Accredited webinar: Bridging gaps in PTLD care
Transcript: Anticipating second‑line PTLD care
Supported by Pierre Fabre
Sylvain Choquet, MD.
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I think it's a good point to think about anticipating second-line PTLD care, and with that I'll give to you your stage please, Sylvain. –Thank you. So, I will speak about a generality about eligibility and access, some troubles some days we have to treat this patient in second lines. Just to begin to have a general overview of the prognosis of second line, I mean relapsed/refractory PTLD, we have some data from several years ago, a few years ago, before the availability of anti-EBV CTL showing that EBV-positive PTLD in relapsed/refractory situations have a very poor prognosis. After allogeneic stem cell transplantation, it is less than 1 month, and after solid organ transplantation, it is around 4 months. So, clearly at this moment during which this study has been made, there was an unmet medical need. And so we need to have a precise diagnosis and to save time to treat these patients in second line. And there are different kinds of second-line situations. The classical one is, okay, we have done all the first line and the PET–CT shows that the patient relapsed or progressed or did not respond but sometimes the situation could be quite different. For example, for the few patients for which we just begin with decrease of immunosuppression, for example in non-destructive PTLD, at this time we have the second line in which we will be able to use rituximab like the first line in aggressive PTLD. So, in these situations we have a long time in front of us and so usually the prognosis is very good. We have a lot of options. In some other situations, it could be at the opposite more difficult. For example, we begin first line with rituximab, and normally in first line we know that the classical way to treat the PTLD if rituximab does not work is to use four cycles of R-CHOP. But, sometimes, there is a cardiac insufficiency or the bone marrow is too low, for example, after allogeneic stem cell transplantation. So, in these situations a failure of rituximab goes directly to second line.
So, it's very short, only 4 weeks after the beginning of treatment we have to decide if we use a second line or not. The other difficult situation are the graft dysfunctions, kidney insufficiency. So, we have some difficulties to choose a good treatment and to avoid some side effects, and also, sometimes, we have very few option or specific options to treat second line, for example, the rare plasmablastic PTLD, for which we do not have so many options, the T-cell PTLD with very, very poor prognosis and usually in second line it's very difficult to find some way to treat these patients, and CNS PTLD, for which R-CHOP is not a good treatment. So, we have specific treatment since few years to help us to treat in second line. So, in this specific PTLD, the second line will not be the same in front of the classical PTLD. Obviously, depending on the access to a specialist therapy in this very rare disease, it could be difficult to have the good choice very quickly. For example, if the transplant unit is not the same in which the diagnosis of PTLD will be made without any specialist of this rare disease. There is some different factor that influence the eligibility and the access for the second-line treatments. For the eligibility, to know if really we have to treat the patients and how but depending on the patients. The first one is very important, is the evaluation of the response of CNS PTLD because usually if you use classical way to have an idea of the response in immunocompetent patients, the classical criteria are not the same in immunodepressed patients. You can have still some gadolinium presence in these patients and so we have since 2 years a publication showing and proposing a new score to have a good evaluation of response of primary CNS lymphoma and to avoid to say it's a failure, we have to go to second line, and in fact usually it's a good response and you just have to wait. So, a good evaluation is very important. Second aspect is the referral. We have already spoken about this, the referral to specialist centers. It could be very important if you do not really know how to deal with PTLD to refer the patient to these centers or at least to make a regional or national multidisciplinary meeting. Obviously, the general status of the patient will help us to choose the treatments. The kidney and graft dysfunction already we have spoken about this.
The access of some treatments, we will see that, for example, tabelecleucel is not allowed and not reimbursed in all countries. So, it depends where you live, where the patient lives and if it is reimbursed or available or not. And for this treatment and others, for CAR-T for examples, we would know that we will have to wait some time for the manufacturing of the products, around 1 month for CAR-T cells, around 1 week for tabelecleucel. And there is also general affecting factors like availability of specialists, like we have already spoken about this, reimbursement of the treatments and the availability in your regions or in your country. And also, sometimes if the biopsy have been made outside your specialist units and you are not sure of the response, it could be important to have a specific pathology review of the biopsy by a specialist of PTLD to be sure that the first diagnosis was the good one and also to have the good markers like CD30, like EBV, made on the biopsy and, if it is not possible or you have still adapted, and it could be very important in a relapsed/refractory situation, it could be very important and useful to make a new biopsy. If you have in mind to use tabelecleucel, it could take some time to have the high-resolution HLA typing of the patient if he had a solid organ transplantation. So, it could be interesting since the beginning of the diagnosis to have this high-resolution HLA typing in case of relapsed/refractory status for these patients. And for the end we have some opportunities with new treatment, with new biological tools for us in PTLD treatments. And mainly these new options are risk-adapted and individualized treatments specifically for EBV in relapsed/refractory treatment with CTLs specific for EBV epitopes but also some antibodies against CD30, which could be effective in PTLD. We have not only chemotherapy to use in these treatments, it increases the help and the opportunities to treat the patients. And we have also new and very specific techniques to see very early if the patient responds or not. We have the PET–CT and MRI but we have also the EBV viral load and probably in the next future the circulating tumor DNA. We have also evolved our way to treat the patients. At the beginning, a few years ago, if the patient was not in complete response after the four rituximab we went directly to R-CHOP and since two publications we enlarged the possibility to use only rituximab in patients in partial response but with an initial IPI at less than 3. So, we increase the potential of keeping the patient without chemotherapy and still in first line. We clearly developed since 2 to 3 years ago the cellular therapy and specifically against EBV. We have new data using some treatments for which we do not have authorization for the use in PTLD, like brentuximab vedotin, but we have publications showing at least in a few cases that it is an option that could be very helpful for these patients.
And, as I told you a few minutes ago, we have new criteria to make good evaluation of CNS response. So, in conclusion we have clearly a good option, an improvement of the overall survival of patients, specifically when they are EBV-positive. So approximately 50% of solid organ transplanted patients and nearly all patients after allogeneic stem cell transplantation. We have some new antibodies. We have very few data but quite interesting with bispecific antibodies and also specifically for targeted therapy like BTK inhibitors that could be used in PTLD. So rare disease but more and more data to use and to help these patients. I thank you for your attention.
Thank you very much, Sylvain. I would like to invite you to the panel discussion and just give you the questions, Sylvain. You spoke about clinical, pathological and, response factors that prompt you to second-line therapy in PTLD. Does it vary across different PTLD subtypes and transplant settings? Can you comment on this? –Yes, for the response factors, there is only specific evaluation for primary CNS lymphoma, but for all the other PTLD, systemic PTLD, we can use PET–CT. This is probably the best way to make a good evaluation. And, after the question of second-line therapy, could be very difficult depending on the anatomic pathology of the patients and mainly for two markers to be very specific in second line. CD30 is very important and EBV status of the tumor is very important to use new treatment for them and the other kind of anatomic pathology setting. It depends. For T cells, we do not have so much idea to have good response in these patients. For Burkitt, we can look at what we have in immunocompetent patients. And for plasmablastic, we mix treatment from multiple myeloma and from lymphoma to try to have a good response. –Okay, thank you very much.
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