Guest commentary: Most anticipated studies on chronic lymphocytic leukemia at ASH
In this Guest Commentary, Ryan W. Jacobs, MD, principal investigator of clinical trials for chronic lymphocytic leukemia at Atrium Health’s Levine Cancer Institute, reviews studies on CLL that will be presented at the ASH Annual Meeting and Exposition. The most anticipated trials will reveal new information on BTK plus BCL-2 inhibition, updates on major clinical trials — including the CLL14 and MURANO trials — early data on CAR T-cell therapy, and more.
There are a lot of studies updating us on new treatment options for CLL, which is not surprising given how rapidly the field has been progressing. Essentially all the major newer drugs being used to treat CLL have some significant updates. There is also a lot to be excited about regarding where the field may be progressing to in terms of chemotherapy-free small molecule inhibitor combinations that are administered over a defined timeline, produce deep remissions and are well tolerated. This will be a review of the notable oral presentations in CLL.
BTK plus BCL-2 inhibition
There has been evidence and recognition for a while now that using both BTK and BCL-2 inhibition together makes sense in terms of complimentary mechanisms of action, the potential to reduce possible mechanisms of resistance, and how well these drugs treat disease in different sanctuaries of the body. For example, ibrutinib (Imbruvica; Pharmacyclics, Janssen), a BTK inhibitor, targets disease well in the enlarged lymph nodes and spleen. Venetoclax (Venclexta; AbbVie, Genentech) is really good at clearing out the circulating disease quite rapidly.
There are five noteworthy oral presentations evaluating the combination of BCL-2 inhibition and BTK inhibition. The most significant in terms of the number of patients on the trial and the length of follow up is the phase 2 CAPTIVATE study (Tam CS, et al. Abstract 35), which looked at the combination of ibrutinib plus venetoclax for 1 year after a 3-month lead-in with ibrutinib (I acknowledge I may be biased as I am a contributing author). The study enrolled 164 patients aged younger than 70 years, which is more than double the number of patients compared with the other oral presentations that are investigating this combination. CAPTIVATE is also unique in that it is not restricted to high-risk patients, which one of the other trials specifically focuses on. This trial looked at MRD negativity in both the peripheral blood and the bone marrow at the end of 1-year combined therapy. That is the information that is going to be reported because the median follow up is only 14.7 months so far, which is not long enough to fully analyze PFS data. The combination seems to be very effective — close to a 100% overall response rate. At the 1-year mark of combined therapy, the highest reported rates of bone marrow MRD negativity was 71%. The concordance rate between MRD negativity and peripheral blood was very high at 93%. This means that most of the patients who were MRD negative in the blood were also MRD negative in the bone marrow.
This report has shown that ibrutinib plus venetoclax is a very effective combination — maybe more effective than anything that we have seen so far in terms of the bone marrow MRD negativity rate. It has also shown that the combination regimen is well tolerated in a large number of patients. The discontinuation rate was only 7%, which is really exciting. We are obviously very interested in the longer-term follow-up data. This trial is going to answer a lot of interesting questions because it is going to take these MRD-negative patients and blindly randomize them to either continuing ibrutinib or placebo. We will better understand whether we can stop therapy in an MRD-negative patient safely and potentially save patients from unneeded toxicities, including financial toxicity. It will be exciting to continue to see these data emerge over the next several years.
As for the other studies surrounding what I see the field moving toward, which is combination, time-defined therapy with BTK and BCL-2 inhibition, there will be a study led by researchers at The University of Texas MD Anderson Cancer Center that evaluates frontline ibrutinib plus venetoclax in 80 high-risk untreated patients (Jain N, et al. Abstract 34). In this study, treatment was continued for 2 years. We of course wonder if 1 year of combined therapy (like was done in the CAPTIVATE study mentioned above) is enough. Two-year information is available for 29 of the 80 patients. Their bone marrow MRD-negativity rates increased from 65% at 1 year to 79% at 2 years, indicating that at least in the high-risk population, there might be some benefit to remain on combined therapy for more than 1 year. It is an interesting observation; however, this is just one small trial with only a small number of patients having completed the 2 years of therapy at this point.
There is another MD Anderson Cancer Center study (Jain N, et al. Abstract 359) assessing this combination in the relapsed setting. Patients could stop therapy at 2 years if they were MRD negative in the bone marrow. Information is available for 24 of 80 patients. After 2 years, the MRD-negative rate in bone marrow was 67%. So, this is a combination that appears to be effective in the relapsed setting to a high degree as well as the frontline setting. That is great to know.
There is a really interesting presentation that looked at patients who received ibrutinib for at least 1 year in the frontline or relapsed/refractory setting (Thompson PA, et al. Abstract 358). Venetoclax was added on late in the course of treatment for a planned 1 year. All patients had detectable disease and fell into high risk classification. For example, they had a poor prognostic finding such as 17p, 11q or IGHV mutations. In this presentation, 26 patients were available for evaluation, and 67% were MRD negative in the bone marrow at 1 year after adding venetoclax. Those patients are going to have the option to stop treatment with both drugs, or continue treatment with ibrutinib. Depending on what the data show, that is potentially going to have very broad implications on ibrutinib-treated patients who are continuing treatment with the drug. If this trial were ultimately successful, many patients who are currently on ibrutinib indefinitely may be able to come off treatment if they respond deeply after the addition of venetoclax. I know I have a lot of patients in my clinic who will be very interested in the eventual outcomes of this study.
There is a small study looking at the recently approved BTK inhibitor acalabrutinib (Calquence, AstraZeneca) plus venetoclax (Lampson BL, et al. Abstract 32). Not surprisingly, it looks pretty effective, but we will need a larger study to confirm these findings. I am sure those will come later.
Those are the oral presentations that I am most excited to hear about at ASH this year. I think the field is moving toward the combination of BTK plus BCL-2 inhibition. We will need to figure out the best combination and duration.
The approval of acalabrutinib for CLL in both the frontline and relapsed setting was partly based on the ELEVATE treatment-naive (ELEVATE-TN) study, which is also going to be presented at ASH (Sharman JP, et al. Abstract 31). Acalabrutinib outperformed obinutuzumab (Gazvya, Genentech), which is not surprising. But it is a significant study in that it resulted in the approval of what the developers behind acalabrutinib are hoping to be an alternative BTK option that will be better tolerated than ibrutinib. A head-to-head noninferiority comparison — the ELEVATE relapsed/refractory study — is still pending between acalabrutinib and ibrutinib. When that is reported, we will get the gold standard for comparing the respective toxicity profiles. But looking at the data in ELEVATE-TN, the atrial fibrillation rate was only 3% to 4% in the acalabrutinib arm, which seems to be less than what we would see on ibrutinib treatment.
There are two acalabrutinib arms in ELEVATE-TN. In one arm, patients received acalabrutinib as a single agent. In the other arm, patients received acalabrutinib with obinutuzumab. We always wonder whether adding a monoclonal antibody to BTK inhibitors are beneficial. In this case, it is not clear yet. The response rates appear to be a bit higher when you add obinutuzumab to acalabrutinib, but we will have to wait to see data on long-term PFS. We know at this point that adding rituximab to ibrutinib does not seem to make a significant difference from prior studies.
The main excitement regarding venetoclax will be updates on large trials that have led to recent approvals. Earlier this year, venetoclax was approved in the frontline setting based on the CLL14 study that was presented at ASCO. Now there is a presentation at ASH this year looking at rates of MRD — which appears to be a really good indicator of how long patients will respond to therapy — with longer follow up on that study (Fischer K, et al. Abstract 36). The PFS is 89.1% at 2 years with extended follow up in patients with MRD-negative peripheral blood vs. 69.1% among MRD-positive patients. That brings up the question, should we continue to think about stopping treatment if patients are MRD positive? We need more critical trials to answer that question specifically before we change our treatment strategy.
Also being presented at ASH are 4-year data on the MURANO study (Seymour JF, et al. Abstract 355). This trial led to the approval of venetoclax with rituximab in the relapsed setting in 2018. After 4 years of follow up, including 2 years of patients being off treatment, the median PFS still has not been reached. Fifty-seven percent of patients are free of disease progression. The OS difference persists at 4 years — 85% of patients receiving venetoclax-rituximab are still alive vs. 67% of patients receiving bendamustine-rituximab. The researchers included some interesting data about the bendamustine-treated patients as well. With chronic leukemias and lymphomas, sometimes it is hard to show OS differences because of sequencing; however, it looks like this survival benefit persisted even though 80% of the patients who progressed on bendamustine-rituximab went on to receive other novel therapies, predominately BTK inhibition. They had decent overall response rates — up to 60% of the patients responded to BTK inhibition after progressing on bendamustine-rituximab. But even so, the OS difference is still statistically significant. So that leads us to believe that maybe using BCL-2 therapy with venetoclax earlier on in the disease course (particularly before chemoimmunotherapy) would improve OS long term, despite sequencing therapies later. One bit of worrisome information I found is that the researchers looked at a small number of patients who progressed on venetoclax. There was only a 32% ORR when they were treated with novel therapies after venetoclax, the majority of which received BTK inhibition. That is troubling; we expect BTK inhibition to be better than that. Other retrospective studies that I have contributed to indicate a higher response rate for ibrutinib after venetoclax.
On the ibrutinib side, a lot of the more interesting data are from real-world, large scale evaluations and longer follow up of existing studies. At last year’s ASH, researchers presented 34-month data from the ECOG 1912 (E1912) study during the late-breaking presentation session. E1912 compared ibrutinib-rituximab with FCR. This year, researchers present 45 months of extended follow-up data. There is still a difference in OS favoring ibrutinib, and there are a couple of interesting points of additional information included in the update. Only 7% of patients who received ibrutinib have progressed at this point while 20% have discontinued treatment for reasons other than progression. That is a higher discontinuation rate than what has been reported on prospective industry trials. The PFS difference continues to persist in patients who are IGHV unmutated favoring ibrutinib, but patients who are IGHV mutated do not have a difference in PFS when comparing the two arms with extended follow up. So, for the physicians out there who are still enthusiastic about FCR, they could point at the lack of difference of PFS at 45 months in the IGHV-mutated patients as a reason that FCR should continue to be considered in this patient population. FCR still has a role, but we need to look at the updated data because there is a statistically significant difference in OS still in the overall patient population, and they are supposed to update this with additional information at the presentation.
There are a handful of largescale Medicare and non-Medicare analyses looking at real-world ibrutinib uptake in the frontline setting, which I find interesting from an economic and macroscopic level. A flatiron evaluation from 2014 to 2019 shows that 29.1% of CLL patients used ibrutinib in the frontline setting (Huntington SF, et al. Abstract 797). That analysis indicates that 40% of all frontline-treated CLL patients are now being treated with ibrutinib. The discontinuation rates are encouraging compared with some other reports that we have seen, particularly in older patients. Overall, the discontinuation rates in this large-level flat iron analysis with more than 5,000 patients was 16.2%. It does hold true that older patients, particularly older than 80 years, have higher discontinuation rates. These patients had a 26% discontinuation rate vs. 9% of patients under 60 years.
Along those lines, another evaluation specifically looking at Medicare patients indicated higher discontinuation rates and higher atrial fibrillation rates (Olszewski AF, et al. Abstract 265). The researchers reported an alarming atrial fibrillation rate of 23%, which is higher than anything that I have seen reported. The Medicare evaluation also included some financial information. By 2016, ibrutinib comprised about $29.2 million worth of Medicare spending. That was compared to $18.5 million with all other therapies for CLL. This is why we are interested in finding defined treatment timelines to reduce cost.
There will be a presentation evaluating Juno’s liso-cel CAR T product for relapsed/refractory CLL, which was associated with an 80% overall response rate and a 45% complete response rate in a small number of patients who received the treatment (Siddiqi T, et al. Abstract 503). Some of these responses appear to be durable beyond 6 months. It is very early follow up, but we hope to ultimately have a CAR T option for CLL patients with multiply relapsed/refractory disease.
Finally, there are two oral presentations on the LOXO noncovalent BTK inhibitor (LOXO Oncology). The idea is that this inhibitor will be active in patients who have progressed on previous BTK inhibition, even if they carry C481S mutations, where ibrutinib or acalabrutinib are no longer effective. The LOXO noncovalent BTK inhibitor binds on an alternative site to C481S. One study demonstrated 30-fold higher potency of BTK inhibition, even in C481S patients, compared with ibrutinib (Naeem AS, et al. Abstract 478). There is also a phase 1 study reporting 88% overall response rates (Mato AR, et al; Abstract 501). This includes a small number of patients with C481S mutations. Still very early data on that product.
Disclosure: Jacobs reports serving as a consultant for AbbVie, Gilead and Juno Therapeutics. He also reports receiving speakers bureau fees from AbbVie, AstraZeneca, Genentech and Pharmacyclics LLC; honoraria from TG Therapeutics; and research funding from Pharmacyclics LLC and TG Therapeutics.