Inhye Ahn, MD, discusses the background and management of chronic lymphocytic leukemia and small lymphocytic lymphoma.
talk to us about um CLL and S. L. L. And we're very glad to have her here. Thanks Austin. Um And thanks everyone for remaining to the very last very last talk of this course so so I will talk about um a little bit of background on CLL and current management uh in this disease I have no conflict of interest. So starting with the case with an indolent disease, she is a 64 year old female who presented with palpable cervical lymph node without any be symptoms on physical exam. She had small cervical and bilateral axillary lymph node and spleen was also palpable white count was 12,000. Um absolute length was 9000 no side api via peripheral blood flow. Saitama tree showed immuno phenotype of the B cells. Um Typical of CLL with Cd five Cd 20 dim and cd 23 positive cells. Prognostic markers were twice only 12 and mutated Igh V. And cycling. The one gene rearrangement was negative which rules out mantle cell lymphoma. So what other prognostic markers would you test? And would you treat or observe? The second question is pretty much straightforward. She's asymptomatic. There's no sight of pina. The lymph nodes are small, not compromising her roles and functions that we do not have to treat her. Um So I would focus my talk more on the prognostic impact um of CLL and S. L. L. This is a disease that is most commonly found in the us. And um with over 21,000 new cases in this country. Cll does not have a disease defining mutation. So it's defined by the surface markers of the cells and these cells circulate and reside in three areas of our body, blood bone marrow and lymph node. So the current IWc allow guideline recommends um fish Tp 53 sequencing and I. G. H. T mutation. Uh status assessment as mandatory tests At the time of diagnosis for clinical trials. Conventional carrier type of stimulation is also a desirable test and lead it to micro globulin is highly recommended and the reason why I needed to micro globulin is important is that it is um an independent prognostic marketing CLL and it's also a part of Cll International prognostic index. Cielo I. P. I. Is a five factor um integrated prognostic system which categorizes patients into one of the four risk groups with distinct overall survival and time to first treatment. I want to highlight that the patients with very high risk group should have. Um TP 53 aberration and either on mutated GHB and high duty to micro globulin. This highlights that genomic status, immuno genetics and serological markers of disease activities are really the hallmarks of the disease that are important for prognosis prognosis in this disease. Okay now we have more sophisticated tools to understand the genetic profiles of the disease. So um this is a paper generated um from Dr. Cathie Wood's group where they took samples from 21 Cll patients with distinct growth dynamics patients with either um exponential growth logistic growth or intermediate growth and by doing whole exon sequencing um with multiple samples collected from these patients, investigators found that patients with exponential growth had higher numbers of mutations and larger shifts in their clonal fractions so they're genetically more complex in other words. However, even if we find more complex genetics or even high risk markers such as TP 53 operations, we do not jump into therapy unless they meet the treatment indications. And the reason why I watch and wait as the standard of care in asymptomatic patient is really based on a large series of randomized patients. A randomized trials shown here is the CLL trial ist data published in 1991 where they showed no difference in overall survival in patients who had immediate chemotherapy and deferred chemotherapy. Most of these patients received chloramphenicol based regimen which we know is not the most active patients in CLL. So the German Cll seven study investigated a more intense regimen called FC are in high risk disease and the study um showed no overall survival difference at five years. How about targeted asians? The German Cielo 12 study compared to placebo and that this study did show improved event free and progression free survival. However early treatment with was associated with toxicity and overall survival benefit has not been demonstrated and therefore watching late is standard of care. So what I do in patients who are undergoing watch and wait is to really focus on managing their immune failure. This is a data from Mayo clinic which had over 1000 CLL patients diagnosed between 2000 and 2019 With the median follow up of five years. And they divided their patients groups into based on C. L. I. P. I. And found that um cl progression was the leading cause of mortality in higher risk groups and infection and second cancer were the leading cause of mortality in the lower risk groups. So based on this data I would recommend doing a really vigorous vaccination strategy against covid influenza disaster and strep pneumonia. Now moving on to a more symptomatic patient, this is the same patient we just discussed who underwent observation for years. Then she developed fatigue and worsening silopi mia. Her lymph node and spleen had minimal changes over time. But the white count was up to 47,000 hemoglobin dropped to 11 and platelet is now below 100,000. So would you repeat prognostic markers? Um It's beyond mere biopsy indicated. And do you want to treat? And my answer is yes to all of them regarding prognostic markers. I would repeat fish and T. P. P. P. Three sequencing. I would not repeat Igh V. Status because this does not change over time. I would do Bonera biopsy especially for patients with a nuanced outside a pina. So um with the prognostic markers. I wish we could stratify our patients into a match targeted agents. The reality is that we um use targeted agents in the vast majority of the patients, regardless of their genetic status. These are preferred treatments for most patients with CLL, particularly those with high risk markers, older age and comorbidities. There are largely two strategies continuous treatment with BDK inhibitor And fixed duration treatment with the NATO clacks, plus CD 20 monoclonal, anybody. Chemo immunotherapy with Fc R has still a limited role in young fit patients when these patients have mutated Igh V and there is no high risk genetic markers. So here is the current N CCN guideline for frontline treatment of cll calibration of and Xander are preferred B D K inhibitors that are used as continuous therapy Then. Plus Robin is given over one year. The list of preferred regimen for the relapse Cll is very similar to the front line. Um the difference is that right talks a map is combined with the NATO clacks and the veneto. Klax is given longer for over two years instead of one year following the murano study. Um Xander has not been approved in CLL yet but NCC and guideline was really forward thinking and put this agent in the preferred regimen as the drug is expected to be approved soon for the CLL indication. And these preferred regimens really are based on a randomized trial that proved better efficacy of these targeted agents. Starting with the Alliance trial and elderly CLL patients equipment whether without Cytoxan map was better then bend the mustang and the toxin map for PFS. OnePlus three Taksim map was compared to Fc R. And the E cox study in the UK UK flare study. And both of these studies showed PFS benefit in the E cox study additionally showed overall survival benefit. The taliban IB was combined with amenities, a map and compared to chlorine, brazil and amenities a map similarly then plus Oban was compared to chloramphenicol and amenities. Um and and of course the targeted agents were much better. The longest follow up data are available from the alliance study that tested the blood on it and the german cll 14 study that tested then plus Tobin and the four year PFS you can see we're really similar, 76% for a buddhist based regimen and 74% for Benito Clacks plus or Ben autism. These data suggest that the activity of these um continuous versus a fixed duration targeted therapy regimens are almost equally equivalent. The only exception to this rule perhaps um comes from the recent follow up data from the german cielo 14 study Is that the patients with TP 53 operation may not do as well with the fix situation therapy shown on the left side is data from Cielo 14. The two year progression free survival of these patients treated with Ben Ben Tobin was 80% when the patients had TP 53 aberration and this rate was numerically lower than what we saw in the single asian treated patients with TP 53 aberration. So based on this data, um I would argue that continuous treatment with B. T. K. Inhibition would be better in offering a more durable control of the disease. So, um moving forward, what are the active questions in the field? The first is we have so many B TK inhibitors now available in clinic and in the pipeline. So is there any difference in safety and efficacy profile of these drugs? And the second question is that there are several CD 20 monoclonal but anybody's as well, which one is the better drug to combine with prenatal class? So starting with the B. T. K. Innovator question here is a table that compares commercially available covalin B. T. K. Innovators, It is the first in class B. T. K inhibitor that has taken once daily. The caliber unit and santa boots are taken twice daily. The taliban, it is approved in Cll santa but have not yet. Both of these drugs are more selective for B. T. K. Um compared to a button it. And so there is an elevator, our our trial that randomly assigned relapsed CLL patients to either a calibration it for this study was a non inferiority study and showed no PFS difference in the two treatment arms. However, the safety profile was very different. Um favoring a Caliban in it. All of the non hematologist toxicities were lower. With the exception of headache, which was mild and manageable. The weight of acid and hypertension was nine and 9% for a caliber ethnic group and 16 and 23% for subordinate group. So much safer in terms of the cardiovascular toxicity as well. Well, daniel Boone was recently compared to be are in treatment naive CLL and of course the progression free survival was better. In the sequoia study. What was really notable from this study is the rate of profit was only 3% in the sandy bottom arm, including only one patient who had grade three or higher a fib. And this rate was comparable to the control arm treated with VR. So there is actually a study um an alpine study that randomly assigned patients to Xander Botnet and Brunette. And the study showed a really provocative finding shown here is the progression free survival of the sandalwood and treated patients um at one year it was about 10% higher than that compared to the Buddhist group. So why is that breaking down the responses and treatment discontinuation is summarized in the table on the right side. The overall response rate of the Bell 17 piece upset was 54% in the Buddhist Group which was really an underperformance of this group. When these were these patients were treated with the boudin. It also the shorter duration of treatment and higher rates of um treatment discontinuation observed in the farm may have contributed to this difference in progression free survival. Um This data was presented as an oral abstract last year in the european hematology meeting. So longer follow up and the cause of death and progression breakdown would be necessary to better understand the efficacy difference observed in the preliminary data set. Okay so the next question is what is the better CD 20 monoclonal or anybody to combine with the needle tracks to answer this question. German cl 13 study um was launched with four treatment arms, chemo immunotherapy arm with Taksim at plus the NATO clacks arm open plus the NATO cracks arm and the triplet arm that adds subordinate to open. Plus the NATO clacks. One of the co primary endpoint of undetectable M. R. D. And P. B. Um was reported at last year's ash and it was much higher inability is a map containing arms of this study, notably the patuxent plus Ben group at 57% undetectable M. R. D. In blood which was similar to the rate of um Rd observed in the chemo immunotherapy group. So this really speaks to us that ability is a map is a better antibody in clearing the disease. Um And achieving undetectable M. R. D. In blood. However it does come with some toxicity. The rate of from beside a pina was higher with the ability to map containing arms further the addition of a boudin. It increased the non pharmacologic toxicities including neutropenia infection bleeding and 1/5. So do we really need triplet regimen in CLL uh We do not have long term progression free survival data. Um Nor randomized trial data to answer these questions. So I brought bond marrow undetectable M. R. D. Reported at the end of combination therapy across the frontline treatment trials in this disease. Starting from the left side. The data from CLL 14 using Ben Oban for one year and this study used a little bit different approach by looking at peripheral blood M. R. D. Using a method called A. S. O. P. C. R. And the rate was 76%. Uh In the field it is accepted that about 10% lower rate of um RD was achieved in the bond american apartment. So I would think of this as about 60% bond there m. r. d. And you can see that by using a botnet plus the NATO clacks. Um The rate of um RD and bond mary is about 60% as well by adding monoclonal antibody to I plus B. Regimen of the osc group reported 67%. Um R. D. Similarly the german cl study group That a exclusive trial for patients with TP 53 aberration and the um are the rate was again 66 More recently. Um our Dr. David's at our institution reported the study results from the Taliban event plus open. Um and the rate of um R. D. was one of the highest at 86%. So taken together, it appears that the rate of um R. D. Is similar across the doublet regimens. The addition of monoclonal antibody may be able to increase somewhat the rate of um R. D. Although more data is needed whether this is a huge difference um and and translate into an outcome difference. So um coming back to the double therapy question. Um Dr Davids and his colleagues have recently launched a randomized phase three study in front line CLL. The study randomized patients to either a caliber orbital abilities and that combined with the NATO clacks and continues to drug for about a year. Um And if they're MRT positive, continue the combination for another year and everyone stops therapy at 24 months. So this could be a very good fixed duration. Um M. R. D. Guided treatment approach testing um The doublet treatment approach in Cll um for patients with relapse refractory Cll Dr Brown has recently activated this Xander baudinet, the NATO Clacks combination study. But this study will enroll patients based on their prior exposure to B. T. K. Inhibitor or the NATO cracks. And we would specifically exclude patients if they had if these patients have been progressing on BDK inhibitor with B. T. K. C. For it one mutation. And the reason for this is that the c. a. c. 41 mutation confers resistance to Daniel Boone in it and the combination and it's less likely to work and I'll talk more about the mechanism of resistance. Starting with our last case, the patient was the one that I took care of when I was a fellow at the NIH um She was a 72 year old. I'm sorry. He was a 72 year old male with S. L. L. Del 17 P. And un mutated GHB treated with two cycles of Pr and his lymph node just grew right after the the two cycles we did a biopsy there was no transformation just CLL. So the patient moved on to the next like next line of therapy with our chopped received six cycles. Lymph nodes were persistent and then began to grow after six months he had another lymph node biopsy that showed no transformation. So he was enrolled to a clinical trial at the time um and was treated with. And within two months the Linfield began to shrink. This was first that ever happened to him very excited. However at about six months on the on this trial his lymphocyte count just began to jump and um later we banked a sample and realized that he did have the B. T. K mutation. There are two patterns of disease progression on D. D. K. Innovator first is large cell transformation termed Richter's transformation and the second in a more common type of progression is cielo progression with B. D. K. Or PLC gamma two mutation. B. T. K mutation alters the drug binding and PLC Yana to mutation activates the Visa receptor signaling pathway. So making the B. T. K. Inhibition at upstream ineffective. Um Off the two B. D. K mutation is more common. About 2.5 to 3 fold higher incidents in patients who progress on D. D. K. And bitter. And uh most frequently it alters the sustained 481 residue to an alternative immuno asset and remove the colon bond between the target and the drug. So one strategy to overcome resistance is to use a drug that does not rely on this covalin binding. It's called non covalin DDT indicators and there are many in in clinical development. Um The furthest along the way is proto uh Puerto but it is also highly selected for B. T. K. And the data has been published by DR Medal Medal and Lancet oncology last year and the data was updated at last year's ash. Um This study enrolled over 200 patients with who were previously treated with a B. T. K. inhibitor. 40% of these patients at C. 41 mutation and the remaining 50% did at a wild type of B. T. K. C. 41 the progression free survival were similar among these groups regardless of the B. T. K mutation status. Another surprising data from this study is that the rate of toxicities were relatively low. The rate of acid and flutter was only 50%. I'm sorry 2% and are thrilled to hemorrhage and hypertension were below 10% range taken together. Um, selected B T. K inhibitors have more favorable safety profiles than this includes sanya, which is expected to be approved in CLL soon. And protoblood, a non Covalin BDK inhibitor that is effective against B. T. K mutant CLL. The benefit is a map is a better antibody than buttocks. Unmapped combined with the NATO cracks by achieving higher rates of undetectable disease and blood. However, we do not have a study of then plus open combination and relapse refractory CLL and therefore NCC and guidelines list then Plus right talks a map as preferred regimen in real life setting, simultaneous targeting of B. T. K and BCL two is feasible and applications, we now have two randomized studies showing I plus B regimen is better in terms of PFS compared to karam, brazil and open it to Samantha in treatment naive CLL So I Plus V is likely lead to the label change later this year. And at the Dana Farber we now have upcoming trials um including a plus fever versus B plus oh comparison and treatment naive Cll and Xander broadened plus veneto collapse and relapse refractory Cll thank you very much for listening and I would be happy to answer any questions with with my colleagues. Dr john thank you so much for that. Um just very crisp and concise and clear presentation. Um I don't see any questions from the audience at this time but I think I just wanted to highlight um what you had said for these patients who are on watch and wait and who have low risk disease there. Um primary cause of mortality is infection. And I think you highlighted really well the importance of um immunizations and trying to minimize that risk because I know sometimes in clinic it seems like they come and we don't do anything, we just watch them. But um I think you're highlighting that is a really important thing that, and we need to be kind of continue to be vigilant for when we see these patients, so.
