Vice Chair of the B-Cell Lymphomas NCCN Guidelines Maps Critical Changes From 2024

A plethora of changes in the NCCN Clinical Practice Guidelines in Oncology for B-cell lymphomas not only spanned mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and follicular lymphoma, but also included the omission of Castleman Disease as it is now its own guideline, according to Leo I. Gordon, MD, vice chair of the B-cell lymphomas NCCN guidelines.

“It’s key for community oncologists to recognize that these treatments in B-cell lymphoma are changing quickly based on both basic and clinical research,” Gordon said in an interview with OncLive^®. “There have been a number of changes in follicular lymphoma, MZL, and MCL in this latest iteration of the guidelines.”

The Most Notable 2024 NCCN Revisions in B-Cell Lymphomas:¹

• Castleman Disease has been removed and published as a separate guideline
• For Follicular lymphoma:
  • For first-line therapy:
    • Rituximab (Rituxan) was moved from other recommended regimens to preferred regimen for patients with a low tumor burden
  • For second-line therapy for older or infirm patients:

• Tazemetostat (Tazverik) moved from other recommended regimens to preferred regimens

• For third-line and subsequent therapy:
  • Epcoritamab-bysp (Epkinly) was added as a preferred recommendation (category 2A)
  • Lisocabtagene maraleucel (liso-cel; Breyanzi) was added as a preferred recommendation (category 2A)
  • Copanlisib (Aliqopa) was removed as an option
  • Regimens preference was stratified
    • T-cell engager therapy was moved under preferred regimens
    • Tazemetostat was moved under other recommended regimens
    • Zanubrutinib (Brukinsa) plus obinutuzumab (Gazyva) was added to other recommended regimens (category 2A)
• Allogeneic hematopoietic cell transplantation (HCT) moved from second-line consolidation to third-line consolidation therapy in selected cases

• For marginal zone lymphoma (MZL):
  • For second-line and subsequent therapies as well as second-line and subsequent therapies for older or infirm patients:
    • Pirtobrutinib (Jaypirca; after a prior covalent BTK inhibitor) was added as a preferred recommendation (category 2A)
  • For third-line and subsequent therapy:
    • CAR T-cell therapy was stratified as a preferred regimen
    • Copanlisib was removed as an option
  • High-dose chemotherapy/autologous stem cell rescue moved to second-line consolidation therapy (optional)
  • Allogeneic HCT in highly selected cases moved to third-line consolidation therapy
• For mantle cell lymphoma (MCL):
  • For induction therapy:
    • Rituximab plus bendamustine and cytarabine was moved from less aggressive therapy to aggressive therapy
    • Continuous acalabrutinib (Calquence) plus rituximab was added to other recommended regimen for less aggressive therapy (category 2A)
  • For second-line and subsequent therapy:
    • Liso-cel was added as a recommendation (category 2A)
    • Pirtobrutinib and brexucabtagene autoleucel (Tecartus) were moved from the third-line and subsequent therapy setting to the second-line and subsequent therapy setting for progressive disease after a prior covalent BTK inhibitor
  • For classical TP53-mutated disease:
    • Zanubrutinib/obinutuzumab/venetoclax (Venclexta) was added as a recommendation (category 2A)
• For diffuse large B-cell lymphoma (DLBCL):
  • First-line consolidation with lenalidomide maintenance (category 2B) was removed as a recommendation for patients 60 to 80 years of age with stage I to II disease
  • For first-line therapy for stage I to II disease (excluding stage II with extensive mesenteric disease):
    • Pola-R-CHP (polatuzumab vedotin-piiq [Polivy], rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin], prednisone) was added as a regimen (category 1).
  • For third-line and subsequent therapy:
    • CAR T-cell and bispecific antibody therapies moved under preferred regimens
    • Loncastuximab tesirine-lpyl (Zynlonta) and selinexor (Xpovio) moved under other recommended regimens
• For high-grade B-cell lymphoma/DLBCL with MYC and BCL2 rearrangements/HGBL with MYC and BCL2 rearrangements with or without BCL6 rearrangements:
  • Pola-R-CHP was added as a recommendation (category 2B)

In the interview, Gordon detailed major changes published in the 2024 NCCN guidelines for MCL, MZL, and follicular lymphoma. Gordon is the Abby and John Friend Professor of Oncology Research and a professor of medicine (hematology and oncology) at Northwestern Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, Illinois.

OncLive: What 2024 NCCN guideline updates have had an immediate influence on how you treat B-cell lymphomas?

Gordon: In follicular lymphoma, one of the more important things is the addition of T-cell engager therapy as third-line [and subsequent therapy options]. That includes both bispecific antibodies, specifically epcoritamab which was added as a category 2A [preferred recommendation], and CAR T-cell therapy, specifically liso-cel [which was also included as] a category 2A [preferred recommendation].

In MZL, for second-line and subsequent therapy of older or infirm patients we’ve added the use of a non-covalent BTK inhibitor with pirtobrutinib [as a category 2A preferred recommendation], after [receiving a] prior covalent BTK inhibitor.

In MCL, there have been a number of things, [including] the way we think about TP53 mutations, for example. We have relied upon next-generation sequencing [NGS] as the way to determine if there is a TP53 mutation, which turns out to be a fairly significant prognostic factor in MCL. One of the questions is whether immunohistochemistry [IHC] on the pathology specimen is a reasonable surrogate for NGS. We’ve revised one of the footnotes in the MANT-1 section of the MCL guidelines [from] ‘TP53 by IHC is not a proven surrogate for a TP53 mutation or deletion 17[p],’ [to say] that ‘TP53 sequencing is preferred’.

However, because NGS may not be available everywhere and all the time, [we believe] in the frontline setting [TP53 testing by] IHC can be used as a surrogate, but ultimately should be confirmed with sequencing. [This] addresses how we measure that important prognostic factor. Because it’s so important, we’ve now allowed IHC to determine [its status]. The other question is, ‘how much expression of P53 do you need by IHC to be the equivalent of the mutation by NGS?’ Anywhere from 30% to 50%, certainly greater than 50%, suggests it’s probably going to be mutated if you order NGS.

Are there any additional notable changes from the guidelines that you’d like to highlight?

Another important change came in the MANT-3 [section]. In patients with classical TP53 mutations the combination of zanubrutinib, obinituzumab, and venetoclax—which has been the subject of [investigation in] the phase 2 BOVen trial [NCT03824483]—has been added as a category 2A recommendation. Whereas that [regimen] was [previously] only available on clinical trials, we believe that should now be a category 2A recommendation for patients with TP53-mutated MCL, even off a clinical trial. It’s an important change in the guidelines and offers physicians and patients the option for what appears to be one of the more effective, at least from what we can tell from early data from the trials, ways to treat [patients with] TP53-mutated MCL.

In the second-line and subsequent therapy [section of the MCL guidelines], we added liso-cel, which is another T-cell engager, as a category 2A recommendation. In MANT-A section 3 of 5, we revised a footnote, which may not be thought by many to be that significant, but I believe it’s important. [In that footnote] we added that obinutuzumab can be optional and substituted for rituximab at the discretion of the treating physician.

In terms of other notable changes, we’ve moved Castleman Disease, and this is something that’s important for community physicians, from the B-cell lymphoma guidelines and published that as a separate guideline. We’ve also changed the name of follicular lymphoma grade 1/2 to follicular lymphoma or classic follicular lymphoma. Additionally, CAR T-cell therapy and bispecific antibody therapy are now referred to as T-cell engager therapy.

What is key to note for community oncologists who are adapting to these recent changes?

It’s [necessary] to know that we’re talking about bispecific antibodies and CAR T-cell therapy when we say T-cell engager therapy. It’s also important to communicate that older patients are now [referred to as] elderly patients in the guidelines. For community oncologists who are adapting to these changes, it’s important to know where to find [this information] because the [guidelines] are somewhat dense, and the algorithms can sometimes be difficult to follow.

It’s important for community oncologists, if they can, to maintain a relationship with lymphoma specialists at academic institutions for advice and to not change where the patients are treated but know that we now have treatments such as these T-cell engager therapies that may not be available routinely, and that referral too late may affect care. It’s important for the community oncologist to use the guidelines to know when to refer patients for novel treatments like these T-cell engager therapies.

Have you faced any challenges in integrating these changes into your practice?

Yes. Communicating these changes to insurers who don’t necessarily update their approval algorithms to coincide with the guidelines [can be challenging], and sometimes we find ourselves being told that something is not in the guidelines or not approved when we’ve just written them into the guidelines. It’s on us to educate everybody and to do so in a congenial way. Sometimes we get into arguments with insurance companies, and that’s not useful for anybody. It’s key to make sure that they’re aware of the importance of the guidelines and that the guidelines are changing in real time.

How do communicate guideline changes to your patients?

I tend not to use the guidelines in day-to-day patient discussions. They help to inform the way I approach bringing ideas to patients, but, similar to insurers, I stress that the field is moving quickly and what was standard of care a year ago may not be standard of care today. It’s important not necessarily to say, ‘the guidelines now say’ or ‘we wrote in the guidelines now’, but to say from our best information and based on our best research this may be the better way to approach this. I prefer to do that communication not guideline-based, but where I believe the field is moving.

What changes do you anticipate coming up in 2025 following these guideline updates?

There are two things that I hope will be addressed in 2025. First, in DLBCL, there are some new combinations of T-cell engager therapies, specifically bispecific antibodies, together with chemotherapy in relapsed/refractory DLBCL either before or after CAR T-cell therapy. I’m anticipating that those [regimens] may be included in the guidelines come the next iteration. Combinations such as those that we saw in the phase 3 STARGLO study [NCT04408638] of gemcitabine and oxaliplatin [with glofitamab or rituximab] look very promising. There are data looking at bispecific antibodies and lenalidomide [Revlimid], which look exciting. I’m expecting to see some additions in DLBCL.

[Secondly], it’s hopefully coming to be time where we can begin to look at the question of transplant in patients with MCL in complete remission 1 [CR1]. We had updated the guidelines the last time to include data from the phase 3 TRIANGLE study [NCT02858258], [indicating] that transplant does not necessarily add anything if you include chemotherapy plus a BTK inhibitor as upfront therapy and for a period of maintenance. We’re starting to see a change in the utility of transplant in patients with MCL in CR1, and the phase 3 ECOG-ACRIN EA4151 trial [NCT03267433] is looking at that question in a different way. It’s coming time where we may see some data emerge from that study, hopefully in the next year or so.

Reference

1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2024. Accessed November 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf