Info
Video sum of Relapsed Refractory Disease of Diffuse large B-cell lymphoma
00:01 great thank you very much I always enjoy being invited and um I certainly I’m looking forward to today so what I’m going to do is I’m going to be discussing where things have moved to and relapsed or factory diffuse large b-cell lymphoma I know that sometimes these slides can be overwhelming because I am going to show you some actual data slides that were presented by some of the authors as information has emerged but I’m going to focus on what I think are the most important points and really trying to 00:37 get through the concept that things are really changing that we’ve had development of Novel therapies that are opening up new options and I think it’s a very exciting time right now we’ve seen change like we have never seen before probably in in the history of dlbcl in the last three to four years so these are my disclosures I do Consulting for various companies but everything I say today is going to be based on my opinion so this so we know that um relapse refractory dlbcl can be a fusing area because there are more options now 01:20 and and what I’m going to do is talk a little bit about a brief overview of relapse refractory aggressive B cell lymphoma or dlbcl I’m going to review select data mainly highlighting some of the novel therapies that have been recently approved or are currently in development but really focusing on the treatments that are currently in clinic or may soon come into the clinic so we know that beyond what I’m talking about today there are many many new things in development but I’m going to focus on 01:51 what really is going to be either currently available or imminently available so to remind everybody diffuse large b-cell lymphoma is the most commonly rapidly growing non-hodgkin lymphoma that we treat so this is a very common problem that usually from the very beginning treatment is based on a combination of chemotherapy and the monoclonal antibody with toximab and with that it can often be cured in many patients but we know that there’s still room for improvement so before we kind of go on and talk about novel therapies I did want to talk 02:34 about sort of what our standard approaches for treatment and of course that is based on chemotherapy sometimes people don’t you know the chemotherapy is not a treatment it’s a group of drugs that have been designed to hurt cancer cells but most chemotherapies are generally not what we call targeted they have a very broad-based effect on many cells in our body and and they’re really designed to damage the DNA in our cells so that cells can’t grow and divide So based on how most chemotherapy drugs 03:09 work it’s not targeted as I said and the goal is to try and interrupt DNA from replicating itself because that’s how cells make more of themselves so it’s got a very broad-based mechanism and because of the broad-based mechanism the side effects can also be quite broad because we know that many cells in our body can also be affected by how chemotherapy works so the standard chemotherapy that continues to be used right now for the first line treatment of diffuse large b-cell lymphoma is chop chemotherapy which usually gets given 03:51 every three weeks for four for four to six Cycles depending on uh whether or not patients are limited or Advanced stage a major development and treatment of dlbcl is when we added the monoclonal antibody retroxima so we’re toximab was probably one of the initial forms of immune therapy that we had available in that it is an antibody designed to tack on to diffuse large B cell lymphoma or normal B cells and it kind of harnesses the immune system to come in and works together with the chemotherapy to make the treatment better so again 04:31 it’s been about 20 years now that the combination of chop Pulsar toximab has been our Frontline standard of care and with that we’re seeing a lot of success so this is just a curve of outcomes that we see across a population in this case this is population data from British Columbia where I work and we know that with chop plus rituxima we can now cure about 70 percent of people with diffuse large B cell lymphoma but as I said there is room for improvement because we want to make this better and I know that at this 05:07 meeting there’s been a lot of talk on how we’re going to make first line treatment better but we’re going to focus on today is you know what do we do if this first treatment doesn’t work so if the first treatment doesn’t work we realize that there are probably different reasons for this so we think of diffuse large b-cell lymphoma as one entity but we know that it’s biologically very diverse and I think that probably you know the mechanisms that play in individual people with diffuse large B cell lymphoma are very 05:44 different and the reasons why perhaps chop and rituximab didn’t do what we wanted to do and that is to eradicate the lymphoma may be very different from person to person so we know that there’s differences in the biology of the lymphoma itself in between people we also know that the immune system may be different between different people and and the what we often call the immune microenvironment can affect how people respond to treatment and then there are different differences between individual people that may change how they 06:22 metabolize the drugs that we give may change how their body sees the drugs so we know that all of this variability may make different reasons why chop Plus or toximab didn’t work so I think it’s exciting to think that in the relapsed refractory setting because we know that there may have been different mechanisms at play as to why people were resistant to the initial treatment that it the more different options we have in the relapse refractory setting the more likely we are to be able to tackle you 06:56 know and and have better effects across everybody with relapsed refractory lymphoma so that’s why I think it’s extremely exciting that we’re having more and more options becoming available so this is the standard algorithm that we’ve used for a little while now with Once people do have either progression of their lymphoma after our job or have their lymphoma come back after our job and importantly we’ve often distinguished sort of two scenarios and and sometimes this is referred to as being transplant eligible versus 07:34 transplant ineligible or candidate or not a candidate for transplant and that’s because until recently I would say the main the main treatment we’ve had that allows us to potentially cure lymphoma that has grown through or comes back after our job has really relied on autologous stem cell transplant so in the past you know this was the biggest next question about can somebody go on to a transplant or not and unfortunately because transplant is a fairly intensive treatment we know that it’s not suitable for everybody 08:13 based on age and health status and so probably only about half of people are considered transplant candidates if people are considered transplant candidates usually the next step is to go down a route of what we call Salvage chemotherapy it’s a different kind of chemotherapy from Art Shop but it’s aimed at trying to start getting the lymphoma under control and to prove that that lymphoma is still what we call sensitive to chemotherapy so that it makes sense to move on to the transplant unfortunately um along the way not everybody had you 08:48 know still has lymphoma that’s very sensitive to chemotherapy so sometimes we need to divert to other options for people that aren’t transplant candidates generally we would move down to those other options and and in the past most of those options revolved around other kinds of chemotherapies but as we’ll be talking about now we have many many more options available just a word on autologous stem cell transplant so we you know I think it’s still a mystery to some people when we talk about transplants there are 09:22 different kinds of transplants that can be done but generally when we talk about transplant in the second line setting for diffuse large b-cell lymphoma we’re talking about an autologous stem cell transplant so that involves actually taking some of those baby blood cells what we call stem cells which can now actually be harvested just from filtering the blood and and getting out the nice baby blood cells called stem cells they get put in literally the freezer and saved on the side and then the stem cell transplant involves getting higher doses 10:00 of chemotherapy than we can safely give without removing the stem cells so it’s really a way of of pushing up the doses of chemotherapy that generally can’t be safely given without the stem cell transplant because we know that one of the most sensitive cells in our body are the normal white blood cells red blood cells and and platelets and if we push the chemotherapy up too high it causes uh real damage in those cells and it’s not safe so this is a way of taking out those baby blood cells then allowing the 10:35 body to safely get higher doses of chemotherapy and then giving the baby blood stem cells back and they replenish the bone marrow so so really the secret behind the stem cell transplant is the ability to be able to give higher doses of chemotherapy and although this can be very successful for some people and can actually cure diffuse large b-cell lymphoma and the relapse refractory setting we know that not everybody can be cured with a transplant and one of the biggest predictors of who can do well with transplant sometimes relates to the 11:12 timing of relapse so this is a curve that just looks at outcomes again in my province of British Columbia based on when the lymphoma comes back from the time of initial diagnosis and for those people that have their lymphoma come back more than two years after their initial diagnosis we can see in the red line here that outcomes can be very good and and more than half of people can be cured or half of people can be cured with a transplant in people who have their lymphoma come back very early though again that’s 11:47 probably representing more chemotherapy resistant disease and although the transplant can sometimes be successful unfortunately it’s not as successful in that setting and it’s probably because as I said the transplant relies on higher doses of chemotherapy and and probably the earlier the lymphoma comes back it’s really declaring itself to be more chemotherapy resistant so it’s really exciting to see that we now have another option that can offer a Curative potential Beyond transplant particularly for people that have either 12:31 had their lymphoma come back after a transplant or people who may not be suitable for an autologous stem cell transplant so chimeric antigen receptor therapy or car T Cell Therapy is a very sophisticated new form of immune therapy it’s often referred to as a cellular therapy I’m sure that you are actually hearing a lot about this at this meeting um but just to really Briefly summarize a car T Cell Therapy treatment involves taking out some normal T cells T cells are and a really important part of our immune system and they’re the cells in 13:15 the immune system that help fight off bad cells like cancer cells and car T Cell Therapy involves taking out some normal T cells again from the bloodstream and then they get altered very sophisticated way in the laboratory or or really processed through the pharmaceutical companies that make them and designed to actually specifically Target something that is on diffuse large b-cell lymphoma and some normal B cells that we have and that’s called cd19 so they’re they’re basically normal immune cells taken out of the individual 13:58 person and then genetically modified to want to seek out a specific Target called cd19 so when they get put back into the bloodstream they create basically a little army of cells looking specifically for the lymphoma and can harness the immune system to come in and attack that lymphoma so it’s in a form of cellular therapy and that the actual treatment is based on the cells that have been designed to seek out the lymphoma and try and kill the lymphoma and basically it is um a form of immune therapy in that it 14:38 does also Corral the immune system to do its job so this has been a very exciting therapy that has become available really only in the last five years or so when it was initially tested in people who had had their lymphoma come back after at least two lines of Prior treatment we saw that there were three products in development that are just shown here diagram in a diagram but these three products all had very good success at trying to eradicate the lymphoma and what we saw is that for people that had diffuse 15:17 large B cell lymphoma that had come back after at least two lines of therapy about 35 to 40 percent of people treated in these initial trials had their lymphoma go away and many patients had their lymphoma go away for good I would say that when the data first came out we weren’t sure whether or not this was going to actually offer a cure and we needed to have a long enough to follow up to prove that people weren’t having the lymphoma come back but at this point we now have follow-up that goes beyond 15:52 five years in some of these initial trials and there are many people that are well without their lymphoma so I think it’s really time that we can start using the word Curative capacity with um with car T Cell Therapy that it does have the potential to cure some cases of diffuse large B cell lymphoma what’s also exciting is that since these products have now become clinically available and they’re available for use we have more and more data emerging for what can they accomplish in a real world environment so we know that they’re 16:31 within a clinical trial sometimes at the beginning they do enroll the healthiest people that you know that can maybe have easier ability to take on intensive treatment and and now we’ve seen in a real world environment so what can they accomplish in the clinic and there’s more and more data showing that what was shown in those initial trials where about 35 to 40 percent of people might actually have their lymphoma go away and and achieve a complete remission we’re seeing that across a much broader group 17:07 of people that are being treated you know in their own clinics and and outside of clinical trials so it’s been very encouraging to see this day data emerging again reaffirming the potential value of car T Cell Therapy in some cases of diffuse large B cell lymphoma that has come back but most of this data that we have is really revolved around people that have had at least two prior therapies because this is where car T Cell Therapy was initially tested and developed and approved for use but it really does beg 17:44 the question if it is such an effective therapy for some people should we use it sooner and should we use it perhaps instead of planned Salvage therapy and a transplantation for some patients particularly those that we consider to be of higher risk like people that have their lymphoma come back sooner after our job and this was an important question that was actually asked within three very important clinical trials that were designed to see whether or not it would be of value to use a strategy of car T Cell Therapy instead of the strategy of 18:25 Salvage chemotherapy and stem cell transplant for people with higher risk lymphoma in this case the higher risk was based on timing of relapse after Frontline treatment so these three trials really looked at people that either had their lymphoma not benefit from our job or had their lymphoma come back within a year of having received archa I’m going to go through some of the data just briefly again I don’t want you to get overwhelmed by all of the details on these slides but the first trial that was presented was called The 19:02 Zuma 7 trial and this looked at the car T Cell Therapy called cell this was a randomized trial so it was performed in people with diffuse large b-cell lymphoma and other aggressive b-cell lymphomas that had come back after initial treatment or had grown through initial treatment sort of within 12 months and half of the people on this study went down the standard route of Salvage therapy and Transplant and the other half went straight to car T cell therapy and what we learned from this trial is that the people who were 19:41 allocated the car T cell therapy right away actually had a higher likelihood of getting into a remission in a higher likelihood of having their lymphoma controlled so this data has emerged in the last year and is still relatively early but it was a good example that the strategy of going to car T Cell Therapy rather than transplant for these higher risk people might be beneficial there were two other trials as I mentioned the second trial used the car T Cell Therapy that we refer to as lysocell and it showed exactly the same 20:23 thing that people that were allocated to the car T Cell Therapy in this higher risk group did better in terms of having their lymphoma controlled and and um and without need for additional treatment the third trial however did not show this benefit this used the car T Cell Therapy that we call teaser cell now there were details between these trials that were a little bit different in how they were performed and in this trial I would say that the feeling was that some of the design elements in the trial and the delay in administering the 21:05 car T Cell Therapy that occurred in this trial might have led to the fact that it didn’t show a benefit so I I think that they based on the weight of the data and the way the trials were designed and with the two trials showing a clear benefit it was approved by the FDA now this occurred just last April so for patients with diffuse large B cell lymphoma who as I said are of higher risk so either didn’t benefit from our job or had their lymphoma come back within 12 months now the two products that I mentioned the axisal and the 21:47 lysocell are actually approved to be used ahead as as the second line strategy as we say rather than going to salvage and stem cell transplant so that really was a huge shift in our practice of what we do after the lymphoma comes back or or after Frontline therapy so rather than thinking about everybody for transplant or no transplant now we actually ask the question if we’re thinking about this being suitable for transplant what was the timing since Frontline therapy and if it’s been less than a year then currently based on the 22:28 data I showed you car T Cell Therapy is what is currently recommended for most people however if it’s been more than a year we know that the trials that we saw of car T Cell Therapy didn’t test that question and we know that those people can do very well with stem cell transplant so in that setting stem cells transcend would still be considered the next option to consider now one of the questions this data Left Behind was what if people weren’t considered for stem cell transplant to begin with because maybe of higher age 23:12 or other health problems it wasn’t considered appropriate what about using core T cell therapy after our job or after a Frontline treatment rather than waiting until a third line treatment where it’s currently been approved for non-transplant candidates and also very exciting this year we actually saw some data emerge this actually was a study based on lysocell which is one of the car T cell products available and it looked at people who would not generally be considered appropriate for transplant again usually 23:53 that’s because of age or other health issues we know that car T Cell Therapy can be used in that setting so if people are not suitable for a transplant because of age or health status car T Cell Therapy may still be considered and this study asked the question you know is it safe and effective to consider car T Cell Therapy in these people who transplant is not being considered as a second line treatment rather than saving it to third line where you know initially it was approved for use and this trial which was 24:31 considered a pilot trial so it wasn’t a very big trial and it was not a comparison trial everybody on this trial got the car T-cell therapy but what it did show was safety and benefit and based on this actually the FDA has approved Liza cell in the second line setting for patients who are not suitable for stem cell transplant and that is regardless of timing of of relapse so this does open the ability to move car T Cell earlier for people who are not being considered for transplant in the second line setting so again this 25:10 has been a big shift this data has potentially allowed car T Cell Therapy to be accessible as a second line treatment rather than as a third line treatment where it was initially approved so this is again a big shift in practice based on this data that really has just emerged in the last few months so let’s move on now to talk about some additional exciting treatments that go beyond transplant and car T Cell Therapy we know that again transplant and car T Cell Therapy are important components of trying to cure diffuse large b-cell 25:50 lymphoma that has come back or has not responded to initial therapy but after transplant or after car T cell therapy or for people that aren’t necessarily going to go to transplant our car T Cell Therapy if it’s not thought to be appropriate or safe we certainly need other options that go beyond chemotherapy to try and approve outcomes and benefit in this setting and what I’ve listed on this table are four drugs or or treatment approaches I should say that have emerged and have been approved all within the last three 26:31 years so when I say that we’ve seen probably the greatest change in diffuse large b-cell lymphoma treatment than we’ve ever seen it’s based on the fact that really we’ve seen many drug approvals through the FDA in the last two to three years like we’ve never seen before and this is based on excellent development of drugs that are now considered to be targeted toward the lymphomas and what we often refer to as novel therapies so therapies that go beyond chemotherapy that have sophisticated ways of working that rely 27:08 on different mechanisms based on what we know to be sometimes important in the lymphoma cells I’m going to be talking about these individually a little bit and the data that was emerged that emerged to to get them approved by the FDA so but what I really want to stress is again how really treatment for diffuse large B cell lymphoma is greatly changing largely based on our understanding of the biology of diffuse large B cell lymphoma that has allowed drugs that try and capitalize on that understanding of the biology to emerge 27:47 these options I would again premise that they’ve never been compared against each other so we’re going to talk about them individually and whenever we think about you know using a particular treatment in all cases we’re weighing in what do we know about the benefit against the side effects and and right now you know we wouldn’t be we’re not in a position to say that one isn’t necessarily better than the other what they are is different and use different ways of working to try and fight off the 28:18 lymphoma so the first one I’ll talk about is the one that was approved first by the FDA which is called polituzumabidotin this is what we call an antibody drug conjugate so we talked about antibody treatment like rituximab and this these are proteins that are designed to seek out markers on cells but antibody drug conjugates are actually combinations of antibodies together with um drugs that are designed to hurt cancer cells so in this case it is an antibody targeting a marker that’s frequently and almost always present on 28:59 diffuse large B cell lymphoma called cd79b and this antibody has stuck onto it a chemical toxin that is designed to hurt the cell so it is a kind of targeted therapy in that it is directed at the diffuse large b-cell lymphoma cell when it sticks on its surface it actually gets swallowed up into the cell and the chemical rather than being released in the bloodstream gets released right into the cell to hurt the diffuse large B cell lymphoma cell so it is a form of toxic chemical therapy but in this case targeted to the cell itself 29:38 leading to that killing of that cell so in the trial that led to the approval of politus mavidotin it was actually combined with chemotherapy that we call Benda mustine together with rituximatum so it came out in a combination therapy and as part of the approval the study included a comparison arm where it was compared against bendamastine and rituximab all by itself so in this trial that included people who had diffuse large b-cell lymphoma that had come back after at least one prior treatment in people who received the polituzumab 30:23 combined with the Ben domestine and ritoximab there was a much higher rate of having the lymphoma shrink away and and achieving a complete remission and a much higher rate of actually having the lymphoma go away and actually having um a higher survival with the politus map so this was as you can see from the orange curve a big breakthrough in terms of improved outcomes with the addition of this novel therapy polituzumab compared with polituzumab and bandamastine and ritoxinam with all new treatments we know that 31:05 in addition to the benefit we need to think about what are the side effects and the risks of the treatment and I’ve um this was sort of the details of that that was compiled from the study but I’ve listed them here so the main side effects of this combination therapy were primarily the development of low white blood cells which was temporary and a slightly increased risk of infection the polituzumab also has some side effect of what we call peripheral neuropathy it sometimes can cause some tingling and numbness in the fingers and 31:39 toes primarily but that generally was mild and and was a temporary side effect so the next treatment that was approved for relapsed refractory diffuse large B cell lymphoma was a drug called celinexor this has a very different way of working it actually targets a um a protein within the cell itself and blocks what we call the transport system from the nucleus so the cells in our body are quite complicated as a cancer cells of course and this drug is designed to block a specific protein that leads to movement of other proteins 32:25 in the cell allowing them to build up in the crucial area that we call the nucleus of the cell and harm that cell the trial that again got this drug approved that the FDA was performed in people with diffuse large b-cell lymphoma who had already had at least um two to five prior treatments this was a pill drug so it gets given as a pill twice weekly and was continued until it stopped working this is a bit of a busy slide but it basically shows the main results of this and that is that about a third of patients benefited from this pill and 33:13 about 10 percent of people actually had their lymphoma go into what we call a complete remission so it was able to control lymphoma for a period of time in about a third of people who received it again all potential drugs have side effects that we need to think about in this case I listed some of the main side effects here similar to many of the treatments that we use low platelets was seen with this drug but not so much in the way of low white blood cells that can be seen sometimes with chemotherapy but there 33:48 were some physical symptoms that people experience like some nausea tiredness Sometimes some bowel upset or weight loss and these were things that needed to be managed sometimes with some other support medications foreign treatment that has been recently approved for relapsed or fractin diffuse large B cell lymphoma is actually quite an interesting treatment in that this is a form of immune therapy so the drug that was approved was called taffa Cinema it is a kind of monoclonal antibody so again antibody treatment 34:26 like ritoxamab here the antibody is targeting the marker on the cell that it’s actually the same marker that car T Cell Therapy targets called cd19 in this combination treatment it was combined with a pill medicine called lenolidomide which has been available for some time now and used for other kinds of b-cell cancers and in this combination of the taffacetamab and lenolidomide it was designed to really Corral the immune system and Target the immune system around the diffuse large B cell lymphoma so the trial that got this 35:07 drug approved again was performed in people who had had at least one prior treatment for diffuse large b-cell lymphoma this trial the drug is given to have acetamine is given as an IV treatment initially quite frequently so it gets given weekly for three months and then gets given every two weeks kind of indefinitely until their sign of lymphoma growth and the lenolidomide which is a pill gets given for the first year only in this trial we saw quite a few people benefit so the about 60 percent of people actually had shrinkage 35:48 of their lymphoma and just over 40 percent of people actually were able to achieve a complete remission with this treatment and in some cases it was a very long period of control that’s been going on for more than three years in some of the follow-up that we have again focusing on what are some of the side effects that we see with this treatment which are listed on this side of the slide the main side effects that were seen were some low white blood cells red blood cells and platelets some bowel symptoms like diarrhea or fatigue 36:27 and some risk of infection most of these side effects interestingly were seen in the first year of treatment and would probably do more to the lenolidomide than the taffacetamine antibody the final treatment I’ll mention that was recently approved for relapsed refractory diffuse large b-cell lymphoma is very similar in that it’s the kind of class of drug of the politusumab that I talked to it about at the beginning is called an antibody drug conjugate so an antibody connected to a chemical toxin this drug has a big name it’s called 37:06 lancastoximab tesserine but in this case the antibody component again is targeting the cd19 on the cell surface this is the same Target as car T Cell Therapy it’s the same Target as taffacidumap that we talked about here are the chemical toxin is something called a PVD dimer which again is designed to hurt DNA but it is a form of targeted treatment so similar to the polituzumab that we talked about it gets stuck on the cell it gets swallowed up by the cancer cell and the toxin is released in the cancer cell itself 37:48 the trial that got this drug approved by the FDA was performed in patients with relapsed refractory diffuse large b-cell lymphoma that had come back after at least two prior treatments this is an intravenous drug that was given initially every three weeks for up to a year and then was continued after that every three months indefinitely until the lymphoma progressed these are the results that were shown in this initial study and again what we saw was a fairly good activity where about half of people actually had their 38:30 lymphoma shrink and benefit from this treatment and about a quarter of people actually achieved what we call the complete remission with their lymphoma being unmeasurable on the treatment and again some of this data is still relatively early but for some people that benefited it has been continuing now for more than two years of time what were some of the side effects that were seen with this treatment well the main side effects again had to do with some low blood cells mainly low white blood cells red blood cells and 39:05 platelets and also a temporary increase in some of the liver enzyme blood test that was generally not of any concern but was noted in this trial and was generally temporary so with that I hope I’ve impressed that we’ve got many new options to use in the relapsed refractory setting which option we would use really depends on what our goal is so with stem cell transplant or car T Cell Therapy I would say the goal based on the data we have is to try and cure the lymphoma with those potential treatments for some 39:46 of the novel therapies I showed you four novel therapies that are available now based on FDA approval I think it’s too early to say whether or not any of those treatments have potential to cure diffuse large B cell lymphoma I think it’s encouraging that many people have responded to those treatments that have had their lymphoma shrink away and achieve a complete remission but for all of those treatments I would say we need longer follow-up to see whether or not we can say they have the potential to cure 40:20 lymphoma but it certainly leading to you know really good benefit for many people and and I think we look forward to seeing a longer follow-up because a lot of this data really has only been developed and emerged within the last few years I said that none of those treatments have been compared against each other so which treatment should you use I would say that you know in most cases doctors are probably having conversations with their patients talking about the data talking about the side effects and Which choice might be 40:54 the next best treatment for any individual person might be different based on on who that person is and their underlying health status keeping in mind some of the side effects that we talked about and also patient preferences because as I said some of them are pill drugs and very convenient others might involve going to the clinic fairly frequently to get an IV infusion and and the good news is we now have options and all of these things can be weighed in an individual person to decide what might be the next treatment to use I think the 41:30 future goal would really be to develop blood tests or biomarker tests as we call them that tell us more about the individual biology of the lymphoma in an individual person and Link that biology up with the best drug that might work against that biology I’d say we’re not quite there yet but there is a lot of work going on trying to understand what it is about the lymphoma that does respond so well to some of these unique targeted therapies so that we can probably use them in a smarter way and pick the right drug for the right person 42:08 and I’m hopeful that in the future we will have those kinds of tests that allow us to use them in a smarter way I’m just going to finish briefly on a new treatment that is coming very soon that we think might be approved this year for relapsed refractory diffuse large B cell lymphoma and because I’m sure that there are other talks in this meeting that are addressing this I’m just going to briefly mention this so we’re very excited about the new class of drug that we call bi-specific antibodies these are antibodies that are 42:41 designed to have two Targets one target is on the B cell lymphoma the other Target is on normal T cells as I said earlier an important part of the immune system that’s designed to fight off lymphoma and there are many by specific antibodies in development that have slightly different designs and they’re all showing very encouraging data I’m just going to mention some of the data from one of these called glofittimab that was recently presented at the American Society of clinical oncology meeting in this last year this was a 43:19 bi-specific antibody tested in people with relapsed refractory diffuse large B cell lymphoma who had had at least two prior lines of treatment this is given intravenously and it’s given every three weeks initially with a bit of a step up dosing so small mini doses weekly in the first cycle and then every three weeks after that for up to a year of treatment what was very exciting is that this was a novel kind of immune therapy and these trials are showing great benefit with in this case more than half of people 43:57 having their lymphoma shrink down and benefit and about 40 percent of people actually achieving a complete response with their lymphoma no longer measurable now data is still quite early but we are seeing people have very nice control even up to more than a year but we don’t have very long follow-up to know how long this benefit can last but it is something that perhaps can be reused in people sorry to get even longer benefit so this is data that’s just emerging what are the side effects of bi-specific 44:35 antibody therapy it does come with a bit of a novel side effect excuse me um called cytokine release syndrome what we do know is that when the immune system goes into action too quickly sometimes chemicals can be released by the body’s own immune system that can cause some side effects like high blood pressure low blood pressure asthma-like symptoms and sometimes difficulty breathing and and this is something that needs to be monitored for that’s why we have the little mini doses in the first cycle to try and reduce the likelihood 45:10 of this happening although it is a potential side effect of bispecific antibodies it’s something that can be treated with a drug called tocilizumab and it’s generally mild in most people and only incurs generally in the first cycle so it it’s a unique side effect that will need to be managed with this treatment but it’s something that is very manageable aside from that it can cause some low blood cells as well and some temporary elevation in the liver tests so to summarize this is a lot of information but hopefully I’ve oppressed 45:47 upon you that there are now numerous novel therapies that have shown benefit for relapsed refractory diffuse large b-cell lymphoma and other aggressive B cell lymphomas they’ve now actually made their way into the clinic and are available for use many of these options rely on unique mechanisms that are very different from chemotherapy and in many cases targeted some of these treatments are what we call immune therapies and it really has been a very powerful proof of principle of how important the immune system can 46:26 be and how we can harness the immune system to fight off diffuse large b-cell lymphoma and um I think what’s most exciting is that all of these treatments really are improving outcomes in relapsed refractory diffuse large b-cell lymphoma and making a real difference in people