MPNforum Magazine

Nicolaus Kröger, MD,  is a Professor and Medical Director of the Department of Stem Cell Transplantation at the University Hospital Hamburg-Eppendorf, Germany. He is the current president of European Society for Bone and Marrow Transplant (EBMT) and Chair of its Scientific Council.

Stem cell transplantation: Expected outcomes.

Z:   I’m concerned with outcomes. We don’t know what the stem cell transplant (SCT) outcomes are going to be.   One problem I see is that the data we use might be skewed because by the time people come into SCT they might be at high risk or even worse, at end stage  so overall survival figures are poor.   What do you think about that?

Kroger: Yeah so the question still is,  to speak simply, the intention with transplant  is always to cure the patient of the underlying disease, in this case myelofibrosis. But there are actually three options, The first is cure, the disease can be cured. The second is there could be problems, the disease can be cured but it comes back. This is what we call relapse.  And the third is you can get some problems not only during the transplant but even one year fter transplant  or the year after like an infection or a Graft Versus Host (GVH) reaction that is so severe that the patient will succumb from this cause rather than the underlying disease.   In other words, the myelofibrosis can be cured because it is absent but the patient is dying form the complications,

Three possibilities. Three risk factors.

And these are the only three possibilities. And at the end you should always have 100%.  So if you do the transplant very early, if the patient is young in good condition and the disease  is not very advanced, then the rate of cure is higher, the rate of problem is lower, and the risk of dying is lower as well.

So you have always three risk factors, One is the disease itself like the DIPSS (Dynamic International Prognostic Scoring System) score for instance. The other is called patient-specific risk factors, for instance if the patient is in very bad condition, poor perforamce even in low risk disease but complications.  You can have the same patient with low risk disease according to DIPSS but the outcome is completely different because the patent’s condition is different.

Third one is transplant related factors. For instance if you have the same patient the same disease but one patient has an HLA (Human Leukocyte Antigen) identical sibling donor and the other has only a mismatch unrelated donor, The outcome for this patient with the mismatch or unrelated donor is poorer. So you always have a lot of variables that influence the outcome.

A comprehensive risk score

Z So how do we put those all together into an algorithm that can can come up with a reasonable sense of what the outcome might be?

Kroger: Exactly. So therefore this is just the focus on the transplant  So then we are currently developing score that does not exists so far. People are looking for  outcome based on high risk low risk or low risk.  But you have to develop a score that includes includes all risk factors, Patient specific. Tranplant specific and disese specific.

This actually is  what we at EBMT (European Society for Blood and Marrow Transplant) are working on and CIBMTR (Center for International Blood and Marrow Transplant Research) in America are working on.  They are also collecting a lot  of patoents who receive transplant, collecting all this information and then trying to create a score that can predicet the  the outcome, can predict non-relapsed mortality (NRM),  which means dying from complications,  and can predict the outcome regarding overall survival

Z:  How far are along is that work?

Kroger:  At ASH we will have one or two presentations.  I’m not sure how far along CIBMTR is.  EBMT will have a presentation at ASH and we sent also some data to CIBMTR.  The Memorial Sloan Ketteirng group is working on this scoring  and we gave our samples as a validation score to check whether their progress is correct.  And we get data the other way around to get validation from our cohort.

And once we have  this score we can at least predict the outcome as to NRM and survival outcome, but this is just for the timing, But then you can really counsel the patient  this is your risk and this is your likelihood and probability of being cured,  of getting a relapse,  or dying of therapy related causes.

So many variables

This is actually what we need and what we don’t have for Myelofibrosis so far. For this you need a lot of patients, You cannot get a score with 100 atients.  There are so many variables so you need at least five or six hundred or possiblky more  On the other hand what is also important for the decision to go to transplant is the outcome without transplant. So if you don’t go for transplant  what is your life expectancy?    I counsel the patent best as I can.  If you don’t do the transplant here is the outcome for you in the next years.

And the DIPSS and the MIPSS (Mutation-enhanced International Prognostic Scoring System) is quite useful because they include age and other factors. But we can only recommend as the decision is always an individual decision.  With all this scoring we don’t have the personality  of the patient,  we don’t have the social factors,  the family, is he alone, does he have a lot of support?  Which is very importatant for the outcome.  Because if you are alone and 65 years of age and you don’t have any relatives with you, usually this is not a good sign.  The patient needs support after the transplant.

The abstract that isn’t

Z:  On your paper Which Patients with Myelofibrosis Should Redeive Allogenic Stem Cell  your 10000 patient retrospective decision model seems roughjly based on DIPSS score not on disease specifc or patient-specific factors…

Kroger:  The idea  was just to make the community aware that if you have at least Intermediate 2 or High Risk disease you should consider transplant and not wait too long.  And if you have a Low Risk disease there’s no need to go for transplant immediately .  This was the intention   This disease is a continuum. IF you have Low Risk today doesn’t mean you have Low Risk tomorrow.,

Z: In your model you had a delay between initial diagnosis  and onset of conditioning of 21 months. During that interval   couldn’t there have been an advance in risk category?

Kroger: This is the model actrually.  If you look carefully at the survival curve even in the High Risk and the Intermediate-2  was better than the non transplant  but the curve wasn’t very encouraging because you ended up with only 20 or 30% survival, This survival curve is only a model, not a reality.  I’ll tell you why.  In the true prospective study  we say OK, you have no risk disease today and you will get transplant or non transplant  and we follow you up for 20 years and we will see what happens in 20 years

But this is unlikely to happen. We cannot follow up patients for 20 years. We look for registries. We have  lot of patients here in the DIPSS community so we follow them at diagnosis and on the other hand we have the data in our registry of the transplant.

But the transplant  is very rarely done at time of diagnosis.  You have to wait until the patient becomes worse or you have to wait for a donor, whatever. We don’;t know this retrospefctively  To do this analysis you can’t  compare transplant to non transplant. For instance if you have  no Intermediate 1 Risk you should look also for the time interval between diagnosis and transplant because in this time period  patient can die. All from the disease. So simpy spoken you can  get the transplant only if you’re alive at time of transplant. If you die you cannot get the transplant. So you have to assemble patient data  theoretically … This this is a statistical model called Less truncation. This is the proper name for it.  Let me say just say it is an estimation to get closer to the truth.

Z:  You showed an NRM 25%  for those who did get a transplant and 59% death rate for .. expressed 25% five year survival of 59%  or  a death rate of 41% ?

Kroger: Yes… In one case w’ere talking about an NRM of 25% other of survival of 59%./ 25% died within five years of SCT and 41 % of the non transplant group died during that same period

Are you referring to the Blood paper with Passamonti.  it was not ruxolitinib because ruxo not approved .. the nontransplant was all in the pre-ruxo era.. We did no followup of ruxo,

Z:  I’m looking at the Marchetti and Kroeger abstract in  Blood…

Kroger: Ah, that’s only an abstract presented at ASH…it compares outcomes for patients assigned to SCT or ruxolitiib.  This is something different which she did.. Published presented at the ASH conference… it was her work. She compared all the literature she found ruxo treated and stem cell traed patient and mixed all up and tried to figure out which was better which not… it was based on all the literature… I wouldn’t’ pay too much attention to it.

The SSTT and missing data

Z:  The SSTT (SCT Spectrum Transplant Timing tool) concerns me. It’s useful to start the conversation but it lacks all mutational and genotypic inputs.  More importantly that conversation it stimulates will be with a hematologist who almost certainly is not going to be an MPN specialists in an environment of uncertain outcomes.. It is good to warn the patient of risk levels but  are we providng a pathway for improved outcomes?

N:  We could suggest the patient ask for the molecular genetics or the driver mutations.  I still think it’s pretty early in the development cycle.   What comes out if you look at the MIPSS score,  the CALR mutation is a bit better, the triple negative and ASLX-1 a bit worse.   Currently, to be honest, we can’t make any decision based on moledular genetics.  It may help sometimes but it’s only a disease specific factor. At the end it come out we still have to confirm all the data concerning molecular genetics.

I don’t think it’s a major problem The major problem is awareness. Awareness of the hematologist and maybe the patients.   Your country is large so if there is a candidate he should be referred to a center for transplantation  then he should be followed up and the decision should be made with transplanter and hematology and made very early when the risk of dying is low and the likelihood of cure is the higheset.

Z: What causes the risk of relapse.  Is it incomplete conditioning>

N: There’s a great risk of relapse. Mostly it’s the biology of the disease. There are papers coming out on reduced intensity and myloablative conditioning.   We just recently saw — we haven’t published  yet — but we recently  looked at a large cohort and there’s not a ig differernece.   I think the intensity of conditioning myelofibrosisis is not so importat. The risk of relapse is more the biology of the disease. The more advanced the disease the higher risk. More blasts more anemia more history of transfusion dependency and so on

The transplant itself is only 4 weeks getting the graft into the patient but actually then the patient is discharged, They go back home but the process has onlystarted.. The immune system  should do the work. The could kill the residual myelofibrosis cells but they could  also induce GVH disease.

The double edged sword – Cure, relapse and GVHD

This is the double side of the sword. Graft  Versus Host DIsease can be dangerous but it can be very helpful. And we need a lot of experience, a lot of balancing to help patients  harness this effect. And you can nicely does this by look at the  Jak mutated patient or CALR or whatever.   Use this mtuaiton  to look in the peripheral blood and looking very closely to see if there is still residual myelofibroisis  or not  And if there is still residual MF you can reduce the immune system a bit  to get more of this immune system to the MF cells the leukemic cells  And so the post transplant monitoring and treatment is very important  to prevent relapse.

At the end if you have a lower risk of disease you have a lower risk of relapse if you have a higher risk of disease you have a higher risk of relapse   If you have a higher risk of disease and are also in bad condition or poorer condition then the risk of dying from therapy related causes is also higher

Z: That would related to GVHD as well?

N: Yah.  The GVHD is crucial  Not always deterimetnal but also good. Having a small mild GVHD is preventing relapse.  Therefore in some cases you should encourage it but it needs a lot of experience/   Its like playing with fire. IF you don’t take care it could be burning. You could lose control completely.   You should be very careful to get this effect therefore you need to see the patient in the beginning maybe once weekly or at least very frequently

Awareness and decision making

The most important thing is creating awareness… In the end it’s always an individual decision and the patient should be very well informed and should have the best option for their life and for what they wish.  And we should not say this is bad for you or you should do this. We’re trying to include the patient, to give them as much information as possible  but also to give them some help because for the patient it’s very difficult and they need some guidance. If they want to go this way then we say OK we go with you this way and we try to do our best.

Z: One sentence in that abstract had to do with a gain of greater than six months survival balanced against the quality of life (QOL) detriments imposed by SCT..

N: First of all the  QOL is an issue but’s really it’s not bad and it’s really becoming better.  We did a study together (WITH THE XXXX GROUP???) and they will submit something to ASH with Jeanne Palmer  howing how this QOL increases  over time with these patients.   If the patient survives for two yers then the quality of life is generally better than before the transplant  and can be even better than the general  population because the patient before transplanting had apretty bad QOL.

The Median is not the message.

Second is median survival.   In transplant you cannot compare the median survival.   if you look at the  score, the DIPSS S score in MF,  you start at 100 and then the curve goes slowly  down in High risk ir goes down fast.   But if you follow the curves very carefully you can see that it goes down. At the end you are at zero, If you say median survival you just check to see what happens where 50% of the patients are dying  and you look and can  say OK this is the median survivor.

In transplant if you see the curves go down in the beginning the curve is quite steep because this is therapy related mortality But then,  after one or two years, the curve turns becomes the plateau and there is no further death or relapse. The median survivor is not the best thing to compare the transplant .

I will see what happens in five years. And then because the transplant has no further relapse, it is significantly better. If you look only after one year than the transplant is worse because you have this Non Relapse Mortality which doesn’t exist for example in Intermediate risk.

This is the reason why it is so difficult to compare by median survival.

N: Here is the chart.  So if you open the first line it is just Risk Socring system according to DIPSS.

If you look at the right curve the Kaplan-Meir curve.. The HIgh Risk you can see the left side 0.5 at this time point 50% of the patients are alive and 50% of the patients are dead. Yeah?  If you go from this point and go down you can see this is about two years. That means at 0.5 all that is up have died already, what is down is still l alive  If you look at the Intermediate 2 curve you end up about 5 years.   You can see 50% is then dead,. 50% still alive. And you can see the curve is still going down.

Going down and 10 or 15 years is nearly zero. For this patient, just for argument sake, you always have two years and you have this five years.  And if you go to the next line. According to DIPPS the High Risk in the beginning, the blue one,  the curve goes steeply down.  If you look at 50% at 0.5 you end up at 2 years.  So if you just  look at Median survial you can say the median survival between transplant and non transplant is the same only about two years.  Here in contrast you can see the other 50%  plateau… no further patient nobody dying,..  Therefore if you compare transplant and nonptranplant you should not take the median survival.

Z:  You delivered this Presentation at EHA. in Stockholm (European Hematology Association).. Pretty much the same finidngs in MYSEC. (secondary myelofibrosis).  5-% High risk 2 years of 2.5 years..

To what do you attribute early death, to the therapy or to the condition of the patient primarily?

N:  It’s both.   We call it Non Relapsed Mortality (NRM)… which means actually all causes of death which are not caused by the disease.  It can be done by the treatment itself but if you are older if you get the transplant at 60 and die at 70 from a heart attack it’s also NRM.  In older patients NRM is always a bit higher because over the years expecially the likelihood of dying is higher in older than in younger patients.               …