This video features Shazia Nakhoda, MD presenting on Chronic Lymphocytic Lymphoma. This presentation was given at our April 11th New Directions in the Diagnosis and Treatment of Hematologic Cancers Symposium in 2023.
Good evening. My name is Shazia Kota. I am a malignant hematologist here at Fox Chief Cancer Center. I specialize in the management of chronic lymphocytic leukemia and B cell lymphoma. I'm very excited to present the clinical updates in C L L with a focus on key studies from the most recent American Society of Hematology Conference. We are fortunate to have a plethora of both efficacious and well tolerated treatment options in C L L but choosing between these regimens can be challenging tonight, I will review the long term follow up data of our current standard of care options in the frontline setting as well as some interesting updates from trials looking at combination BT K inhibitor and vaneta claques in the relapser factory setting. I'll present exciting results from the alpine study as well as longer term follow up data in a of a calibre and Perroni. For now, the current standard of care remains either vaneta claques open and choose mab as a fixed duration regimen or continuous BT K inhibitor for the vast majority of patients in untreated C L L. The resonate two study provides us the longest term follow-up data for targeted therapies with a 40% progression free survival at eight year follow up. However, the rates of deep responses with BT K inhibitors is quite low when given as a monotherapy duration of anna claques. And Obtusa was studied in the C L L 14 study and it is the only approved nonchemotherapy regimen C L L that offers high rates of deep responses and also a fixed duration dosing with a favorable side effect profile. However, long term follow up data shows that the rates of undetectable M R D do decline steadily over time. Nonetheless, the five-year progression free survival is still high at 63% with a five year time to next treatment of 72%. Now, this demonstrates that patients who do develop a low burden of detectable disease often have no clinical evidence of relapse or no clear clinical indication for retreatment and therefore can be afforded prolonged periods off of chemotherapy. And this can be very important to patients from a quality of life standpoint. However, we see that patients with high risk disease treated on this regimen did not do quite so well. Compared to chemo immunotherapy. The neola Abizaid does improve survival rates for patients with del 17 P and T P 53 mutated disease. But we see now that chemo immunotherapy is no longer a viable comparator arm in the current era of target therapies, especially with longer term follow up data for the better tolerated. Second generation BT K inhibitor, a calibri nib and this agent does indeed provide long term disease control for patients with C L L at six year. Follow up from the initial phase one and two studies, we see remarkable progression free survival of 87% and event free survival of 78%. This does compare quite favorably to the data from front line A Bruni but showed a 70% progression free survival at the five year time point. But what is most exciting about the A Cali group of longer term follow up data is the sustained responses in the high risk subgroups. As you can see here compared to the effects and obtusa regimen. That was a fixed duration. We see that continuous BT K inhibitor does continue to provide more durable responses and is preferred for that reason. We see that Zana Bruni has also been studied in the frontline setting and has promising two-year progression free survival data but longer term data is still underway. Next, I'd like to talk about the addition of Obtusa to a calibri with two updates provided at ash this year. The first was a post talk analysis of the elevate study. This study looked at a calibre with or without obtusa versus chemo immunotherapy. It was powered to compare either Acaroni regimens to chemo chemo immunotherapy, but not specifically the addition of Betus to Acaroni prior data which had compared riTUXimab to Ibrutinib had not shown much benefit in this space. However, on post talk analysis of the elevate study, we see that there was a four year progression free survival benefit of adding obita to a Cali. What's also very promising is that there were sustained responses with either approach for the high risk mutated disease in the range of 75 to 76% at four years. A retrospective study was also conducted looking at cool data from the elevate study combined with the C L 003 study. In this study, they found an overall survival benefit amongst patients with unm muted immuno globe and heavy chain or absence of del 17 P or T P 53 disease. In terms of overall survival, we did not see the same benefit in patients with high risk disease which included the del 17 P population T P 53 the complex Caro type patients. This may partially be due to smaller sample size of these higher risk patients. Nonetheless, these both these studies do support the use of Obtusa App and select patients based on patient preferences and toxicity considerations. Lastly, I'll present an interesting retrospective study presented by Doctor Archbald and his colleagues. Looking at the benefit of BC L two versus BT K I inhibitor therapies in the frontline setting. As there is no head-to-head prospective data available yet, they used a large deidentified Cota database. Patients were then compared using a propensity match scoring system for demographics time to first therapy T P 53 status and immunoglobulin heavy status. And they found that the patients treated with BC L two inhibitors had a higher three-year progression free survival, but similar three-year overall survival. Notably, the patients who received Pantic clas had shorter term follow up because this regimen was more recently approved in terms of cytogenetic risk. The groups were quite similar aside from a higher rate of trisomy 12 in the Vennela group, what likely does bias this study is the fact that the BC L two inhibitor treated patients were younger and had a shorter time to first therapy. This was 16 versus 24 months. And while broad conclusions are very difficult to make in these types of retrospective studies, I find the similar rates of three or overall survival to be very reassuring when guiding patients on upfront therapies, fact that both approaches are highly reasonable. Next, let's review fixed duration therapies that are currently being studied in C L L as well as the M R D guided approaches that may help guide whether combination therapies lead to longer survivals with based on deeper response rates. Now, this is a bit of a busy slide reviewing the various fixed duration regimens. I found it very striking that the rate of bone marrow, minimal residual disease responses between the fixed duration therapies that were doublets were quite similar in the range of 55 to 65. Whereas the triplet regimens appeared to have a much higher and deeper response rate. Nonetheless, long term follow up data will be crucial to see if these deep responses correlate to longer survival. The first study I'd like to delve a little deeper into is the captivate study. This looked at younger patients with C L L who received fixed duration ab Bruni and van attacks for one year. These patients were then randomized to receive either placebo or continuous aro amount of therapy. If they achieved an undetectable M R D, they found similar rates of end of treatment M R D as the C L L 14 study at about 52 57% respectively. But unlike the C L L 14 study, we see that the rates of undetectable M R D were sustained even in the placebo arm at three years post follow up. As you can see here, the rates of undetectable M R D was 58% for those patients. Both placebo and a Bruni had arms had promising disease free survival of greater than 85%. And the two-year progression free survival was 84% in the del 17 p mutated patients compared to those with 90 compared to 95% for all commers. The number of high risk patients was small, only six and 20 in the placebo and a brut artist respectively. This was out of a total of 86 patients who had confirmed undetectable M R D and underwent randomization. This data supports a fixed duration M R D guided approach that is oral only and seems to be quite feasible. Next. Next, let's talk about the MD Anderson study. Now, this study was designed to evaluate outcomes for high risk patients, specifically, those who were over the age of 65 or had high risk mutations including del 17 P TB, 53 DEL 11 Q or unm mutated immunoglobulin heavy chain. In comparison to the cap debate study in which patients stopped combination therapy after one year of undetectable M R D, these patients continued for two full years amongst patients who had persistent M R D. At that point time point, they either went on to IBRO monotherapy or continued a third year of combination therapy. This study provided some interesting insights. First, they showed that the addition of a 2nd and 3rd year of combination therapy actually converted an additional 17 out of 43 patients who were M R D positive into an undetectable M R D status. The clinical implications of achieving the responses is not yet clear, but we do see that regardless of undetectable M R D status, the four year progression free survival was still a remarkable 95% in the 26 patients who had either DEL seven P or TB 53 mutated disease. The four year progression free survival was 91%. The only factor that seemed to predict the rate of M R D recurrence after initially achieving undetectable M R D status was an early rate of deep response at six months. Interestingly, the only variable that seemed to correlate with achieving undetectable M R D at baseline was having an immunoglobulin un mutated status. Now, this is very interesting because historically, mutated disease was characterized as a good risk feature as it correlates with better response to chemotherapy. However, with combination attacks, I unm mutated immunoglobulin heavy chain predicted for deeper response. Let's talk next about the Glow and Flare study. Both of these studies looked at a group of veneta plaques in patients who did not have a 17 P or T P 53 mutated disease. As the comparator arm for these studies was chemo immunotherapy. What's particularly interesting is the results of this combination target therapy arms based on M R D kinetics. Both of these studies confirmed the findings of the MD Anderson experience specifically achieving undetectable minimal residual disease early on during combination therapy predicted persistent sustained responses at 18 months follow up. They also found that unm muted immuno gly and heavy chain predicted for deeper response. Triplet therapy has also been investigated with all three approved B D K inhibitors combined with menelaos, we have updates from the ARNI and a Cabin studies. The Autin study which looked at patients with DEL seven T P or T P 53 mutated disease should a promising through your overall survival of 93%. But the three year progression free survival was only 80%. We see here that in patients who had seven and P, they had significantly worse outcomes in the patients with complex Caro type and unm mutated immunoglobulin heavy chain. We see that they had a trend towards worse outcomes. The A calibri invent obita study was done slightly differently with an initial all comers cohort followed by an additional expansion cohort specifically for T P 53 mutated patients. Here we see a similar rate of undetectable M R D between these groups regardless of T P 53 status. And the median pre progressive Preser 35 month fall was 93%. Of course, long term data is necessary to see if the added toxicity of triplet therapy is warranted and how this correlates with long-term follow-up and survival. In conclusion, the current standard of care remains second generation BT K inhibiter for high risk cytogenetic subgroups or fixed duration fanatic claques and obtusa. For all comers. To me, the updated data from all four Ab Bruni and Venetic claque space regimens confirms the finding that early undetectable M R D predicts for more sustained responses. And these sustain responses can be seen even for one and two years out after combination therapy, which was not seen with bela two fixed duration therapy in the skill of 14 data. Now, while I do think progression free survival and overall survival are clearly the most important endpoints we had. I'm curious to see if M R D guided approaches can safely provide high risk patients a period off of therapy without sacrificing survival. To me, this is a crucial question both from a quality of life standpoint but also from a cost perspective, we now also see that a traditionally high risk group of patients with unm mutated immuno glove and heavy chain achieve deeper responses with phonetic lacs and AB bru combination therapy. And this is likely due to a higher dependence of this subtype of patients on the B cell receptor pathway compared to patients with a hyper mutated immunoglobulin heavy chain which have historically done quite well with chemo immunotherapy when other high reto genetic features are absent. Ultimately, we need head to head comparison data of combination regimens versus sequential therapies for the last few minutes. I would like to talk about longer term follow up data in the relaxer factory setting as well as results from the alpine study, Suzanna Bruni was studied in the alpine study against Ironi. This was a highly anticipated multinational phase three study. This showed a progression free survival benefit at one year. Follow up with a favorable toxicity profile as you can see here. Now, we do see higher rates of hypertension and neutropenia with Zana Bruni but not higher rates of infection. Otherwise rates of other cytopenias were relatively similar and the rate of rate of atrial fibrillation was lower. Patients tended to continue Zana Bruni at higher rates than a Bruni and required less dose reductions while the progression free survival is very exciting. In the alpine study. I do caution against direct cross trial comparison between the elevate study and the alpine study. The elevate R R study was also presented at this ash conference and we now have more mature data. This study looked at a Cali Bruni versus a Bruni in a head to head comparison and was a noninferiority study showing similar rates of medium progression free survival with lower to CD rates with a Cali Bruin. This study only included patients with dealt with a del 17 P or Dell 11 Q. Now we see here with the alpine study, we only have one year follow up data. Whereas with elevate, we have four year follow up data. And while the rates of toxicities do appear to be a little different between these two regimens, I would like to point out that cumulative doses over longer follow up may show higher rates of toxicity. Additionally, the elevate study here, elevate study presented here shows the A cabin and Iive curves had initially separated and then met again around the three year follow up time. So again, it's all important to avoid comparing Xan Bruin and Acalabrutinib specifically based on these initial studies. But regardless both of these studies confirm that second generation BT K inhibitors should be preferred over a Bruni, both in terms of toxicity with either equivalent or improved efficacy. Finally, we have updated data from 18 month follow up of proto group. This is a highly selective non covalent or reversible E T K inhibitor. We get very exciting data from the prior ash of 2021. And now we can see that about half of patients continue to maintain a response even in this pretreated pop heavily pretreated population at 18 month. Follow up. What's exciting about Proto Bruni is it appears to be efficacious in patients with prior BT K resistant disease or intolerance. Specifically, the rates of responses were equivalent regardless of AC 481 S mutation. AC 481 S mutation is one of the most common mechanisms of resistance to first generation I Bruni or a Calium. I would like to point out that the resistance mechanisms across the various BT K inhibitors does not, does not seem to be the same. We see here that in one study, patients who had prior Xa Bruni treatment had a higher rate of L 5 to 8 mutations, whereas the treated patients had a higher rate of the C 481 S mutation. And more importantly, this L 52 18 mutation seems to also be seen in patients with proto resistance. Now, Perroni was recently approved in the space and is also being evaluated in larger phase three studies and is yet to be seen how sequential therapies with BT K inhibitors is going to be affected. Now, as Zanabin acalabrutinib are used more frequently. In conclusion, we now see longer term follow up data with the second generation BT K BT K inhibitors that have been studied both head to head against a brut nib and show that we have equal if not better survival outcomes with superior toxicity profiles. The most important conclusion however, is that the treatment options in C L L are rapidly evolving. We have seen the rise and fall of toxic chemotherapy regimens as well as the P I three K inhibitors over the past few years. And we may see a similar change in how we practice as we better understand the correlation of M R D and points and survival and gain more ins insights into novel resistance mechanisms with newer agents being put into the earlier lines of therapy. With that, I'd like to conclude my presentation and take any questions.