Hoffman Explores Frontline Treatments in CLL

Marc Hoffman, MD

Marc Hoffman, MD, assistant professor, Hematologic Malignancies and Cellular Therapeutics, University if Kansas Medical Center, reviewed a case of a 61-year-old ma with chronic lymphocytic leukemia (CLL), during a virtual Case Based Peer Perspectives event.

Targeted Oncology™: Given this patient’s comorbidities, cytogenetics, and disease characteristics, what therapy are you most likely to select for this patient?

HOFFMAN: We have a number of treatment options for consideration. There is ibrutinib [Imbruvica] or a combination of ibrutinib and an anti-CD20 monoclonal antibody, acalabrutinib [Calquence] or a combination of acalabrutinib and an anti-CD20 monoclonal antibody, venetoclax [Venclexta], and an anti-CD20 monoclonal antibody, or chemoimmunotherapy.

If you were giving chemoimmunotherapy to a patient such as this who has an unmutated IGHV status, you’re doing them a disservice. If they are IGHV mutated, then all bets are off, and I will happily sit back and tell you that depending upon other risk factors, you may be making a perfectly acceptable decision.

Typically in patients [who] have a del(11q), I prefer not to give chemoimmunotherapy. It is inferior. A del(11q) is not the highest-risk cytogenetic abnormality, but it is a higher-risk one. With an unmutated IGHV and del(11q), chemoimmunotherapy is wrong. You could make a strong argument for any of the other treatment options.

How do patients who have not previously been treated with a Bruton tyrosine kinase (BTK) inhibitor respond to this type of therapy?

I will tell you from my personal experience that patients who are BTK naïve and have not seen a BTK inhibitor tend to respond well. It is similar to how an individual who was pretreated with a chemoimmunotherapy regimen [would respond].

I treat a variety of patients who have been heavily pretreated, including with venetoclax combinations, who will then respond to BTK inhibition if they’re relapsing. That’s an N of 1 telling you what my personal experience is, but you clearly are getting diminishing returns from BTK inhibition the later that you use it.

What evidence do we have for giving the patient acalabrutinib?

We can base our decision on findings from the Elevate CLL TN trial [NCT02475681] that were published in the Lancet.1 It evaluated single-agent acalabrutinib versus acalabrutinib plus obinutuzumab [Gazyva] versus obinutuzumab and chlorambucil.

Obinutuzumab and chlorambucil have been billed as a chemoimmunotherapy regimen. Chlorambucil was a minimally effective drug in CLL. Comparing a treatment with obinutuzumab and chlorambucil is not particularly effective. Any study that you see with a small molecule [compared against] obinutuzumab and chlorambucil—I don’t care if it’s ibrutinib, acalabrutinib, or venetoclax—[the small molecule agent is] going to blow it out of the water. You take a drug that is minimally effective and compare it against something that is extraordinarily effective, and you’re going to see a huge result.

The interesting thing is the investigators allowed patients with del(17p) into the trial. Several people thought that...giving obinutuzumab and chlorambucil to a patient with del(17p) was unethical, but [regardless], that’s the way the study proceeded.

Not surprisingly, [the investigators reported] seeing a dramatic interval benefit [associated with] acalabrutinib, regardless of giving it with or without obinutuzumab, compared with obinutuzumab and chlorambucil.

The investigators showed that acalabrutinib is clearly [more effective for this patient population than chlorambucil and that] acalabrutinib monotherapy is clearly better than obinutuzumab with chlorambucil.

There are other data indicating that obinutuzumab monotherapy is equally as effective as giving obinutuzumab with chlorambucil. I’m not suggesting obinutuzumab should never be given. I have used my fair share of the drug, but I would recommend you do it as monotherapy. Giving it with chlorambucil is going to get you nothing but extra thrombocytopenia.

In the patients with mutations, acalabrutinib was not clearly better than chemoimmunotherapy, which I think is an interesting observation. If you give the combination of acalabrutinib and obinutuzumab, potentially the argument could be [made] that the obinutuzumab is adding something in these patients.

It is interesting and [goes along with] the idea that IGHV mutation is a marker for sensitivity to chemotherapy. If a patient is IGHV mutated, the patient is far more likely to be sensitive to chemotherapy.

The response rates were relatively high in this study. There’s a bit higher response rate...with combination therapy compared with monotherapy. There was no significant difference in the overall survival [OS] at this point. There was a fair number of patient crossover, however. I believe it was 40% or 50% of patients who progressed on obinutuzumab and chlorambucil crossed over to acalabrutinib monotherapy.

How was the safety profile in the Elevate CLL TN trial?

Infusion-related events are relatively modest. Atrial fibrillation rates are in the 3% to 4% range. I always find it interesting that there was an atrial fibrillation event on the obinutuzumab and chlorambucil. It just goes to show that these patients are generally older and that they can get atrial fibrillation on their own.

If you’re looking at a trial comparing a targeted therapy that’s given indefinitely, such as acalabrutinib, and you’re comparing that to a time-limited therapy—in this case, the obinutuzumab and chlorambucil—be careful about toxicity comparisons. These are treatment-emergent adverse events [AEs] and an agent that you’re giving for 3 years, that is, acalabrutinib, compared with obinutuzumab and chlorambucil that you’re giving for 6 months, will result in significantly different AE profiles. Be careful about making those comparisons.

A lot of us have recommended that these be fairer, that they follow those patients and make sure they’re not just treatment-emergent AEs. Some of these patients were going to end up having a hemorrhage, hypertension, infections, and other problems anyway just because you’re treating an [older] population. Looking at a lot of these AEs, I think it is a bit challenging when you’re trying to compare those 2 types of regimens.

In terms of other AEs, there’s more pneumonia in the acalabrutinib and obinutuzumab arm. My personal experience is that when I give obinutuzuamab, it is often well tolerated, but I do [see] more infections, especially if you use it in a triplet. You will definitely see more infections and more long-term chronic hypogammaglobulinemia. These are the patients [who] end up with recurrent sinusitis and recurrent low-grade viral infections of the lower respiratory tract.

Also, headache is a unique toxicity associated with acalabrutinib. It happens in about one-third of patients, and it usually peaks around 4 to 6 weeks and then it goes away. It’s often responsive to minimally invasive therapy, so acetaminophen.

What has been your experience using obinutuzumab?

In my personal practice, I think the added benefit of obinutuzumab up front is probably modest. I’m not suggesting that you should or shouldn’t use it, but I generally do not add anti-CD20 antibody therapy when I’m giving single-agent BTK inhibitors.

There’s a lot more toxicity, a lot more infections, and you have to bring the patient in for infusions. From my perspective, I’m not sure that it’s beneficial. You can read the data as you will. I think that the modest increase in [progression-free survival (PFS) is] worth it, especially because patients can receive repeated anti-CD20 therapy.

The other issues [are] biological. All BTK inhibitors will downregulate CD20 expression on CLL cells. The CD20 doesn’t really start to recover until after about 12 months of therapy.

Does the use of BTK inhibitors lead to minimal residual disease (MRD)–negative remissions?

The BTK inhibitors on their own generally do not lead to MRD-negative remissions. The goal of therapy with ibrutinib or acalabrutinib is not to get this patient into a deep remission and stop therapy. [These agents] are wonderful disease modulators.

[In my practice], a patient with CLL comes in who is highly symptomatic. You start them on therapy, and it’s just absolute magic. They come back a couple weeks later, and they want to hug you. They feel so much better, even though their white count is likely [elevated]. It’s an odd set of diseases.

What were the key findings from RESONATE-2?

The RESONATE-2 trial [NCT01722487] put ibrutinib on the map for all frontline patients.2 It evaluated treatment-naïve patients who were [older] with CLL. The treatment arm received ibrutinib at 420 mg once daily versus chlorambucil at 0.5 mg/kg and on days 1 and 15 of a 28-day cycle for up to 12 cycles.

Not surprisingly, because chlorambucil is a minimally effective drug, as soon as people stopped it, you start to see people fall off the curve who are clearly progressing on it. Ibrutinib provides excellent and durable long-term control. The median PFS is still not reached. I don’t know what the median follow-up on this was when they presented it, but you get nice, durable responses with BTK inhibition as a single agent.

When reviewing the subgroup analyses, we see that patients with del(11q) mutations don’t do well on chemotherapy. Patients do much better with targeted therapy. Regarding IGHV status, ibrutinib is largely agnostic regarding IGHV mutation.

What was significant about ECOG E1912?

ECOG E1912 [NCT02048813] evaluated ibrutinib and rituximab [Rituxan] compared with FCR [fludarabine, cyclosphosphamide, and rituximab].3 This study was presented as a late-breaking abstract in the 2018 ASH [American Society of Hematology] conference. Patients were given ibrutinib and rituximab. Patients received 6 [cycles] of monthly rituximab, and they continued ibrutinib until progression versus FCR that was given in a standard fashion.

What changed the tide and what made this a late-breaking abstract are the following data....The PFS was clearly better. Most people were not particularly surprised by that. A certain number of people are going to fall off the curve, but the OS was substantially improved in the ibrutinib-containing arm.

This was a study that was stacked to favor FCR. The investigators excluded patients who had del(17p). Then patients were enrolled in a 2:1 fashion, so the number of patients on ibrutinib was double the number of patients on FCR.

There were 4 deaths in the ibrutinib/rituximab arm compared with 20 deaths in the chemoimmunotherapy arm because the randomization was in a 2:1 fashion. The hazard ratio for death was significantly higher, and most of these patients were dying of progressive CLL. They did not die of infectious complications or other issues related to the therapy.

If you look at the unmutated status, not surprisingly, this continues to show a benefit. Again, unmutated IGHV confers a lack of sensitivity to chemoimmunotherapy. This was not a surprising finding for anyone. There was no clear OS benefit at this stage, but I will tell you [that] there will be. It’s just a matter of waiting until there’s enough event.

Would you describe the details of CLL14?

CLL14 [NCT02242942] examined obinutuzumab and chlorambucil compared with obinutuzumab and venetoclax. The obinutuzumab was given for 6 months regardless, and it was the standard ramp-up dosing where it was day 1, 2, 8, 15, and then on day 1 of each subsequent cycle. The venetoclax was started on day 22 of cycle 1. This was first-line CLL.

The investigators actually picked patients who were in relatively poor health, so folks [who] either had reduced creatinine clearance or had a CIRS [chronic inflammatory response syndrome] score greater than 6. The CIRS score is similar to an APACHE [acute physiology and chronic health evaluation] score but used on an outpatient basis, and it looks at comorbidities and, in general, the frailty of patients.

The venetoclax and obinutuzumab combination is certainly better than the chlorambucil and obinutuzumab combination [HR, 0.31; 95% CI, 0.22-0.44; P <.0001]. Again, the result is not surprising. This occurs when you take a significantly effective drug and compare it with a marginally effective drug. You’re going to see a significant benefit.

In patients with IGHV, venetoclax and obinutuzumab is significantly better, [though] the benefit is seen more prominently in patients who are IGHV unmutated. Again, not extremely surprising, given that sensitivity to chemoimmunotherapy is the primary predictor that’s associated with IGHV. There’s still a benefit to giving venetoclax and obinutuzumab to a patient with the IGHV mutation. It’s just not quite as pronounced as in [patients who are IGHV] unmutated.

Regarding TP53 status, this was significantly better. You never want [a patient] to have a TP53 mutation or del(17p). If you look at the aberrations, about 8% to 10% of patients will have a TP53 aberration in the frontline setting. That number goes up to around 30% in the relapse setting. Half of those patients will have a del(17p), and about half will have a TP53 mutation. It doesn’t matter which one the patient has. If there’s inactivation of TP53, those patients do just as poorly.

I would recommend you don’t necessarily need to send a broad next-generation sequencing panel, especially if that’s not available to you. I would, [however], recommend before you start therapy to send off a TP53 mutation analysis on your patients because of all the different prognostic factors; that’s the one that significantly changes things. If the patient is TP53 mutated or has a del(17p), there is a distinctly worse OS compared with patients who do not have that abnormality.

What role did the MRD rate play in CLL114?

In terms of the MRD negativity rate, this was much higher in the venetoclax and obinutuzumab arm. There are a couple of interesting factors to point out here.

One is that with obinutuzumab alone, you’re getting 17% MRD negativity, which is interesting. It’s just a pure anti-CD20 therapy, so that’s providing the patient some benefit. If you look at the rates and the differences between peripheral blood and bone marrow, there’s about a 20% delta between those 2, which is I think an important result to consider.

If you’re going to measure MRD, I recommend that you do it sequentially. That is, if [the patient’s] peripheral blood MRD is negative—meaning you send off a flow [cytometry] and the flow does not show any CLL, and you’re intrigued to know whether or not they’re bone marrow negative—you should get a bone marrow to confirm that. The bone marrow is the big arbiter of whether they’re going to be MRD negative.

The other thing that is interesting here—and this has to do more with iwCLL [International Workshop on CLL] response criteria—is that there is a good number of patients who are undetectable MRD [who] are not in CR [complete remission].

If you look at the number who are in CR, it’s 34%. That means 23% of patients who have bone marrow undetectable disease are still not in a CR. That’s just due to their nodal volumes. When you look at the response criteria in a CLL study, be careful about looking at response rate. Response rate often does not dictate how well these patients are going to do. I would recommend looking at either a survival outcome like PFS or OS, and if you’re interested in MRD, I would recommend strongly that you look at bone marrow MRD. That’s going to...tell you [what’s] going on with the patient.

Peripheral blood MRD is not nearly as reliable. The investigators measured this after completing therapy, and there was still this significant discord. There is evidence that if you do peripheral blood MRD analysis on a patient who’s still actively on therapy, the therapy can affect that assay in the test tube—so you may be getting false-positive results if the patient is MRD negative when they’re not. It’s interesting that this was all done 3 months after completion of therapy. I found this to be quite an intriguing result.

If your patient is MRD negative, they do better than if they’re not. It doesn’t matter what they received in the trial. If the patient got chlorambucil and obinutuzumab and happened to be in that lucky 17% that was MRD negative, then they did well. If they get venetoclax and obinutuzumab or [if they’re] in the much larger group of patients that have undetectable MRD, they do significantly better.

If the patient is still negative for MRD on the peripheral blood and the bone marrow biopsy was positive, do you change your treatment plan?

There is no evidence that doing anything with an MRD-positive bone marrow result is going to make a difference to that patient’s outcome. The caveat I would make is that in CLL14, it’s only 12 months of treatment.

If a patient has a del(17p) or a TP53 aberration and they’re MRD positive at a year, I strongly consider prolonging the venetoclax for another year. There are no data to indicate that [to be] true—so don’t [ask me to] recite why that’s true—but it makes sense that if they have longer drug exposure, they may convert into an MRD-negative state. In patients who do not have del(17p) and TP53 [aberrations], there are no data [indicating] that adding therapy at that point is going to improve their outcome. In general, we’ve been discontinuing.

After a year of treatment, when do you measure MRD status?

If you go according to CLL14, you’re going to stop treatment. Let’s pretend we stopped treatment today, and the patient has finished off the year of therapy. You’re going to have a patient [who’s] off treatment for 3 months before you establish their MRD status.

I’m encountering this with a patient now who doesn’t have a TP53 mutation or a del(17p). He does have an SF3B1 mutation, which is deleterious at least in the chemoimmunotherapy era and predicts a shorter time to progression. When you see that mutation, it’s a splice-site binding mutation, and it predicts a shorter time on observation.

He’s a young guy. He’s a healthy guy. He said, “Why don’t you [give me a] bone marrow [biopsy] at 12 months and see how I’m doing?” If he’s MRD negative, I’ll stop treatment. If he’s MRD positive, I’ll keep him on treatment. If he’s MRD negative [post treatment] at 3 months, we could biopsy him again 3 to 6 months later and make sure he’s still MRD negative. Then we’ll have a longer discussion.

I think this requires some level of discussion with your patient about what your expected outcome is. If you’re in that club that is 57%, I mean that’s a compelling curve. If you’re not, that’s not a particularly great curve to be on. We don’t have any good data on how these patients should be effectively salvaged. If they’re mutated, should you give them chemoimmunotherapy? If they’re unmutated, should they go on BTK inhibition immediately? I don’t think anyone has the correct answer to that. That’s an area of active investigation. The number of patients who we’re seeing now who are relapsing after venetoclax exposure is increasing, so we’re getting more experience with that, but the data in this setting on a long-term basis are severely limited.

_References:

_{1. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2}

_{2. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x}

_{3. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi:10.1056/NEJMoa1817073}