Obinutuzumab and Liso-Cel Revisions to CLL/SLL NCCN Guidelines Mark Most Notable Changes of 2024

Matthew Cortese, MD, MPH

The addition of venetoclax (Venclexta) plus obinutuzumab (Gazyva) to preferred regimens in the second- or subsequent-line settings for patients with and without deletion 17p (del[17p])/TP53 mutations and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) represents one major change to the latest version of the NCCN guidelines. Additionally, the first CAR T-cell therapy approved in CLL, lisocabtagene maraleucel (liso-cel; Breyanzi), is a notable advancement in the relapsed/refractory setting, according to Matthew Cortese, MD, MPH, member of the NCCN guideline panel for CLL/SLL.¹

“As a take-home message, chemotherapy has fallen from favor into the special circumstances bucket,” Cortese said in an interview with OncLive^®. “New mutations are being looked at all the time. As far as predicting the future and response, minimal residual disease [MRD] testing is also emerging. There are some new treatments available for relapsed/refractory CLL and SLL, namely pirtobrutinib [Jaypirca] and CAR T-cell therapy with liso-cel with some others we expect in the near future as well.”

The Most Notable 2024/First Quarter of 2025 NCCN Revisions in CLL/SLL:

• For CLL/SLL without del(17p)/TP53 mutations:
  • First-line setting:
    • The first option therapy has been revised from a BTK inhibitor with or without an anti-CD20 monoclonal antibody to a covalent BTK inhibitor with or without obinutuzumab
    • Ibrutinib (Imbruvica) plus obinutuzumab (category 2B) and ibrutinib plus rituximab (Rituxan; category 2B) have moved from other recommended regimens to useful in certain circumstances and have been revised as ibrutinib plus an anti-CD20 monoclonal antibody (category 2B)
    • Ibrutinib plus venetoclax has been updated from a category 2B to category 2A other recommended regimen
  • Second- or subsequent-line settings:
    • Venetoclax plus obinutuzumab has been added to preferred regimens
    • Venetoclax plus rituximab (category 1) has been moved from preferred regimens to other recommended regimens
    • A useful in certain circumstances regimen has been removed
• Revisions were made to treatments for relapsed/refractory disease after prior therapy with a BTK inhibitor and venetoclax-based regimens
• For both CLL/SLL with and without del(17p)/TP53 mutations:
  • Relapsed/refractory disease after prior BTK inhibitor- and venetoclax-based regimens:
    • Liso-cel and pirtobrutinib, if not previously given, have moved from other recommended regimens to preferred regimens
• For CLL/SLL with del(17p)/TP53 mutations:
  • First-line setting:
    • Ibrutinib plus venetoclax has been updated from a category 2B to category 2A recommendation
  • Second- or subsequent-line settings:
    • Venetoclax plus obinutuzumab has been added to preferred regimens
    • Venetoclax plus rituximab (category 1) has been moved from preferred regimens to other recommended regimens
    • Useful in certain circumstances regimens have been updated
• For chemoimmunotherapy-refractory or del(17p)/TP53 mutations:
  • Liso-cel has been added as additional therapy (category 2A)
• Suggested regimens have been modified if chemoimmunotherapy is not preferred

In the interview, Matthew Cortese, MD, MPH, detailed notable 2024/2025 updates to the NCCN guidelines for CLL/SLL that have affected his practice and treatments to look forward to in the future. Cortese is an assistant professor of oncology in the Department of Medicine-Lymphoma and the Department of Cancer Genetics and Genomics at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

OncLive: What 2024/first quarter of 2025 NCCN updates have had an immediate influence on how you practice when treating patients with CLL and lymphoma?

Cortese: It’s my honor and privilege to serve on the NCCN guidelines on behalf of Roswell Park Comprehensive Cancer Center. There were a couple modest revisions over the past year, and a bigger revision from a couple years ago. But the overall theme is that targeted therapies, particularly the second-generation covalent BTK inhibitors like acalabrutinib [Calquence] and zanubrutinib [Brukinsa], are now preferred over ibrutinib.

As a bigger generational shift, 2 years ago when I had the privilege of starting on the panel, chemotherapy had gone from a preferred option to other accepted regimens for some patients. But, by and large, targeted therapies have now taken [preference] over chemotherapy, and now the less toxic and equally, if not more effective, second generation covalent BTK inhibitors are the preferred option over ibrutinib.

It’s also worth noting that we’ve liberalized [guidelines] in [certain] settings—we’ve [added an] anti-CD20 therapy as opposed to just rituximab partnered with the BCL2 inhibitor venetoclax. The reason for that is two-fold: One is with insurance denials for obinutuzumab as a preferred antibody in CLL. [It has shown] higher rates of overall response and especially deep remissions. That’s now also an option in the relapsed/refractory setting, despite it not being [under evaluation] in that original pivotal phase 3 MURANO study [NCT02005471] which was venetoclax given for up to 2 years with rituximab. There’s now plenty of data to show us that obinutuzumab remains very effective in the relapsed/refractory setting and we wanted to [add that to] have the opportunity to let patients get it.

Then, there [have been] key FDA approvals over the past year. Pirtobrutinib is now FDA approved after 2 prior lines of therapy for patients treated with a covalent BTK inhibitor and venetoclax. That is a very effective option in the relapsed/refractory setting with ongoing studies in the frontline setting to look out for in the future.

Also, liso-cel is now the first CAR T-cell therapy to be approved in CLL for patients with double-refractory CLL, and that’s after over 10 years of research. But unfortunately, [for] most patients with CLL who’ve been treated with CAR T-cell therapy, that treatment does not serve them as well as we’d like. It’s important to get a well-tolerated, very effective CAR T-cell option in the guidelines as well.

Are there any other notable guideline updates in CLL that you want to highlight?

TP53 is the most deleterious mutation in CLL and with that, deletion 17p. We know that deletion 11q, for example, is also high-risk, but there have been very little additions [of data] as far as other mutations despite lots of growing calls for help in input from community physicians and academic physicians alike.

[Therefore], we’ve put together a very abbreviated initial foray into the other mutations in CLL. Some of them [include] BIRC3, NOTCH1, NOTCH2, and SF3B1. There are other mutations that we know are becoming increasingly important, especially as we see differential outcomes for patients who are uniformly treated, and there’s going to be more to come on that in the future with readouts from ongoing, large phase 3 studies with correlative data to dig through.

Over time, we’re going to be getting to sequencing of therapies [too]. We don’t have great data yet, that’s a need. Do you start with a BCL2 inhibitor first or BTK inhibitor? We think that some of these other mutations that are buried in a lot of these next-generation sequencing [NGS] reports we get now to look for TP53 will help yield some of those answers and insights over the years to come. But for now, we don’t have great data on that, so we’re left with a couple different preferred options in the relapsed/refractory setting.

We’re working on Richter transformation guidelines as well so stay tuned for that—that’s still in the revision stage. We’re taking feedback and requests for help and clarification very seriously with my colleagues on NCCN and are hoping to fully answer some of these important questions.

What is key to note for some of the community oncologists who are adapting to the recent guideline changes?

First and foremost, it’s important to know that chemotherapy has fallen from favor. [Additionally], even if we have our best patients so to speak, it’s important to check for [mutations]. A lot of patients are not being sequenced looking for some of these high-risk mutations that I’ve seen. The fall of chemotherapy [in recent years] off the preferred list is the number one [takeaway] given that most of our randomized trial data suggests that chemotherapy has less efficacy and more toxicity potential, especially in patients who are immunocompromised with CLL. Chemotherapy is falling from the top to a lesser preferred backup option now.

With the sequencing results, we’re also finding that there are other genes that are implicated in chemotherapy resistance that are also not checked for that may help explain why targeted therapies have risen to the fore and beaten chemotherapy in lots of these pivotal trials. That’s something else to keep in mind—stay tuned [for data on] some of these other mutations that we currently don’t act much on, but that’s probably going to change in the future.

One of the things to note is that if patients have double-refractory disease, know about pirtobrutinib [which is] now FDA approved. Hopefully, with the addition of it on the guidelines, we’ll get less resistance from insurance companies because it is an effective, well-tolerated drug, and the same with CAR T-cell therapy. If you have a patient who you’re starting on pirtobrutinib or who has been class exposed and [is] relapsing quickly or slowly, referring to a CAR T-cell therapy capable center is important now that we have FDA approvals for CAR T-cell therapy. [There are] lots of other ongoing clinical trials as well that many of our large centers, like here at Roswell Park, can offer.

Have you faced any challenges when integrating updates to the guidelines into your practice?

Personally, I have not. I graduated from the Cleveland Clinic 3 years ago, so I’m in the new generation approach. I’ve never prescribed chlorambucil and probably never will, but I respect everyone who has been in practice for a long time and recognize the comfort level that a lot of [clinicians] have with chemotherapy regimens such as bendamustine and rituximab or fludarabine, cyclophosphamide, and rituximab. I’m blessed to be in this position, but I don’t have as many clinical preferences yet because I haven’t been in practice quite that long.

One of the things that is not in our guidelines yet, but it’s certainly coming, is MRD testing. Currently, we use clonoSEQ or at least flow cytometry for fixed-duration therapies. It’s important to continue to check for those types of things as our clinical trials are reading out and we learn more insights about MRD and its importance as far as predicting the overall outcome and expected time to next treatment or progression-free survival with a fixed-duration therapy. Currently, we don’t modify the duration of treatment so far with the data we have available, we don’t treat to MRD-negative [status] yet. [However], it may be evolving over the coming years, certainly over the next decade.

How do you approach conversations when you’re talking with patients who are receiving treatment and could change therapy based on guideline changes?

The key example right now would be ibrutinib—if a patient is receiving ibrutinib, you could try a dose reduction which can reduce risk for a lot of those other off-target BTK toxicities such as hypertension, sometimes skin or fingernail toxicities, [or] ventricular arrhythmias. If it’s working well, the patient has been on the drug for a long time, and you’ve looked for all the potential adverse effects from that drug compared with the others in the BTK inhibitor class, and as long as you’re comfortable and those things are managed and discussed in clinic, then [it could still be an option]; I still offer ongoing ibrutinib for people who have been prescribed it in the past.

But if a patient has cardiovascular risk factors, high blood pressure that’s not well controlled and may have been worsened by ibrutinib for example, certainly I would consider switching to the second-generation BTK inhibitors.

Other things to talk about would be chemotherapy; if a patient has gotten chemotherapy in the past, they can still experience a response. I wouldn’t go yelling at physicians for giving chemotherapy just yet. Certain patients can benefit for decades with chemotherapy, and just because they had chemotherapy and the guidelines have changed, does not mean that they didn’t get any benefit in the past. But I would not recommend chemotherapy as a frontline treatment or even a preferred relapsed/refractory treatment as of right now based on the plethora of data that are emerging with these targeted therapies showing how safe and how much more effective they are, especially for some of these baked in chemotherapy resistance genes we’re finally starting to understand with more in-depth sequencing.

Finally, I would make sure that all the risk stratification laboratories have been done at some point throughout the clinical course—IGHV mutation status, fluorescence in situ hybridization for CLL, or even MRD-based testing as a reference point to have for the future. Those are all things to talk about with your [patients].

Reference

NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2025. Accessed November 5, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf