You can also see if your patient
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  can, can go to the NCII think they they may still have access.
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  But but other than that, it's really the, the, the questions
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  we usually ask ourselves. Should I reuse a purine
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  analogue? And they are the the the depth
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  of remission first time round and the length of the duration
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  of remission is a topic. Also the age of the patient.
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  Do you have someone who's 79? You don't necessarily have to
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  worry about long term effects as much as if you have someone
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  who's who's very young. And then the the question, how
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  do they present in relapse? Do you have time to kind of get
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  organized or is there an infection where which would
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  always argue for a for AB RAF inhibitor.
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  And I mentioned that, um, most of the time we now use
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  Memoraphanip and CD20 antibody if we don't want to go back to a
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  pure and analog and then that's kind of the scenario we use.
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  So there are different guidelines.
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  I think the Harry Cell Consortium is coming up with a
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  new guideline. There's also going to be an AHA
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  guideline. And these, these guidelines are
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  always interesting to write it in the absence of a lot of data.
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  So, but I, I'm involved in the, in the international guidelines
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  like only in a minor way, but I'm also involved in the German
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  guidelines. But I specifically pulled out
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  the French guidelines because I don't think I agree with the
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  concept that if you have someone that you put on a pure analog
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  without rituximab, for example, and they respond well for two
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  years, you go back to purine analogue.
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  It just seems like a very short period of time.
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  So you can go to purine analogue and an antibody hoping that this
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  will now be phenomenal, which is a realistic scenario.
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  But the trajectory of just repeating purine analogues
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  doesn't, doesn't appear to me. So what the French group have
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  done is they've suggested if it's more than five years, give
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  it another shot, but they've also put rituximab plus purine
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  analogue. So, so my interpretation of the
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  field is in first line, if you were a patient, you would want
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  to have purine analogue and CD20 antibody.
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  But somehow in the physician community, people have not taken
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  up because there's, and in a lot of places because there's, there
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  hasn't been the randomized big trial to show, but all the data
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  suggests that it's just so much more effective.
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  And in terms of the side effect profile, I mean, we use these
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  combinations all the time. There have been all these big
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  FCFCR trials that we, we are, we're not, we, we shouldn't be
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  afraid. So, so my prediction is more
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  people will use combinations because it's clearly more
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  active. Yes, you can get away with just
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  the purine analog and for the vast majority of patients it
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  won't make a huge difference. But if we now focus on on
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  relapse, you really need to look at how did patients respond.
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  So I, I continue to do marrows on young patients after six
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  months because I want to know did they get a complete
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  remission, right? This is something else.
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  If you have a lot of cells in the marrow that just sit there,
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  I'm so, so I, I usually recommend for younger patients
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  to have the marrow and, and, and, and most patients will will
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  accept this. Let's discuss the question on
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  how, like, after how many years of response would you go back to
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  a, to a pure analog? To me, it's a function of age
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  function of response. And I like the five years right
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  with Harry said, in contrast to many of the other lymphomas,
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  very hard to predict how that second round will like.
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  Sometimes you see longer response with the second round.
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  So maybe there's a like a cumulative effect on the DNA
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  that that further paralyzes these these cells.
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  I'm not sure. I've I've been very tempted to
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  do that second round of purine analog at six months.
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  If you have patients with your primary refractory, which is
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  which is exceedingly rare or patients with a short response.
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  Often if they relapse within two years, I will for sure go for
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  rituximab and them them roughen it.
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  But even their I expect patients to to relapse.
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  I mean, some of the responses are so deep that it's, it's
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  really seems to be an excellent, excellent regimen.
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  There's a basket trial looking at Mac and B RAF inhibition,
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  which shows very, very good response, probably more CRS and
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  with just the the B RAF inhibitors.
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  I, I haven't been able to use it outside of a trial because of
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  the the vastly different mechanisms of action.
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  I would be tempted to continue to use B RAF inhibitor with CD20
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  antibody and then in, in, in later lines there's and people
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  to big centers, people continue to get referred for the question
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  of our transplant. I've like we've not I've never
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  sent a patient to to to transplant.
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  I think there's some trials with car TI don't I don't know if if
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  that's something that that you have access to, but it's really
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  exceptionally rare because what we haven't mentioned here is
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  that you so you put someone on a behalf inhibitor on a CD20
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  antibody, then they they respond and you stop after three months
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  and then they come back, you know, in a year or two or three
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  and then they couldn't they can be be re exposed.
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  So, so I think the the question of sequencing of of different
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  treatment is may not be so very relevant, but I do want to raise
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  your attention to this question of should you just go back to
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  Cladribin because it was easy to apply after two or three years.
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  I really prefer this kind of five year interval because there
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  are all these these other treatments that are available.
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  I think the roughing man refraction is an excellent
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  salvage regimen. But with the follow up of our
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  trial it's clear that yeah, there there is a small substance
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  of patients that at 5 or 6 years is free from relapse, but many
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  patients still relapse. In the trial they were they had
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  a meeting of three prior lines of therapy and it's clear that
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  for I would say the majority of patients after so many lines of
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  therapy, this is not a curative regimen.
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  And so I think that upon relapse after the miralfy plastic
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  taximab, yeah, one can repeat it if the duration response was
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  nice. But otherwise other options
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  should be pursued like BTK inhibitors or even venetoclax.
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  We, we had a relatively good experience in patients in a
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  small number of patients relapsed after being roughly
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  plus ritaximab that venetoclax was able alone or with relaxment
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  to reinduce remission. Although it took quite a while
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  to recovery of cytopenias like with ibrutinib.
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  And so I think it's very difficult to eradicate this this
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  disease long term, perhaps with Claddington plus retaxium
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  upfront, maybe we will see with the long term outcome of the
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  follow up of the trials that have been done, perhaps we will
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  have like decades long remissions that we translate
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  into a functional cure. I don't think we need to
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  eradicate the disease, right. We need to get to complete
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  remission for a long period and we need to be careful with side
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  effects. We need to be very careful with
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  infections. We had a young patient dying
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  from he had tuberculosis and hemophagocytic syndrome and
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  COVID. I think that most of the
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  attention should be, you know, do not batter your patients too
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  often with urine analogues. Take advantage of some of the
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  other agents. But it's all around, yes,
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  supportive care. Also patients who present with
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  infections where people are maybe hesitant to do something.
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  I think the B RAF inhibitors are really huge advantage.
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  A comment about repeating cladribine one of my
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  observations. I'm not sure how reproducible it
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  is that often the degree of marrow hypocellularity and and
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  stem cell compromise is very significant at relapse with even
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  moderate hairy cell infiltrate. So I'm very hesitant to repeat
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  cladribene exposure where you've got ongoing impaired stem cell
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  reserves. So I would then tend to use a
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  BRAF inhibitor. We have dabrafinib rather than
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  vimarrafinib. I think a dozen patients,
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  abrafenib with rituximab, I think 9 out of 12 responders,
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  those sorts of numbers. Can you comment on any
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  mutational profile or escape mutants when they do become B
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  RAF inhibitor resistant? So there's work from the UK that
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  Ras mutations can can occur, but it is rare.
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  These mutations occur if you have, if you're doing continuous
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  treatment, if you'd only do a few few months, but usually it's
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  the Ross activation.