FAQs: Incorporating Novel and Emerging Treatment Combinations Into the Management of Aggressive B-Cell Lymphomas

Key Takeaways

• The efficacy and safety profile of BTK inhibitors has made them the therapy of choice in second-line mantle cell lymphoma, and novel BTK inhibitor–based combinations are on the horizon.
• Combinations of novel agents with chemotherapy look promising in the management of newly diagnosed diffuse large B-cell lymphoma.
• CAR T-cell therapy is an important option in the treatment armamentarium for patients with relapsed/refractory diffuse large B-cell lymphoma.

In this commentary adapted from a discussion among Julie M. Vose, MD, MBA; Jeremy S. Abramson, MD, MMSc; and Grzegorz Nowakowski, MD, the experts address important clinical questions about how to integrate novel and emerging therapies into treatment strategies for patients with mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL).

What are your thoughts on the use of the BTK inhibitor ibrutinib as a single-agent vs in combination with venetoclax for patients with MCL harboring TP53 mutations?

Julie M. Vose, MD, MBA:
I have used ibrutinib in combination with venetoclax in patients with relapsed MCL harboring TP53 mutations but was underwhelmed with the treatment outcomes. Unfortunately, patients with TP53 mutation–positive MCL generally do not derive benefit from most standard therapies. Certainly, CAR T-cell therapy has a better track record of efficacy in these patients even though the reported data, so far, is based on a very small patient population. 

Jeremy S. Abramson, MD, MMSc:
For patients with relapsed TP53 mutation–positive MCL, I typically use a BTK inhibitor. I tend to use acalabrutinib or zanubrutinib, which have more favorable safety profiles than ibrutinib. In my clinical experience, giving a BTK inhibitor as a single agent to a patient with MCL harboring TP53 mutations does not yield particularly durable responses. I typically phase in venetoclax if a patient is having suboptimal response to BTK inhibitor alone. Now, I also know that I have brexucabtagene autoleucel as a subsequent treatment option, if needed. This is also a group of patients for whom I would be eager to administer a BTK inhibitor as a component of frontline therapy. The phase III SHINE trial results provide us with the opportunity to treat with ibrutinib plus bendamustine and rituximab in the frontline setting, which would be much more appealing than bendamustine plus rituximab alone in patients with TP53-mutated MCL.

Based on the results of the phase III POLARIX trial of polatuzumab vedotin plus R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for patients with previously untreated DLBCL, in which subset of patients would you use this regimen?

Grzegorz Nowakowski, MD:
As yet, there is no FDA approval for the combination of polatuzumab vedotin with R-CHP for patients with previously untreated DLBCL. Currently, I do not use the combination in routine clinical practice; however, if the combination receives FDA approval, I would consider it in patients who meet the eligibility criteria for the POLARIX trial. The subgroup analysis of progression-free survival (PFS) is interesting and hypothesis generating, especially with classifications according to age, International Prognostic Index (IPI) score, and cell of origin. Perhaps future studies will help us understand whether patients older than 60 years of age, patients with an IPI score of 3-5, and patients with the activated B-cell (ABC) subtype of DLBCL truly benefit more from the combination compared with patients aged 60 years or younger, patients with an IPI score of 2, and patients with the germinal center B-cell (GCB) disease subtype, respectively.

Jeremy S. Abramson, MD, MMSc:
The subgroup analysis of the PFS data is easy to overinterpret, so I would apply these data based on the eligibility criteria of the POLARIX trial rather than an underpowered subset of analyses. Although these subset PFS findings are based on univariate analysis, patients are typically multivariable beings. The data suggest that polatuzumab vedotin plus R-CHP may not be as effective in patients aged 60 or younger, patients with an IPI score of 2, or patients with the GCB subtype of DLBCL. So, should you not use this treatment for a patient younger than 60 years of age but with a high IPI score of 3-5 and non-GCB DLBCL? The most appropriate answer to this question is to treat eligible patients based on the study results overall. If approved, I anticipate considering this regimen in patients with an IPI score of 2 or higher, regardless of the cell of origin, or age using the eligibility criteria used for enrollment on the study.

Julie M. Vose, MD, MBA:
We will have wait to see whether the combination of polatuzumab vedotin with R-CHP receives FDA approval and treat patients with newly diagnosed DLBCL according to the indication, when approved.

Which adverse event(s) would you closely monitor and be concerned about in patients with newly diagnosed DLBCL who are receiving polatuzumab vedotin plus R-CHP?

Grzegorz Nowakowski, MD:
Adverse events associated with polatuzumab vedotin plus R-CHP include neutropenia. Therefore, monitoring for neutropenic fever is important, and primary prophylaxis with granulocyte colony-stimulating factor is required with this regimen. Another adverse event to watch out for is peripheral neuropathy. Surprisingly, however, there was no significant difference between the frequency of peripheral neuropathy between arms in the POLARIX trial. Patients with underlying peripheral neuropathy due to conditions such as diabetes should be carefully monitored when using this regimen.

Julie M. Vose, MD, MBA:
Yes, it is surprising that there was no difference in the occurrence of peripheral neuropathy between treatment arms.

Jeremy S. Abramson, MD, MMSc:
Of note, the POLARIX regimen is different from other regimens, such as brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine, in which 2 microtubule toxins are combined. In the polatuzumab vedotin plus R-CHP regimen, polatuzumab vedotin replaced vincristine. In essence, only 1 drug in each of the treatment arms is associated with peripheral neuropathy. In my experience, there are qualitative differences between the type of peripheral neuropathy induced by each drug. So, it is important to dose reduce polatuzumab vedotin for a patient who is experiencing any significant neuropathy.

Grzegorz Nowakowski, MD:
There is also the probability of a higher incidence of peripheral neuropathy associated with the use of vinca-alkaloids in the second-line or later-line setting because the patient may have previously experienced peripheral neuropathy with upfront treatment, and the condition worsens with subsequent lines of therapy.

In your initial workup, for which subgroup of patients with DLBCL do you routinely order a genetic test?

Julie M. Vose, MD, MBA:
I would recommend ordering testing by fluorescence in situ hybridization for the presence or absence of MYC, BCL2, and BCL6 translocations for all newly diagnosed patients with DLBCL.

Jeremy S. Abramson, MD, MMSc:
I agree. For all my patients with newly diagnosed DLBCL, I recommend testing for MYC, BCL2, and BCL6 translocations.

Grzegorz Nowakowski, MD: 
Testing for all 3 genes at once and up front would be ideal. However, in my institution, due to the laboratory’s workload and rapid turnaround time, we use a cost-effective sequential testing approach. First, we determine the MYC translocation status. If positive, we test for the presence or absence of BCL2 and BCL6 translocations.

In your clinical experience, what are your thoughts on the R-CHOP plus “X” strategy to improve on the efficacy of R-CHOP in patients with DLBCL?

Grzegorz Nowakowski, MD:
The strategy of finding an effective agent “X” to add to R-CHOP does not mean that “X” must be a single agent. It could be multiple agents, such as doublet or triplet combinations, in addition to R-CHOP.

Julie M. Vose, MD, MBA:
Well, I am not sure about the possibilities of combining single or multiple novel agents with R-CHOP. It is not clear where that will lead to at the present time. We have already tried to add several different agents to R-CHOP, and most strategies have failed.

Jeremy S. Abramson, MD, MMSc:
I would be a little more optimistic about additional agents to R-CHOP. Although several of the trials investigating this approach have failed, it is probably because we have not combined the most appropriate and newest agents with R-CHOP. We now have access to more efficacious drugs. For instance, even though the combination of polatuzumab vedotin with R-CHP may have produced underwhelming results, the data with this combination are better than what we have achieved in the past. In other words, there is plenty of room for improvement with regard to novel combination strategies in DLBCL.

Several bispecific antibodies are being investigated in combination with R-CHOP in newly diagnosed DLBCL. For example, there is an ongoing phase I/II trial of the bispecific antibody mosunetuzumab in combination with CHOP for newly diagnosed or relapsed/refractory B-cell lymphomas (NCT03677141). A phase II trial is evaluating epcoritamab plus R-CHP and polatuzumab vedotin in newly diagnosed patients with treatment-naive DLBCL (NCT05283720), and a phase I/II trial is evaluating glofitamab plus R-CHOP as initial therapy for patients with DLBCL (NCT04914741). Loncastuximab tesirine is an anti-CD19 antibody–drug conjugate that is being investigated in the phase II LOTIS-9 trial in combination with rituximab in previously untreated unfit/frail patients with DLBCL (NCT05144009).

The phase III ESCALADE trial is investigating the BTK inhibitor acalabrutinib in combination with R-CHOP in previously untreated non-GCB DLBCL (NCT04529772). The phase III frontMIND trial is investigating the anti-CD19 monoclonal antibody tafasitamab with lenalidomide plus R-CHOP in newly diagnosed patients with intermediate to high-risk DLBCL (NCT04824092). Of note, the combination of tafasitamab plus lenalidomide may be particularly appealing in a non-GCB population of patients with DLBCL. We will have to wait to see what the results from these trials show.

Overall, with the different emerging novel agents in DLBCL, the R-CHOP plus “X” strategy is more promising now than it has been in the past. I am hopeful that the “crack in the dam” created by the combination of polatuzumab vedotin with R-CHP will blow wide open with more viable options in the near future.

In the management of patients with relapsed or refractory DLBCL, should tafasitamab be used before or after administering CAR T-cell therapy?

Grzegorz Nowakowski, MD:
In my opinion, where tafasitamab truly fits in the relapsed or refractory setting is still unclear. Because of the abundance of CD19 in DLBCL, it may be reasonable and beneficial to use CD19-directed agents in multiple subsequent lines of therapy. In fact, in the open-label, single-arm phase II LOTIS-2 trial, the overall response rate with loncastuximab tesirine among patients who previously had received CD19-directed CAR T-cell therapy was comparable with that observed in the overall patient population on the study.

It is known that appropriate selection and sequencing of therapies is critical for optimal patient care, and we continue to learn about the best sequencing approaches as we continue to gain more experience with the use of these newer agents. The actual stability of CD19 in patients is still an unanswered question, and ideally, this should be studied in a clinical trial. Real-world studies where patients are followed as they progress and receive next-line therapies also will help to better understand how these newer anti–CD19-directed therapies interact.

Jeremy S. Abramson, MD, MMSc:
I agree with Dr Nowakowski, but I tend to be more cautious in my treatment approach. I do not typically recommend giving a CD19-directed agent such as tafasitamab to a patient who will likely receive subsequent treatment with a CD19-directed CAR T-cell therapy until we better understand if prior CD19-directed therapy will affect the curative potential of subsequent anti-CD19 CAR T-cells. I also do not recommend giving those patients bendamustine with the goal of preserving T-cell health. So, I tend to modify how I approach the treatment of patients who will be eligible to receive CAR T-cell therapy in the third-line setting, should second-line therapy fail. So, polatuzumab vedotin plus rituximab is a good treatment option for those patients. 

CD19 is a pretty stable antigen, but the tumor cells can develop mechanisms of resistance even if the antigen is not lost. Rituximab, which targets CD20, works better as initial therapy than it does in subsequent lines of therapy, even with preserved CD20 expression. So, I worry about other mechanisms of resistance and do not want to diminish the curative potential of a CAR T-cell therapy.

Of importance, effective post CAR T-cell treatment options are simply not clear at this moment because available data in this setting are limited. Post CAR T-cell therapy, tafasitamab plus lenalidomide is a reasonable strategy—especially because lenalidomide can potentially enhance activity of the T-cells. In my experience so far, however, treatment outcomes with this regimen have been disappointing. It is essential to note that this patient population is usually very heavily pretreated, more so than patients studied in the pivotal L-MIND trial of tafasitamab plus lenalidomide for relapsed/refractory DLBCL. I often use polatuzumab vedotin plus rituximab as either bridging therapy or for the treatment of relapse post CAR T-cell therapy because, as of today, CD79b is a previously untargeted antigen in these patients. The use of loncastuximab tesirine in a patient with CD19-positive disease is also an appealing and promising approach post CAR T-cell therapy if CD19 is still expressed. In addition, I try to avoid using a bendamustine-containing regimen as bridging therapy to not exacerbate the risk of prolonged cytopenias, which already are seen following fludarabine and cyclophosphamide lymphodepleting therapy and CAR T-cell administration.

Julie M. Vose, MD, MBA:
I agree that polatuzumab vedotin plus rituximab is a really good regimen, before and even following progression on CAR T-cell therapy. It is easy on the patient and can be used to temporarily contain the disease while waiting for CAR T-cell therapy. Instead of using a bendamustine-based bridging therapy for a patient who is about to receive CAR T-cell therapy, I sometimes recommend radiation therapy either as bridging therapy or afterward, depending on whether the patient has isolated disease.

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