Hoffmann Examines Data for 17p Deletion in Treatment-Naive CLL

Marc S. Hoffmann, MD

Associate Professor

Hematologic Malignancies and Cellular Therapeutics

Medical Director of Lymphoma, Hematologic Malignancies and Cellular Therapeutics

The University of Kansas Medical Center

Kansas City, KS

CASE SUMMARY

History and presentation

• A 66-year-old woman presented with fatigue and unintentional weight loss
• ECOG performance status: 1

Comorbidities

• Hyperlipidemia
• Chronic kidney disease (stage III)

Medications

• Atorvastatin
• Omeprazole

Imaging studies

• CT scan: largest lymph node: 3.2 × 1.9 cm
• PET scan: standardized uptake value (SUV): 3
• Splenomegaly: 17 cm along the long axis

Laboratory profile results

• White blood cells: 66.8 × 10⁹ cells/μL
• Absolute lymphocyte count: 55.1 × 10⁹ cells/μL
• Hemoglobin: 9.7 g/dL
• Platelet count: 175 × 10³/μL
• Lactate dehydrogenase: 240 U/L

Molecular testing results

• Karyotype: not complex
• FISH (fluorescence in situ hybridization): deletion 17p (del[17p])
• IGHV: unmutated (VH1-69)
• Mutations of interest: mutated TP53

The patient is in the unfavorable risk category.

Peers & Perspectives in Oncology: What was the significance of the SEQUOIA study (NCT03336333) for patients with del(17p) in chronic lymphocytic leukemia (CLL)?

Hoffmann: SEQUOIA was the phase 3 registration study for zanubrutinib [Brukinsa], and it’s an interesting study. There were 3 cohorts in this study. Cohort 1 was a group of patients with therapy-naive CLL who did not have a 17p deletion by central FISH. The p53 mutation was not routinely tested for, but they did test for 17p. Those patients were randomly assigned to…receive BR [bendamustine plus rituximab (Rituxan)] or zanubrutinib. That’s one cohort, which is a randomized cohort. Cohort 2 is a universal group of patients. There were 111 of them who had a 17p deletion, and they all received single-agent zanubrutinib. That [cohort] is not randomized. We were just looking at the progression-free survival [PFS] curve for some sort of historical suggestion of how that patient population may do compared with historical controls who have del(17p) disease. The remainder of the inclusion and exclusion criteria are quite straightforward. The primary end point from cohort 1, the randomized portion, was PFS.

It’s not surprising that zanubrutinib performed considerably better than BR. The 54-month PFS rate was 80% [vs 44.6% with BR].¹ The 60-month or 5-year PFS was 76% [vs 40.1% with BR]. When you start looking at the [Kaplan-Meier] curves, when you get out to 54 and 60 months, you’re starting to run out of patients. The median follow-up was [61.2 months]. It is a nice long follow-up, but I would not take these numbers of 54- and 60-month PFS rates home because the number of patients at risk is relatively small in both…these cohorts, and we need a longer follow-up before you get solid numbers for those, but it looks quite attractive.

In terms of mutated and unmutated IGHV, you can see a dramatic difference between the curves. Looking at the IGHV-mutated disease and the IGHV-unmutated disease, there’s a dramatic difference when you give [BR], but when you give zanubrutinib, it doesn’t matter. Those curves are essentially overlapping. It doesn’t really matter whether you’re mutated or unmutated; you do equally well with a single-agent BTKi [Bruton tyrosine kinase inhibitor]. There is maybe a suggestion that the mutated group does a little bit better, but by and large, those curves don’t look different to me.

In terms of overall survival [OS], there was not a significant difference at the 54-month [87.7% for zanubrutinib vs 86.0% for BR] or 60-month level [85.8% vs 85.0%, respectively]. This is not surprising. These patients do tend to live longer, and OS is questionable about how relevant an end point it is. I think if you’re going to look at 15- and 20-year studies, it is relevant. In a study of this duration, where we have a median follow-up of less than 5 years, it’s a little hard to meet an OS end point in a disease where the vast majority of patients are going to die of other causes.

How was zanubrutinib tolerated in this population?

The adverse event [AE] profile was significantly better, favoring zanubrutinib. When you’re reviewing these types of studies, not just for CLL [but] for any study where you have a time-limited therapy like BR for 6 months compared with an indefinite therapy like zanubrutinib,…these are all treatment-emergent AEs, [but] in the BR arm, they are only capturing AEs for 6 months. If you develop a pneumonia at 7 months, then that is not a serious AE; that is not an AE that’s captured, and that’s not considered treatment related, so they’re not going to pick that up and report that. Whereas, if you’re on zanubrutinib for 7 years, for that entire 7-year period, anything that happens to you is considered an AE.

The neutropenia is significantly greater in BR. That’s not particularly surprising. Hypertension is a bit higher with zanubrutinib. That’s a clearly related and demonstrable AE. [In terms of] the cardiac risk profile, the atrial fibrillation and atrial flutter rates are normalized for exposure adjustments. It’s telling you that the zanubrutinib has a similar rate of atrial fibrillation compared with BR [Table²].

One of the things that we found, and these are true of the mantle cell lymphoma subgroups as well, is when you do placebo-controlled studies with BR against a BTKi, BR plus placebo has about a 6% to 8% atrial fibrillation rate. There’s clearly a lot going on with these patients’ disease that seems to be precipitating these arrhythmias that keep [oncologists] up at night…. But in terms of these parameters, the zanubrutinib probably still has a class effect of having more atrial fibrillation than nothing, but it’s not considerably more than BR. There is a risk of hemorrhage and a minor risk of major hemorrhage. These are all class effects of the drugs.

What other BTKi study is relevant in this patient population?

ELEVATE-TN [NCT02475681], the acalabrutinib registration study, [was] all patients with treatment-naive CLL. Patients who had 17p deletion were allowed to be included in this study. There were 2 investigational arms. One was acalabrutinib [Calquence] plus obinutuzumab [Gazyva]. The other was acalabrutinib monotherapy, and then the control arm was obinutuzumab/chlorambucil, which was the traditional [comparator for drugs seeking] an FDA approval. Chlorambucil probably does very little for CLL….

At 6 years, not surprisingly, obinutuzumab and chlorambucil performs poorly with a fairly rapid drop-off and multiple progression events.³ When you get out here to 6 years, there are still 17% of these patients who do well with obinutuzumab/chlorambucil. [I think] every single one of those patients has mutated IGHV status, [as] those patients do really well. I have a couple of these patients who got obinutuzumab in 2015 or 2016, and they’re still in remission. If you have older patients with a pure IGHV mutation, single-agent obinutuzumab is not a bad choice. I don’t know that I would sign up to be on that curve, but the patients with the mutation can do well, and you can potentially resist some toxicity.

There is a persistent and demonstrable separation in these curves between the obinutuzumab and acalabrutinib arm compared with the acalabrutinib arm that persists up to 6 years, which I think was surprising to a number of us from a PFS standpoint [78% vs 62%, respectively]. It’s questionable how much this matters. Is this an additive effect? If you were to give obinutuzumab and acalabrutinib in a sequential fashion, would you arrive at a similar PFS? The study doesn’t answer that question for us. You are adding toxicities when you add obinutuzumab with risks of long-term hypogammaglobulinemia. You have infusion-related reactions and other things that you have to [manage].

I think acalabrutinib/obinutuzumab is a relatively underutilized regimen. I generally don’t give it. That doesn’t mean it’s wrong; it’s just my practice pattern. I don’t judge anyone if they’re compelled by these data. If I have a time-limited combination that I can offer [instead], it doesn’t accomplish my goal of having somebody on limited therapy, and I have all…the problems that are associated with giving intravenous treatments. I generally don’t think that this PFS benefit is worth [using the combination for], for me.

This is the PFS by del(17p) and p53; none of the patients with obinutuzumab and chlorambucil do well, but those with del(17p) do particularly poorly. Everybody does significantly better with the acalabrutinib arms, and there is not a significant difference here. The acalabrutinib/obinutuzumab arm has some separation of the curve. It looks like potentially giving obinutuzumab to those patients without del(17p) may offer some assistance in terms of PFS that you’re not seeing in the [acalabrutinib single-agent] arms, where there doesn’t appear to be a whole lot of difference [between] if you’re giving just single-agent acalabrutinib between the [patients with] del(17p) and those who do not have that abnormality.

For OS, there was no significant difference between any of these curves other than that acalabrutinib/obinutuzumab is superior with statistical significance to obinutuzumab and chlorambucil [HR, 0.62; 95% CI, 0.39-0.97; P = .0349], but there’s no OS difference between acalabrutinib and acalabrutinib/ obinutuzumab [HR, 0.69; 95% CI, 0.44-1.09; P = .1220].

What adverse event profiles did investigators see in ELEVATE-TN?

It’s best to compare acalabrutinib with acalabrutinib/ obinutuzumab. Both of these are long-term, indefinite therapies, so you’re looking at apples to apples in terms of the timing of these AEs, and the atrial fibrillation rates in this particular study were somewhere around the 7% to 9% range on long-term follow-up. Major bleeding rates are [9.0% at any grade for the combination vs 5.6% for single-agent acalabrutinib]. Some patients can get headaches with acalabrutinib. They’re typically mild and grade 1 and generally show up within the first month and resolve within 6 weeks, but sometimes they can be more severe and problematic. The neutropenia rates are higher in the acalabrutinib/obinutuzumab arm. Infections and a lot of the other difficulties that you’re used to seeing when you give monoclonal antibody therapy, [such as] long-term hypogammaglobulinemia and more severe infectious episodes, are all present and bear out in this data set.

What other regimen was investigated in the del(17p) population?

Going back to SEQUOIA, we presented the data on zanubrutinib vs BR and the monotherapy data on patients with del(17p).⁴ This is another investigational cohort that was looking at patients who had either a del(17p) or p53 mutation vs those patients who did not. All…these patients received zanubrutinib and venetoclax [Venclexta]. I’ll explain a little bit about how all…these dosing combinations are done. These patients all receive—it doesn’t matter what the BTK inhibitor is, whether it’s ibrutinib [Imbruvica], acalabrutinib, zanubrutinib—…a lead-in period of somewhere around 2 to 3 months of BTKi monotherapy. That accomplishes 2 major things. The first thing is that it debulks these patients, so you considerably reduce their burden of disease, and as a consequence, you reduce their tumor lysis syndrome [TLS] risk. It facilitates your uptitration of venetoclax to the point where we don’t see TLS when you give patients venetoclax. This is not a whole lot different compared with obinutuzumab and venetoclax, where in the CLL14 study [NCT02242942], all…the TLS events were during the obinutuzumab portion and not during the venetoclax ramp-up and consolidation. When you debulk these patients, initially you do not see any significant tumor lysis. It facilitates a much easier outpatient administration. You will generally never need to admit these patients, and the package label on venetoclax does offer some parameters, but the nodal disease will shrink quite dramatically and generally will not end up with significant enough lymphocytosis to do that.

So that was the way this study was designed. They had a 3-month lead-up period of zanubrutinib monotherapy. There was a 4-week dose escalation of venetoclax to full dose, and then they had a discontinuation that was driven by their minimal residual disease [MRD] status.… So in patients who had undetectable MRD after 1 year of combination, they were offered to either discontinue or continue for an additional year of therapy prior to stopping, and everybody stopped thereafter.

The PFS looks good [estimated 24-month PFS of 94%]. This is just the patients with del(17p), and their PFS is excellent. This is probably the best PFS curve that has been seen for a pure 17p deleted cohort.

[The overall response rate was 100%], but I think response rates in CLL are misinformative. Our response criteria have not caught up with the advent of MRD testing, and unfortunately, if you have any lymph nodes that are greater than 1.5 cm, that’s considered a partial response. Interestingly, if you have a partial response and your MRD is undetectable, you do better than if you have a complete response and your MRD is detectable. Clearly, response rate is not the best measure. I’m using it simply to illustrate the point that when you see response rates in CLL, you can largely ignore them. MRD detectability and undetectability are a much better crude way of assessing how effective a drug is if you’re waiting for those PFS curves to come out.

What stood out about this regimen’s safety profile?

There were a considerable number of infections [56% grade 1 or 2, 15% grade 3 or higher]. These were all treatment-emergent AEs. A number of these patients [55%] had COVID-19; this did happen during the pandemic. There is some neutropenia that you’ll see with this regimen [22%]. When you give these doublets, you will see some neutropenia. The neutropenia is annoying; it is not anything that’s life threatening. The rates of neutropenic fever are extraordinarily low. These patients are not getting cytotoxic chemotherapy, so those tight junctions in their gut are not opening up and allowing for translocation of their own gut bacteria, which is the most common way that patients actually get neutropenic fever when they are on cytotoxic chemotherapy. Their gut junctions are nice and intact. They happen to be neutropenic. You do not need to stop the drugs. You generally don’t need to dose reduce unless they continue to have persistent neutropenia, and pegfilgrastim [Neulasta] is your friend. You should be able to get pegfilgrastim, particularly if you code it as chemotherapy-induced neutropenia, which this is. You [should] keep them on therapy and give them pegfilgrastim. You may need to give it once or twice as you’re doing the dose escalation, sometimes not at all, but you can aggressively treat through the neutropenia. These patients are at a much lower risk of getting sepsis and having significant complications. I’m not suggesting you don’t watch them and don’t check weekly counts on them if their counts are low, but what I am suggesting is you generally get early neutropenia that is quite manageable with pegylated growth factor, and you’re able to continue them on therapy.

DISCLOSURE: Hoffmann previously reported consultancy roles with AbbVie, AstraZeneca, BeiGene, Eli Lilly, Janssen, Kite, Novartis, Pharmacyclics, and TG Therapeutics.

REFERENCES:

1. Shadman M, Munir T, Robak T, et al. Sustained superiority of zanubrutinib vs bendamustine + rituximab in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN CLL): 5-year follow-up of cohort 1 from the SEQUOIA study. Blood. 2024;144(suppl 1):3249. doi:10.1182/blood-2024-194864

2. Munir T, Shadman M, Robak T, et al. Zanubrutinib (zanu) vs bendamustine + rituximab (BR) in patients (pts) with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): extended follow-up of the SEQUOIA study. HemaSphere. 2023;7(suppl):e15364af. doi:10.1097/01.HS9.0000969460.15364.af

3. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of Elevate-TN. Blood. 2023;142(suppl 1):636. doi:10.1182/blood-2023-174750

4. Ma S, Munir T, Lasica M, et al. Combination of zanubrutinib + venetoclax for treatment-naive (TN) CLL/SLL with del(17p) and/or TP53: preliminary results from SEQUOIA arm D. Presented at: 29th European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract S160.