Program curriculum developed and presented by: IZIDORE LOSSOS, MD

Transcription

1 Program curriculum developed and presented by: IZIDORE LOSSOS, MD Professor of Medicine, University of Miami Director, Lymphoma Program Sylvester Comprehensive Cancer Center, Miami, FL SONALI M. SMITH, MD Associate Professor, Section of Hematology/Oncology Director, Lymphoma Program The University of Chicago, Chicago, IL

2 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 2 Evolving Treatment Strategies for MANTLE CELL LYMPHOMA in Elderly Patients Slide 1: [Title] Izidore Lossos, MD: Welcome to the CME-certified webcourse, Evolving Treatment Strategies for Mantle Cell Lymphoma in the Elderly Patient. This educational activity is jointly provided by the Potomac Center for Medical Education and Rockpointe Oncology, and supported by an independent educational grant from Celgene Corporation and Millennium, the Takeda Oncology Company. Slide 2: Steering Committee My name is Izidore Lossos. I m Director of Lymphoma Program at the Sylvester Comprehensive Cancer Center at University of Miami. I am pleased to be joined today by my colleague Sonali Smith, Director of Lymphoma Program at the University of Chicago. Slide 3: Disclosures Disclosures are shown on this slide. Slide 4: Learning Objectives The learning objectives of this educational activity: At the conclusion of this activity, participants should be able to review diagnostic and prognostic considerations in mantle cell lymphoma; evaluate emerging and evidence-based frontline approaches for elderly patients with mantle cell lymphoma; and review the current and emerging treatments in the relapsed/refractory setting of patients of mantle cell lymphoma. Slide 5: MCL Incidence Mantle cell lymphoma is one of the subtypes of non-hodgkin lymphoma, accounting for approximately 6%-8% of all the non-hodgkin lymphoma cases diagnosed in the United States. Slide 6: MCL-Epidemiology The mean annual incidence of this disease is two to three cases per 1,000 patient population per year. And in the United States, we usually see between 3,000 to 3,500 new cases; while in Europe, approximately 4,000 cases. The disease is more predominant in males, with frequency of 4 to 1 in majority of its patients. Median age of the diagnosis is around 68. Slide 7: [Subtitle] In this CME activity, we will discuss approach to mantle cell lymphoma in a newly diagnosed elderly patient, initially, and then we ll discuss the approach to relapsed patients. So let s start with a newly diagnosed elderly patient. And I will present a case that I have seen and treated in my clinic during the last year. Slide 8: Newly Diagnosed Elderly Patient An 80-year-old white female complains on progressive shortness of breath without any additional new symptoms. On specific information, the patient denies presence of B symptoms.

3 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 3 Slide 9: Past Medical History Her past medical history was remarkable for bradycardia due to sick sinus syndrome, with intermittent paroxysmal atrial fibrillation, and she was on chronic anticoagulation and had a pacemaker. She also had a history of hypertension, chronic obstructive pulmonary disease, hypothyroidism, and surgery for short small-bowel syndrome obstruction that resulted in short, small-bowel syndrome following resection of gall bladder and small bowel. Slide 10: Physical Examination On physical examination, when I have seen the patient initially, a physical examination was remarkable for the following findings: On the lungs, there were clear sounds on auscultation, but there was evidence of bilateral dullness in the lung bases, more on left than on the right, with decreased air entrance and decreased egophony. There was also finding of a small non-rubbery lymph node measuring one over one centimeter in the upper anterior neck, bilaterally. No additional lymphadenopathy was appreciated on physical examination. Slide 11: Laboratory On routine laboratory work-up, we discovered white blood cell count of 8,300 with hemoglobin of 11.4; platelet count of 242,000. LDH was in the normal range. And beta2 microglobulin was slightly elevated 3 milligrams per deciliter. Slide 12: Peripheral Smear Examination of peripheral blood smear, as we usually do in all the newly resected patients with potential hematological diagnosis, disclosed presence of rare but easily detectable cell, as you can see on this slide. The cell is well larger than red blood cells, as you see on the slide. They contain hyperchromatic nucleus with very, very prominent nucleoli. The nuclear to the plasma ratio was high and, clearly, it was abnormal cell. More importantly, there was quite variability in the appearance of this abnormal cell on peripheral blood smear. Slide 13: CT Scan/PET CAT scan and PET scans were performed and they revealed presence of bilateral pleural effusion, presence of axillary gastrohepatic, porta hepatic, peri-pancreatic, and para-aortic lymph nodes. All of her lymph nodes measured up to three over two over five centimeters. On this slide, as you can see, you can see everything of lymph nodes in the mediastinal and the lateral pleural effusion. Slide 14: Question 1 At this point of time, I would like to ask, Sonali, what other test would you perform to make a diagnosis? Bone marrow biopsy and aspiration, lymph node biopsy, pleural tap, flow cytometry of peripheral blood, or all of the above? How you would do it if you would see such a patient in your clinic? Sonali M. Smith, MD: Well, first of all, thank you for presenting such a great case that brings up a lot of very important points diagnostically and also as it comes to treatment, which we will get to in just a little bit. But just if I can comment on the case for a moment, this is, in some ways, a very typical patient in that she is elderly, she is frail, she has disseminated disease, and, of course, has the comorbidities including cardiac dysfunction that is going to have an impact on our discussion down the line.

4 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 4 On the other hand, the things that are a bit atypical is that she is female as opposed to male and, of course, has additional less common toxicities including part of her GI tract being resected. So all of these issues that play into some of the management decisions. For our practice, when we have somebody with a newly diagnosed hematologic malignancy, we do the same thing. We look at the blood smear. We note that she does have these atypical lymphocytes. But I do think that the key diagnostic material for her will be a lymph node biopsy. Now, some people could argue that doing just flow cytometry alone, particularly if has the the key and seminal features of mantle cell lymphoma -- such as cyclin D1 overexpression, the CD5 co-expressed with CD20 -- could be very helpful and may mean that the lymph node biopsy won t be necessarily to make the diagnosis. However, in our practice, we would do that for a couple of reasons. One is, as we may discuss, that the lymph node biopsy gives us a little bit of information about the proliferation of the disease, which is very important prognostically. In terms of the remainder of the tests that are here, we would do a bone marrow biopsy and aspiration to get an idea of marrow reserve and, particularly in an 80 year-old, to make sure that there is no other disorder -- for example, previously undetected myelodysplasia or hypocellularity -- that might compromise our ability to give any type of treatment. So we would do a bone marrow biopsy and aspiration. We would do a lymph node biopsy to confirm the diagnosis and get some information on proliferation. In terms of the pleural tap, I think, because she is symptomatic, that is something that could be considered if it is safe. On the other hand, it may be that many patients with mantle cell lymphoma, once therapy is started, there is a relatively quick resolution of symptoms. So I think the pleural tap is the one thing on here that I would perhaps think twice about. And I would go ahead with the flow cytometry, as well. So I m leaning towards all of the above, but perhaps the pleural tap I would wait and see, depending on how she looks clinically and how quickly treatment could get started. Dr. Lossos: Thank you, Sonali. So I absolutely agree with you about your approach. In this specific patient, we did a slightly different approach, and I will explain why. First of all, her lymph nodes, on physical examination, were quite not impressive. And the accessible lymph nodes that could be biopsied were internal lymph nodes, so they are not easily approachable lymph nodes. So in all the other patients, when we have peripheral lymph nodes that are really accessible for open biopsy, we do a biopsy. But, in this case, because of the fragility of the patient and the fact that it would entail a CT-guided biopsy that would give us only small call and also may risk the patient because the majority of the lymph nodes were in the mediastinum, we decided to proceed, first of all, with all the other tests. And only in the case that we would not have a diagnosis, we will proceed with lymph node biopsy. I explained it to the patient. Now, with regard to the pleural tap, as we will discuss later on, pulmonary involvement in mantle cell lymphoma is not well reported; it is reported only in a few series. And, therefore, when I saw this patient in the clinic, and despite the fact that I know that pulmonary and pleural involvement may be part of the presentation, we usually like to rule out additional disease, additional potential disease, so that is why we decided to pursue, also, this pleural tap. Slide 15: Diagnostic Tests

5 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 5 So we performed the pleural tap, flow cytometry of peripheral blood, and bone marrow biopsy and aspiration that all demonstrated identical findings. Presence of B cells was well as CD20- positive, CD19-positive, CD5-positive, FMC7-positive. They were negative for CD23, important for discrimination from CLL. And, once again, very importantly, by immunohistochemistry, the cells were all cyclin D1-positive. Ki67 expression was present in 15% of the cells. And we will discuss in a moment what is important. And, once again, when you have the potential patient with mantle cell lymphoma, frequently, to come from the degree of mantle cell lymphoma, you perform the FISH test for classification 11;14; this includes resecting the cyclin D1 gene, as is shown on the slide and it was positive in the majority of the cells. Dr. Smith: Before you go to the next slide, Izidore, may I ask one question? The Ki67 that was done, was that done on the bone marrow biopsy or on the percentage, or how was that performed? Dr. Lossos: It was done on the bone marrow biopsy, and it was also done with cytospin from the pleural effusion cells, and we stained the cytospin cells for the Ki67. But I absolutely agree with you, that the best estimation of Ki67 is usually achieved in the lingual, and it is a very, very good point. Slide 16: Classical MCL Immunophenotype OK, so all these tests suggested to us that we are dealing with a patient with mantle cell lymphoma. And why? Because the entirety of the patient s cells expressed classical immunophenotype of mantle cell lymphoma that is characterized by CD19 and CD20 positivity, usually, the cells expressed cell immunoglobulin IgM and IgD. They are almost always FMCpositive, and they usually express cyclin D2 in their cytoplasm. And it is very, very important that normal lymphocytes are usually cyclin D1-negative. Majority of the mantle cell lymphoma is expressed more commonly light chain lambda than kappa. And, for differentiation from other malignancies, especially what we call small intermediate lymphoma, it is important to rule out possibility of follicular lymphoma CLS, so stains for CD10 and BCL6 are usually that are usually markers of germinal center-originated tumors. And CD23 for differentiation from CLS are usually done and should be. It should be remembered that, in the rare cases of blastic transformation or blastic presentation of mantle cell lymphoma, the cells may be CD23-positive and may express CD10 on their surface. So in these cases of blastoid variance, it should not lead to exclusion of possibility of mantle cell lymphoma. Slide 17: Cyclin D1-negative MCL It is also very important to remember that the diagnosis cannot be solely based on expression of cyclin D1 or presence of complication 11;14 because, on rare occasions, the counts are less than 5% of mantle cell lymphoma, these cases may be negative for cyclin D1 and usually have histopathology of typical mantle cell lymphoma. More importantly, in studies that I will show in a moment that have gene expression profiles classical for mantle cell lymphoma, but they lack the classical complication of cyclin D1. And from studies that were published in the literature, it appears that these specific and rare cases usually overexpress cyclin D2 or D3 that pathophysiologically contributed to the disease.

6 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 6 Dr. Smith: But if you do have a case of cyclin D1-negative mantle cell lymphoma that you confirm with either SOX11 or cyclin D2 and the morphology, do you approach them in the same way? Is there any prognostic importance to the fact that cyclin D1 is negative? Dr. Lossos: So we approach it with the same way the reality in which there is no clear-cut data to show if these cases have a worse outcome or not. These cases vary, so we don t have a good large series to compare. But, based on my experience, usually, they don t behave differently than the classical. What is more important here is to remember that, especially in non-academic institutions, pathologists very frequently will make diagnosis of mantle cell lymphoma only if the cells express cyclin D1 or whenever the translocation 11;14. And that should not be the case because, in these cases, you will miss these rare cases that are clinically, classically mantle cell lymphoma but they don t have the translocation. And only experienced hematopathologists may suspect that, despite the absence of expression of cyclin D1, these cells can directly represent mantle cell lymphoma. Dr. Smith: I completely agree with that. Slide 18: MCL: Distinct gene expression signatures Dr. Lossos: OK, as I promised, on this slide, you can see studies that were established by Andreas Rosenwald and analyze a cohort of mantle cell lymphoma patients, and compare gene expression to small lymphocytic lymphoma and subtypes of different types of lymphoma, and identify a signature of 42 genes that are quite different and remarkably different for all the subtypes. But, more importantly, for our discussion today, on the right side, if you will compare gene expression of cyclin D1-positive and cyclin D1-negative mantle cell lymphoma, you will see that these cases have identical gene expression patterns. But they indeed lack cyclin D1 expression and cyclin D1-negative cases but overexpressed other cyclins. Slide 19: Case Summary So, til now, I presented to you an 80 year-old symptomatic patient -- as Sonali said, quite symptomatic -- with stage IV-A disease, with MIPI mantle cell lymphoma, International Prognostic Index of 6.4, high rate. Slide 20: MIPI So what is MIPI? It is very important, clinically to calculate the prognostic parcel that was first published by Hostel from Europe, that is best in contrast to IPI that is usually used first in lymphomas on the following clinical parameters: age, ECOG performance status, LDH levels in the blood compared to the upper-normal level, and white blood cell count total white blood cell count, not the malignant white blood cell count. Each of these markers have several potential subclasses. For example, age you have four categories, ECOG performance status you have two different categories, and you give one point to each of them. And, by calculating the number of these points, you are getting to the MIPI. This is a simplified version of the MIPI, but more precise version of the MIPI can be achieved through access to the Web, or there is even an app, a website that is shown on this slide. So we usually have an app on our cell phones, and we calculate the MIPI in the clinic using the actual MIPI, not the simplified MIPI. What are you doing, Sonali, using your median? Dr. Smith: Yeah, we do the same thing. We go to the Web and we calculate the MIPI. But I wanted to emphasize what you had said, which is that the white count is the total white count and not the degree of lymphocytosis. That has come up a couple of times just in terms of

7 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 7 calculating the MIPI. But this calculator version that s on the Net is very easy to use and gives you a very quick read-out, immediately. Slide 21: MIPI PFS Dr. Lossos: Yeah, I agree. And what s important is the MIPI, so this is one of representative multiply published survival curves of mantle cell lymphoma patients that were subdivided based on the MIPI, into the three categories: low risk, intermediate risk, and high risk. And you can easily appreciate that patients with the high-risk MIPI have significantly worse outcomes than patients with the low-risk MIPI. in this specific case for progression-free survival, but it also applies for overall survival. Slide 22: Biological MIPI Now, cyclin D1 is a protein that is involved in regulation of cell proliferation. And that s one of the pathognomonic features of the disease. There are more advanced cases when the expression of the protein is high, and we expect that the cells will be more fragile. So that s why you can, in reality, try to introduce this biological parameter into the clinical MIPI and combine clinical MIPI with Ki67 expression, and then you re getting the subproliferation MIPI or biological MIPI that now includes the same clinical parameters but also Ki67 level, but, in reality, it gives you very, very similar results, once again, with high-risk patients, the highest clinical risk patients, usually with high Ki67 expression. But it better refines the different subtypes and we usually try to get Ki67 levels on every patient. I assume that you do the same. Dr. Smith: We do. And, you know, it actually is a source of discussion. Again, when we get to management, we know that having a very high proliferation rate by the Ki67 is an adverse prognostic factor, but it does not yet direct the specific therapy. And I think that s the source for a lot of debate, at least in our group, is that we often will have somebody with a high MIPI and a high proliferation rate, and the question is how to treat them differently. So I think all of these tools are very, very helpful. I think they re very important to think about for each individual patient. But when it comes to directing therapy, I think that s where we don t know exactly how to use these. But they are very important, prognostically. Dr. Lossos: I absolutely agree with you. In reality, based on the literature that, once again, we will discuss later on, in reality, the efficacy of the current therapies are not as great in the highrisk patients as in the lower-risk patients. So even despite the fact that you will identify this patient and deal with our current treatment paradigm, we do not have good choices of therapy for these adverse patients with nodular clinical and biologic parameters. Slide 23: Specific Diagnostic Features What I want to emphasize during this presentation is that, once again, as we already discussed, it is very important to look for peripheral blood involvement in this disease. And, if you do it carefully, you will see it in 60% of your patients simply by taking a blood smear and going under a microscope without any use of flow cytometry or immunohistochemistry. As I already mentioned with regard to this specific patient, the fact that it is not commonly recognized but, in our study that was published but also other studies, pulmonary involvement and pleural involvement is quite common. We observed it in 27% of our patients. It should be remembered that CNS involvement is relative, and gastrointestinal involvement is very common in this disease. And if you perform specific studies using colonoscopy or endoscopy on routine patients, you will discover it in 60% of the cases, usually microscopic involvement.

8 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 8 So I have a question to you here. What is your experience with pulmonary and pleural involvement in mantle cell lymphoma? And do you routinely do endoscopies and colonoscopies on your mantle cell lymphoma patients? Dr. Smith: And those are two very, very good questions. The pulmonary and the pleural involvement I think this is a fair assessment. We see it somewhere between one-fourth and one-third of the time, that there will either be small pleural effusions or there will be some component of shortness of breath due to the disease. We have not done the thoracentesis unless, as we were discussing earlier, we feel that it is so imminent that we don t have time for the therapy to be involved. But I appreciate your perspective on doing the thoracentesis and proving that that is involved. I think that is very helpful. So we consider it but we probably don t do it as often as we see the involvement. The harder question is really on the frequency and the need for doing a colonoscopy. We ve had things happen in both ways. On one hand, we have had patients having a routine colonoscopy be diagnosed with mantle cell lymphoma, and, in that case, the colonoscopy has been done. And then we have other patients where, you know, we discuss whether or not to do the colonoscopy as part of the routine evaluation. And I would say, most of the time, we do perform that, partly because we would like to know the extent of GI involvement. It is not very common to have a perforation related to mantle cell lymphoma, but, occasionally, we will do that. And then just a last point I would make on this slide is that the CNS involvement is rare, and the only time we would consider doing a spinal tap or CNS prophylaxis is if we have the blastoid variant, a very high LDH, or multiple risk factors for CNS involvement. But, otherwise, we do not routinely perform a lumbar puncture in our patients with mantle cell lymphoma. Dr. Lossos: Oh, I absolutely agree with you. We also usually don t perform routine lumbar puncture, only if we have symptomatic patients. So, in my practice, I never have seen a mantle cell lymphoma patient without symptoms neurological symptoms that had involvement of CNS in presentation that relapsed into different remission. Regarding gastrointestinal involvement, on clinical trials, we usually routinely perform colonoscopies and/or endoscopies on all these patients in clinical practice, also the clinical trials. If the patient is asymptomatic, we don t do it routinely. Slide 24: MCL-Treatment Dr. Lossos: So the next question is treatment. What is the current therapy for mantle cell lymphoma? So, unfortunately, the disease is still incurable with the standard therapy. And despite the fact that median survival is improving with the current therapy, the majority of patients still remain resistant to disease, they relapse and eventually die. Slide 25: Question 2 So here, I will ask you the second question. Which of the following treatment options would be appropriate for an unfit, newly diagnosed patient, like in this case, that is not transplant-eligible, and recent development of B symptoms?

9 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 9 So I have four options. And, Sonali, let me ask you to try to address it, how you will discuss the potential therapy for such a patient. Dr. Smith: Yes, you ve listed all the important options on here. So I can go through them one at a time and just talk through how we might approach it. So, again, remembering that this is an elderly, unfit patient where transplant is not going to be part of the discussion, there are several different things we would consider. In terms of watching and wait, I don t think this patient or anybody who has symptoms should be observed. I think watch and wait is really restricted to the indolent subtype of mantle cell lymphoma, which I think we re going to discuss. But this is a group of patients that has a relatively favorable outcome and presents, clinically, more like a CLL with lymphocytosis and splenomegaly. Now, this patient has dyspnea on exertion, and she has widespread adenopathy and pleural effusions, and she would not be appropriate for option number one. I like option number two the bendamustine and rituximab. Even though bendamustine is a cytotoxic agent, there is a dose range. Sometimes, for our very elderly and frail patients, we will start at 70 milligrams/meter 2, but 90 milligrams/meter 2 is also, I think, a very well-tolerated and reasonable dose when combined with rituximab. I think challenge to option number two is whether or not there is a role for maintenance rituximab after bendamustine and rituximab. Much of the maintenance data in mantle cell lymphoma has been after other regimens such as R-CHOP or others, and so, after bendamustine and rituximab I think that is something we can discuss. But I would certainly favor bendamustine and rituximab for this particular patient. And although option number three is very reasonable for a non-transplant patient, she had cardiac disease. And I would favor bendamustine-rituximab over an anthracycline-containing regimen. And then, although option number four is very intriguing, this is yet to be proven in a front-line setting for a large number of patients. Dr. Lossos: I absolutely agree with your discussion. And, in reality, for this specific case, as you discussed, my choice was to use bendamustine with the rituximab. And, once again, the question of maintenance rituximab in this setting. We have an answer for R-CHOP patients, but we usually extrapolate. So the choice of therapy for this specific case was entirely to bendamustine. And I will show you in a minute why, based on the literature, that was the decision. While doing it in this specific case, I knew immediately that I m going to see the problem, because this patient already had a short-bowel syndrome with frequent bowel movements, and one of the most common side effects of bendamustine is diarrhea. So I knew and I explained it to the patient that we may be facing problems with gastrointestinal movements, as indeed happened. So what other treatments for newly diagnosed transplant-ineligible elderly mantle cell lymphoma patients? Slide 26: Treatment of Newly Diagnosed

10 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 10 When you approach such a patient, the first thing that you need to assess is the sickness of the patient. If the patient is sick, and sickness is not only the performance status; it is their activity, it is other diseases, it is mental status, presence of Alzheimer s. This goes on and on. If the patients are sick, even worse, if the patient is frail, and very important to discriminate the classical mantle cell lymphoma from indolent and leukemic phase, as I will discuss here shortly. So, for the sick patient, usually, it is suggested to use conventional chemotherapy toxins followed by maintenance with rituximab that was established with R-CHOP therapy. But many people using these other therapies and, today, we will discuss R-CHOP data, bendamustinerituximab data. And I will also mention R-CHOP followed by Yttrium and the VcR-CVAD data. In unsick patients that do not tolerate toxic chemotherapy, usually, we don t use R-CHOP, so these choices are to use bendamustine-rituximab, as was used in this patient, or you can go and use R-CVP or R- chlorambucil. By knowing the response that you will expect will be significantly at lower rate and of shortened range. In the frail patient, they usually can tolerate rituximab- chlorambucil and maybe the newly agents like ibrutinib -- that we still don t have data in prospective trials for this may be useful for this population. Slide 27: R-CHOP for MCL OK, so let s review a few of the studies that help us to guide our decisions on the treatment. So, Howard made a use of R-CHOP for mantle cell lymphoma in 40 patients. And this should be noted that this is not only elderly patients. The complete response rate in this study was 48%, and partial response rate was 48%. But what was discouraging here was that the progressionfree survival in this group of patients was only 16.6 months. So the majority of the patients developed relapse within a year. And there are in this specific study, they did not observe difference in progression-free survival between patients that achieved molecular CR or not. Slide 28: CHOP vs R-CHOP in MCL The last published study that compared CHOP vs R-CHOP in mantle cell lymphoma. It was one of the few randomized studies in mantle cell lymphoma. A total of 151 patients were enrolled and were randomized to R-CHOP vs CHOP. Slide 29: CHOP vs R-CHOP in MCL In this study, it was shown that R-CHOP therapy was significantly superior to CHOP in terms of overall response rate and complete response rate. However, unfortunately and surprisingly, in contrast to other lymphomas, there was no difference in progression-free survival and definitely not in overall survival. And, once again, important to remember this study was including also younger patients. Slide 30: StiL: BR vs. R-CHOP Recently, Rummel presented and published data from a StiL Study. Therefore, in reality, study that compared therapy with bendamustine-rituximab vs rituximab-chop in indolent and mantle cell lymphoma patients. And, for today s presentations, we will focus on mantle cell lymphoma. Primary endpoint of this study was to prove a non-inferiority of BR vs R-CHOP in event-free survival. Slide 31: Comparison BR vs R-CHOP

11 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 11 And as can be seen in this survival data, treatment with bendamustine-rituximab vs R-CHOP demonstrate superior and statistically significant improvement in progression-free survival. There was no difference in overall survival. And that is one of the studies, in reality, suggests to us that bendamustine-rituximab may be a better therapy in this patient population, and that is why we more frequently choose bendamustine-rituximab vs R-CHOP. Sonali, what do you choose, usually -- R-CHOP or R-bendamustine? Dr. Smith: We have a very similar approach to what you re saying. When our team has looked at this data, and when I interpret this data, again, the non-inferiority was the primary endpoint. So to be able to show superiority in that type of a setting suggests that BR is really a very important and very active regimen in this setting. We would choose BR over R-CHOP for most patients based on not just the PFS advantage that we see here but also because, this way, you avoid not only the anthracycline but also the vinca alkaloid and the steroids, which symptomatically have significant effects both in the short-term and in the long-term. But I wouldn t say we use it for everybody. There are still some patients where R-CHOP and maintenance rituximab, would be appropriate. But for most of our patients, we do the same as you. We would select bendamustine and rituximab for this type of a patient. Dr. Lossos: I agree with you. Slide 32: BRIGHT Trial BRIGHT Study that published this year in Blood was another study that tried to compare outcomes of patients with indolent lymphomas and mantle cell lymphoma that were strictly the BR vs R-CHOP or the BR vs R-CVP. It was a complex design, but we will concentrate only on the results of this study with regard to mantle cell lymphoma. Slide 33: BRIGHT Trial Only 67 patients with mantle cell lymphoma were included in this study, and 34 were treated with BR, and 33 were treated with other agents. As you can see in the last row, the CR rate in patients treated with BR was significantly better than in patients that were treated with R-CHOP and R-CVP. There was no marked difference in CR plus partial response. But it should be noted that out of the 33 patients that were treated with non-br therapy, only 22 received R-CHOP, and the remaining with the R-CVP. And that is already mentioned of CVP we already know that it is associated with an inferior response, so it is not surprising that, in this particular study, it seems that results with BR are better than results with non-br agents. Dr. Smith: I think the difference between the BRIGHT Trial and the StiL Study, which was shown on the previous couple of slides, is this inclusion of R-CVP, which makes it a little bit more difficult to interpret. And then I think, as you were about to say, we still do not have the PFS and overall survival data to the degree of detail that we would like. So it is a very difficult study, sometimes, for me to put into context. Dr. Lossos: I agree. So, for me, even sometimes I see it as an -- exciting results but still premature.

12 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 12 Dr. Smith: Exactly. Slide 34: European MCL Network Study Patients >60 years Dr. Lossos: OK. So European Mantle Cell Consortium always performs exciting studies on mantle cell lymphoma, and one of the studies was published in 2012 in the New England Journal of Medicine. Specifically in elderly population, in which they randomized patients to treatment with R-CHOP vs R-fludarabine-cyclophosphamide. It was a large study. There was no difference in the first pertinent randomization in the time to treatment failure. However, there was improved overall survival in patients that were treated with R-CHOP vs patients that were treated with R-FC because of more side effects and because of a higher mortality. And that is why, in reality, our R-FC is currently not considered to be one of the best choices, and we really don t recommend it to use. So R-CHOP, in this study, was shown to be better therapy for elderly patients. There was a second pertinent randomization of these patients for both groups, that once they achieved complete remission or partial remission, they were put in maintenance. All maintenance was interferon therapy, the standard approach in Europe for patients with mantle cell lymphoma and even sometimes for indolent lymphoma. All maintenance was rituximab giving slightly different than we usually give maintenance in many other indolent lymphomas every eight weeks. Slide 35: MCL Elderly And what are the results of this study? So I already discussed the results of the upfront randomization, but the more interesting results came out from the second randomization of the maintenance. Patients that received maintenance with rituximab have significantly better response duration. They have significantly better progression-free survival. And, more importantly, they have significantly better overall survival. So this study, in reality, led to establishment of rituximab as part of the standard therapy for elderly patients in maintenance for mantle cell lymphoma patients. However, as we already discussed, this data applies only for R-CHOP patients, and we still don t have seminal data for patients who were treated with rituximab-bendamustine. Slide 36 T-CHOP Yttrium-90 Ibritumomab I want to mention a few smaller studies, OK, so a recently published study by Mitchell Smith from ECOG, in which we analyzed R-CHOP therapies followed by Yttrium/Ibritumomab is this study included both younger and elderly patients. CR(u) was 55%. Partial response was 27%. Median TTF was 34.2% months. Again, if you will take a look on the curves, there was better outcome in younger patients than in elderly, and that is not surprising. Slide 37: VcR-CVAD with Maintenance R And, more recently, Chang published a study using a modified type of treatment with bendamustine. Once again, very similar results. Complete response rate of 68%, partial response rate of 27%, and three-year progression-free survival 67%. So that s two potential alternative approaches for the treatment. Slide 38: Indolent Non-nodal MCL

13 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 13 I want to mention in several cohorts the indolent non-nodal mantle cell lymphoma. The physician needs to be aware. These patients usually present with splenomegaly, leukemic involvement, and no lymphadenopathy. All lymph nodes are very small and not remarkable. By pathology and molecular findings, they are typical, blastoid, or small-cell morphology, because this is usually typical for mantle cell lymphoma. CD38 is usually less often expressed. Most of these patients have mutated immunoglobulin compared to other mantle cell lymphoma patients, and they may be not expressing or expressing low levels of SOX11. Slide 39: Non-nodal MCL Favorable OS And when you compare outcome of these patients with the classical mantle cell lymphoma, definitely, the patients with the leukemic phase have a longer survival and even longer time to the need of therapy. We say that it is most important to remember that some of these patients may have difficult p53 or other mutations that may make their course more aggressive, as we have recently published. Slide 40: Case Summary So, in summary, this current patient was treated with bendamustine-rituximab, with frequent duress that was addressed symptomatically. And, eventually, patient achieved complete response. She had three hospitalizations for the duress and for fever without neutropenia while we managed through the cycle. And, presently, this patient is in continuous, complete response, and she is receiving rituximab maintenance therapy. Slide 41: [Subtitle] Dr. Smith: Wonderful. Hopefully, she ll do well. So I will go now to the next case. And the rest of the discussion focuses on the approach to mantle cell lymphoma in a relapsed and elderly patient. Slide 42: Case Presentation #2 So the case that I ll present is a 72 year-old man who -- in contrast to this poor 80-year-old woman was just discussed, this man has no comorbidities. He has an excellent performance status. And he comes in with subacute fatigue, chest pain, and dyspnea on exertion, and shortness of breath. An evaluation shows leukocytosis, anemia, and thrombocytopenia. And a bone marrow biopsy is done and is a diagnostic specimen that shows CD20-positive, CD19-positive and, as Dr. Lossos already pointed out, the hallmarks of mantle cell lymphoma with CD23 negativity, CD6 positivity, cyclin D1 positivity, and 80% involvement of the marrow. And I did not include it here, but the morphology was also quite classic for mantle cell lymphoma, and he did have FISH performed, confirming the 11;14 translocation. At the time, he was doing quite well, and we elected to treat him with R-CHOP and maintenance rituximab for two years, particularly since he had no comorbidities and was doing well. This was actually right around the time that the StiL Study was being presented for the first time, so a few years ago. Slide 43: Case Presentation #2 (con't) He did well, but three years later, he is now 75 years old and develops recurrent evidence of marrow involvement. And a bone marrow biopsy confirms that he has relapsed mantle cell lymphoma.

14 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 14 Slide 44: Question 3 So, perhaps, Izidore, I could ask you at this time, in thinking through the management options, which of the following regimens would you or would you not consider for this patient? Dr. Lossos: So the choices that are shown on the slides are all correct choices based on the literature, and I will discuss each of one. One of them is more favorable for me than others, but let s discuss how I would approach. In my practice, in reality, if a patient did not receive upfront bendamustine-rituximab, we use bendamustine-rituximab as a first choice for relapsed patients, for elderly patients because, based on what we published, we observed 90% response rate with more than 60% complete remission rate, and quite durable response. I think that you will mention it in one of your slides. Bortezomib is approved therapy for this disease based on several trials. However, the response rate, as you observed, is well in the range of 30%-40%. And, usually, the majority of this response is a partial response rate. There is a high frequency in this elderly population of peripheral neuropathy, and that s why, in my personal clinical practice, I almost never use bortezomib at all as a treatment for relapsed patients with mantle cell lymphoma. But I do think that, based on the current data, our experience and published literature, bendamustine-rituximab is a better approach. Based on the literature, again, studies published from European colleagues definitely show that FMC plus rituximab is excellent therapy. But if I would have to choose here, I would go with bendamustine-rituximab. Dr. Smith: Exactly. No, we had the same discussion in our group and felt that, for somebody who has not had prior bendamustine, that this would be the appropriate option. And I ll go through some of that data. Slide 45: Treatment approach to relapsed MCL So similar to considerations in the frontline, I think whenever you have a patient with relapsed mantle cell lymphoma, it is important to sit down and remember that the treatment approach is based on a couple of premises. The first is that this does remain an incurable disease, and no matter what treatment is used, patients do relapse. There are a variety of options available that we ll cover, and there is no treatment algorithm or no treatment standard that we can universally apply to all patients. And I think it is helpful to think about what the goals of therapy are, perhaps more for a clinical trial in terms of complete response/progression-free survival. But I think even on a patient s perspective, we would like to be able to relieve symptoms and help people live longer and, hopefully, in remission, and not needing continuous therapy unless that continuous therapy is nontoxic. Slide 46: Approved agents for r/r MCL So there are now a number of approved agents for relapsing/refractory mantle cell lymphoma that are listed on this slide. Chemotherapy agents remain an important part of the discussion; although, I think they are quickly being replaced by some of the newer agents that we ll go through. But these include agents such as bendamustine, cytarabine, and purine analogs. But I think that what is more and more becoming used are some of the more biologic agents and pathway inhibitors such as bortezomib, lenalidomide, and ibrutinib.

15 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 15 Now, monoclonal antibodies such as rituximab are often added to one of these eight backbones, either the chemotherapy or to the biologic agents. But they can be used even on their own in a purely palliative setting. In radioimmunotherapy -- although it is listed, for example, in NCCN Guidelines you have to be very careful and make sure that the bone marrow does not have more than 25% involvement, or else you ll run the risk of marrow suppression. And then I included temsirolimus which is approved in the European Union for relapsed/refractory mantle cell lymphoma, but not in the United States. Slide 47: Chemotherapy in r/r/ MCL And bendamustine we ve spoken about quite a bit, and I will show a curve on the next slide just showing what we can expect. But, in general, patients who receive bendamustine and rituximab in the relapsed and refractory setting, as you stated, there is a very high response rate. And, in fact, there is even a very high complete response rate, and a durability and median progressivefree survival that is usually about 18 to 24 months; and we can see that in the next slide. Cladribine I listed here mainly because there was a Blood publication several years ago showing that cladribine, with or without rituximab, can also be very palliative if the patient can handle that type of therapy. Slide 48: Bendamustine is Active in MCL When it comes to bendamustine in mantle cell lymphoma, we now have a series of trials that have been published. Some of the numbers of patients are fairly small, as you can see in the box on the bottom of the slide, but the larger studies show that the response rates are in excess of 90%, and the duration of response is between one and a half to two years. Slide 49: Phase II Study of Bendamustine + Rituximab If we look at the survival curves that are shown here on this slide, the median duration of response for mantle cell lymphoma, in one of these studies by Robinson and colleagues, was 19 months. But you can see that there are still some patients, even beyond that, who remain in an ongoing remission, at least not needing for the therapy at that time. And, importantly, none of these studies that were done early included maintenance rituximab as part of their management. Slide 50: FCM vs R-FCM in Relapsed Indolent Lymphoma When it comes to fludarabine, we discussed in the frontline setting, in particular in the Phase III randomized trial of R-CHOP vs the fludarabine-containing regimen, that the fludarabinecontaining arm was too toxic. And I think that s true for a number of patients, especially if they are older and have poor marrow reserve. But fludarabine, as our European colleagues have shown us, is an active agent. This study by Forstpointner shows, amongst 128 patients with relapsed lymphomas, there were 48 that had relapsed mantle cell lymphoma. The addition of rituximab to FCM improves the overall response rate, dramatically improves the complete response rate, but may have a slightly more modest effect on progression-free survival. Slide 51: Immunomodulatory Agents in MCL I think what is exciting in mantle cell lymphoma is that there are a number of new agents that are developed and approved based on understanding a little bit more about the biology and

16 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 16 what it is that drives mantle cell lymphoma cells to survive and proliferate. And I put here just a cartoon that shows some of the more important pathways that are included in mantle cell lymphoma, and these include: both B cells receptor signaling as well as an NFkB and the ubiquitin pathway. Slide 52: The MCL-001 Study (EMERGE Trial) Immunomodulatory agents are among the first one or two agents to be FDA-approved for mantle cell lymphoma. And, in large part, this was due to the EMERGE Trial, which was published by Andre Goy. So the EMERGE Trial was a very simple Phase II open-label study that was multicenter, and evaluated patients with mantle cell lymphoma who had relapsed or progressed after bortezomib therapy. So out of 134 patients, which I really think is a very large study for a mantle cell lymphoma population, patients received lenalidomide as a single agent for days one through 21, at a dose of 25 milligrams per day, and repeated on a 28-day basis. And progression or toxicity were the reasons to come off the study. Slide 53: EMERGE Study The results show that lenalidomide was active in patients with relapse and refractory mantle cell lymphoma, with an overall response rate of 28%, a much more modest CR rate, and a median duration of response of 16.6 months, and an overall survival of 19 months. For a monotherapy in patients who have had full prior therapy, this led to FDA approval for lenalidomide for relapse and refractory mantle cell lymphoma. And you can see the curves over on the right side. So, again, remembering that this is monotherapy in a heavily pretreated group of patients without any rituximab or other agents. Slide 54: Targets in Mature B-cell Malignancies So I ll move on to pathways that I think everybody is learning much more about, and I think there is a tremendous amount of enthusiasm about understanding B cell receptor signaling. And what this cartoon shows, up on the top left, is that the B cell receptor or surface immunoglobulin is on the surface of all mature B cells. And we know that there is a very potent survival signal that is mediated by tonic B cell receptor signaling as well as antigen-mediated. And there is a number of kinases that transduce the survival signal. Many of these kinases, such as SYK and BTK, and PI3 kinase were genes that had been identified in some of the original gene expression profiling and now really make a very nice story in terms of their function downstream of the B cell receptor. As might be expected, now that we know that these kinases are mediating the B cell receptor signaling pathway, there is a number of oral small molecules that have been developed -- these are kinase inhibitors -- against some of these signaling nodes. So the one that of the two on this slide that are FDA approved, one is ibrutinib, which blocks BTK, or Bruton's tyrosine kinase, and we ll go over that in a moment. And then a little bit downstream is an NFkB signaling, and bortezomib, of course, inhibits the proteasome and was actually the first drug to be FDA approved for relapsed and refractory mantle cell lymphoma. Idelalisib is not yet approved for mantle cell lymphoma. And, as we mentioned before, the mtor inhibitors are active but not approved in the United States. Slide 55: Bortezomib in MCL

17 Evolving Treatment Strategies for Mantle Cell Lymphoma in Elderly Patients Page 17 In terms of bortezomib, the trial that led to FDA approval was the PINNACLE Study. And this has now been published, believe it or not, almost a decade ago, but looked at bortezomib given twice weekly in patients with recurrent mantle cell lymphoma. And patients were able to continue up to a maximum of either four cycles beyond their initial complete remission, a maximum of six 17 cycles, or they had to come off for progression of disease. Slide 56: PINNACLE Updated data from the PINNACLE Trial shows that the overall response rate was 31%, that the complete response rate was 8%, and the durability of responses with similar was nine months for those patients who had any type of response, and 15 months for those patients who had a complete response. And this led to FDA approval back in Slide 57: PINNACLE (update) It was Andre Goy who updated the PINNACLE Study, and that was published in And you can see that many of the responses were quite durable. And, in fact, of those patients who achieved a CR or a CRU, which were the minority of patients, there are some that remain in remission even years later after the study was completed. One of the issues that I did not include on this slide is that the major toxicity, of course, is neuropathy and has been dose-limiting, and does kind of preclude repeated therapy with bortezomib. Slide 58: PCI (Ibrutinib) So, as we ve discussed, B cell receptor signaling is a very valid target for B cell malignancies. And one of the first oral kinase inhibitors to attack the B cell receptor signaling is ibrutinib, formerly known as PCI So this is a very potent and highly specific small molecule against Bruton's tyrosine kinase, and it has pharmacokinetic properties that allow once-daily dosing. The initial Phase I study, published in JCO about a year and a half ago, was a dose-escalation study that was somewhat unique in that patients who the dose-escalation cohort were based on either a maximum tolerated dose or three dose levels above an active-site occupancy, and the company had created a very unique pharmacodynamic test to evaluate whether or not the compound was binding to its target. Slide 59: Phase I Trial of Ibrutinib in What is important in the Phase I study is two things. One, as you can see by the waterfall plot, there were responses observed across histologies and, in fact, in the majority of patients who were included. But the other key feature is that there was no maximum tolerated dose identified. There were no dose-limiting toxicities that precluded escalation, and they went three dose levels above which they had first proven occupancy of their target, and that is the dose that is selected for all further studies. Slide 60: Ibrutinib in Bortezomib-naïve or exposed MCL Well, given the signal in that Phase I study, a subsequent trial that is a multicenter study was performed, and this is ibrutinib- and bortezomib-naïve, or exposed mantle cell lymphoma. Again, an open-label Phase II trial in which they stratified patients by being either bortezomib-naïve or bortezomib-exposed. All patients received daily continuous ibrutinib at 560 milligrams per day until progression on 28-day cycles. Slide 61: Treatment and Patient Characteristics