Available Third- and Further-Line Treatment Options for Transplant-Ineligible R/R DLBCL

EP: 1.Case Presentation: A 64-Year-Old Man with Diffuse Large B-Cell Lymphoma

EP: 2.Chemorefractory Disease in Second-Line DLBCL Treatment

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EP: 3.Available Third- and Further-Line Treatment Options for Transplant-Ineligible R/R DLBCL

EP: 4.R/R DLBCL: Safety and Efficacy Data from the L-MIND Trial

EP: 5.R/R DLBCL: Data from the RE-MIND2 Trial

EP: 6.Unmet Needs and Future Directions for Patients with R/R DLBCL

Case Overview: A 64-Year-Old Man with Diffuse Large B-Cell Lymphoma (DLBCL)

Case History

June 2020: A 64-year-old man presented with DLBCL

Stage III disease

ECOG PS 2

Serum LDH=3.7 x ULN

NCCN-IPI score=6 (High-risk)

History of hypertension (well-controlled)

Patient does not harbor MYC, BCL2, or BCL6 rearrangements

July 2020: Patient began treatment with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction therapy

Patient had neutropenic fever and limiting fatigue that was controlled with growth factor support; also had mild neuropathy

Underwent interim CT scan after 3 cycles/9 weeks and again at completion of therapy (6 cycles/18 weeks)

Patient achieved a metabolic complete response at 18-week PET-CT scan

May 2021 (6 months post–RCHOP completion): the patient complained of recent weight loss, fatigue

Followup CT scan revealed that the patient had relapsed disease

Patient started salvage chemotherapy with R-GemOx (rituximab, gemcitabine, oxaliplatin)

Most Recent Follow-up Notes/Labs

November 2021: 6-month for-cause CT scan and subsequent biopsy revealed that the patient was refractory to GemOx

The patient lives 50 miles from a healthcare facility that administers CAR T-cell therapy and does not have reliable transportation or continuous caregiver support; he and his clinician decided to start 3rd-line tafasitamab/lenalidomide

April 2022: The patient remains on tafasitamab/lenalidomide; fatigue has mostly resolved

Matthew Lunning, DO, FACP: With third-line therapy, at least in my practice, at the time of relapsed/refractory diffuse large B-cell lymphoma, we’re having a discussion about second-line therapy. I’m already starting to introduce the spectrum of therapies that could be used in the third-line setting, because the odds are against the patient to obtain a response that allows them to go to consolidative autologous transplant, often regardless of when they relapsed.

Many times, anti-CD19 CAR [chimeric antigen receptor] T-cell therapy may be in the discussion, but it takes an army to have 1 CAR T cell done. It doesn’t mean that it can’t be done. It just needs to be a well-oiled machine, and there are very important steps along the way. That’s a partnership between the community oncologist and a CAR T-cell infusing center. Sometimes they’re already at the CAR T-cell center, but there are very similar checkpoints along the way. There are 3 approved CAR T cells in the third-line setting: axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel. In the third-line space, none of them have been compared head-to-head against one another, so to look at the efficacy and toxicity data, you have to look at the individual constructs and what best fits for your patients and their timelines.

In regard to non-CAR T-cell therapies that could be used for this patient, after 2 prior lines of therapy, polatuzumab plus or minus bendamustine plus or minus rituximab could be used. With pola–BR [polatuzumab vedotin, bendamustine, rituximab], if you’re going to use BR [bendamustine, rituximab], then polatuzumab in that third-line treatment setting would be reasonable. Because the heavy lifting in that study and what led to the survival advantage was likely because of the polatuzumab vedotin, which is a CD79B antibody-drug conjugate, with the warhead being an MMAE. That’s a warhead similar to what’s carried with brentuximab vedotin in Hodgkin lymphoma, lymphoblastic large cell lymphoma, and very rarely some CD30-positive diffuse large B-cell lymphomas.

In this patient’s case, they received tafasitamab-lenalidomide, and we can go into further detail about that regimen and the intricacies that I see with that regimen. There’s also a newly approved drug called loncastuximab tesirine, which is a CD19 antibody-drug conjugate. Different from polatuzumab vedotin, this warhead is a pyrrolobenzodiazepine, or PDB, dimer. It’s a different warhead, and there are potentially some different adverse effect profiles. A lot of the adverse effect profiles are at least mitigated by some of the experience of using this drug, but also the dosing strategy of this drug, where in the initial 2 cycles, the dose is higher and then cut by 50% for the remaining every-3-week doses for up to 1 year of therapy.

Selinexor is an oral therapy. It’s an XPO inhibitor, a fairly new class of medicine. We’re trying to figure out how to use this drug in relapsed/refractory diffuse large B-cell lymphoma, but it has been seen and is going to be used in later diffuse large B-cell lymphoma. Clinical trials are always a good option for those who have clinical trial access and meet the eligibility criteria. We’re seeing some drugs being put in combination, whether it’s with chemotherapy or other more targeted therapy approaches in clinical trials. Bispecific antibodies are 1 type of clinical trial drugs in the relapsed/refractory setting that’s garnering a lot of attention. Best supportive care comes down to a long discussion about the disease biology and whether we could do palliative radiotherapy to areas that are causing pain or threatening organ function.

While they were retrospective data, if there’s anything that SCHOLAR-1 taught us, it’s to have very low expectations for that third-line chemotherapy-immunotherapy regimen. We’ve seen across the board what gem-ox [gemcitabine, oxaliplatin] has done in that setting, where you may see responses, but the median PFS [progression-free survival] is very short. Even in those individuals who are obtaining a response, at the next response evaluation, they’re already progressing. That’s in older data sets. Now we have third-line CAR-T cell, where you’re seeing curves plateauing around 40% at 4 to 5 years post-CAR T cell in the clinical trial arena, and we have real-world data in CAR T cell showing similar initial outcomes and hopeful durability over time.

There’s still space for other therapies, because CAR T-cell therapy is having difficulty accessing all available patients who may be amenable to CAR T cell or may not be willing or in the right situation to get CAR T cell. In that case, there are third-line therapies like tafasitamab-lenalidomide, loncastuximab tesirine, and polatuzumab–BR [bendamustine, rituximab]. If I’m going to use polatuzumab-BR [bendamustine, rituximab], it’s going to be in a population that I’m going to potentially have something for afterward.

I’ve started to use polatuzumab-rituximab more as what I call pre-apheresis bridging or as a pre-apheresis holding therapy to hold the disease in check while I try to get them to their CAR T-cell therapy. Clinical factors and prior treatment regimens may influence this a little more as CD19-engaging technologies move into potentially the second-line space, like tafasitamab-lenalidomide, and even in the third-line space with loncastuximab tesirine. If a patient has received a CD19-engaging agent prior to CAR T cell, that doesn’t necessarily mean that I’m not going to give them CAR T cell. We’re going to see data of the situation that I just described come out of the real world. We’re going to have to learn what having gotten a CD19-engaging agent means to the efficacy of cellular therapy. There are in vitro data looking at this that say it may not be as big of a deal as we’re concerned about, but that often has to bear out in experience over time.

Transcript edited for clarity.