Chapters Transcript Video Treating Lymphoma in the Older Adult Population Back to Symposium Patrick Johnson, MD, discusses treating lymphoma in the older adult population. um dr Connor Connor johnson from Mass General Cancer Institute instructor of medicine at Harvard Medical School. And um one of our um recently graduated fellows and um he is a research interest and um was published in elderly patients with lymphoma which um is really in terms of what we see in the clinic, a lot of what we do. So I think this will be a very relevant talk. So thank you. Terrific. Thank you so much Austin. And I just want to mention it is such a privilege to be here. What an incredible set of speakers and um uh an awesome opportunity to talk about lymphoma this morning. Um As mentioned, my name is Connor johnson, I'm from Mass General and in the center from lymphoma there. Um and this talk is really focused on treating lymphoma in the older adult patient population. And the intent of this is to be case based, practical and to go through a few data points in terms of studies and other elements to try and provide practical clinical management. Before we dive into the first case, I will mention when we talk about the older adults, even even that has a little bit of controversy. As you know, the I. P. I defines older adults is greater than 60 some years, 65 although I would say oftentimes in clinical practice 75 is sometimes an age where we think about an older adult from a from a from a change in terms of chemotherapy toxicity and all those types of elements, although it's very very heterogeneous as as we know. And so our first case is a 79 year old female with diffuse large B cell lymphoma. Non gCB subtypes of biopsy proven not double hit lymphoma. Despite that she's quite ill. She's actually hospitalized has bulky 12 centimeter actually at Ganapathy has some S. V. C. Syndrome accompanied with that pretty sky high LDH has mentioned here on the slide multi station at Ganapathy. So this is advanced stage disease and actually has a tight beetle lactic acidosis On top of that. Her I. P. I. S. For overall performance status. Despite this is reasonable at two and that's peacock performance status and medical history is fairly modest. She has atrial fibrillation. She actually had some bradycardia and how to pace her place because of that. But otherwise not a whole lot of other medical problems. And in terms of her baseline functionality. She resides alone. She actually still works, she doesn't do a whole lot of moving with her work. But she's in a factory doing assembly and so does all of her activities of daily living as well as instrumental activities of daily living. So when we see a case like this you know how do we actually approach therapy and somebody who is in their seventies but presenting with with a new disease. So before we dive into that as as everybody here knows I just want to impress upon that this is a common problem. And it's a challenging one. The median age of presentation around 67 years for the few start to be self lymphoma and the percentage of patients who are in their 70s and 80s continues to rise across the United States across the board. And so this is becoming a more and more prevalent problem and will continue to be so As we move closer to 2030, um older adults though this is the most common sort of set of patients presenting with the L. B. C. L. Or the cohort that have a higher risk of toxicity. And that's for myriad factors that co morbid illnesses, changes in metabolism of chemotherapeutic agents. Um Some biologic changes in terms of the disease sometimes and then changes in physical function, cognitive function and social function as patients age. Despite this is incredibly heterogeneous as we see in clinical practice. And so the differences between chronological age and biologic age and how all of these factors interplay make it very challenging to conduct studies and really tease out who should get what. So with all of that. How do we actually assess pre treatment fitness and try to understand who's going to have the best and the worst outcomes with therapy or who should get those modifications of therapy. There are a few tools, all of us or most of us use echoed performance status, which is a fairly rudimentary tool. There are studies across oncology showing that gestalt of oncologist is not as good as doing more robust assessments for toxicity. Um That said there are some specific tools to try and assess toxicity risk cardigan crash are actually chemotherapy toxicity calculators. They are for all of oncology. I will note the crash tool when it was prospectively designed included about 15% of patients with non hodgkin lymphoma, But these are definitely not designed specifically for diffuse large B cell lymphoma. There more broad and they do require time to input variables into a calculator online that can be somewhere on the order of 5 to 10 minutes. But because these are not specific to our disease, that's I'd say there's there's limited uptake of these of these tools to assess toxicity, but they do exist. A more robust tool is a conference of geriatric assessment. This is certainly the gold standard in geriatrics in general. Conference of geriatric assessment refers to multi domain assessments um and there's not a single one that's sort of an array of different tools. These can be very lengthy in time and can be as much as an hour. And so the practicality of doing this for patients who, you know, hospitalized with the aggressive lymphoma is relatively limited and so I'd say the uptake of this on on a sort of national scale is limited because of that. There actually is a relatively recently published simplified geriatric assessment that I'd like to mention just on the next slide developed by the Italians. Um And then finally there are some tools such as gait speed, which our colleagues at the dana Farber have shown Is associated with mortality and if you start to B cell lymphoma, it's a fairly simple sort of metric. Um and there are also screening tools like the vulnerable owner survey 13 which has been associated with mortality in large cell lymphoma patients as well. And hopefully in the future will continue to get screening instruments that are more rapid that can kind of help us gauge fitness. Here is the simplified geriatric assessment. And then again I'd like to just mention it briefly because it's relatively recent has been validated in large patient population. So our colleagues in Italy published this version of a geriatric assessment and what it uses our age with a cut off of 80, less than 80 versus 80 plus. A co morbidity score called the service G. Which just looks at various different co morbidity organ systems and a score of three or four refers to a serious comorbidities that's really impairing functionality. Um And then it incorporates activities of daily living which are sort of the most basic things that one needs to do to function such as dressing oneself toilet ng and instrumental activities of daily living which are things like using the telephone paying bills and by looking for impairments of these and age patients get stratified into fit, unfit or frail as you can kind of see on this chart which is a modified version of what's in the paper um you need to be 80 plus and have these impairments and functionality or comorbidities, scores to be frail. And whereas if you're younger and have these impairments you're unfit or if you're older than 80 or 80 plus and have no impairments you're also considered unfit. And each of these categories fit unfit and frail are highly correlated with mortality. Um And so you can bucket patients into mortality risk and I would say frail patients are probably the ones where you're the most concerned about how curative intent therapy may impact them. Despite these tools going through each one of these and mentioning the geriatric assessment which is specific by the way the sda that simplified is for the L. B. C. L. Patients. These are still prognostic tools. They're not definitive prediction tools about who actually should not get curative intent therapy or who should have modifications of therapy. And that is our major unmet need. There's not a robust tool to help us gauge that. So these can help us understand who is maybe going to have a worse mortality outcome or who is less likely to have the mortality outcome that we want but it won't necessarily predict what's going to happen with therapy. I would say the conference that geriatric assessment is useful across all of oncology but because of its time intensity it's I think limited in its uptake and practicality for patients with aggressive lymphomas. So in some you can make assessments basically by gestalt or sort of whatever tool you want because there are not valid prospective tools to gauge modifications of therapy. But I was impressed to say that age alone is really not the way that I would make these assessments for therapy. And generally speaking, multi domain evaluation. Even if it's a gestalt evaluation of functionality falls nutritional status, cognitive status and co morbidity profile or what needs to be utilized to try and integrate Um decision making around fitness for chemotherapy and fitness for curative intent therapy. And I do want to mention that relative dose intensity is another important concept. Um generally speaking, there is data that higher relative dose intensity is important for patients. I will say that there's at least systematic review data that suggests that potentially in patients 80 plus that this is less clear. Um there may be some evidence that relative dose intensity is less critical for cure in the 80 plus patient cohorts than in the younger patient cohort. So that tends to drive at least for me personally, I'm more interested or sort of it's a greater goal of mine to have relative dose intensity in the younger than 80 patient cohort. So now let's transition to talking a little bit about some data, specifically an older adult patient populations. I want to mention pre face treatment. This is a difficult patient population to study. So in that context. Pretty good data for pre face therapy. So this is a study that took 100 patients, half of patients have been Christine on day minus six and print is alone for seven days, 100 mg. The other half did not with this. The vast majority of patients who received pre face therapy achieved a good peacock performance status prior to therapy. And the rates of FNN were actually cut in half. It's a pretty impressive mitigation of toxicity with a relatively easy intervention. And so in practice and based on data that shows it's essentially similar. A lot of folks will give 100 mg of predniSONE alone for seven days prior to therapy. And I would say in the patient population 65 plus um this is a relative low risk intervention that has the potential to augment ps and mitigate toxicity. And so I tend to use this in practice really quite frequently. I also want to mention our mini child. So our parody and colleagues in 2011 published a prospective phase two study. It's a pretty impressive study. 150 patients, all 80 years of age or older, median age was 83. Everyone had any cock performance status of two or better patients did receive riTUXimab at full dose, 375 mg per meter squared and the dose continuations of Cytoxan dr Robinson when Christine and predniSONE. I'll note that this is a pretty sick population, though half of patients approximately have impairments and instrumental activities of daily living. About 50 patients had bulky disease. The vast majority of patients had high I PS four's despite that the majority of patients, almost three quarters were able to complete six cycles of therapy. And the outcome data though by no means equivalent to sort of the full our top data that we know are the data that includes younger patients is still pretty reasonable, with a two year survival of approximately 60% and a two year progression free survival approaching 50%. And so here is the actual curve from that study, looking at the survival probability over time. And I'll just note that this is potentially curative therapy In a patient population who's in their 80s with a median age of 83. And so I do think this this gives us good data to show that does attenuated are chopped is feasible to do in at least a sizeable percentage of patients in their 80s. I'll also mention that there is a relatively recent study, the senior trial published in 2021, which was a randomized controlled trial 1-1 of our mini chop with or without revlimid or thalidomide for six cycles. Everyone in this study was 80 years or older. The economic performance status similar to the Pierotti study. It was all too or better and everyone's revised I p. I was wanted higher. Everybody in this study notably got pre face. So within Christine and predniSONE. Um And so this was a unfortunately a stone called negative study in terms of the addition of thalidomide. That said I just want to draw attention to for the Armani chop arm. The two year survival approach was 66% and the two year progression free survival was actually more than 50%. So still not what we'd expect to see with full dose our top but pretty reasonable outcomes in a patient population. That can be very challenging to treat. Though acknowledging these are patients that were able to approve to a trial. Um The majority of patients did receive six cycles of therapy and you know various analysis just to think about what are factors associated with survival. Um ideal scores. So their ability to do instrumental activities of living lower is worse by the way and the M. And A. Which is a nutritional score lower is worse. Um Those predicted survival but on multi varied analysis the only variable that was associated with survival was actually hyper album anemia. So even though again this doesn't give us anything definitive about how to modify therapy. I do tend to pay attention to hyper Albany mia. Just to keep in my mind that that's associated with survival and the older adult population. So now just to sort of put that together and think through if you start to be stolen from a framework. Um My general sort of comment would be I start with an evaluation of multiple domains. So not just age alone as we mentioned cognition falls co morbidity profile and sort of try to integrate that together to think about whether the patient is fit for curative therapy or whether they are not fit for curative therapy. I try to do pre face steroids in just about everybody to augment performance status. As I think it is a relatively low risk intervention that does have data. I will note there is some data that the first cycle is where we're particularly worried about this. Um and so I do think of seven day prefix steroids with augmentation and performance status mitigation of fNN risk can sometimes improve performance status to the point to make us feel more comfortable about fitness for therapy for patients that are fit for curative therapy. This is where I am then choosing between our chop and our mini chop. I will note that I have a pretty high bar for omitting curative intent therapy. In this patient population, you know, we don't have great perspective tools to say who definitively should not get curative intent therapy. There clearly is a lot of gestalt or sort of you know, subjective interpretation of that But I tend to have a pretty high bar for actually committing that. And so typically I'm often choosing between full dose therapy or does attenuated therapy and again it's a multidimensional assessment but in patients who are 80 plus, I think my general approach is going to be leaning towards our mini chop. Although there are some exceptions to that And for patients younger than 80 That's where oftentimes I'm thinking about full intensity therapy or trying to at least maximize our D. I. Although the patient population whose 75-79 years, that is a very case by case basis and then oftentimes patients younger than 75, there can be either comorbidities or other things that implement us needing to think about those continuations there as well. For the patient population that's truly not fit for curative intent for curative intent therapy, I think there still are some very good palliative intent options, reduction amount of therapy. The relapse setting has had a response rate on the order of 35%. And so for patients where you really can't give curative intent therapy but still want some type of retaliation that with steroids plus minus and Christine are all things that could be contemplated. In addition, palliative radiation therapy is always a good option, particularly for disease that has a single fight that's particularly symptomatic and can get good disease control and improvement of palliative symptoms with that R. J. Mox. Although that's often a therapy I'm thinking about in the second line setting for patients um where I have concerns about tolerable. Itty of more intensive therapy is still another regimen that could be utilized and has pretty good tolerable. Itty data even in patients in their 80's and then triathlon will talk a little bit more about in the second line. I just want to spend a little bit of time talking about relapse disease. As I'm sure we've been talking about the gold standard for fit patients that younger patients has been salvaged, chemo immunotherapy followed by transplant. Although as recently as yesterday we now have FDA approval for actually captain jean Carlo lucero in the second line setting. I mean so this is changing before our eyes. Although there's a lot to talk about about those types of pursuits of therapy, transplant has historically had general age cutoffs whether that's 75 years are being pushed up dependent upon disease centers. But that generally there is an age cut off. I will note that for car T. Cell therapy we have data now for the second line for both access L. And Liza cell being superior to salvage chemotherapy. Although with lots of caveats, patients in these studies were refractory disease or relapse within a year. But I would say there's not a true age limits. Unlike unlike transplant with car T. Cell therapy. Um in terms of access L there's published data that for patients older than 65 the outcomes were comparable to patients younger than 65 there were patients in their seventies on the axis Cell Studies for sure. For Liza cell and other 41BB products, there is a lower toxicity risks with these products. Just given the co stimulatory domain In the pivotal Eliza cell study, 10% of patients were 75 years or older, the oldest was 86 years. I will note that in our in my own practice that we have treated patient patient 91 years of age with car T cell therapy. So that's probably the oldest sort of patient that I have personal experience treating with car T cell therapy. And we don't yet have a standard approach for fitness assessment with car T cell therapy. There's no specific instrument for car T cells for how to gauge fitness. Um I would just say that in that context, probably similar similar approaches as we would use for chemotherapy fitness not age alone, but a multi domain assessment. Um And these are probably different than transplant assessment and hopefully will develop specific tools for assessing this fitness over time. I don't want to spend a minute on top to sit in my plus linda linda mind. This is relatively recently approved therapy and the relapse setting. I know we just had a great set of talks on the few start B cell lymphoma. Talking about therapy, tapas cinema because it is an anti cd 19 monoclonal antibody with synergy with linda linda mind. And in the L mind study which is a multi center phase two study led to FDA approval as early as the second line setting for those who are transplant ineligible. The logistics are a little bit tricky attack. A city map given at 12 mics per kig analytics given orally 25 mg. Days one through 21 out of every 28 days for a year and then tap monotherapy indefinitely. So indefinite therapy. The first month is a lot of taft that's given on days 148, 15 and 22. And then weekly for cycles two and three and then every two weeks beginning at cycle four. So logistically it can be a little bit complicated and that can be a factor for some patients and making a decision. But that said, here's the data for some of the at least for the original paper. Looking at the response rates are pretty good. Um 60% response rate, a little better response rate and non GCB subtype. And then in the original paper for those that had a response to median duration approaching Two years. And an updated data around 40 months, median duration of response. And so this is a therapy that can lead to durable responses in patients that you can give as early as the second line therapy that doesn't include chemotherapy. And I'll note that the toxicity profile is pretty manageable. Um in this study, patients were in this study about half of patients were older than 70. And so there were plenty of patients in their seventies, there were a few patients and eighties that accrued to this study. Um And the toxicities are fairly manageable side of pena's rash, edema cough. Um And so this is a therapy that can offer a pretty favorable toxicity profile that can be utilized as early as the second line. Now, how to integrate that with car T cell therapy is an evolving concept. If patients are eligible for car T cells would probably go down that paradigm and not with cd 19 directed therapy with teflon. Although this is an ongoing and evolving area in the last few minutes, I want to shift gears and talk about follicular lymphoma. So to frame this, we have another case. So this is an 88 year old female who's presenting with a new diagnosis of low grade follicular lymphoma. So on biopsy, no evidence of transformation. She has symptomatic disease meeting gulf criteria with a slightly larger than seven centimeter inguinal node causing some discomfort of symptomatic disease. She has medical history but it's fairly modest. She has osteoarthritis, hypertension and hypothyroidism. The latter two requiring medications. Her performance status is good. Bye, ecology is a one and a baseline from a functionality standpoint. She resides with her son is retired and ambulance with a cane but does do her ideals and ideals actually gets herself to the doctor's office. She cooks, she cleans, she dresses herself. So how do we approach follicular lymphoma therapy in this context. So you want to draw your attention to one study, which is the relevance trial. So this is a phase three study that compared riTUXimab and linda linda mind to riTUXimab with dealers choice chemotherapy the maximum and a little bit of mine was given in combination for a year and a half and then we'll talk some and was given every eight weeks for six consolidated doses when Letterman was given at a dose of 20 mg for 21 out of each 28 day cycle. And then after that at 10 mg I assume. And then after that at 10 mg, if a CR was achieved. So the dose was dropped by 50% For those that had a pr the full dose was continued and for those who had impaired creatinine clearance, the initial dose was dosed attenuated for that and I'll note that the three year PFS of our land was pretty impressive and comparable to that of chemotherapy with nearly 80% of patients achieving progression free survival at the three year mark. And in this study, the oldest patient was 89 years of age, about 16% of patients were older than 70 years. And in my own personal practice I've given too little undermined. The patients in their ninety's not that every patient in their nineties would be set for life. And in my therapy. But just to illustrate that age alone also, I'm not a contra indication to combination therapy for follicular lymphoma or other indications where our land is a consideration the level of the mind is originally dosed and then I usually give aspirin for venous thrombosis, embolism profile access given that risk with one goal in mind. So here's a framework approach for follicular lymphoma and then we have some great talks on follicular lymphoma. So just to focus on it and the older adult patient population as we all know, not all patients need therapy. And so active surveillance is a great option for patients, particularly when we have a concern about toxicity. And so that is important to make sure that we really think therapy is indicated. But when therapy is indicated, I think, you know, a tumor burden assessment of low versus high is a very helpful paradigm For the low tumor burden patient or toxin. And monotherapy can have high response rates around 75%. The durability of response is not that compared to chemotherapy edition, but that often is less. So something that we are as concerned about in in the older adult patient population. And I think it's a very good treatment option. And then I don't forget, don't forget about how the radiation therapy, even a single four grade those are radiation to a site of disease that's causing symptoms can achieve disease control. It can be very useful in patients with follicular lymphoma for those with high tumor burden. Um the sort of branch point is then whether the patient is fit for chemotherapy and I would say there is no specific follicular lymphoma tool to gauge who is fit for chemotherapy and who is not. And so the same paradigm would apply as to what we talked about with diffuse large B cell lymphoma, a sort of multi domain assessment, not using age alone but incorporating multiple components for those that are not fit for chemotherapy. I do think Arlen, as mentioned through the relevance trial is a very good option and something to think about. You can have attenuation of the little into my dose for patients, renal function or fitness and you can modify that as you go through therapy if necessary. And that's the therapy that has data to show a durability of response for patients that you do think are fit for chemotherapy. There's a smorgasbord of options which I'm sure will be discussed in full detail was included. Benda must mean with maximum or with the and then chop based therapy with maximum or minimum for the older adult patient population. I'm generally more concerned about toxicity and the toxicity risk is higher. And so that's oftentimes where I'm choosing therapies where I may choose a therapy with a lower risk of toxicity um with a with a lower likelihood of PFS benefit, there's no difference in survival outcomes amongst these different therapy options but it is very personalized to the fitness of the patient. Um and to sort of the goal of therapy in terms of PFS or not. Um And then generally speaking I would say for maintenance therapy particularly in the era of covid, I'm more reticent to use maintenance therapy particularly in an older adult patient population given toxicity concerns as well as the covid 19 pandemic. The last thing I'd just like to spend a couple of words on or just supportive care for older adults. Um I would say proud of care and hospice use are both things that are historically underutilized or have low rates of use in patients with humans. Logic malignancies and dr who's who's one of our speakers here has published a great work on this. Um palliative care use does have good data for early integration just across oncology and with an emerging set of data for patients with pharmacologic malignancies. Um DR has published some data for patients with stem cell transplant for example, um prospects and does have numerous barriers to use. And so transfusion support the fact that we have palliative therapies that can be very effective for disease control or significant barriers to hospice use. And hopefully the system will continue to evolve to really tailor hospice and taylor palliative care integration to the unique needs of patients with pharmacologic malignancies. But it is worth considering the fact that that these are things that have historically been used less frequently in the human logic malignancy patient population. So I know this has been a whirlwind of different data and I hope this is a useful set of points clinically. I want to just make a few summary comments. Number one lymphoma treatment and older adults is a common problem. It is complex problem. We don't have a gold standard for how to tailor therapy based on pre treatment assessment. We do have tools the C. P. A. The simplified geriatric assessment which is specific for diffuse large B cell lymphoma. And we have carbon crash chemotherapy toxicity calculators. Each of these has weaknesses though. And they're not gold standards for being able to tailor therapy. They're not predictive tools for being able to omit therapy for example. So I would say, you know, chronological age is insufficient. And use multiple domains to make your own assessment about the security, content, therapy versus palliative intent therapy and about how to tailor therapy. And then hopefully in the future we can refine prediction tools and augment the interventions we have besides prefaces steroids to help improve, tolerable itty and more personalized therapy. Doctoral schefty, for example, has led to trial looking at by specifics in the older adult patient population. And so hopefully in the future we'll be able to really refine and personalized therapy more and so stay tuned for that as we continue to evolve. That component of therapy in the future. And here's a couple of other references and again, it's just my absolute privilege to be here today. And I welcome any questions at any time. My email address is included here or if I can ever be of assistance with anything. Thank you so much. Connor for that talk. Um We have one question already um from the audience was asking about our chop and the increased risk of fractures. Um Yeah. Yeah. You know I think that I don't have a specific management recommendation around that. Um I think it's it's an excellent point, particularly with the fact that we're including steroids and prefix steroids. You know I think a lot of my colleagues and myself have more and more been checking vitamin D. Levels and there's some associations with vitamin D. As well with in terms of therapy implications. Although that's not robust data. And so I think you know I think with any older adult population including a vitamin D. Check including fracture management as part of your consideration including that as part of your survivorship management. But I don't have any specific sort of management that I do differently related to fractures in older patient population. Yeah, no I agree. I think oftentimes these patients need treatment urgently so you don't have a lot of time to um to waste. But I will say I really um I agree with the predniSONE prefaces something I've been doing more recently, not necessarily even with elderly patients but a lot of patients. Um And I will say I just, from personal experience I do think it does patients performance status improves it does seem like they tolerate treatment better. Um So I'm glad you really highlighted that. Yeah I think that's a great point. You know obviously it's it's 100 patients study that I cited but that said these are hard studies to do and that's pretty pretty good data for improvement in performance status and and there there really was a lower toxicity rate particularly with FNN with the first cycle. And there's I'd say some data suggest that that's the cycle where you're you're certainly concerned about immediate toxicity risk. And so I think I'm pretty reticent not to do that is what I would say overall I think it's a relative low risk intervention. I agree. And this last question I have is um I know in your clinic do you do you um are you able to like work with the geriatrician or do you, I know it's I don't know how you know your clinic is or I know that's not a luxury everyone has but sometimes we found that can be very helpful. We don't specifically have a geriatrician. We have a robust geriatric practice that we can refer to Dr Christine. Ritchie is one of the leaders of geriatrics at our institution. You know it'd be great to have a geriatrician that was really focused on our patient population. Unfortunately we don't have that at our center and I think that point is extremely well taken. Um And you know I think uh if you if you have access to that co management with geriatrics is really something that can identify geriatric domain impairments and particularly potentially improve therapy. Tolerable. Itty It will be great if we can eventually get interventions across all kinds of different aspects that can help us understand exactly who needs that. Um there is an instrument called the v. s13 which has been shown in pretty large studies to correlate with sort of screening risk in terms of older adult patient populations and dr flowers and colleagues have looked at that and deal BCL and so potentially down the road. We may see that screening instruments can help us identify patients and and streamline who goes to full geriatric assessments or supportive interventions with geriatrician. Well thank you so much. Um I will I will be seeing more of you at the panel discussion. So um alright so I will share my screen. Published May 26, 2022 Created by Related Presenters Patrick Johnson, MD Hematology/Oncology
