Austin Kim, MD, Oreofe Odejide, MD, MPH, Ann LaCasce, MD, MMSc, Erin Parry, MD, PhD, Inhye Ahn, MD, and Philippe, Armand, MD, PhD, take audience questions and discuss cases of Classical Hodgkin Lymphoma, Chronic Lymphocutic Leukemia, and Small Lymphocytic Lymphoma.
right. Um at this time I don't see any questions but we can start the panel, I wanted to introduce two more of our colleagues. Um dr oreo fio Deputy Assistant professor of Medicine at Harvard Medical School. Um She does a lot of our outcomes research. Doctor johnson had actually alluded to her during his presentation on elderly lymphoma. Um And um also dr Aaron Perry um his instructor medicine at Harvard Medical School and um there's a lot of research in CLL in particular um Richter syndrome. So um I think we have a really nice group. So um I think maybe we can start with a case um that dr O. J. Today um brought um don't know if you want to share your screen, I can share my screen as well. Um Oh you beat me to it. Great, so I can go ahead and share my screen. Thank you so much, dr kim and thank you for all the great presenters. Um So I thought that I would share a case um this afternoon um slightly shifting gears to an older patient with Hodgkin lymphoma. So this was a patient I met um some years ago, 65 year old with early stage classic Hodgkin's lymphoma. He noticed a lump on the right side of his neck which he brought to the attention of his primary care physician and his tt neck was ultimately done that reviewed. Right. Super, particularly, but not the third dimension around three by 3.5 centimeters. He subsequently had a pet scan that showed that the disease was limited to the right supercar particular area and the superior right media style. Um And the largest area was 3.5 centimeters there wasn't anything but no empathy or F. D. G. I would uptake we look at that from. He subsequently had an exceptional rights. Supercritical liver biopsy which was consistent with classic Hodgkin human nodule sclerosis, subtype The new plastic cells with CD 30 and city 15 positive negative for CD 20. and Bieber And his baseline laboratory studies were notable for an everyday sight sedimentation rate of six mm/h. This past medical history was not able for hypertension, hypercholesterolemia, guard and depression. So I've been thinking about this um sort of gentleman. And the first thing he's thinking about the staging of his disease based on the imaging studies showing that the lymph retinopathy was located all above the death from any of the absence of um unexplained fevers, night sweats a week, loss of greater than 10% of his body weight. This was consistent with stage two A disease. And when I approach patients that was sort of thinking about this stage with this patient having early stage, this is the next key question for me, does the patient have favorable on favorable risk factors? And for this patient thinking about the german hodgkin's study group risk factors. The things to consider their three or more. My sites. Not all sites that are involved for patients without these symptoms is the sa regular than 50. And for patients with these symptoms is equally than 30. Are there extra other sites um of involvement And it's the largest area of involvement in the media steinem more than a third of the maximum site and the thorax. So when we think about all these risk factors, this particular patient had none of the unfavorable risk factors based on the german question study group. So this would be favorable. Mhm. Early stage disease. And then comes the next question of how to approach his care, what sort of treatment regiments to recommend? So, as dr lackeys presented earlier when we think about younger patients, she emphasized in her presentation that she typically will prioritize the omission of relation therapy in younger patients because of the risk of complications and secondary malignancies. Um in patients that are older like this. Um The latency period before you have the risk of secondary malignancies is not as high as the consideration in this population. So one may think about combined modality therapy anticipations versus chemotherapy only something we think about this particular patient. He really fits the eligibility criteria that was used in the german Hodgkin's study group HD 10 study that enrolled patients between the ages of 18 to 75 years of age and about 62% of patients in that study had stage to a disease. So that was a non inferiority study that had a factorial design where patients got either two cycles of a B. B. D plus 20 or 30 grill relation or four cycles of a B. B. D. Plus 20 or 30 degree of radiation. And the non inferiority imagine was set at 7%. And the study found that you know, 22 cycles of a BBD followed by 20 degree of radiation did not cross the inferiority margin. So that was the discussion I had with this patient about getting two cycles of the DVD plus relation. Um If we think about other strategies where uh relation wants to be omitted, this patient would also fit the eligibility criteria of the C. I. A. L. G. B. Now Alliance five or +604 study of note as dr the case mentioned that was not the randomized study that was a pet director study on a much smaller study than it You 10 study. I think they were 1 65 patients in that study. Um And the majority of them had pet negative weapons negative at their interim pet scan which was defined in that study as before 123. And um for patients who were pet negative they could go ahead and get two more cycles of a DVD without radiation while those were positively escalated to be a cop. Um So that would also be an option even though I'm a little bit more leery of that approach in patients. So for this particular patient, you know, all things started with two cycles of a BBD. Anyways. So he got two cycles of a BbD and after that I had to show that he had A Great Pet Scan with a score of two and the patient had a lot of difficulty even just with two cycles of a DVD with a lot of fatigue developed some shortness of breath. I'm not doing risk of demonizing toxicity is higher in an older population. So based on the HD 10 study based on his great head scan, the decision was to complete his treatment with 20 degree of radiation which is completed and has remained in complete remission since then. It's been about three years since in ST since his treatment. So I thought it would be a good case to illustrate the HD 10 study C. L. G B. And to also give scenarios in where you can use two cycles of a DVD plus relation. So I will stop them. And I will also ask our resident, a great expert in Hajj coming from my doctor the case. Um in younger patients there are scenarios where you would sort of use the sgh D 10 trial even in this population where we often try to avoid relation. Yes. Yeah. All right. I'm glad you brought up that case. I think that is a scenario that we do see there is a second peak in patients with Hodgkin's over the age of 55. So we definitely see these patients. I think one of the difficulties is if this guy had been a little bit older or you had renal insufficiency, you know, would probably not give leo missin even, you know, two cycles is generally safe and obviously was included in the HD 10 study and your patient did well. But I think if, you know, if the patient were a little bit older maybe would omit leo missing altogether. And then then the question is, I think that's the problem with treating patients in the real world. They don't fit the criteria of who was included in the studies and you give a little bit more Chemo or sometimes we'll use 30 gray instead of 20 gray. Um but to get to your question for younger patients, I think for patients who have neck only disease. Um and its unilateral um we would definitely offer on two and 20, I think it's a very good option. The one, you know, the toxicities that you can see late from radiotherapy to the neck include carotid disease. But in a younger patient we follow on exam for brew ease and uh you know, follow the cholesterol and cardiovascular risk factors. And hypothyroidism is not uncommon though with depending on the location of the nodes. I think in a in a male patient who had axillary only disease, I think that would be reasonable or in a woman who is um you know, we think of the risk of breast cancer as being particularly high up to 30 to 35. So if you had a 45 year old woman with Just Axillary Disease two and 20 would be a very appropriate choice. And I think you just as you did with your patients, you have to discuss the risks and the benefits with patients. And you know I have a patient who is a physician who had stage two disease with involvement in the chest and she wanted chemo plus radiation because she wanted the absolute the lowest risk of recurrence uh and was willing to accept you know, potentially later toxicity from the radiation. So you know, I think that's both you know the beauty and the difficulty of treating patients in the real world. You know there's a lot of nuance. Uh and I think for Hodgkin it's particularly tough Because there are so many good options. The outcomes are so good that you're really thinking about, you know, 30 year toxicities which many other diseases don't have the luxury of doing. And yeah, just echo um dr Odis od or you did such a great job just outlining the ah unfavorable, favorable um risk factors because I I find Hodgkin is is not the most straightforward to treat because you have to know those criteria well. Um and you have to then be able to then explain to patients what the risk is with radiation or chemotherapy alone. Um And now also an advanced stage disease we have Brent Taksim av um and with the data that dr Lucas shared. And then now with that um press release that there is an overall survival benefit. Um I guess just one question I would have is um an advanced stage disease. Um Is there anyone you wouldn't give Brent talks mob aivd to maybe other than someone who has really bad peripheral an opportunity to begin with? Um I guess that's something I guess we're trying to figure out maybe or is it we just started giving it across the board. I don't know the answer to that question. And I think you know the prognostic indicators you know for early stage disease we have both the german and then the E. R. T. C. But in the advanced stage we have the I. P. S. And you know it does correlate but pet status is probably you know is another thing that we look at. And I think again you have to talk to the patient about the toxicity because when you give Brent huck cinabbon aivd together particularly for a young patient. Um You know they tolerate it better in terms of the neuropathy but you have to give growth factor because there's a higher risk of fnn. So those patients get bone pain because they're young and you drive up their white count and people just generally feel you know not across the board but it's it's harder to tolerate. It really is a harder to tolerate regimen and I've had patients who were pet too negative and said okay okay I've had enough of that print Taksim and let's do a V. D. And you know I think that's not unreasonable. And uh you know it would be very interesting to see the randomized trial with no volume abs though that's a whole nother can of worms in terms of rare but very serious side effects compared to a B. B. D. Which is just incredibly well tolerated I think with appropriate uh anti medics and things. So yeah it's a it's a lot of discussion with the patients. Yeah I find I just saw a patient clinic on friday who has an I. P. S. Of one I think you know so should do very well with a BBD. Um We did go with D. V. A. V. D. She's having a really tough time with just abdominal pain. Constipation. Um Just feeling crummy like you said. Uh And um like someone I would definitely consider maybe dropping different toxin. Maybe if um cycle to pet um shows a cr but um yeah it's too bad. That wasn't a pet directed study. And you know it does seem like the younger the younger patients benefit more from the addition of Brent Taksim mob and if you have a young patient you don't want them to go to salvage and an auto transplant. So you know I think it's uh it's hard and now with this overall survival benefit. I mean it's interesting that we learn about these things through press release and not a paper um You know it's hard to ignore that because there are very few things in Hodgkin lymphoma that have been associated with a survival benefit given our very good salvage regimens. And you know um transplant outcomes. I completely agree with sort of that persists to this. It's really hard in younger patients not to do B. B. Plus DVD. And um I was in clinic when DR King was in that patient who is having all these side effects from the treatment. I I really wish I had a study where you know the escalating after a couple of cycles was studied. I think that's what a lot of people are doing in clinical practice because it's often quite hard for patients to go through all the uh six cycles with Vivian A. D. D. You know the the Evans regimen that I mentioned um where you where you do the sequential approach and you get two doses of B. V. And then you get a B. D. For up to six cycles of tolerated them. Four doses of BV out back and in patients who were over 60 the outcomes were very very good. You're getting half as much BV. And you're separating the BV from the been blasting and I you know use this and patients well into their seventies and the majority tolerate that very very well. Um So it you know it begs the question, you know, giving them together. You know, could we get the same benefit if we change the schedule around or gave the BV out back or did something because I think you're right. It's when you give in blasting and and bring Taksim together that really I think causes the significant toxicity. Um Thank you. We'll switch over to the C. L. L. S. L. L. Discussion. I know um dr on and perry had some cases if you wanted to share your screen. Not fair. There you go. Oh sure. So we have a couple of cases to go through for frontline CLL treatment. So the first case is a frail 77 year old woman with a mutated CLL presented initially a couple of years ago with cervical Adan apathy and lymphocyte ketosis. And was diagnosed with rice stage one. Um CLL she had a natural mutation in normal side of genetics and was initially observed for a couple of years but then presented with worsening anemia and lower platelet count. And this was confirmed to be due to bone marrow involvement by Cll. Um She's now also having fatigue with her anemia and her past medical history is notable for significant coronary artery disease including a four vessel cabbage as well as hypertension. So um wanted to bring up the approach. The question of how how would um we go about approaching her care now And so this is a patient that I had seen in clinic um and this was someone that we had elected to start on then and open in the frontline setting. She is someone that I think nicely fit the criteria of the CLL 14 study um sort of being in a sort of more frail elderly population with comorbidities um and also with her significant cardiovascular history. Um veneta clocks was an attractive option as opposed to B. T. K. Inhibitor um given potential cardiovascular side effects that we know. Although they seem to be much less with the second generation B. T. K. Inhibitors. Mm hmm. So I would agree to erin's point. Um I really like this place because this patient can also receive B. T. K. Inhibitor. But given the cardiovascular toxicity I would favor a limited duration of um one year duration of therapy. Um The one thing that I also want to highlight is that we know insufficiency which is often found in these patients is not a contra indication to benito clacks. In fact, the german cl 14 study included patients with the Jeff are less than 30. So up to 30 we can use it mm hmm. It would increase the risk of PLS but that can be managed sometimes as an inpatient setting if necessary. And I would just add the one thing I like about this regimen is I think with the way that we start with open a twosome app that really helps sort of reduce that TLS risk by the time we get to introducing the veneta class. Okay I'm gonna advance to the next slide. So the next case is a 68 year old man who had a mutated cll. Um this is a patient that was sort of incidentally diagnosed on imaging. So actually did not have any symptoms attributable to cll. Um the patient had a natural mutation and also try some a. 12. And the scans um actually showed quite bulky disease. So this was a patient that had lymph nodes in the abdomen conglomerate greater than 10 cm and several other bulky sites of disease of 5-6 cm in size. Um There were no side of penis present. Um And so this patient's past medical history is notable for cns bleed that occurred five or four months prior to the patient being seen in clinic with a bulky lymph nodes. And this required a very invasive neurosurgical repair and hemi craniotomy. Um The patient otherwise is an excellent performance status and actually recovered completely well from the surgery. Um and just has a past medical history of hypertension for which he's on a single anti hypertensive. Yes and so I'm thinking of how I would approach this patient's care. Um So this is a patient who while not having any symptoms. Attributable to disease. Is someone that I would think about treating um given the size of Islamabad in apathy. So he meets sort of the I. W. C. L. L. Criteria based on sort of disease, bulk. Um And so we did discuss starting this patient on therapy and I think um in his particular case his history of cns bleed. Um given that sort of extent of that um was thought to be sort of something that would be a little bit more give me a little bit more pause before starting him on a B. T. K. Inhibitor. I think that given his young age if he needed a B. T. K. Inhibitor therapy in the future I think that the more that we were removed from that bleeding event that would certainly be something to consider. But given that this was in his sort of immediately recent history of just a few months prior this was another patient where we discussed the idea of Benedict collects and amenities a map and again the option of time limited therapy duration was something that was very attractive to this patient as someone who was young and quite active and really doing well overall physically. Hey honey I agree erin um the I was just thinking about the portable unit which is a selective um nonviolent DDT inhibitor and it's just thought to be one of the highest selective BdK inhibitor in the field. I think the bleeding rate there was still 20% lower than other BT candidates but still there so there's definitely a class effect of platelet dysfunction and DDP and efficient. Um One question that I had, you had quite a lot of natural mutated cases. Do you have any comments related to that and then cardiomyopathy? Any worry about victor's transformation? Mhm. Yeah. So that's a great question. Um uh And I do sort of it gives me a little bit more pause when I do see a natural mutation because I do think that these patients, especially when we start to see them with trisomy 12 and bulky lymph nodes. Um We do see a sort of a higher incidence of Richter's transformation and patients with a not underlying natural mutation um in these two patients. Um uh Neither of them sort of had we both had sort of imaging over time um and um physical appearance that was sort of reassuring for victor's. So neither of them had very elevated LDH. Um uh This patient here had actually had scans five months apart um both from the incidental initial diagnosis and the timer seeing him in clinic. And while the lymph nodes are quite bulky, they actually hadn't changed much in size. So that was also reassuring. I think if I have a patient that has had sort of rapid lymph node growth, especially if it's happened within sort of one region as opposed to sort of systemic or if they're presenting with the symptoms of an elevated LDH. This was certainly a patient I'd think of staging with pet before. Embarking on CLL directed therapy just to make sure that there was not something concerning for transformation, totally agree. I tend to get a lot of lymph node biopsy even if the suv level is below 10, if it's above 56 then I would just go ahead and get it because there is some data that between those five and 10 range you could still get victor's transformation. So suv uptake is um not a definite um indicator of yeah, totally reasonable given the clinical. Absolutely agree. Um so this is my case fit 45 year old man with a mutated cll. So cl does happen in younger patients. Actually cl diagnosis before the age of 55. It's about 10% of the cl population. So small subset but it does happen. He presented with Olympus psychosis diagnosed with Stage one CLL um and had Del 17 P and TP 53 mutation concurrent deletion and mutation is very common for the TP 50 operation self group. So he has felt initially he underwent watch and wait and about a year later had huge splenda Mickley fatigue anemia and from the site of pina. So you got a bomb marrow biopsy cl was there. Um The lymphocytes were activated. Um and the pathologist would call it as increased prelim facility but not quite at the prelim pathetic leukemia level which requires 55% of the marrow. So still Cll he has um he was pretty fit. Um just out of hypertension but otherwise not on any other medication. So how would you approach his care And um I want to highlight he had TP 53 mutation, very aggressive disease. Um you know the current entity and guideline recommends all of the b t K inhibitor and then plus open approach. But my preference is to give this patient BDK inhibitor for continuous control of the disease. Um Again, there is no randomized trial data to support that. So I'm curious to hear what Aaron or other people think on this topic. I think that that I think has been something that um a lot of us sort of do prefer. Um but that I think that especially if the patient had a strong preference otherwise for time limited therapy, it could still be discussed. Um I would also say that these are the type of patients that I think sometimes may benefit the most from some of the trial type options. Like you mentioned any. A so whenever I see a patient like this, I also think about whether there might be combination based therapy trials or things like that that we may have to offer. Um the patient. Yeah. Great point. Um actually dr David um a civil trial which is a calibrated data collection of venice is a master um had a about 10 patients and that original publication with tp 50 aberration and um rd rate was over 85% in that subgroup, similar to the rest of the patients without tp 50 aberrations. I think that's that's a great option to think about. Um So my last cases, an unfit seven year old female with mutated Cll and cardiovascular disease um she presented 10 years ago with lymphocytes. Um Normal fish mutated by GHB no T 53 underwent which watch and wait for quite a long time and then developed worsening anemia and bulky lymph nodes, hemoglobin sound to nine plate that sound trending white towns 300,000. I repeated the fish. It was normal. Still no Tp 53 mutation, so that's good. Um But she has quite a lot of disease um similar to the case that Aaron presented and she was on aspirin and Coreg or carvedilol which is a PGP innovator. So how would you approach your care now? So this actually happened to me and um I was actually entering the NATO clacks when the system captured the drug interactions. Um So um what I did for her was to call her cardiologist to see if I can change carvedilol to another asian and proceed to benito cracks based therapy. Um But in the off chance that she can she absolutely has to stay on carvedilol. Um Then I would prefer to use um BDK inhibitor in that case preferably second generation, including a calibration of insanity movements of available. Oh sorry erin go ahead. I was just gonna say I think this case brings up, you know, great points for discussion and that you know I think most of us are very aware that there's some drug interactions to look out for for veneta clocks with major sip interactions. But I think that there's very common cardiovascular medicines with like Coreg and cultism that we also have to watch out for isn't an original medicine or other to antibiotics that I haven't thought about, that. It's a PGP innovator. So something to think about it's that you know, we are so fortunate to work with an amazing group of um pharmacists who and you know these systems within epic and there's so many checks and balances which is so great. Um but is there any uh suggestion that you could adjust the dose of genetic lax and and move forward and and the other thing I would bring up is that you know with a calibrated nib there are a lot of issues with proton pump inhibitors that you know, many many of our patients are on too. And uh that also sometimes factors in so great points. I don't know if erIN you have any input on this, they can build upon that um Yeah I mean I think that one of the nice things about santa Brutus is um that you know we can use it with patients with P. P. I so I think that's been one of the very attractive features of that drug in comparison to a calibrated because it seems like the majority of our patient population is on you know a P. P. I. Yeah I totally agree with Aaron's point and I heard a taliban it has another formulation that does not require P. P. I. The company has not commercialized it yet but it's um soon to come. So we'll see. Um And then regarding the dose reduction of the needle clacks if it's a strong pgp inhibitor, weekend does reduce the needle clacks by 50%. But again the preference is to change the drop possible because we've had that issue with some of the antifungal Z. As well as Aaron knows well that this came up recently. Yeah. And speaking of antifungal there was one question in the Q. And A about prophylaxis. Um So for the NATO clacks based therapy I do not do prophylaxis um for rebooted or other BDK inhibitors I do use prophylaxis usually Bactrim or alternatives. And a psycho fear of valacyclovir for PCP prophylaxis for at least a year on therapy and this is not mandatory based on NCC and guidelines. Something to consider. Um But the recent um UK recommendation published in the british Journal of hematology does recommend um prophylaxis and altercations. So that's what I have been doing. You know the practice can be different amongst us so please feel free to pitch in and and I I also wanted to ask you a question about I like erin really liked your comment about you know thinking about the patient's immune system who's on observation and we follow I. G. G. And sometimes people need um replacement and you know can you talk about when you would replace somebody and what your target I. G. G. Level is And you know, how well do these vaccines work? You know we always tell people, you know I'm a huge fan of shin bricks though. Now I've had quite a few breakthrough and you know as we're checking these antibody tigers for Covid and realizing that most of most of my CLL patients with any burden of disease, everybody on B. T. K. Inhibitor, they have no response whatsoever. So so thanks again for the question regarding I. V. I. G. Um The guideline is to use um I. G. Level less than 400 and use monthly infusion and being it on the being on the I. V. I. G. For lifelong therapy is quite a commitment. So once the patients get out of the you know frequent infectious period with low um I. G. G. I sometimes you know become flexible by lengthening the interval of infusions to 6 to 8 months or just doing the I. V. I. G. Over the winter months and skipping it during the summer months. So it can be flexible and then regarding vaccination. I totally agree with the shin bricks. And there's data from the NIH group that CLL patients um who were receiving shingles vaccine can respond to the vaccination because it's a recall response. They're already exposed to the virus. Their immune system responds to the vaccine pretty well. So I would highly recommend Covid vaccine is different because hopefully the patient hasn't seen the virus and their immune system is not aware of this virus and therefore they're mounting of antibody response is much less common. It's about 50% for untreated patients, 30% for B. T. K. I treated patients and zero for ben plus open or monoclonal antibody campaigning asian treated patients. So it is really important to push for um the covid vaccination fire to pursuing therapy. Um And the guideline is constantly changing for covid vaccination right now. Three primary series is recommended followed by a booster and I believe the CDC recently updated their guideline to give another booster. So those number five um as an optional management four months after their last night. So it um we've we've had fun with these discussions and I did see our patients with B cell um monoclonal B cell lymphocyte oasis at risk of infection. Um Question from an audience which is actually a very good question. Um And yeah yeah yeah they they are at risk of infection. Seems like their immune system is just not you know very well even when the disease is is not that proliferated. Yes they are at risk of infection and I would apply the same principle in terms of vaccination. Um and you know covid precautions really agree. Um Alright, so we're a couple of minutes early so we will let people enjoy the rest of their saturday. Um but I want to thank everyone who joined and um all of the speakers and all of our audience and I also wanted to again introduce our um chief of our lymphoma group at Dana Farber um Dr Armond who helped um help us get this together as well. Um I love it. I need to be introduced twice a rare treat. I didn't see where I went to elementary school and stuff. Don't disappoint but anyway, so I'll join my thanks to yours to first to all of you guys for doing such a terrific job on the on the talks and on the discussions on the panels which was very uh instructive and and I I thank everybody in the audience for as you said, for giving up your saturday morning and hope that you also found the presentations instructive and entertaining. A huge huge thank you to you Austin for putting this whole thing together which was a massive effort. Um and I think you you pull it off marvelously and then for for those of you who who share patients with us, we're very thankful to to to be part of the care of your patients and uh and hope that, you know, we're here for anything that that you need for consultation for discussion of clinical trials, discussion of clinical conundrum anything anytime, we're delighted to be of help and and honored when you when you send your patients to us for questions. Uh so, so many thanks to everybody. Have a great rest of your weekend and hope I hope that we can do this again next year and I very much hope that we can do it in person then. Thank you. Thank you everyone. And just a reminder the courses available for one month after on videos. You know you missed the session because yeah, you have to take your dog out for a walk or something. So uh so it is available for for a month afterwards and be sure to fill out the evaluation at the end of the course to get your CMI credit. So, and thank you big shout out to the Harvard Medical School um crew here that made this process very seamless in terms of the green room and it was a very, really nice experience. So thank you. And if you can please fill out the evaluation of the the link is in the chat. All right, have a great the rest of your weekend. Thank you
