Transcription
[Music] Foreign. [Music] [Applause] [Music] So, we are ready to start. Participants, my name is Maria Rodriguez. I am the dissemination manager for Europe Blood Net, and it is my great pleasure to welcome you on behalf of Europe Blood Net to the Thursday webinar of Professor Olivier Tonnellier on Prolymphocytic Leukemia. A European online educational program targeting health professionals, organized by Europe.net. Thursday webinars are educational activities designed to promote interesting, highly innovative topics with the goal of disseminating the latest advances in hematological diseases through healthcare professionals. So, we will be attending a lecture on Prolymphocytic Leukemia, and so, the Iranians, please welcome the speaker of this today's session, Professor Olivier Tonnellier. Professor Olivier Tonnellier is a hematologist attending physician at the University Hospital of Clermont-Ferrand in France. He teaches hematology at the Clermont Auvergne University and he is the chairman of the T-cell Lymphoma Informative Community of LISEA and a member of the board of directors of the FILO group and of the board of the French Society of Hematology. His research is focused on clinical and translational research in B-cell lymphoma, T-cell Prolymphocytic Leukemia, Chronic Lymphocytic Leukemia, and Gray Zone Lymphoma. So, final harsh rules before starting. Still some technical information. The session is recorded because this session will be implemented in the European learning environment. So, if you are not comfortable with this, please turn off your camera. Also, please be advised that your microphone is muted. If you have any questions about the presentation, please write them down in the chat. They will be answering the questions in the question and answer session at the end of the webinar. You will find the chat at the bottom of the screen, at the cloud symbol. The Iranians, please welcome with me the speaker of today's session, Professor Tonnellier. Professor, the floor is yours.
Good afternoon, everybody. Thank you, Europe.net, for inviting me to give this webinar on T-cell Prolymphocytic Leukemia. There was some misunderstanding on the name of the topic, called T-lymphoproliferative Leukemia, which is not an existing entity. And we will clearly talk about T-cell Prolymphocytic Leukemia, which is T-PLL. These are my conflicts of interest. So, the learning objective of the webinar is to define what is T-PLL, how to diagnose T-PLL, and to give insight in its management, focusing on actual available tools. So, the clinical presentation. T-PLL has been recognized not so long ago. It was in 1973 by Daniel Catowsky, and this had been published in Lancet. It's a mature T-cell neoplasm arising from the adaptive immune system, and this is quite different to peripheral T-cell lymphoma or T-cell prolymphocytic lymphoma or TAL. So, it's a clinical presentation of a mature T-cell neoplasm. And these T-cell neoplasms, even in the same group of other peripheral or nodal T-cell lymphoma proliferations, but it's confined in the peripheral area of these mature T-cell neoplasm. This is a rare disease, two per million per year, and it's only 2% of mature leukemias.
So, the clinical presentation. Median age is around 65 to 70 years old. The typical presentation is acute, widely disseminated, with progressive lymphocytosis, which can reach extremely high levels, spleen enlargement, adenopathy, cytopenia, and B symptoms. The alternate presentation can occur. Some patients can have primary extranodal including involvement of pleural effusion, peripheral edema, skin lesions, CNS, more frequent at relapse. But usually, these extranodal involvement will occur with the typical presentation. And there is also very indolent forms, eventually evolving to more aggressive forms. The overall survival of this disease is short. The overall survival can be seen in other very severe cancers like pancreatic cancer. This overall survival here is a mix of patients who are frontline, relapse, and also patients with indolent initial form of the disease. So, it's important to have a look at some difference on survival depending on the status of the disease. As you can see, frontline patients will obviously have a longer survival than salvage patients, here 14.5 months compared to 4.4 months. And in indolent patients, there is a time to first progression of 2.3 months in this series. So, indolent forms can be diagnosed on, for example, on a blood count with very few symptoms, and such patients have a progression of 62% at 33 months. The median progression rate to an active form is 33 months. So, these indolent forms have a longer overall survival. But once the indolent form becomes aggressive, then the survival is the same as the aggressive form.
The clinical presentation here is a resume in the table. We have these median age around 60 to 70. And these. So, when you have patients with indolent form, 5% adenopathy. But when the form is active, it's around 50 to 60%. Splenomegaly is rare in indolent, more frequent in active form. Also skin involvement, hepatomegaly, effusion, and also cytopenias. So, in the indolent form, you have only 10% cytopenia. But it's up to 30 to 50% in active forms. So, T-PLL can develop in the context of Ataxia-Telangiectasia, which is an inherited disease with ATM and B and A mutation. And in this condition, there is cancer predisposition. Your respective French cohort of 278 ATM and AT patients with a follow-up of 15 years, we call there are 70 cancers with three T-PLL. So, the incidence of T-PLL is 68 per 100 million.
How do we do the diagnosis? The diagnosis is first based on cytology of the blood. And the classical type of T-PLL cell is in cytology, medium-sized with high nucleus-to-cytoplasm ratio, condensed chromatin, one visible nucleolus, and these particular blades around the cells. But there is variance in cytology here. So, these are clearly T-PLL. But here, there is CLL-like with a nuclear non-visible or only mildly visible. And here you can see the beginning of a blade. And there is also patients with irregular nucleus, either cerebriform or flower-shaped nucleus. And such T-PLL can be mistaken for Sezary or ATLL. Flow cytometry is a second major tool for diagnosis. Usually, you may need to have a rather complete panel to be sure of your diagnosis. Well, it's positive for CD3, possibly low negative for these two markers of maturity, CD71a and TdT. This is what these markers are positive in acute lymphoblastic leukemia, T-cell phenotype. So, this is a major tool for differentiating the two conditions. Positive for various, the form of CD45, positive for CD2, CD5, and CD7. No aberrant loss of positivity of these three T-cell markers with a variable expression of CD4 and CD8, with this very classic but not very frequent double positivity CD4, CD8. And there is rarely a double negativity of both. Clonality can now be done by flow cytometry using TRBC1. It can be really helpful if you have this on your panel. There are additional panel markers which can be very useful when the diagnosis is not sure, including the expression of CCR7, which is mostly alpha-beta, and CD52 can be important for treatment. And it's CD25 negative in 80%. And CD16 and CD56 negative, which is an important difference. TCL1 positivity is tricky in flow cytometry because you need to do permeabilization. Conversely, if you have tissue available, it's much easier by immunohistochemistry.
TCL1 is involved in the most frequent abnormality in cytogenetics of T-PLL. So, you have abnormal karyotype in more than 90% of cases and a complex karyotype in 70-80%. At the TCR locus at 14q11, it can be rearranged with the TCL1a and B genes in 70% of cases, and in less than 10% with the MTCP1 gene at Xq28. These are founding events and major diagnostic features of T-PLL. There is gain of 12 along with abnormality of chromosome 8 in 35% of cases. 70% of 11q23 deletion of ATM gene and 20 to 30% TP53 deletion or abnormality are frequent. The karyotype TP community complex in 73%. So, this is an interesting case of a 70-year-old woman with isolated, slowly progressive lymphocytosis which reached 5.5 in 2019. So, the cytology was medium-sized cells, highly T-cell, high NC, basophilia, nucleoli. The phenotype was CD3 positive, CD2 positive, CD5 positive, CD7 positive, CD4 positive, CD8 negative. Pan-T-cell diagnostic. And the result of the karyotype was 46 XX in 20 mitosis. Well, we had some trouble to do the diagnosis of this T-cell natural proliferation and had to do the karyotype. The proper mitogen here is 72 hours with IL2, CpG, which is used to do the karyotyping. Standard BCL was done routinely in our lab. But when you ask with the proper mitogen on the same patient on the same day, you have these very complex karyotypes with these abnormalities involving 14q11, 14q32, and abnormality of the chromosome 10. So, be careful of the condition of the karyotype, which can be tricky.
And back to the diagnostic procedure. So, based on clinic, cytology, cytometry, cytogenetics, FISH, you can apply the recently published criteria of the T-PLL ESG published in Blood by Philip Staber recently. And you have three major criteria: more than 5x10^9/L in the blood of T-PLL phenotyping typical cells, clonality, and abnormality of TCL1 or MTCP1 gene. These are the three major criteria. Then the diagnosis is done. But if you don't have these criteria, you can still make the diagnosis of T-PLL in the so-called TCL1 family negative T-PLL group, which is a heterogeneous group. Well, we will probably know more in the future of this kind of patients. And to clearly study such patients, we need more tools, including targeted NGS, extended flow cytometry, and tissue histology. What's inside one and relation in the CD for this year, the TCR, TCL1, and MTCP1. So, targeted NGS will uncover the molecular features of the disease. And the molecular landscape has been extensively studied by Helen Stenger and then by Shaffer. And there is these important frequency of ATM mutations and TP53 mutations, much less frequently, and also on the JAK-STAT pathway. So, on the STAT pathway, there are four described kind of mutations, not frequent IL2 or STAT5 mutations, but especially more frequent JAK1, JAK3, STAT5 mutations. STAT5 mutations are in the SH2 domain, while JAK1, the expression of the pseudo kinase domain. And there is some almost hotspot mutations, like the G295S mutation, conferring a particular possibility of the disease.
So, in summary, molecular landscape information. You have DNA damage repair defects in up to 100% of the cases, either ATM mutation and or deletion. Sorry, I have you can have TP53 mutation and or deletion, and both are virtually exclusive. There is 57-75% JAK-STAT pathway mutations, and there is also epigenetic mutations on other mutations, including CDKN1D deletion. So, Shaffer published a few years ago, proposed clonal evolution of T-PLL. The first step could be the alteration of TCL1 expression, which increased TCRL1 expression. And the second step, ATM mutation and loss. So, you have the healthy cell becoming a T-PLL with the consumption of ATM defect and TCL1 input. And then there is you have pre-leukemic cells, and you need more steps to become an active T-PLL. And these steps can be MLL rearrangement, loss of 17p, gain of 12, and especially gain of 12. And the last abnormalities are the mutations occurring in the JAK-STAT pathway.
So, the prognostic. As we mentioned earlier, the disease is aggressive with a poor survival. And prognostic is impacted, especially by these statistics. So, you have a patient who is in indolent form of T-PLL. This patient can have more than five years of overall survival in median. You have a patient with an active form, then obviously the survival is shorter. The same is with the not the same difference, but such difference can be seen also on the frontline, there's some salvage patients. So, when you look at the level of survival on the whole group of this rare disease, then we want to put every patient together to have a big series. And you have different kinds of patients with indolent form, frontline, and relapse. And obviously, such patients related to the disease that we have different survival. There have been attempts to describe some biological markers of aggressivity, including anemia, LDH, CD52, microglobulin, and TR3 mutations. But there is no clear and useful tool to predict in one group of disease statistic patients, like one group of first-time treatment, who will be the patient who will do poorly compared to the other. Maybe JAK3 computation is the most relevant.
Now, about the management. Patients with indolent course should not be given early treatment, but they need to have close follow-up because the disease can go from indolent to aggressive form rapidly from one appointment to the next appointment at six months. So, it's better to see at the minimum patients every six months with indolent T-PLL, no less, and to have blood count every three months, no less. Then patients with active disease are to be treated. And mostly the reason to treat the patients with T-PLL with your current constitutional symptoms, symptomatic bone marrow failure with anemia and progressive anemia, cytopenia, rapidly enlarging lymph node, spleen, and liver, rapidly increasing lymphocytosis, and extranodal involvement.
Okay, what are the treatment options? We have retrospective analysis showing first that in patients treated by CHOP or single agent alkylator or irradiation, the overall survival is below 12 months. In the early 90s, have been developed the pentostatin treatment. And here, as you can see, in patients in relapse after alkylator, you have a 40 to 40% overall response rate with a PFS of six months. And moreover, recently, in a 14-French cohort, published a series of 15 patients treated with bendamustine every three weeks. He's a 50% of overall survival, but this was both in relapsed refractory and frontline treatment. So, these two options are possible options of treatment of T-PLL. But as you can see, there is many groups and many well, there is literature on alemtuzumab. So, I will concentrate here on prospective trials on alemtuzumab-based treatment. So, as you know, alemtuzumab is an antibody directed against CD52. And this CD52 is constantly expressed by T-PLL. But the expression can be lost after anti-leukemic treatment. But and should be rechecked before any retreatment is expressed. And alemtuzumab-based treatment in all these prospective trials, frontline, the high overall survival here, you know, with these 32 patients treated by monotherapy, we have 91% of overall response rate, 81% complete response rate, and 35% of overall survival, 35% survival at 48 months, and 60, and the PFS of 67% at 12 months. So, in summary of alemtuzumab alone or in combination, frontline, you have the high overall response rate of at least 80 to 90% in the complete response rate of 80 to 90%, but with a PFS which is a little bit over one year, and overall survival which remains below four years.
It's a standard. We used alemtuzumab a lot in CLL during the year 2010 to 2015, before the arrival of BTK and BCL2 new routers. And so, we had learned a lot in the management of patients with CLL treated with alemtuzumab. And it's very important to provide patients supportive adapted supportive care. First of all, you have to manage infusion reactions to try to improve tolerance and then drug acceptability. And you don't want to stop drug after one week. So, we have to communicate with the patients about side effects a lot. Subcutaneous administration provides better tolerance for alemtuzumab versus IV, that's been shown by their building. You have to use a romper and also to use steroid etc. to manage the to mitigate the infusion reaction. Penicillin screening and prevention is mandatory, both pneumocystis jirovecii pneumonia, CMV, EBV reactivation, fungal disease, etc. You can have immune reconstitution syndrome for weeks after the end of alemtuzumab. You can have autoimmune disease. You can have a negative impact of T-cell and T-cell engraftment after allogeneic transplantation. Then you need to observe a washout of alemtuzumab but at least eight weeks between the end of alemtuzumab and allogeneic transplantation. And also, and last but not least, there is a constant risk of drug toxicity with this agent. So, the medical community has to stick together to maintain this drug available because we need this drug to treat T-PLL patients.
Long survivors for these entities have been described by Claire Durden, and her conclusion is that all these survivors beyond 72 months are those who receive consolidation with hematopoietic stem cell transplantation, either auto or allo. These patients were either frontline or relapse. 86% of patients. So, allogeneic transplantation has been reported retrospectively with the exception of these studies, which were prospective data collection and not really a clinical trial. And as you can see here, patients, so there is a wide range of years and of years of value. So, it's difficult to compare patients from supporting 20 years ago and now. But so, we have to be careful in making this comparison. And almost all patients had been pre-treated with alemtuzumab. The disease that used before transplantation was either CR, mostly CR, but somewhere in stable disease or progressive disease. And usually, there was an HLA matched. Usually, the donors were HLA matched and already the alternative donor. But there were some exceptions in the occurrence of patients who have been transplanted with mismatched donors or cord blood. Always violence. So, the overall TRM is 30% in all these series. There is an important rate of cumulative incidence of relapse of at least 40% with a 30 to 40% overall survival.
Thank you. These are two studies of the European Society of Transplantation. And this is a series of 2017. T-PLL, 63% with reduced intensity conditioning and radiotherapy. Considering conditioning. And here you have a 40 to 50%, 50% cumulative incidence of relapse. And if you compare to 285 cases of peripheral T-cell lymphoma from another major lymphoma, the cumulative incidence appears much higher in T-PLL than in PTCL. Well, you cannot ensure by doing this kind of cooperation, but some that there is something wrong in T-PLL. And this is also seen in other series. There is also the problem of non-relapse mortality, which is around 30% at least in all these series. Finally, we have this prospective data collection done by the EBMT and published by Victor Gergely. And patients were below 65 years old for almost all of them. They had mostly been transplanted in first complete remission, 22 in first PR, and very few patients in stable disease or progressive disease. And they all had almost all had been pre-treated with alemtuzumab with a median time of alemtuzumab with the role of 75 days. And here you can have a, there is a certificate, the habitual picture of this disease, 38% relapse rate, 42% of overall survival. With alemtuzumab, nothing. If you have 32% is a favorable TBI on the relapse rate and a longer interval between diagnosis and allo. For the numerals, not only two way, but no impact. I will end to zoom up when given below the 68. I find this result passing because there is a clear information provided in the CLL area with this EBMT analysis of more than 600 patients showing that with two weeks before allo, this very is associated with a much lower event-free survival, higher cumulative incidence of relapse, etc. And there is also no, there was a trend of the use of full conditioning on the trade. And here is this very big CIB and TR analysis, the MAC, the full conditioning, these much less survival than the position.
So, and finally, I will give you this drug development example of what can be done based on NGS. And this is a recent report of Xiang in 2021 in 15 patients treated by a JAK inhibitor. They were almost all in relapse, and almost all they were all either ineligible, refractory. Sorry, here it's another ineligible patients. And overall response rate is 73%. And there is in this retrospective analysis, which is not a clear clinical trial, a potential impact of JAK-STAT pathway mutational status on the progression-free survival. As you can see, there is patients who are still in remission after one year. I have one of these patients still in remission after almost two years of the combination of ruxolitinib and venetoclax. And this patient had been treated by. So, in conclusion, T-PLL is a clear entity. Diagnosis is based on 4C: clinic, cytology, cytometry, cytogenetics, and it's good to apply consensus criteria published in Blood in 2019. There is an aggressive behavior and a prognostic, but possible. And all indolent forms submitted to close watch follow-up. Molecular landscape has been extensively characterized, and there is to know the abilities and targetable mutations. The example of JAK mutations, STAT reduction, include alemtuzumab, pentostatin for frontline, higher response rate, but with a PFS just below one year and overall survival which is below four years. And you have to use this drug description. And then allogeneic transplantation remains the only curative option. It's an overall survival of 30 to 40%, but a high relapse rate around 40%. And autologous transplantation is just mentioned here, but has been clearly underreported.
And I will finish with recommendations. These recommendations have been copied by Claire Durden and Ash in 2015. So, wait and watch in indolent phase. Frontline alemtuzumab plus fludarabine and allogeneic transplantation with auto or allo. Ineligible patients and in relapsed refractory patients, you can repeat the alemtuzumab if the patient is CD52 positive. You can still have 50 to 60% response rate at a shorter duration of response. You can use bendamustine and you can try to use experimental agents. And of course, consider SCT if not done before. And I propose this RTNA, this optimization of clarity and proposal. So, in patients with frontline below 70 years old, original, you have to consider allo at first response. And then you have to contact immediately the center with the allo. It can be your center, it can be another center, but you have to be quick to contact the center to begin your donor search at the same time. It's good to send a sample for NGS. It can be useful at relapse and also try to prepare a way to follow MRD afterwards. And at 10 weeks of alemtuzumab response evaluation, donor check, you have a donor, you are in CR, PR, or in MRD depending on the possibility. You will add pentostatin. But in patients with CR, PR, it's this addition of pentostatin is used as a bridge to allow to do the washout of alemtuzumab. But in patients with no response or progressive disease, plan to study added to alemtuzumab can increase significantly available to the lab and induce to obtain a response. And at the time of allo, the choice of TBI is a matter of centers. I am not absolutely not sure of the impact of TBI on the results. And I conversely think that MRD and primarily monitoring by flow cytometry is very important. The post-transplant to monitor the CSA, SQL store in tacrolimus, and the use of Tri. So, I thank you very much for. Oh, sorry, these are the take-home messages. So, first, let me say it is T-PLL. Diagnosis is based on 4C with a demonstration of TCL1 or MTCP1 gene implication. Two, molecular landscape has been well described. Above and beyond TCL1 or MTCP1 rearrangement, discovering potential targetable mutations. These landscape include very frequent ATM mutations and deletion, and frequent mutations on JAK-STAT pathway. Three, aggressive forms and prognostic identity. Alemtuzumab remain a standard treatment with a PFS just below, a little bit above one year. But allogeneic transplantation, only curative option, should be considered in individual patients. I thank you very much. So, you have to. I am ready to answer your questions. And I have to have a look at the chat if there is a question in the chat. So, the audience, we encourage you to start writing all your questions in the chat. We will leave you five minutes, five minutes to write them. Thank you so much. And also, thank you so much, Professor Tonnellier, for this amazing presentation. There is a first question, Professor. Yep. Yes. The question is, how does the therapy with CD52 impact the detection of T-PLL MRD by flow cytometry?
It's, there is a CR you can obtain a CR using alemtuzumab in T-PLL. And there is not, and in CLL, when you obtain a negative MRD by assessed by flow cytometry, you had an extended overall survival. There is a demonstration of the impact of the negative MRD in T-PLL, has an impact. But this demonstration has not been made like in CLL, especially in the context of combination therapy. The MRD assessment in T-PLL is important when this MRD is used to monitor a treatment, like when it can be. And then the example is that MRD assessment can help you to manage the immunosuppression after allogeneic transplantation. So, if you have persistent positive MRD or raising MRD after allo, that's the time to add something. First, if you have something, let me to add a JAK inhibitor, maybe to taper the dose of cyclophosphamide.
Quickly, for example, if there is no GVHD. But usually, the duration of alemtuzumab is 12 to 16 weeks. And we stop. We will wait three more minutes. So, please write all your questions in the chat. Thank you. So, I think there is no more questions from the audience. So, we're going to finalize this amazing presentation. So, Professor Tonnellier, thank you so much for this interesting presentation and discussion. And before the closing, I would like to remind the audience to answer the survey that we will be sent to you after the in few minutes. And moreover, I do not forget to follow us on social media channels to be updated on the last learning advances. So, thank you so much, everybody. Good afternoon. Thank you. Thank you so much. [Music] [Music]