Accredited webinar: Bridging gaps in PTLD care
Transcript: PTLD risk stratification and escalation planning
Supported by Pierre Fabre
Daan Dierickx, MD, PhD.
All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
So, please, Daan, your stage risk stratification. –Yeah, thank you very much, Nina. So, similar to other lymphoma subtypes, risk stratification is very important not only to predict prognosis but, as already told, also to guide first-line treatment. So, risk assessments should include disease-related, transplant-related, and patient-related factors. Disease burden, anatomical extent and performance status are actually covered in the traditional International Prognostic Index score. And in addition, involvement of particular sites, in particular the CNS, and the histological subtypes are of utmost importance for optimal treatment planning. When we focus on transplant-related factors, the type of transplantation is very important. So, it has been shown for rituximab-based therapy that thoracic organs have a poor prognosis compared to abdominal transplants when treated with rituximab therapy. This was shown in the PTLD-1 trial. Knowledge on previous rejection episodes, current immunosuppressive therapy, and graft function is also essential to guide the therapy. As you already know, reduction of immune suppression can be done more intensively when rescue organ-saving therapy is present, like, for example, dialysis in kidney transplant recipients. Whether EBV status is a prognostic factor remains still a matter of debate with controversial data. The PTLD-1 trial for example showed no difference in prognosis after rituximab-based first-line therapy when EBV-positive, CD20-positive PTLD was compared with EBV-negative, CD20-positive therapy. Several prognostic factors have been proposed but the problem is that most of them were only described in very small PTLD cohorts and, on the other hand, none of them has been validated in larger cohorts. So, at this point I think the traditional IPI score, which was initially in the '90s developed for aggressive lymphoma, still is the most reliable risk score awaiting, of course, new biomarker-driven risk approaches like, for example, cell-free DNA.
So based on this risk assessment, the optimal first-line treatment can be planned. Several questions need to be addressed. So, the first question is can immune suppression be safely reduced? Although no uniform guidelines actually exist, most physicians will agree to decrease the doses of the calcineurin inhibitors and stop the antimetabolites like mycophenolate and azathioprine. And as I already told, the degree of reduction of immune suppression is also organ dependent. So, the second question to be raised is whether risk alone is likely to be sufficient. Although I think limited disease and histological subtype, in particular, the non-destructive PTLD, might be treated with reduction of immune suppression alone, I think as Sylvain and Susan already told, I think rituximab is now often given in first line but, of course, together with a reduction of immune suppression, as I already said. Also, of course, histological subtype is important. So, for example, a Burkitt lymphoma, a Hodgkin lymphoma, I don't think it's a good idea to treat them with rituximab alone. For example, in Burkitt lymphoma you need more specific therapy in those very rare histological subtypes. So, the second question is should escalation planning begin at initiation? I think, yes, of course. In particular, if you have high-risk clinical features based on the stage or on the histological subtype, it's important to already think about escalation and then, as already told before, you have to think about EBV-directed therapies in case of EBV positivity. And the last question, is early rituximab-based therapy warranted? I think as I already told, in all CD20-positive disease, rituximab is now standard of care either alone or as part of a risk-stratified sequential treatment strategy. But once again, it's important to state that rituximab should always be given in addition to reduction of immune suppression. After start of the first-line treatment, response assessment, interim response assessment, is a further important step to determine the need for treatment escalation.
So, it was already told that serial EBV monitoring in EBV-positive cases is important and, of course, also the interim PET–CT using the Deauville criteria is currently a standard of care. So, in case of progressive disease, treatment plan should need to be changed and second-line treatment should be started as soon as possible. The use of other metabolic parameters, for example, the metabolic tumor volume, or replacing CT by, for example, whole-body MRI and the use of cell-free DNA are potential future assessment methods. So, based on this assessment, triggers for escalation include failure of reduction of immune suppression, inadequate response at that interim staging or early progression, which is mainly clinical, biochemical, or by means of the EBV serial monitoring. So, in conclusion, I think it's important to define response checkpoints very early and subsequently anticipate early referral requirements to discuss patient disease and transplant-related factors. Given the fact that there is often organ and an even life-threatening situation, it's very important to avoid any delay between identifying the need for second-line treatment and acting on the treatment failure. So, I thank you for your attention and happy to answer questions. –Thank you very much, Daan. I would like also to follow with the panel discussion, panel questions, and the first question goes to Sylvain. Sylvain, in the absence of universally adopted PTLD-specific risk model, which disease-, patient-, and transplant-related factors have the greatest influence on your initial treatment strategy? –Yeah, I would say that as Daan said that probably we have, thanks to the IPI, a good and simple and very known by the hematologist risk model for the PTLD, as we have for immunocompetent diffuse large B-cell lymphoma, but it will not directly induce us to choose the treatment at its beginning, it could be the same. But we have several aspects which tell us to be very careful with the patients, specifically the general status of the patients, the kinetics of the tumor, and if we have some organ dysfunctions like kidney, heart, or something like this because sometimes we won't have enough time to begin the treatment and so, as we said before, the time between diagnosis and treatment sometimes could be very important, I would say, specifically after allogeneic stem cell transplantation in which one day could be definitely very important and could lead to death if we do not begin very early the treatment. So, the time, the general status, a bit the IPI score but not so important, and graft dysfunction could be really essential for us to begin the treatment, to have at the beginning an idea of the chance for the patient to respond to first line and also for the rare cases which are not CD20-positive PTLD or very aggressive ones like Burkitt, in which the prognosis is a bit less good and the other one like plasmablastic, which we know really since the beginning that probably it will be difficult to have a good response.
Okay, thank you. The next question, Susan. How do you decide whether a patient is suitable for more conservative approach such as reduction of immunosuppression versus early rituximab-based or even more intensive treatment? –Sorry I missed the end of that. –How do you decide what type of therapy you provide to your patient, reduction, rituximab, or even more escalation at the beginning? –Yes. So in the hematopoietic transplant setting, if somebody is shown to have both viremia and PTLD, typically it's combination of reduction of immune suppression if you can do that with rituximab. We usually in the hematopoietic transplant setting do not depend on reduction of immune suppression alone. There are many patients for whom reduction in immune suppression is not something that can be done. These are patients who've had either recent graft-versus-host disease, in which case they're already tapering off steroids, but hastening that taper can frequently risk a flare of graft-versus-host disease. I think what we, the way we frequently approach this, is to understand that having both active graft-versus-host disease and PTLD at the same time is much higher risk than having, being on baseline immune suppression, controlling the graft-versus-host disease and treating the PTLD. So, I'd say in the hematopoietic transplant setting it can be very challenging to reduce immune suppression. If somebody is a little farther out from transplant, has never had graft-versus-host disease, then typically we will reduce the immune suppression, usually not tapering it off. At least in our practice we don't usually taper it off, but people will change the target of, for instance, a calcineurin inhibitor from the higher target to a lower target. I don't know if that's similar to what other people are doing.
Yeah, that's pretty similar. Thank you very much, Susan. –Daan, you mentioned already during presentation but maybe you can comment more in detail. At what point should escalation planning begin in PTLD, and which risk features would prompt you to prepare for treatment escalation from the outset? –I think that's an important question. Of course, if you have the interim PET scan, that's the moment you will escalate. But between start of the treatment and the interim assessment, you have of course the clinical point of view. So, if you have a patient who has growing lymph nodes or who progresses in an organ, it's important also. You have to follow the biochemical tests. So, if LDH is going up, you have to be aware of early progression and, as already told, for the EBV-positive cases, I think if you have a patient who has an increasing EBV viremia under rituximab therapy, I think it's a real warning sign to see if your imaging needs to be done earlier. –Okay. Thank you, and maybe a very brief short question and short answer please, Sylvain.
What findings during response assessment are most concerning for treatment failure? For the treatment failure, we have the imaging like PET–CT or MRI for CNS lymphoma as a reference for the response but sometime it's difficult to assess, but there are a reference, and as Daan Dierickx says, the clinical progression, the clinical aspect and presentation of the patient could also be very important and instructive for us to have the idea of progression. If we clearly see a progression of nodes, it's not necessary to wait for PET–CT to see that the treatment does not work and go directly to a second line. So, we have the clinical aspect and the imaging, MRI and PET for systemic PTLD. –Thank you so much.
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