Awan Weighs Options for Treating a Patient With High-Risk CLL

Farrukh Awan, MD

During a Targeted Oncology Case Based Peer Perspectives event, Farrukh Awan, MD, associate professor, Department of Internal Medicine Member, Division of Hematology and Oncology Harold C. Simmons Comprehensive Cancer Center, William P. Clements Jr. University Hospital at The University of Texas Southwestern Medical Center in Dallas, TX, discussed the various treatment options for a 61-year-old patient with high-risk chronic lymphocytic leukemia (CLL).

Targeted Oncology™: What factors influence whether you recommend therapy initiation for a patient like this?

AWAN: Is fatigue an issue? I struggle with that personally, because I don’t know whether the fatigue is from CLL or if it’s from...the thyroid, depression, or anxiety, or [whether] it’s just the [patient’s] personality. That’s the hardest decision for me to make, especially in somebody who’s not anemic or thrombocytopenic. Clearly, this person is anemic, and she would be fine if you decided to treat. But if she only had fatigue and mild anemia, then I’m not sure. Those are the hard [cases] that I feel are difficult to decide [on].

As I’ve [become] older, I’ve realized that this is a serious problem for a lot of our patients which goes unrecognized. I don’t know whether there are any hard data on this, but I feel that younger women tend to have symptoms out of proportion to their disease…burden. Fatigue is a predominant symptom. I’ve seen people with debilitating fatigue. They are labeled as [having] rheumatoid [disease], fibromyalgia, or depression and anxiety. Then when I treat them, they have no psychiatric issues and no rheumatologic issues.

Now I’m beginning to think maybe I undertreat some of my patients. But this is such a difficult, subjective measure. How do you measure fatigue? You have those patients who can’t even walk a block [and in that case, treatment is] an easy decision. But then there are patients who just feel awful all the time. I feel that it’s underrealized and we brush it off as if their disease is [not severe].

How do you assess for risk in newly diagnosed CLL?

Around 10% of the patients in this country get IGHV testing done. We’ve been trying to get people to do IGHV testing more and more, but it’s a small number [who receive it]. Similarly, only around 7% to 10% of patients get TP53 mutation analysis done. Many patients, 50% to 60%, get FISH testing done, but 30% to 40% are treated without FISH. Ninety percent don’t even know the IGHV status or whether TP53 is mutated.

The point I would like to make here is that the mutational status never changes. If the gene is mutated, it’s always mutated. If it’s unmutated, it’s always unmutated. And at least in the CLL field, the decision to use chemotherapy is easy nowadays. There [are] enough data for me to justify not using chemotherapy in every setting that’s out there. Every theoretical scenario you can give me, I can convince you, with data, that there is no reason to give chemotherapy, except…maybe to patients who have mutated IGHV and who are otherwise in excellent shape. And that’s with the FCR [fludarabine, cyclophosphamide, and rituximab (Rituxan)] data, which is the only regimen we haven’t been able to change or beat so far. But I think that will get [changed] in the future with the ECOG [-E1912] study [data (NCT02048813)].

That mutation status only has to be checked once. The reason I do that [is that] is how we decide when to see the patient [again]. You have a patient with del(11q) who has lymphadenopathy and splenomegaly. They have a high white [blood cell] count. Just like patients with trisomy 12, they have a live CT20 expression. These are nuances that you can get by doing FISH testing on all of your patients. Similarly, patients with unmutated IGHV tend to have more aggressive disease. They need to be treated sooner. Those are the kinds of patients I will see every 3 to 4 months. But if [the gene] is mutated, I might push it out to 6 months. This is how I use prognostic markers.

[It is] important to know the TP53 mutation status, which is done through sequencing, and del(17p) by FISH, because both of them add to the prognosis. It’s not just one or the other. One or the other is fine, but both together are even better than either one of them alone. This is why I strongly recommend that we do the FISH analysis, the mutational analysis, and the TP53 mutation analysis. After that, you get the [International Prognostic Score], and follow up with the patients.

Why do patients with CLL get worsening of their disease all of a sudden?

Another reason why we need to do the IGHV status is that this can predict whether patients are going to have clonal evolution. If you look at patients who have mutated IGHV, they almost never undergo clonal mutation or clonal evolution. Their [disease] would always behave gently. They will never go from del(11q) to del(17p) without any intervention. I’m talking about untreated patients now. If you throw in chemotherapy, then all bets are off and you cannot predict what’s going to happen.

If you [treat patients with] any drug, you’ve changed the disease biology. Then it’s all unpredictable. But if you have an untreated patient, there is 0% [chance of] clonal evolution in mutated patients. Almost all evolution [occurs] spontaneously, from del(13q) to del(11q), from del(11q) to del(17p); that almost exclusively happens in patients with unmutated IGHV. That tells you that the unmutated clone is unstable and they might start off as a low risk but then suddenly take off. That is not uncommon but happens only in [patients with] unmutated [disease].

Do the National Comprehensive Cancer Network (NCCN) guidelines support using these regimens for this type of patient?

I think NCCN has a different way of listing things, because they have to include everything and then they have to justify why or why not [to choose a particular regimen], but it’s helpful.¹ Essentially, at this point, NCCN has every regimen [in the guidelines], but they’re trying to get away from chemotherapy. They still have a fair [number] of chemotherapy regimens [in the guidelines].

Which data support the use of acalabrutinib in this patient?

The ELEVATE [TN] study [NCT02475681] was a study of untreated patients [with CLL]. Patients were randomized to acalabrutinib plus obinutuzumab [Gazyva], acalabrutinib monotherapy, or obinutuzumab plus chlorambucil. Basically, [it included] all treatment-naïve patients who would ordinarily not get chemotherapy, so, [those with a high] CIRS [Cumulative Illness Rating Scale] score, which is the European or German way of [quantifying] a higher risk of comorbidities. The primary end point was progression-free survival [PFS].²

Acalabrutinib was better than obinutuzumab and chlorambucil. Acalabrutinib was definitely better than what is considered standard for a lot of patients who may not be candidates for chemotherapy, after the German data that established obinutuzumab and chlorambucil as one of the options for the older patients or patients with comorbid conditions.³

Every subgroup benefited, and I think it’s a no-brainer. If you look at younger patients [under 65 years], they did well [with the acalabrutinib combination and monotherapy versus obinutuzumab/chlorambucil]. Across the board, it appears that acalabrutinib was better than the competitor, and maybe obinutuzumab adds a bit to it in most cases, and possibly even by key disease.

The study was not followed to detect differences [by molecular baseline characteristics], so I’m not going to comment on that too much. But what about this particular patient scenario? For del(11q), both the acalabrutinib monotherapy and combination did better than the comparison with obinutuzumab. In patients with unmutated IGHV, there was an improvement. The only time there was not [statistically significant] improvement was when acalabrutinib was used with the obinutuzumab and compared with the obinutuzumab/chlorambucil cohort in patients with mutated IGHV [HR, 0.69; 95% CI, 0.31-1.56].

That means that patients who have [low-]risk disease don’t necessarily show that much more benefit from acalabrutinib. But when you add the obinutuzumab, it definitely improves it. Now, there [are] 2 ways to look at it. One, we need more follow-up. And with more follow-up, we will hopefully see the improvement in survival outcomes in that group because those patients would be expected to do well anyway. That’s why you’re not seeing a follow-up—you’re not seeing a difference at the early follow-up point. [Two,] these are patients who do not have a lot of issues anyway. These guys will do fine regardless of what you do, whatever regimen you use. It’s hard to find a difference in that group of patients who are mutated right now. That’s been consistent across all studies that we have seen.

The response rate was similar to what we’d seen previously: almost 80% to 90% responses. We don’t see complete responses with single-agent acalabrutinib; we see a small percentage of patients getting into a complete remission. But when you do combine a CD20 antibody with it, you… see a slightly higher complete remission rate, which is what you would expect.

Overall survival [curves] look impressive for everyone treated on the trial, fortunately. There was obviously a trend toward improvement and survival in the acalabrutinib arms. I think it will be hard to get a survival difference out of any study at this point.

What are the adverse effects (AEs) associated with acalabrutinib?

The AEs were what we would typically see in patients with CLL. We see infections and febrile neutropenia in a small percentage of patients, but no major problems with the acalabrutinib plus obinutuzumab arm. Febrile neutropenia was definitely higher with the chlorambucil/obinutuzumab arm.

AFib [atrial fibrillation] is talked about all the time. A small percentage of patients, around 3% or so, had [this AE]; 1 patient had grade 3 or higher AFib. That means the signal is pretty clean.

Do you think comfort with using other agents, such as ibrutinib (Imbruvica), is the reason behind some physicians staying away from acalabrutinib?

I think that’s a valid point. I think we all need to get educated. As we get more experience with a particular drug, we get used to using it. I was exactly in those shoes not too long ago.

What [has been] shown is that in patients who discontinue ibrutinib because of an AE and…switch to acalabrutinib, [a] small percentage…less than 20% or so, will have the same issue happen again. The vast majority of patients don’t have recurrence of their issue, which is encouraging.

The other thing is that BTK [Bruton tyrosine kinase] class effect is probably bleeding. I think there are more and more data coming out [showing] that bleeding is probably a class effect. But the hypertension and cardiovascular AEs, the aFib and ventricular arrhythmia, [are] probably not a class effect.

Which data support the use of ibrutinib in this setting?

In the phase 3 RESONATE-2 study [NCT01722487], ibrutinib was compared with chlorambucil in the treatment-naïve population. No surprise, ibrutinib won. For median PFS [HR, 0.16; P < .001] and even at the 5-year follow-up [HR, 0.146], the advantage remains.^4,5

In every subgroup, the ibrutinib was better. It was [better] regardless of the IGHV status.

Can you review the results of the phase 3 ECOG-E1912 trial that you alluded to earlier in the discussion?

[These results are] published by now. Basically, this was a study that compared FCR versus IR [ibrutinib/rituximab] in patients who were 70 years or younger. These are previously untreated young patients.⁶

The IR combination was significantly better than FCR [for PFS (HR, 0.39; 95% CI, 0.26-0.57; P < .0001)]. At the 3-year mark, there was a clear-cut overall survival [OS] benefit if you use an ibrutinib combination versus FCR [HR, 0.17; 95% CI, 0.05-0.54; P < .001]. After this, there is little justification for using chemotherapy. But obviously, people who want to use chemotherapy will still use it because it’s all about experience; it’s all about getting comfortable with the new drugs.

What other classes of drugs are available to this patient population?

[There is] the CLL14 trial [NCT02242942], which is basically venetoclax [Venclexta] plus obinutuzumab versus chlorambucil/ obinutuzumab.⁷ This is in the frontline setting in patients with a high comorbid score; treatment was stopped after 12 months, so [it was] a fixed duration of venetoclax.

The venetoclax/obinutuzumab combination was significantly better than chlorambucil [in terms of PFS] both at the early time point and later on. This is the case regardless of the TP53 status and IGHV mutational status across all subgroups. Unfortunately, in the high-risk group, we are seeing a lot of late relapses. This concerns me because if I’m stopping therapy after 12 months, I want my patients to stay in remission for a long time, equally as long as patients without the high-risk burden; otherwise it defeats the purpose of stopping early.

It does result in increased MRD [minimal residual disease]. This is interesting, because if you want to stop treatment, you have to get patients into an MRD-undetectable state. Unfortunately, MRD testing is not readily available; but we just heard that the clonoSEQ assay is now approved for MRD testing for patients with CLL.⁸ It can be done on blood or bone marrow.

Can you discuss some of the AEs associated with venetoclax?

The biggest AE that I have seen is diarrhea. The others that I have seen are thrombocytopenia, neutropenia, thrombocytopenia, and anemia, especially if you start the obinutuzumab and venetoclax at the same time. Cycle 1 neutropenia can be an issue. Fortunately, despite the fact that venetoclax causes a fair amount of neutropenia, the risk of febrile neutropenia is low.

_References:

1. _{NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/ small lymphocytic lymphoma, version 4.2020. Accessed September 10, 2020. https://bit.ly/34vUU7s}
2. _{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}
3. _{Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110. doi:10.1056/ NEJMoa1313984}
4. _{Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388}
5. _{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}
6. _{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}
7. _{Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225‐2236. doi:10.1056/ NEJMoa1815281}
8. _{Adaptive Biotechnologies receives expanded FDA clearance for the clonoSEQ assay to assess minimal residual disease (MRD) in patients with chronic lymphocytic leukemia. News release. Adaptive Biotechnologies. August 6, 2020. Accessed September 11, 2020. https://bit.ly/2ZuGu4m}